Inherited Bleeding Disorders - Guideline for the Management of Children and Young Adults with

Publication: 01/04/2001  --
Last review: 19/04/2018  
Next review: 01/05/2020  
Clinical Guideline
CURRENT 
ID: 68 
Approved By: Trust Clinical Guidelines Group 
Copyright© Leeds Teaching Hospitals NHS Trust 2018  

 

This Clinical Guideline is intended for use by healthcare professionals within Leeds unless otherwise stated.
For healthcare professionals in other trusts, please ensure that you consult relevant local and national guidance.

Guideline for the Management of Children and Young Adults with Inherited Bleeding Disorders

Advice for adult patients should be sought from the consultant haematology team looking after adult patients with bleeding disorders

  1. Algorithms for initial management of common challenges in inherited coagulation disorders
    1. Management of patient with suspected bleed disorder
    2. Interpretation of abnormal coagulation screens and suggested pathway of further investigation
    3. Appropriate blood product for urgent management of non-diagnosed case of suspected inherited bleeding disorder
    4. Appropriate blood product for urgent management of untreated recently diagnosed inherited bleeding disorder
    5. Diagnosis and management of the newborn infant with severe haemophilia A

  1. Acute management - detailed guidance
  1.  

 

I. Algorithms for initial management of common challenges in inherited coagulation disorders

A. Management of patient with suspected bleed disorder

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B. Interpretation of abnormal coagulation screens and suggested pathway of further investigation

PT

APTT

TT

Possible abnormality/further investigation required

N

N

• Factor VII deficiency (congenital/acquired)
• Liver disease (inc. paracetamol toxicity)
• Vitamin K deficiency or warfarin
Measure: Factors II, VII, VIII, IX, X

N

N

• Deficiency of factor VIII (due to haemophilia A or VWD) factors IX, XI, XII or contact factors (intrinsic pathway)
• Lupus anticoagulant or other coagulation factor inhibitor
Measure: Factors VIII, IX, XI, XII, DRVVT, anti-phospholipid antibodies +/- specific factor inhibitors. If FVIII low, request VWD 'screen'(FVIII:C, VWF:Ag, VWF:RCo)

N

N

• Hypofibrinogenaemia
• Dysfibrinogenaemia
Measure: Reptilase time and thrombin time corrections (discuss with laboratory)

N

• Deficiency of factor II, V, X (common pathway)
• Vitamin K deficiency or warfarin
• Liver disease (inc. paracetamol toxicity)
• Massive transfusion
• Oral anticoagulants
 Measure: Factors II, V, VII, X, VIII, IX, XI, XII

N

• Heparin
Measure : Reptilase time and other thrombin time corrections (discuss with laboratory)

• Disseminated intravascular coagulation
• Large amount of heparin
• Severe hypo- or afibrinogenaemia
Measure: D-dimers, Reptilase time and other thrombin time corrections

N

N

N

All tests normal but history of bleeding – consider
Mild von Willebrand disease
Mild haemophilia A or B
Mild factor XI or other single factor deficiency
Factor XIII deficiency
α-2 antiplasmin deficiency
Plasminogen activation inhibitor-1 deficiency
Glanzmann’s thrombasthenia
Bernard Soulier syndrome
Other platelet function disorder
Collagen disorders such as Ehlers Danlos syndrome
Vitamin C deficiency
Consider testing for the above

PT, prothrombin time; APTT, activated partial thromboplastin time; TT, thrombin time; N, within normal range; ↑, prolonged; VWD, von Willebrand disease; FVIII:C, factor VIII coagulant activity; VWF:Ag, von Willebrand factor antigen; VWF:RCo, von Willebrand factor ristocetin cofactor activity; DRVVT, dilute Russell Viper Venom time

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C. Appropriate blood product for urgent management of non-diagnosed case of suspected inherited bleeding disorder

Only treat if clinical concern of active/significant potential bleeding and local measures unsuccessful


Abnormality

Blood Product

Thrombocytopenia or severe platelet dysfunction

Platelet transfusion

Isolated prolonged APTT

Exclude heparin–refer to antithrombotic guideline
Fresh Frozen Plasma (FFP)/Octaplas

Isolated prolonged PT

May reflect non-significant deficiency of factor VII or warfarin so question relevance to bleeding
Trial of Vitamin K if non urgent
If urgent correction needed use Fresh Frozen Plasma (FFP) /Octaplas

Fibrinogen deficiency/ dysfunction

Cryoprecipitate or fibrinogen concentrate

Combined abnormal APTT, PT, Fibrinogen

Consider DIC (disseminated intravascular coagulation) and check platelet count
Trial of Vitamin K if non urgent
Replace with Fresh Frozen Plasma /Octaplas if urgent
Recheck investigations after replacement, if failure to correct abnormal result consider further FFP/Octaplas but if fibrinogen reduced transfuse cryoprecipitate

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D. Appropriate blood product for urgent management of untreated recently diagnosed inherited bleeding disorder

Only treat if clinical concern of active/significant potential bleeding and local measures unsuccessful


Abnormality

Blood Product

Haemophilia A ( Factor VIII deficiency)

Advate (recombinant Factor VIII concentrate)
Coagulation laboratory require notification of concentrate name before assays

Haemophilia B ( Factor IX deficiency)

Benefix (recombinant Factor IX concentrate)

Von Willebrand disease

Desmopressin (avoid in children <2 yrs old)
If concentrate indicated use intermediate purity factor VIII concentrate : Voncento

Factor I (Fibrinogen) deficiency

Fibrinogen concentrate or cryoprecipitate

Factor II deficiency

Prothrombin complex concentrates - discuss with blood transfusion laboratory

Factor V deficiency

Octaplas (Solvent detergent treated pooled  FFP)

Factor V and VIII deficiency

Octaplas (Solvent detergent treated pooled  FFP) and Advate (recombinant Factor VIII concentrate)

Factor VII deficiency

Novo Seven (recombinant factor VIIa)

Factor X deficiency

Prothrombin complex factors II, VII, IX, X (discuss with blood transfusion laboratory)

Factor XI deficiency

Octaplas (Solvent detergent treated pooled  FFP)

Combined deficiency of factors II, VII, IX and X

Prothrombin complex factors II, VII, IX, X (discuss with blood transfusion laboratory)

Factor XIII deficiency

Factor XIII concentrate

Platelet dysfunction

In order:
1.Local measures
2.Desmopressin (DDAVP)
3.Recombinant VIIa
4.Transfusion of platelets

Management of patient arriving as an emergency with an acute bleed in accident and emergency

Introduction:
Children and Young Adults under the care of the Paediatric Haemophilia Centre are directed to attend the Children’s Haematology and Oncology Day Unit during clinic hours and Ward 31/33 out of hours, including weekends and bank holidays.

Personnel:
Triage nursing or reception staff in Accident and Emergency Department.

Equipment:
No equipment required

Procedure:

  1. Patient arrives
  2. Establish type and severity of bleeding disorder and at which Haemophilia Comprehensive Care Centre they are registered. This information can be obtained in one of the following ways:
    • Ask the patient or the accompanying person
    • Check for information on an SOS talisman or bracelet
    • Check for information on the patient’s Special Haemorrhagic Status Card. This should be carried with the patient.
  3. Address immediate urgent medical needs
  4. Advice regarding the management of inherited and acquired bleeding disorders is available from the Paediatric Haematology Registrar who can be contacted via switchboard or the Consultant Paediatric Haematologists who can be contacted via their secretaries on internal phone number 28776. If unavailable please contact the Paediatric Haematology or Oncology Consultant on-call via switchboard who may contact the North and West Yorkshire Haemophilia Network consultant on call.
  5. If the patient requires require resuscitation, x-rays or suturing contact Dr Mike Richards secretary (0113) 3928776 or via LGI switchboard. The Haematology Coagulation Registrar and the North and West Yorkshire Haemophilia Network consultant on call can be contacted via switchboard if Dr Richards is unavailable. If unable to make contact with a consultant, seek advice from staff on Ward 31 on 0113 3927431.
  6. If the patient does not require resuscitation, x-rays or suturing contact:
    Haemophilia Clinical Nurse Specialists
    Sarah Garside (0113) 3926863 Mobile phone: 07717303306   
    Ruth Hughes (0113) 3926863 Mobile phone: 07876597097.
    If unable to contact nurses please contact medical staff as in point 4.

    If the patient is not registered at Leeds Children’s Hospital, in addition please contact the Haemophilia Centre concerned for advice

Please give analgesia as appropriate. Paracetamol/Dihydrocodeine are the drugs of choice.
NB DO NOT give Non-steroidal anti-inflammatory drugs or drugs containing aspirin or intra muscular injections

Patients with bleeding disorders may have all the illnesses that other children have and these should be considered in the differential diagnosis.

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E. Diagnosis and management of the newborn infant with severe haemophilia A

Other diagnoses will need appropriate factor replacement - see table 3

  • At delivery obtain a cord blood sample for coagulation screening and factor VIII assay. The diagnosis should be confirmed by factor assay within the first two hours after delivery. Care should be taken to avoid maternal blood contamination and if there is any uncertainty about the result a venous sample should be obtained from the baby.
  • Where there is a strong clinical suspicion of intracranial haemorrhage (or other bleeding), recombinant factor VIII concentrate should be given immediately and not withheld pending definitive imaging studies. Factor VIII replacement should be with ‘Advate’ (unless alternative already decided) available from blood transfusion laboratory (tel. 23398 at LGI). Initial dose is 50 units/kg body weight. Measure Factor VIII level 5 min post infusion to guide dosing (dosing 8 hourly may be necessary) and keep paediatric haemophilia team closely involved.
  • If treatment needed for acute bleeding during the neonatal period consult coagulation registrar via switchboard in day time or paediatric haematology or oncology consultant out of hours. Post-surgical bleeding, post-delivery cephalohaematomas and intra-cranial and extra-cranial bleeding are well documented perinatal presentations of severe inherited bleeding disorders.
  • Prophylactic factor VIII administration is not justified in all cases but is appropriate in high risk situations e.g. following instrumental or other potentially traumatic delivery. Other unconfirmed risk factors may include prolonged second stage labour (primigravid >3 h; parous >2 h), delivery of preterm infants and infants born with evidence of superficial cranial bruising, as this may indicate a degree of excessive trauma. Prophylactic dose should be 50 units/kg body weight (3 kg infant needs 150units), repeat dose after 12 hours and one dose on day 2. The potential risk of early factor VIII exposure includes development of factor VIII inhibitors.
  • Intramuscular vitamin K prophylaxis should be withheld until the results of these investigations are available but if there is likely to be any significant delay, oral vitamin K should be administered. If FVIII deficiency is diagnosed further dosing with oral vitamin K should be given according a standard regimen.
  • Venepuncture should be undertaken for neonatal screening procedures e.g. Guthrie.
  • Cranial ultrasound scan should be undertaken on day 1 of life and before discharge. Due to the low sensitivity of ultrasound for the detection of subdural bleeding, cranial MRI or CT scan should be undertaken in symptomatic neonates even if an ultrasound is normal.
  • Parents of an affected neonate should be informed of the diagnosis and presenting features of significant bleeding prior to discharge from hospital. Early follow up by paediatric haemophilia team should be arranged prior to discharge.

 

Investigation of children in whom non-accidental injury is suspected

An awareness of the conditions which can be mistaken for non-accidental bruising is essential in the assessment of suspected abuse. Difficulties may arise when other features typical of abuse do not accompany bruising. Bruising or petechiae in a non-mobile well infant however suggests inflicted injury until proven otherwise. Bruising following injury and bruising due to a haematological disorder may share common features and are not mutually exclusive. Some conditions such as severe haemophilia can be readily diagnosed; however, the most common bleeding disorder, von Willebrand disease, as well as rarer conditions, are more difficult to diagnose with certainty. It is essential to discuss interpretation of abnormal results with a paediatric haematologist

Recommended investigations

Full blood count, examination of blood film
Tests of liver and renal function
Prothrombin time
Activated partial thromboplastin time
Thrombin time and Clauss fibrinogen concentration
Factor VIII and factor IX assays
von Willebrand factor antigen, ristocetin cofactor and blood group
Factor XIII assay
Platelet aggregation (or Platelet membrane glycoproteins by flow cytometry in infants)
Platelet nucleotide analysis
Alpha-2-antiplasmin level
(Plasminogen activator inhibitor-1 activity discuss with consultant haematologist first)

If abnormal coagulation screens investigate as in table 1

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II. Acute management - detailed guidance

Guidelines for the urgent management of inherited bleeding disorders in children.

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Introduction

This guideline is intended to provide guidance for the investigation and management of congenital bleeding disorders

An inherited bleeding disorder is only one potential cause of abnormal bleeding in children. Alternative causes of bleeding should be considered and may coexist with a congenital disorder. Alternative causes include the following:

1. An anatomical bleeding point because of a breach in the integrity of blood vessels.  Examples include bleeding following trauma both non-intentional and intentional, following surgery due to haemorrhage from sutured blood vessels, fragile capillaries such as in the nasal epithelium which will lead to epistaxis, menorrhagia and gastrointestinal inflammation or arterio-venous malformations.

2. Abnormal bleeding may occur due to an acquired disorder of haemostasis. This may reflect a deficiency in the number of platelets in children commonly due to immune thrombocytopenia, microangiopathic platelet destruction, or acquired or congenital bone marrow failure syndromes. Abnormal platelet function may reflect the use of drugs notably non steroidal anti inflammatory drugs or acquired disorders such as renal dysfunction. Coagulation system dysfunction may follow liver dysfunction, renal failure, vitamin K deficiency and disseminated intravascular coagulation. The use of antithrombotic drugs including coumarin derivatives such as warfarin, or heparins, both normal unfractionated heparin and low molecular weight heparin formulations will lead to an increased bleeding risk. Other newer anticoagulant drugs are also available.

This guideline is not intended to address the management of acquired bleeding disorders.

Sources of advice

Advice regarding the management of inherited and acquired bleeding disorders is available from the Paediatric Haematology Registrar who can be contacted via switchboard or the Consultant Paediatric Haematologists who can be contacted via their secretaries on internal phone number 28776. If unavailable please contact the Paediatric Haematology or Oncology Consultant on-call via switchboard who may contact the North and West Yorkshire Haemophilia Network consultant on call. It is important to seek specific coagulation advice as much as possible within normal working hours.

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Principles of recognition and investigation of congenital bleeding disorders

Normal haemostasis occurs in two principle physiological stages.

Primary haemostasis
This is a process by which a breach in the blood vessel wall and consequent blood loss is initially arrested. This process involves the release of von Willebrand factor from sub endothelial storage organelles and its interaction with circulating platelets. The platelets form a raft across the blood vessel wall providing a blockage to further blood loss. This process requires functional blood vessel endothelial and structural elements, the normal quantity and function of von Willebrand factor and normal number and function of circulating platelets. Failure of primary haemostasis leads to bleeding typically from mucosal surfaces such as the nose, mouth or uterine lining and cutaneous bleeding. Patients with failure of primary haemostasis will present predominantly with epistaxis, oral haemorrhage, menorrhagia and bruising or petechial haemorrhages. Deep seated bleeding may also occur.

Secondary haemostasis
This stage of haemostasis results in the formation of a fibrin clot that binds the platelet raft and stabilises it to prevent further blood loss. Secondary haemostasis requires the interaction of up to thirteen coagulation enzymes known as factors I to XIII. Deficiency or abnormal function of the coagulation factors will lead to an impairment of secondary haemostasis depending on the degree of deficiency and the individual coagulation factor affected. Patients with secondary haemostatic disorders may present with soft tissue or joint bleeds. Some patients however will also present with the features more commonly associated with primary haemostasis defects. Certain disorders such as von Willebrand’s disease will affect both primary and secondary haemostasis given the dual function of von Willebrand factor in interacting with platelets and also transporting coagulation factor VIII.

The rate of clot formation is controlled by the naturally occurring anticoagulants including antithrombin, protein C and protein S. Significant deficiency of the natural anticoagulants leads to an increased propensity to thrombosis.

Following the formation of a blood clot the body will remodel the obstruction to the blood vessel by lysing the clot by a process known as fibrinolysis. Conditions in which there are uncontrolled rates of fibrinolysis may also lead to a congenital bleeding disorder.

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Management of a patient with a suspected congenital bleeding disorder

The investigation of a child with a suspected inherited bleeding disorder should be supervised by a Consultant Paediatric Haematologist. The following is for guidance only.

The new presentation of an inherited coagulation disorder will generally be noted following atypical bruising or bleeding including epistaxis, prolonged post-surgical bleeding or the presence of a haematoma or haemarthrosis. Life threatening haemorrhage including intracranial bleeds may be the initial presentation. It is essential to take a full previous personal and family history of bleeding episodes and responses to previous challenges such as delivery and the perinatal period, dental work or surgery. In infants and older children always ensure that the results are interpreted in the context of the normal range for that age of child.
         
The investigation of a child in whom a congenital bleeding disorder is suspected should involve the following investigations many of which will require advanced planning with the coagulation laboratory:

Full blood count and blood film, coagulation screen, Clauss fibrinogen assay, von Willebrand disease screen, platelet aggregation, platelet nucleotide content and release, assays of factor XIII and alpha-2-antiplasmin.  Platelet investigation requires significant volume of blood and, if in an infant this volume is impractical, platelet glycoprotein analysis by flow cytometry will be able to exclude the significant bleeding disorders, Glanzmann’s thrombasthenia and Bernard Soulier syndrome. Guidance regarding the appropriate samples and volumes of blood required will be available from the haematology Biomedical Scientist (BMS) on-call. In routine working hours please call the specialist coagulation laboratory on ext 65620. Further interpretation of these results will require assistance from the paediatric haematology staff.

Age adjusted normal ranges must be consulted in the interpretation of results.

Factor VIII levels in mild haemophilia A and von Willebrand factor levels may normalise during stress and result in a normal coagulation screen. Therefore retain a high level of clinical suspicion if bleeding appears abnormal despite normal laboratory investigations. Unless there is an acute emergency always repeat abnormal results.

A prolonged APTT with normal PT and fibrinogen suggests either a deficiency of factor VIII, IX, XI or XII or the presence of an inhibitor, either heparin, a lupus anticoagulant or an inhibitor with a factor specificity. Always exclude heparin contamination either with a repeat peripheral sample or request a reptilase and thrombin time (the reptilase time is normal if heparin has caused prolonged TT). If clinically needed factor VIII, IX, XI and XII levels must be performed as an emergency by the coagulation laboratory even if biomedical staff have to be brought in from home or a sample sent to another hospital. Factor VIII deficiency may represent haemophilia A or von Willebrand’s disease therefore an urgent von Willebrand’s assay, ideally a Ristocetin Cofactor (RiCof) or if not possible von Willebrand’s antigen (VWF Ag), would be needed which, if decreased, would suggest von Willebrand’s disease. Factor XII deficiency is not associated with an increased bleeding tendency and can be ignored.

An isolated prolonged PT with a normal APTT and fibrinogen may represent factor VII deficiency, this may be congenital but is more frequently associated with liver disease (it is an early sign of liver dysfunction following paracetamol overdose) or warfarin or vitamin K deficiency.

Prolongation of both PT and APTT with normal fibrinogen may represent isolated deficiencies of factors X, V or II or combinations of factor deficiencies in the intrinsic and extrinsic pathways.

A prolonged APTT, PT and TT or low fibrinogen may represent a congenital hypofibrinogenaemia or dysfibrinogenaemia or disseminated intravascular coagulation.

It is always possible that a patient with a bleeding disorder may also have an anatomical cause for bleeding which may include trauma in vulnerable children. It is also possible that the patient may have developed an acquired haemostatic defect in addition to a pre-existing congenital disorder.

The management of patients with a congenital bleeding disorder will be guided by the diagnosis. As a general principle alternatives to blood products must be considered first given the associated risks (inhibitors, allergic response and possible infection). If appropriate consider local measures for haemostasis and the use of tranexamic acid but severe bleeding disorders will require the use of specific products, see below for specific advice.

In the event of emergency blood loss with a coagulation disturbance but with no specific coagulation diagnosis, blood products with a broad range of coagulation factors will be needed. This will include use of Fresh Frozen Plasma (Octaplas), cryoprecipitate, platelets and red cells. It is important to assess response following transfusion with repeat coagulation tests as further products may be required. The use of recombinant factor VIIa (Novo Seven) can be considered in life threatening haemorrhage that is continuing despite blood product replacement. The use of recombinant factor VIIa (Novo Seven) can also be considered in life threatening haemorrhage with normal coagulation tests when alternative management including local control of the anatomical bleeding source has been exhausted. Use of factor VIIa in this context is not licensed and has been associated with thrombosis.

This guideline is not specifically addressing acquired disorders of coagulation.

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Management of a patient with a diagnosed congenital bleeding disorder

Children with well established diagnoses will most likely be accompanied by a parent or carer who is very well informed of the diagnosis and management of the bleeding disorder. It is very important to consider the parental history carefully and also their experience of previous forms of management. Patients/carers of children with a congenital bleeding disorder should be carrying a haemorrhagic states card which will define the bleeding disorder, the management protocol and also contact information for the haemophilia centre with which they are registered.  Please ask parents for this haemorrhagic states card if they are presenting.

Patients who are registered in Leeds will have a set of either red folder or buff folder haemophilia notes available in the Leeds Children’s Hospital Haematology notes department which should include a plan for therapy near the front page. Alternative sources of information may be available on the PPM+ database. Should this be unavailable the EPRO digital processing system for letter dictation may have the most recent communication with the general practitioner or other health professionals.

For advice during working hours please contact the paediatric haemophilia nurse specialists, Sarah Garside or Ruth Hughes, on extension 26863 or mobile phones (Sarah 07717 303306 or Ruth 07876 597097). The coagulation specialist registrar carries bleep 4475. Dr Mike Richards is available through his secretary on extension 28776 or via switchboard through his mobile phone.

Initial assessment of a patient with a bleeding disorder must include a complete history and examination and appropriate resuscitation as with any other patient. The possibility of a bleed should always be considered and this possibility should be excluded whilst considering other diagnoses. Young children and especially infants with congenital bleeding disorders may present with vague symptoms which could be ascribed to other more common diagnoses whilst actually presenting with a significant internal or intracerebral bleed. Ask if there has been the use of aspirin or non steroidal anti inflammatory drugs.

General supportive measures include the avoidance of significant trauma with high risk of internal injury including head injury, avoidance of non steroidal anti inflammatory drugs and intramuscular injections.


Adequate analgesia is required; this should not include non steroidal anti-inflammatory drugs or aspirin. Consider paracetamol, dihydrocodeine and opiates. If a joint bleed is suspected institute PRICE – Protection of joint, Rest, Ice (cold compress), Compression and Elevation. Provide sling or splint if appropriate to maintain limb in position of maximum comfort.


Management of bleeding in a patient with a congenital bleeding disorder should consider an anatomical cause and appropriate local measures such as compression of a nose because of epistaxis, cautery of a nose because of epistaxis and use of dental procedures for oral haemorrhage and hormone manipulation for menorrhagia. The use of the anti fibrinolytic agent tranexamic acid is helpful in minor bleeding.


If treatment is required for a patient with a factor deficiency please request that an emergency factor level is be assayed by the haematology laboratory immediately before coagulation factor or plasma infusion and 5 minutes after treatment. Samples are taken in citrate blood sample tubes used for clotting screens (Blue topped bottles). It is important that they are filled to the line on the bottle as under or over filling will prevent analysis of the sample. Label bottles pre and post. Samples taken from indwelling catheters including ‘Port-a-cath’ or Hickman lines should follow a 5ml discard, 5ml flush with sodium chloride 0.9% and further 5ml discard to avoid heparin contamination. Peripheral samples from a cannula used for concentrate infusion require a sodium chloride 0.9% flush and 2ml discard prior to post level. Post levels should be taken 5 minutes following intravenous administration of factor concentrate, 90 minutes following administration of subcutaneous Desmopressin (DDAVP) or 45 mins following intravenous infusion.


Emergency levels are not required if the presentation is for achieving venous access or the continuation of management of a bleed in a well established patient. If however there is failure to achieve an expected resolution of a bleed on standard therapy the possibility of inhibitor development must be considered and pre/post levels and an inhibitor screen considered.


When accessing patients for factor concentrate by venepuncture it is important not to exceed two attempts by the same individual. Administer concentrates intravenously by slow bolus injection, either peripherally via a butterfly/cannula or via a Port-a-cath indwelling venous access device if one is in situ.


Hospital admission should be avoided for straightforward bleeds that can be managed as an outpatient. If sending the patient home provide advice regarding any further doses of concentrate needed and to rest the affected limb whilst painful. Next morning please notify Dr Richards or Sarah Garside/ Ruth Hughes, Haemophilia Specialist Nurses so that appropriate follow up can be arranged. Ask parents to contact the ward or the Haemophilia Specialist Nurses next day.

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Specific diagnoses

1) von Willebrand disease

Background
Von Willebrand disease is a disorder that reflects deficiency or abnormal function of the von Willebrand factor molecule. This molecule has two functions, the binding of the platelet to the vascular endothelium and the transport of factor VIII. Von Willebrand disease is the most common bleeding disorder affecting approximately 1 in 1000 of the population.

The majority of patients with von Willebrand disease tend to present with minor episodes of bleeding. Severe bleeding should lead to consideration of type II or III disease or an anatomical or acquired bleeding disorder in addition to the congenital bleeding disorder.

Symptoms
Bleeding events that may suggest VWD include (adapted from ISTH criteria):

  1. Prolonged epistaxis without a history of trauma that is not stopped within 20 min by compression, or leads to anaemia or which requires blood transfusion. Epistaxis that required control by medical intervention such as packing or has recurred after cautery may also be more significant.
  2. Cutaneous haemorrhage and bruising with minimal or no apparent trauma, as a presenting symptom or requiring medical treatment.
  3. Prolonged bleeding from trivial wounds, lasting ≥15 min, requiring medical attention to control or recurring spontaneously during the 7 days after wounding.
  4. Oral cavity bleeding, such as gingival bleeding, or bleeding with tooth eruption or bites to lips and tongue that requires medical attention or recurs over the next 7 days.
  5. Spontaneous gastrointestinal bleeding requiring medical attention or resulting in acute or chronic anaemia, unexplained by a local lesion.
  6. Heavy, prolonged, or recurrent bleeding after dental extraction or surgery such as tonsillectomy and adenoidectomy, requiring medical attention.
  7. Menorrhagia not associated with structural lesions of the uterus. Menorrhagia that has been present from the menarche or has led to anaemia or required medical treatment increases the likely significance of this symptom.
  8. Prolonged bleeding from other skin or mucous membrane surfaces requiring medical treatment.

Family history
A positive family history compatible with the dominant forms of VWD requires that a first degree relative or two second degree relatives have a personal history of significant mucocutaneous bleeding and laboratory tests compatible with VWD. A complete dominant pattern is often not seen because of incomplete penetrance. When available, the identity of VWF mutations or genetic markers linked to the VWF locus may permit linkage of the phenotype to more distant relatives.

Diagnosis of von Willebrand’s disease

Investigations

First line
FVIII
von Willebrand antigen,
von Willebrand ristocetin cofactor activity

Confirmation
von Willebrand antigen,
von Willebrand ristocetin cofactor activity
von Willebrand collagen binding
Ristocetin-induced platelet agglutination RIPA
(Especially important with reduced VWF:RCo/VWF:Ag or VWF:CB/VWF:Ag ratios or when thrombocytopenia is present)
Blood group
Multimer analysis should be used to distinguish between types 2A and 2M

VWF antigen and function must be assessed on at least two occasions and yield consistent results. Document degree of patient distress with venepuncture

There are three major subtypes of von Willebrand disease:

Table 4 von Willebrand disease subtypes

von Willebrand disease subtype

Von Willebrand factor antigen

Normal range
50 - 150 IU/dl*

Von Willebrand factor function
(Ristocetin Cofactor)

Normal range
50 - 180 IU/dl*

Inheritance

Treatment

I

Moderate deficiency

Moderate deficiency
in parallel to antigen concentration

Autosomal dominant

Most cases respond to desmopressin

II

Normal or moderate deficiency

Major deficiency

vwf function:antigen ratio of <0.6

Variable

Some cases respond to desmopressin (contraindicated in type IIb disease) some require factor VIII/Vwf concentrate

III

Major deficiency

Major deficiency

Autosomal recessive

Factor VIII/vwf concentrate (for dose see text)

 

* Normal ranges will alter periodically as new reagents are used or fresh subjects are utilise to define ranges

Table 5 summarizing von Willebrand disease type 2 variants

VWD Type 2
Subtype

Bleeding
type

Inherit-
ence

FVIII

Vwf-Ag

Vwf:Ricof or
Vwf:CB

RIPA

Multimers

Molecular
defect

2A

Mucosal

AD/
Occ
AR

N/
low

Low/
N

Absolute <50 IU /ml

Func:Ag
ratio
<0.7

Impaired

HMW absent, abnormal triplet pattern

Defective intracellular transport or
increased proteolysis

2B
(Low platelets)

Mucosal

AD/
Occ
AR

N/
low

N/
low

Absolute <50 IU /ml

Func:Ag
ratio
usually
<0.7

Enhanced

Full aggregation at ristocetin <0.75 mg/ml

Use patient plasma and normal platelets

HMW usually absent, less marked than in 2A

Increased binding of vwf to GP1b

Mutations in GP1b binding site

Platelet type vwd
(Low platelets)

Epistaxis
post surgery or nil

AD

N

 

 

Enhanced if cryoprecipitate added to patient PRP

HMW reduced

 

2M

Mucosal

AD

N/
low

 

RiCof
low/v low

Func:Ag
ratio
<0.7Ag

CB L/N

Impaired

HMW present,
possibly ULMW present

Impaired binding to platelets via GPIb binding

2N
(Reduced VWF/VIII
binding)

Trauma

Post surgery

AR

5-30

N

Normal

Normal

Normal

Mutations affecting VIII binding area of VWF

RiCof :Ristocetin co factor; CB : Collagen Binding; RIPA : Ristocetin Induced Platelet Aggregation; Func : Ag Function to  Antigen ratio; GP 1b : Glycoprotein 1 b
PRP Platelet rich plasma

When investigating a patient with mucocutaneous bleeding a diagnosis of VWD can be made when the von Willebrand factor (VWF) activity is <0.30 iu/mL.
Patients with an appropriate bleeding history and VWF activity 0.3–0.5 iu/ml should be regarded as having primary haemostatic bleeding with reduced VWF as a risk factor rather than VWD. We suggest referring to this as ‘Low VWF’. Low/ normal levels are difficult as they may mask a mild disorder because of the elevation of VWF levels associated with the stress of venepuncture.

To diagnose VWD or not then is a matter of philosophy after discussion with the parents/child. It is more a question of will this patient bleed excessively in a given scenario rather than have they got a defined disease. Having an identified disease is not always helpful, we have patients in whom a diagnosis of mild VWD has curtailed career choices and increased insurance premiums.

Management of von Willebrand disease
General treatments

Most patients with VWD types 1 and 2 do not require treatment in the absence of trauma or surgery. The management of bleeding in a patient with von Willebrand’s disease should first consider an anatomical cause and appropriate local measures such as compression of a nose because of epistaxis, packing or cautery of a nose because of epistaxis, use of dental procedures for oral haemorrhage and hormone manipulation for menorrhagia. The use of the anti-fibrinolytic agent tranexamic acid is helpful in minor bleeding caused by von Willebrand’s disease see below.

The most common treatment for von Willebrand’s disease is the use of desmopressin (DDAVP). This functions by releasing von Willebrand factor from its storage organelles. It is effective in type I and some types of type II disorder but is not effective in type III disease. There is a relative contraindication to its use in type IIb von Willebrand disease. It may be used via the intravenous, subcutaneous or intranasal routes. Although most children will respond there is a small subset that do not respond to desmopressin and some who have a transient response. Most paediatric patients with von Willebrand’s disease in Leeds will have undergone a trial of desmopressin and results of this trial should be available in the notes, results server or on the haemorrhagic states card. Full details of desmopressin use are provided later.

Patients with type III von Willebrand’s disease or type IIb or those that have failed a therapeutic trial of desmopressin will require factor concentrate. Rare patients with severe type II or type III von Willebrand’s disease may be on regular intravenous infusions of factor concentrate, a treatment regimen called prophylaxis. This should only be used following discussion with a consultant haematology opinion.

Specific treatments

Age less than 2 years: Conservative as above +/- VWF factor concentrate

Age >2 years:  Conservative as above +/- Desmopressin (DDAVP) or VWF concentrate

Desmopressin (DDAVP)

This will increase the circulating level of von Willebrand factor and factor VIII and is the first line of treatment in children with mild haemophilia A (factor VIII > 5 IU /dl) and type I and some cases of type II von Willebrand's disease for minor bleeds. The use of Desmopressin (DDAVP) out of hours should be discussed with the Consultant.

Dosage is 0.3 microgram /kg. It may be administered by a single injection via the subcutaneous route or intravenously in 50 ml of sodium chloride 0.9% given by IV infusion over 30 minutes or by intranasal spray. The product used for intravenous infusion has a concentration of 4 microgram /ml, the product used for subcutaneous administration has a concentration of 15 microgram /ml. The dose by intranasal spray is 150 microgram single dose for children <10 yrs, 300 microgram if aged >10 yrs or 4 micrograms/kg as a single dose.

Cautions in use

  • Contraindicated in children <2 years.
  • Probably contraindicated in cases of VWD IIb
  • Can cause fluid retention, therefore maintenance fluids only for 24 hours after injection (can cause hyponatraemia and fits)
  • Monitor Blood Pressure during infusion (can cause hypotension)
  • Often causes facial flushing
  • Patients with severe haemophilia A, any form of haemophilia B or vWD type III will not respond to desmopressin. Variable response in Type II A, M, N
  • Efficacy is reduced after 2-3 doses (tachyphylaxis).
  • Contraindicated in patients with atherosclerosis and caution in elderly adults
  • Patients with von Willebrand disease type I and mild/moderate haemophilia A should respond to desmopressin, however some are non-responsive. See details of therapeutic trial in notes, such a trial may be awaited in which case take pre and post samples as described below. The increment following desmopressin may not be adequate in cases of life threatening bleeding even in mild/moderate cases of haemophilia A. If this is the case, use of factor concentrate is indicated.

If oral haemorrhage or epistaxis use tranexamic acid as an adjunct (see below).

Desmopressin (DDAVP) trial

Intravenous infusion
Dose 0.3 microgram /kg iv infusion over 30 mins
Timing of blood samples
Pre
Post completion of infusion: 45 mins, 4 hours
Nature of tests
Pre: VIII, vwf Ag, vwf RiCof
And blood group if not previously performed
Post: VIII, vwf Ag, vwf RiCof
Laboratory requires separate request forms for each sample taken

Subcutaneous injection
Dose 0.3 microgram /kg (use more concentrated preparation)
Timing of blood samples
Pre
Post injection:   90 mins, 4 hours
Nature of tests
Pre: VIII, vwf Ag, vwf RiCof
And blood group if not previously performed
Post: VIII, vwf Ag, vwf RiCof
Laboratory requires separate request forms for each sample taken

Von Willebrand factor concentrates

Potential factor concentrates available include ‘Voncento’, ‘Wilate’ and ‘Willfact’. Always remember that a factor concentrate of this kind is derived from plasma, there is therefore the theoretical risk of transmission of a transfusion dependent pathogen.

Specific guidance as to the dose will be provided in the patient case notes. The aim however is to increase the ristocetin cofactor to normal levels which should be within the normal range (50 -150 IU/dL) with a target of 100 IU/dL. Maintain use of the current specific brand of von Willebrand concentrate if there has been a previous exposure.

In Leeds we use Voncento as our preferred product if this is the first presentation of a patient with von Willebrand’s disease requiring factor concentrate and there is no established treatment plan.
 
The ratio of von Willebrand factor RCo: FVIII varies depending on the concentrate used - for detailed information see product insert.
For guidance VWF:RCo : FVIII:C Ratio for the following concentrates is as follows :
Voncento  2.4:1
Wilate 1:1;  
Willfact 1:0 (if used for an acute bleed it is necessary to administer a factor VIII product with the first injection of von Willebrand factor, in order to achieve a haemostatic plasma level of FVIII:C).

If treatment with von Willebrand factor in the form of factor VIII concentrate is not effective it rarely would be indication for use of a platelet transfusion since platelets contain von Willebrand factor and this particular site of von Willebrand factor may be important for haemostasis.

Dosing see table 6:

Table 6 Target levels for patient with von Willebrand’s disease

Target Factor VIII or VWRiCof level

Indications

50 IU/dL

Uncomplicated non disabling haemarthrosis,
cover for dental surgery

100 IU/dL

Disabling haemarthrosis,
Muscle bleed
Significant trauma especially head trauma
Operative surgery

Factor VIII dose required (units) = Factor VIII increment required (IU/dL) x weight (kg)
                                                                                     2

vwRCof dose required (units) = vwRCof increment required (IU/dL) x weight (kg)
                                                                                      2

2) Haemophilia A

Background
Patients with haemophilia A have a deficiency of factor VIII. The clinical symptoms correlate with the circulating level of factor VIII. This is an X linked disorder so males are affected, females may be carriers and are occasionally symptomatic.

Table 7 Haemophilia severity

 

Factor VIII concentration

Symptoms

Treatment

Normal

50 - 150 IU/dL

 

 

Severe

<1 IU/dL

Spontaneous joint, muscle or internal haemorrhage

Factor VIII concentrate.
Prophylactic administration and on demand for breakthrough bleeds

Moderate

1-5 IU/dL

Trauma induced joint, muscle or internal haemorrhage

On demand, occasionally prophylaxis.
Desmopressin (DDAVP) if responsive or mild bleed.
Factor VIII concentrate if not Desmopressin (DDAVP) responsive or if significant bleed

Mild

5-40 IU/dL

Trauma induced joint, muscle or internal haemorrhage

Desmopressin (DDAVP) if responsive or mild bleed.
Factor VIII concentrate if not Desmopressin (DDAVP) responsive or significant bleed

Treatment
The general management of patients with haemophilia includes the avoidance of significant trauma with high risk of internal injury including head injury, avoidance of non steroidal anti inflammatory drugs and intramuscular injections. Patients with moderate or mild haemophilia may undergo a trial of DDAVP (desmopressin) this potentially will raise the level of factor VIII by a factor of 3 to 4 fold. This option is not available for patients with severe haemophilia A who will require infusion of a factor VIII concentrate to raise their factor VIII levels. In the past factor concentrate was derived from plasma but nowadays for severe haemophilia A the standard treatments are recombinant blood products and have no human plasma constituents.

Table 8 Target levels for patient with haemophilia A

Target Factor VIII level

Indications

50 IU/dL

Uncomplicated non disabling haemarthrosis,
cover for dental surgery

100 IU/dL

Disabling haemarthrosis,
Muscle bleed
Significant trauma especially head trauma
Operative surgery

 

Factor VIII dose required (units) = Factor VIII increment required (IU/dL) x weight (kg)
                                                                                      2

Three standard half-life factor concentrates are used in Leeds, all of which are recombinant products namely Advate, Refacto and Novo-8. It is important to restrict each patient to use of one specific concentrate. Extended half-life concentrates are being introduced in selected patients. The principle factor VIII concentrate used in Leeds is ‘Elocta’ in which the factor VIII molecule is fused with the human IgG1 Fc domain.

Factor dosing of standard half-life products is based on maintenance of trough levels above a specific threshold as long as post levels are not too high. A more formal half-life study is required for extended half-life products to guide appropriate dosing in the event of a break through bleed.

Novel agents are being introduced which do not contain factor VIII. One such agent is Emicizumab which is currently restricted for use in patients with haemophilia A and inhibitors. It is a therapeutic bispecific monoclonal antibody that bridges FIXa and FX to restore the function of the missing FVIIIa that is needed for effective haemostasis. Detailed instructions on use will be included in the patients’ notes and PPM +. Always consult the haemophilia consultant on call for advice about its use. NEVER administer FEIBA in conjunction with this drug.

Children with severe haemophilia A are now started on a prophylactic regimen whereby factor concentrate is infused on alternate days occasionally daily and rarely less frequently to prevent bleeds. This may occur via a Port-a-cath at a young age or via peripheral venepuncture either by the parents or later by the boys themselves. The dose of prophylaxis is between 25 to 40units/dl on alternate days but may be higher to achieve adequate trough levels. If there are repeated bleeds in a joint, increased doses or frequency may be required.
Prophylaxis is instituted usually between the ages of 1 and 3 years the timing of which is dependent partly on the clinical phenotype of the patient, the philosophy and skill of the parents in adopting venepuncture and the mobility and venous access options in the child. We are aiming to maintain trough (pre-dose) factor VIII levels of 3 iu/dl.

The most significant side effect of factor VIII treatment is the development of inhibitors which are antibodies that bind factor VIII and remove it from the circulation. Patients who have an established inhibitor may be started on an immune tolerance regimen in which a higher dose of factor VIII is given daily or on alternate days until the inhibitor becomes undetectable. Whilst an inhibitor is present treatment of a bleed may require the use of bypassing agents such as recombinant factor VIIa and FEIBA (factor VIII inhibitor bypassing activity).

Most patients with haemophilia will not require hospital attendance because they either have bleeds treated at home by the patients or the carers, or bleeds tend to be mild because they have mild or moderate haemophilia. The parents will be very well informed about the child’s condition and frequently they will be presenting because of difficulty in venous access or because of the failure of a bleed to resolve.

At presentation it is important to assess the patient’s history and examination and ensure that emergency therapy is not required. Local measures and use of tranexamic acid should be considered. For patients with mild and moderate haemophilia it is imperative that use of desmopressin is considered before use of factor concentrate. If however a level of factor VIII is required which exceeds that which can be provided by desmopressin, factor VIII concentrate should be given.

If a patient who is receiving prophylactic factor VIII attends hospital with a bleed, inform the on call haematology/oncology consultant immediately. A baseline factor VIII assay will be required immediately. This will need discussion with the on call blood sciences Biomedical scientist at the St James’s Laboratory who may need advice from the specialist coagulation Biomedical scientist on call.

Standard half-life products can be assayed by the one stage coagulation assay.

Circulating FVIII levels following use of long acting products may be more accurately represented by a chromogenic assay which may not be available out of hoursbut thespecialist coagulation Biomedical scientist may be called in, if required. In general the one stage assay underestimates the factor VIII level compared with the chromogenic assay; the chromogenic assay has poor precision at low levels. In practice a one stage assay will underestimate the true factor VIII concentration after infusion of a long acting FVIII concentrate. The factor VIII level following previous treatment with a standard concentrate will be predictable in the absence of an inhibitor but the level following use of a long acting product will be more difficult to estimate. Reference to previous half-life studies will be needed. Once the baseline factor VIII level is available, dosing to achieve a desired increment is identical to standard half-life concentrates but the frequency of dosing will need careful consideration. 

3) Haemophilia B

Patients with haemophilia B have a deficiency of factor IX. The severity of this disorder correlates with the circulating level of factor IX in the same fashion as in haemophilia A. Desmopressin (DDAVP) does not work in haemophilia B. The only standard half-life recombinant factor concentrate used in Leeds is ‘Benefix’. Inhibitors rarely occur in factor IX deficiency but when present they may be complicated by anaphylaxis and nephrotic syndrome. In patients who have not received ‘Benefix’ extensively in the past it is important that they be observed in hospital for the first fifty exposures.

Extended half-life concentrates are being introduced in selected patients. The principle extended half-life factor IX concentrate used in Leeds is ‘Alprolix’ in which the factor IX molecule is fused with the human IgG1 Fc domain or Idelvion’ in which the factor IX molecule is fused with albumin.

The required plasma factor IX levels for clinical presentations are identical to that of factor VIII. The dosing of factor IX concentrate is different to that of factor VIII and the half-life is longer so frequency of administration is reduced, this may only be required once daily for a bleed but more frequent dosing is often required in younger children.

If a patient who is receiving prophylactic factor IX attends hospital with a bleed, inform the on call haematology/oncology consultant immediately. A baseline factor IX assay will be required immediately. This will need discussion with the on call blood sciences Biomedical scientist at the St James’s Laboratory who may need advice from the specialist coagulation Biomedical scientist. Standard half-life and the long acting factor IX products ‘Aprolix’ and ‘Idelvion’ can be assayed by the one stage coagulation assay. The factor IX level following previous treatment with a standard concentrate will be predictable in the absence of an inhibitor but the level following use of a long acting product will be more difficult to predict. Reference to previous half-life studies will be needed. Once the baseline factor IX level is available, dosing to achieve a desired increment is identical to standard half-life concentrates but the frequency of dosing will need careful consideration. 

Table 9 Target levels for patient with haemophilia B

Target Factor IX level

Indications

50 IU /dL

Uncomplicated non disabling haemarthrosis,
cover for dental surgery

100 IU /dL

Disabling haemarthrosis,
Muscle bleed
Significant trauma especially head trauma
Operative surgery

 

Factor IX dose required (units)  =   Factor IX increment required (IU /dL) x weight (kg)

Rarer Factor Deficiencies

4) Rarer factor deficiencies

Fibrinogen deficiency (Factor I)

Afibrinogenaemia refers to the total absence of fibrinogen; hypofibrinogenaemia is a decreased level of normal fibrinogen; dysfibrinogenaemia is characterized by a structural abnormality of the fibrinogen molecule resulting in altered functional properties. Afibrinogenaemia is associated with a bleeding tendency of variable severity including life threatening, spontaneous events, but long periods without problems are also not uncommon. Dysfibrinogenaemia may be associated with excess arterial and venous thrombosis.

For mild bleeding or minor surgery in afibrinogenaemia, hypofibrinogenaemia or haemorrhagic dysfibrinogenaemia, consider tranexamic acid 25 mg/kg up to 1g four times daily. Fibrinogen concentrate is the treatment of choice for significant bleeding. The aim should be to increase the Fibrinogen level to 1.0 g/L and monitor the clinical response. The half-life of infused Fibrinogen is 3–5 days and, in the absence of consumption, treatment is unlikely to be needed more often than on alternate days.

Dose 50–100 mg/ kg to maintain fibrinogen activity >1.0 g/l
Smaller doses may be repeated if necessary at 2–4 day intervals
Check product SPC or insert for more details

Urgent treatment may also be provided using cryoprecipitate 10-20 mls/kg which ideally should be virally inactivated.

Factor II – prothrombin deficiency

This is a rare autosomal recessive disorder. Two clinical phenotypes are recognized – hypoprothrombinaemia (type I deficiency), in which prothrombin antigen and activity levels are reduced concomitantly, and dysprothrombinaemia (type II deficiency) in which prothrombin activity is reduced but antigen levels are normal. Haemarthrosis and muscle haematomas are the most frequent severe bleeding manifestations in this group of patients.

Prothrombin levels of 20–30 IU /dL are thought to be required for normal haemostasis.

For mild bleeding or minor surgery in prothrombin deficiency consider tranexamic acid 25 mg/kg up to 1g four times daily (but do not use concurrently with prothrombin complex concentrates).

There are no specific prothrombin concentrates available and prothrombin complex concentrates are therefore treatment of choice. For severe bleeding or major surgery in prothrombin deficiency, consider prothrombin complex 20–40 (FIX) IU/kg with further prothrombin complex 10–20 (FIX) IU/kg at 48-h intervals if required, to maintain FII activity >20 IU/ dL. The half-life of prothrombin is around 72 h, which facilitates relatively infrequent dosing, usually every 2–3 days. Please consult data sheet for guidance on dosing as this varies according to specific product. The products used in Leeds are ‘Octaplex ‘or ‘Beriplex’.

Tranexamic acid should not be used concurrently with prothrombin complex concentrates because of the risk of thrombosis.

Factor V deficiency

Hereditary FV deficiency is a rare autosomal recessive condition. Homozygous deficiency
is associated with a moderately severe bleeding disorder. It usually presents in childhood with
easy bruising and mucous membrane bleeding, in particular epistaxes and oral cavity bleeding.

For mild bleeding or minor surgery in Factor V deficiency consider tranexamic acid 25 mg/kg up to 1g four times daily.

There is no FV concentrate available for the treatment of FV deficiency. The only blood product available for FV replacement is Octaplas / Fresh Frozen Plasma (FFP). The minimum circulating level of FV that has to be achieved for effective haemostasis is likely to vary from individual to individual but it has been reported to be not less than 15 IU/dL. For severe bleeding or major surgery, consider Octaplas 15–25 ml/kg with further Octaplas 10 ml/kg at 12-h intervals if required, adjusted to maintain FV activity >15–20 IU/dL. Use of agents such as tranexamic acid should also be considered.

Platelet concentrates are an alternative source of FV and have been used previously in combination with Octaplas when Octaplas alone was ineffective.

Combined deficiency of factors V and FVIII

Combined FV and FVIII deficiency is a rare autosomal recessive disorder, mild bleeding symptoms such as easy bruising and epistaxes are not uncommon in affected individuals, circulating levels of FV and FVIII are usually sufficient to prevent more severe spontaneous
bleeding episodes.

For mild bleeding or minor surgery in Factor V and VIII deficiency consider tranexamic acid 25 mg/kg up to 1g four times daily.

The treatment of bleeding episodes is dependant on the nature of the bleed and the FV and FVIII levels. Spontaneous bleeding episodes occurring in patients with combined FV and FVIII deficiency should be treated with both FVIII concentrates and Octaplas / Fresh Frozen Plasma (FFP) the latter as a source of FV. For severe bleeding or high risk surgery consider FV and FVIII replacement with Octaplas 15–25 ml/kg with supplementary FVIII replacement with recombinant factor VIII concentrate 20–40 iu/kg or desmopressin 0.3 microgram/kg and further treatment at 12-h intervals, adjusted to maintain FV activity 15 iu/dL and FVIII activity 50 IU/ dL.

Factor VII deficiency

This is an autosomal recessive disorder. The spectrum of bleeding problems in FVII deficiency is very variable. Epistaxes, gum bleeding, menorrhagia and other mucous membrane-type bleeding are common. Joint bleeds have been reported in patients with severe FVII deficiency although this is not a consistent finding. In patients with severe VII deficiency (FVII <1 IU/dL) bleeding into the central nervous system is well recognised especially in the neonatal period and later in life. Some individuals with severe F VII deficiency have minimal haemorrhagic features.

Although the normal range for factor VII is 50-150 IU /dl, normal haemostasis is achieved at levels of approximately 20 IU /dl.

For mild bleeding or minor surgery in Factor VII deficiency consider tranexamic acid 25 mg/kg up to 1g four times daily.

For severe bleeding or major surgery in higher bleeding risk cases use recombinant factor VIIa (Novo Seven) which has a short half life. The dose to establish haemostasis is 5 to 30 microgram/kg, every 4-6 hours. Very high post infusion factor VII levels may occur so start at 5mcg/kg.

Factor X deficiency

Patients with FX deficiency may present at any age and severely affected individuals (FX <1.0 IU / dL) can present in the neonatal period, with umbilical stump bleeding. The most frequent symptom in FX deficiency is epistaxis and is seen with all severities of deficiency. Other mucosal-type bleeding is less frequent and occurs mainly in patients with severe deficiencies. Haemarthroses, severe postoperative haemorrhage and central nervous system haemorrhage have been reported. Moderately affected patients (FX 1–5 IU /dL) may bleed only after haemostatic challenge, e.g. trauma or surgery. Mild FX deficiency (FX 6–10 IU /dL) may be identified incidentally during routine screening or family studies.

Factor levels of 10–20 IU /dL are generally sufficient for haemostasis.

For mild bleeding or minor surgery in factor X deficiency consider tranexamic acid 25 mg/kg up to 1g four times daily (but do not use concurrently with prothrombin complex concentrates).

For severe bleeding or major surgery in FX deficiency, use prothrombin complex concentrates 20–30 (FIX) iu/kg with further prothrombin complex concentrate 10–20 (FIX) iu/kg at 24-h intervals if required, adjusted to maintain FX activity >20 IU/ dL. Please refer to product insert for guidance regarding dosages. Tranexamic acid should not be used concurrently with prothrombin complex concentrates because of the risk of thrombosis. The half-life of FX is 60 hours and daily treatment is not usually required.

A factor X concentrate has been recently launched but its use is not currently licensed.

Factor XI deficiency

This is an autosomal dominant inherited disorder and is particularly common in Ashkenazi
Jews. Most individuals with FXI deficiency have few problems but may bleed in an unpredictable manner. Local measures and use of tranexamic acid usually suffice for most minor bleeding episodes. However, it is important that surgery and trauma are managed appropriately. Patients with severe FXI deficiency (FXI <10–20 IU /dl) usually bleed in relation to surgery and these patients should therefore receive treatment to increase their FXI levels. Patients with FXI levels between 20 and 60 IU /dl may bleed and in these patients a bleeding history, especially in relation to any haemostatic challenges, and the nature of the proposed surgery, will guide the need for therapy. Some of these individuals may have low von Willebrand factor levels, and it is advisable to measure baseline levels.

For mild bleeding or minor surgery in Factor XI deficiency consider tranexamic acid 25 mg/kg up to 1g four times daily.

The recommended treatment is Octaplas / Fresh Frozen Plasma (FFP) at a dose of 15-20ml/kg and tranexamic acid 15–20 mg/kg up to 1 g four times daily.  FXI has a half-life of approximately 52 ± 22 h and daily dosing may not, therefore, be necessary. For patients with severe deficiency, FXI levels of >30-45 IU /dL are considered haemostatic for minor surgery but target levels of 70 IU /dL should be achieved prior to major surgery.

A plasma derived Factor XI concentrate is available. Use of this concentrate at a dose of 10–15 iu/kg is associated with risks of pathogen transmission and thrombosis if the factor XI level exceeds 70 IU /dl therefore it should be used with caution.

Inherited deficiency of the vitamin-K dependent clotting factors
Factors II, VII, IX and X

Severely affected individuals may present at birth with spontaneous intracranial
haemorrhage or umbilical stump bleeding or in infancy and childhood with spontaneous
haemarthroses and retroperitoneal, soft tissue or gastrointestinal bleeds. Otherwise, presentation may be later in life with easy bruising and mucocutaneous or postsurgical bleeding.

Treatment with oral vitamin K1 (phytomenadione) is indicated in all patients at diagnosis 5–20 mg/d. In poor responders, consider parenteral vitamin K1 5–20 mg/week.

For mild bleeding or minor surgery, consider tranexamic acid 15–20 mg/kg up to 1 g four times daily alone.  

Treatment of bleeds is with plasma derived prothrombin complex concentrates; please refer to product insert for guidance regarding dosages. For severe bleeding or major surgery in use four-factor prothrombin complex concentrates 20–30 (FIX) iu/kg with vitamin K1 5–20 mg. Octaplas 15–25 ml/kg is an alternative if four factor prothrombin complex concentrates are unavailable. Since FVII has the shortest half-life of the factors, replacement therapy should be monitored after 6 hours by the factor FVII assay. Tranexamic acid should not be used concurrently with prothrombin complex concentrates because of the risk of thrombosis.

Factor XIII deficiency

This is an autosomal recessive disorder. Factor XIII deficiency does not lead to prolongation of the APTT. Umbilical bleeding, which occurs a few days after birth, is reported in 80% of cases and is very suggestive of the disorder. Thereafter, patients experience a lifelong tendency to severe bruising, muscle haematomas, haemarthroses, intracranial haemorrhage, miscarriages, postnatal bleeding and bleeding after surgery and trauma. FXIII deficiency also leads to a delay in healing of wounds. Patients with FXIII <1 / dL are at greatest risk from severe spontaneous bleeding. Those with levels between 1 and 4 U/dL are likely to have moderate or severe bleeding.

Levels of 3–10 U/dL are sufficient to prevent spontaneous haemorrhage.

For mild bleeding or minor surgery, consider tranexamic acid 15–20 mg/kg up to 1 g four times daily alone.  

Plasma-derived pasteurised FXIII concentrate is used for treatment although a recombinant product is nearing availability. The dose required to establish haemostasis is 10–40 units/kg; the plasma levels should be monitored and kept in the normal range until the bleeding has stopped. Platelets contain FXIII, and in a haemorrhagic emergency platelet transfusions may be helpful. Since FXIII has a long circulating half-life of 7– 10 days dosing at less than daily frequency will be required.

5) Platelet bleeding disorders

Guidelines for the laboratory investigation of heritable disorders of platelet function

A review of inherited platelet disorders with guidelines for their management on behalf of the UKHCDO

Major platelet disorders

The major bleeding disorders due to platelet dysfunction are Bernard Soulier syndrome and Glanzmann’s thrombasthenia.

Bernard Soulier syndrome is generally an autosomal recessive disorder but dominant pedigrees have been described. It is characterised by large platelets and a mild thrombocytopenia. The underlying defect is the absence or decreased expression of the GPIb/IX/V complex on the surface of the platelets. This complex is the receptor for VWF, so defects result in deficient binding of VWF to the platelet membrane resulting in defective platelet adhesion. This may be characterised by life threatening bleeding.  This particularly affects the mucosal surfaces but also may be associated with more significant internal bleeding.

Glanzmann’s thrombasthenia is characterised by the absence of glycoprotein GPIIb/IIIa which mediates aggregation of activated platelets by binding the adhesive proteins, fibrinogen,
VWF and fibronectin. Purpura, epistaxis, gingival bleeding, menorrhagia and gastrointestinal bleeding are the commonest clinical features; epistaxis is the commonest cause of serious bleeding and is more severe in childhood.

Treatment in patients with Bernard Soulier syndrome or Glanzmann’s thrombasthenia

If bleeding is mild or moderate, treatment with local measures and antifibrinolytic drugs may suffice, especially if the bleeding is mucocutaneous. Local measures may include compression, use of gelatin sponge or gauze dipped in tranexamic acid or topical thrombin applied to superficial wounds. Oral tranexamic acid (combined with tranexamic acid mouthwash) may stop gingival bleeding.

Intracranial bleeding is rare in these disorders; any life-threatening bleeding should be treated with platelet transfusions without necessarily waiting for HLA-selected platelets where this would cause delay.

For non-life threatening bleeding, when local measures and antifibrinolytics fail to control bleeding, the choice of treatment lies between platelet transfusion, rFVIIa and a combination. Recombinant FVIIa should be used in preference to platelet transfusion for non-life-threatening bleeding where the site can easily be assessed, such as epistaxis or oral bleeding, when local measures and oral tranexamic acid are insufficient to stop the bleeding. The recommended dose for treatment of bleeding episodes and for the prevention of bleeding in patients undergoing surgery or invasive procedures is 90 µg (range 80 – 120 µg) per kg body weight at intervals of two hours (1.5 – 2.5 hours). At least three doses should be administered to secure effective haemostasis. The recommended route of administration is bolus injection as lack of efficacy may appear in connection with continuous infusion. The dose given and the number of doses should be assessed individually for each patient; this agent is not always successful. Recombinant FVIIa may be less effective in more severe bleeding or if there is a delay from onset to treatment.

Recombinant FVIIa is generally safe, but thrombotic complications have been recorded.

Platelet transfusions are usually effective in controlling haemorrhage but in Glanzmann’s thrombasthenia and Bernard–Soulier syndrome there is a risk of alloimmunisation by HLA antigens or the specific missing glycoproteins resulting in refractoriness to transfusions. Ideally HLA matched platelets should be used.

Minor platelet disorders

Minor platelet dysfunction - there are large number of minor platelet defects which may reflect receptor defects, absence or reduced release of platelet nucleotides or pathway disorders. These are usually minor disorders and treatment of bleeds should prioritise the use of local measures and tranexamic acid.

Trial of therapies should follow the following order.

  1. Local measures as described in the severe platelet disorders
  2. Desmopressin (DDAVP)
  3. Recombinant FVIIa
  4. Transfusion of platelets.

6. Specific treatments

Desmopressin (DDAVP)
See details under von Willebrand’s disease

Tranexamic acid

The antifibrinolytic agent, tranexamic acid, is useful as a sole agent or an adjunct in the treatment of bleeds especially if the site is a mucous membrane. It may be given orally at a dose of 25 mg/kg body weight (maximum 1500mg) twice or three times daily orally. The intravenous dose is 10mg/kg/dose (maximum 1g) 2–3 times daily.

A mouth wash is also available for oral haemorrhage which may be rinsed then swallowed. In Leeds Teaching Hospitals Trust we use the oral liquid as a mouthwash and dilute 5ml (500mg) with 5ml water to use. If the mouthwash is being used for topical action only, spit out after rinsing. If a systemic action is also needed or acceptable, the mouthwash may be swallowed after rinsing, providing the dose does not exceed the maximum dose for the child in terms of mg/kg for oral tranexamic acid. Child 6–18 years rinse mouth with 5–10 mL 4 times daily.

Tranexamic acid should not be given if there is haematuria in view of risk of clot colic or in cases of disseminated intravascular coagulation.

Factor concentrates

Ensure alternative to factor concentrate options have been considered first.
Determine usual ‘brand’ of factor concentrate used from haemorrhagic states card and hospital notes and/or carers.
A doctor will need to complete a factor concentrate order sheet (kept on the ward or available on Trust intranet on blood transfusion site - see Products available for Transfusion)
Phone the Blood transfusion Laboratory on Ext. 23398 or the on call biomedical scientist to order the factor concentrate – the order form can be sent via the Air tube system or faxed.
The laboratory will ring the ward when the factor concentrate is ready. Portering staff will deliver to the ward.  
On arrival, two people (medical or nursing staff) should check that the correct concentrate has been supplied before administration.
The factor should be reconstituted according to the manufacturer’s instructions.
Administer the factor concentrate intravenously by slow bolus injection, either peripherally via a butterfly/cannula or via a Port-a-cath if in situ.

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III. Management in out-patient setting

Introduction

Paediatric Haemophilia Clinic

Patient population

The patient group consists of children and young adults with bleeding and thrombotic disorders. The age range is from birth to 18 years. There is flexibility as to age of transition to adult practice but we aim to transition by the age of 17 years.

Main subgroups

New patients

Easy bruising/bleeding
Petechiae
Prolonged clotting times
Family studies
Thrombosis/ stroke

Review patients

Severe bleeding disorders
Before prophylaxis
Monitoring of prophylaxis
On demand therapy

Moderate disorders

Transitional care

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New patients, easy bruising/bleeding - suggested diagnostic approach

See new bleeding disorder patient proforma

History-important points

1. Personal history

See bleeding score below for guidance

Pregnancy – maternal bleeds or infections/trauma, pregnancy related thrombosis

Birth history - ease of progression, assistance with ventouse, forceps, use of scalp electrodes etc
Any haemorrhage - scalp cephalhaematoma, excess bruises especially around forceps blades

Infancy- haemorrhagic challenges: intramuscular Vitamin K, Guthrie test, delayed separation of umbilical cord or excess haemorrhage (XIII deficiency/ fibrinogen deficiency/factor X deficiency)
Vaccinations, differentiate between reactions and bruises
Trauma during infancy – dropped, leg caught in cot side
Surgery - always ask about circumcision in appropriate ethnic groups
Toddler, falls whilst gaining mobility especially head injury
Cutting teeth, torn frenulum
Take note that bruising or petechiae in a non-mobile infant must raise suspicion of inflicted injury

Pre-school - nursery bruises, comparison with peers
Surgery - appendicectomy, tonsillectomy, circumcision
Dental work
Sport especially contact sport

Older age sport, work

Drugs including recent vaccinations
Always ask, Ibuprofen often used as antipyretic in infancy if Calpol/paracetamol not effective
Many can inhibit platelet function including antibiotics

Infections
Many autoimmune processes follow viral infections therefore ask specifically

Bruises
Spontaneous/ post traumatic
Sites: unusual sites more important
Palpable or flat?
Duration
Maximum size >area of palm?
Multiple similar sized bruises or shape of implement/hand suggest non accidental trauma especially over soft tissue areas in non mobile infants

Nose bleeds
Unilateral/ bilateral
Duration
Frequency
Needed hospital casualty/ENT attention
Associated with digital trauma

Gum bleeding after dental brushing

Other sites of bleeding
Haematuria
Blood per rectum
Haematemesis
Haemoptysis

2. Family history

Ask about specific haemorrhagic challenges in family members eg.
Post partum haemorrhage
Post surgery including religious circumcision or dental extraction
Menorrhagia in mother - need to ask re passage of clots, flooding, use of towels, pads, tampons frequency of changing protection
Ask about grandparents and siblings/cousins
Try to elicit AR, AD or X-linked inheritance
Ask about specific thrombotic events in family members
Construct family tree noting consanguinity

3. Examination

General overview
Bruises, petechiae, size and distribution
Lymph nodes and hepatosplenomegaly suggestive of possible leukaemia
Body habitus
Heart sounds
Palate - is it high arched?
Spider naevii, signs of chronic liver disease

Assess skin laxity, joint hypermobility, paper like scars

Ehlers Danlos examination
Skin hyperextensibility should be tested at a neutral site, meaning a site not subjected to mechanical forces or scarring, such as the volar surface of the forearm. It is measured by pulling up the skin until resistance is felt. In Ehlers Danlos the skin is hyperelastic, which means that it extends easily and snaps back after release. Widened atrophic scarring is a manifestation of tissue fragility and occurs mainly over knees, elbows, shins, forehead, and chin. It is characterized by splitting of the skin following relatively mild trauma, and formation of 'cigarette–paper–scars', which are wide and thin scars. In areas of repetitive trauma, haemosiderin deposition may lead to dark and anaesthetic discoloration of the skin.

Joint hypermobility is often general, affecting both large and small joints and usually comes to attention when a child starts to walk. Joint hypermobility can be assessed using the Beighton scale which is the most widely accepted grading system for the objective semi-quantification of joint hypermobility. The manoeuvres used in this scoring system are listed below:

  1. passive dorsiflexion of the little fingers beyond 90° (one point for each hand) 
  2. passive apposition of the thumbs to the flexor aspects of the forearm (one point for each thumb)
  3. hyperextension of the elbows beyond 10° (one point for each elbow);                                                                  
  4. hyperextension of the knees beyond 10° (one point for each knee);                                                                    
  5. forward flexion of the trunk with knees fully extended so that the palms of the hands rest flat on the floor (one point).


A score of 5/9 or greater defines joint hypermobility.
This joint hypermobility may lead to occasional or habitual dislocations of joints, such as the shoulder, the hip, the patella, and chronic musculoskeletal pain. This may lead to premature degenerative joint disease.

4. Investigations

Logic suggests platelet type investigations for primary haemostatic type disorders and factor investigations for secondary type disorders however in practice such a distinction is difficult. Also it is worth taking as much blood as possible at one sitting if successful given the stress associated with venepuncture in children.

Level 1 for bruising/ petechiae moderate bleeding history
FBC and film
PT, APTT, Fibrinogen, Thrombin time
Von Willebrand’s Screen
Platelet aggregation, platelet nucleotides
If inadequate sample volume request platelet glycoproteins
And store plasma
(For platelet investigations lab requires prior warning)

Level 2 for significant bleeding history
Factor VIII, IX, XI, XII, XIII levels
2 stage assay of factor VIII
Alpha-2-antiplasmin
Von Willebrand factor Collagen Binding assay

Ideally on stored plasma

It can be argued that if significant bleeding history is present then all coagulation factors should be assayed and the very rare PAI-1 deficiency.

If all normal consider factitious bleeding or inflicted trauma,
PAI-1 deficiency (London or Oxford),
Ehlers Danlos type syndromes

Laboratory details: see appendix

Paediatric Bleeding Questionnaire

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Congenital bleeding disorders – diagnosis and initial management

Factor deficiency/ function defect

History and examination as above
Family history vital as is family tree

Diagnostic requirements
Two abnormal results in our laboratory separated by date
Blood group
Hepatitis A, B, C serology
Investigate pathway where deficiency exists so if deficiency leads to prolonged PT need full extrinsic screen, if leads to prolonged APTT needs VIII, IX, XI, XII and a lupus anticoagulant screen

Factor VIII deficiency
If referred with factor VIII deficiency needs vWD screen and levels of IX, XI, and XII
If not an X-linked inheritance need to check VWD Normandy (Binding assay in Sheffield or DNA analysis)
Check one stage / two stage discrepancy in non-severe cases

Immediately following diagnosis
Once diagnosed with congenital deficiency require:
Haemorrhagic states card – Haemophilia Clinical Nurse Specialists
Parents given paediatric centre specific information leaflet
Parents given leaflet with information regarding UKHCDO database then registration with UKHCDO
Consent form for administration of concentrate
Immunisation see below
Advice about contacting centre/ward 31/33
Avoidance re avoidance of NSAIDs and intramuscular injections

Enquire about female family members who may be at risk of affected children and document in notes

Written information should be offered to patients and, where appropriate, their carers covering at least:

  1. A description of their condition and how it might affect them
  2. How their condition is diagnosed
  3. Genetics of inherited bleeding disorders
  4. Testing for carrier status and the implications of being a carrier
  5. Problems, symptoms and signs for which emergency advice should be sought
  6. Out of hours services
  7. ‘On demand’ clotting factor treatment
  8. Prophylaxis
  9. Self-infusion (or infusion by parent or carer)
  10. Home therapy and use of Haemtrack see http://haemtrack.mdsas.com  
  11. How to manage bleeding at home
  12. Ports, fistulae and in-dwelling access devices (if applicable)
  13. Possible complications, including inhibitors and long term joint damage 
  14. Approach to elective and emergency surgery
  15. Women's health issues (if appropriate)
  16. Health promotion, including smoking cessation, healthy eating, weight management, exercise, alcohol use, sexual and reproductive health, and mental and emotional health and well-being  (if appropriate)
  17. Dental care
  18. Travel advice
  19. Vaccination advice
  20. National Haemophilia Database, its purpose and benefits see www.ukhcdo.org/nhd
  21. Sources of further advice and information 

Useful leaflets are available from the Haemophilia Society www.haemophilia.org.uk and World Federation of Hemophilia www.wfh.org websites. Patient specific information should be included in copy letters.

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von Willebrand disease – diagnosis, treatment / Desmopressin (DDAVP) trial

Review of patient with severe bleeding disorder

1. Patient not yet on prophylaxis or receiving ‘on demand’ therapy

Assess bleeding episodes
Muscle/joint
Soft tissue
Frequency, site, severity, need for treatment, ease of resolution

Examination
General examination
Joint assessment - best by physiotherapists
Concentrate on joints with previous haemarthroses
Annual joint review by physiotherapists

Reinforce advice

Avoidance of NSAIDs

Contact haemophilia centre if any episode of immobilising or severe bleeding

Dose of FVIII or FIX

Ring haemophilia unit or ward 31/33 for advice
If able immediately give single dose of factor as per recommendations for disorder and bleed or access
the haemophilia unit or local paediatric centre for treatment
If no resolution give single prophylaxis dose 12 hours later and repeat 12 hourly until resolution
If no resolution or no improvement 24 hours later ring unit for further advice

Adequate non-NSAID analgesia

PRICEProtect the joint, Rest the limb; apply Ice; apply Compression and Elevate the limb.

Confirm understanding of treatment guidance – see guidance below.
Confirm possession of Haemorrhagic States card
Confirm consent for treatment
Confirm received UKHCDO register information leaflet
Update front sheet
Review Haemtrack entry

Agreement is essential with individuals, and their families, about physical activities and sports. Competitive contact sports including football, particularly in patients aged over 10 years, will increase the risk of haemarthroses and arthropathy; sports with a high risk of head injury including rugby and martial arts should be avoided at all ages. Alternative activities such as racket sports, athletics or swimming should be encouraged, facilitating full participation in school activities with peers and promoting musculoskeletal development and general good health.

Assessment of future management options
Assess parents’ philosophy of prophylaxis/port-a-caths etc.
Involvement of both parents in this process should be encouraged where possible.
Insertion of an indwelling venous access device should be considered if venous access and/or adherence to treatment are difficult, generally after aged 1 year or earlier if early mobility if but try to avoid if parents may be able to cope with peripheral venous access.

Family screening
Please ask direct questions as to whether there are any related girls/women (sisters, cousins, aunts) who may be pregnant or are of child bearing age who may need referral for genetic counselling.

If identified and genetic testing agreed send an EDTA sample with the Leeds genetic test request form (appendix) to the Leeds DNA lab. The genetic counsellors can then review families with results and arrange carrier testing. If patients don't want a genetic test, genetic counsellors could also meet to talk about inheritance patterns.

The key factors to discuss regarding consenting patients for the test are that a genetic change might be identified which is not understood. This would not confirm or refute a diagnosis and testing for other family members could not be offered.

Samples will be stored after analysis so parents should be asked whether they are happy for information to be shared with other family members to assist in counselling.

Straightforward referrals can be directed to any of the genetic counsellors. Referrals can be sent to the department and will be triaged to a counsellor if appropriate. For advice, there is an on-call counsellor and consultant daily, call the department and you will be directed to the appropriate person. For unclear or complex cases, where testing may be more complicated, the genetics department are happy to meet with the family prior to testing, refer those families directly to Dr Rosalyn Jewell, Consultant in Clinical Genetics, Yorkshire Regional Genetics Service 0113 3924439 Rosalyn.jewell@nhs.net.

Specific pre-pregnancy counselling, preferably after carriership has been confirmed, is available at the combined haematology obstetric clinic (Dr Ciantar and Dr Horn).

Dental health
Ensure regular attendance at community dentist
Any operative intervention required referral to Leeds Dental Institute

Physiotherapy input/advice

Social work input/advice

Investigations
See inhibitor and virology below

Review
3 monthly in first year, 6 monthly thereafter if stable but more frequently if recent onset of bleeds other issues

Transition
Consider introduction of transition care ‘Ready, Steady, Go’

Plan of Care
Each patient and, where appropriate, their carer should discuss and agree their Plan of Care, and should be offered a written record covering at least:

  1. Agreed goals, including life-style goals
  2. Self-management
  3. Planned assessments, therapeutic and/or rehabilitation interventions
  4. Early warning signs of problems, including acute exacerbations, and what to do if these occur
  5. Agreed arrangements with school or other education provider and preparation for adult life (children and young people only)
  6. Planned review date and how to access a review more quickly, if necessary
  7. Who to contact with queries or for advice

The Plan of Care should be communicated to the patient's GP and to relevant other services involved in their care. This can be included in GP letters copied to parents/ carers/ patients.

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Introduction of prophylaxis

Prophylaxis should be commenced before the second joint bleed or significant soft tissue bleed.

Children and neonates with severe haemophilia who have had a spontaneous central nervous system bleed should continue long term prophylaxis following initial treatment of the bleeding episode.

Prophylaxis may be introduced by initially administering factor concentrate once weekly but escalating treatment rapidly to more frequent administration as venous access permits in order to prevent the occurrence of any joint or soft tissue bleeds

Prophylaxis should consist of a factor VIII concentrate dose (25–50 units/kg) administered ideally every 48 h unless circumstances dictate otherwise, such as the need for attendance at the haemophilia centre for prophylaxis administration. If three times a week administration is used, the practice of giving a higher dose on the third day is not recommended. An additional dose should be considered in order to ensure that the maximum interval between
doses does not exceed 48 h.

3. Patients on prophylaxis

Complete prophylaxis clinic review proforma

Assess bleeding episodes/treatment
Document compliance/ difficulties
Is home delivery satisfactory?
Document break through bleeds was it:
            on day of prophylaxis/ not
            following a traumatic insult/spontaneous
            what was the response to extra treatment?
Is there a target joint or possible synovitis, if so refer to specific guidance below

Prophylaxis dose adjustment
Prescribe weight adjusted doses of prophylaxis:
25 - 50 units/kg FVIII alternate days
25 - 50 units/kg FIX twice weekly
The prophylaxis dose should be rounded up to the nearest whole vial size.

Recommend prophylaxis in the morning to optimize factor VIII availability during most active periods. Prophylactic doses should be tailored to provide maximum cover for particular physical activities, e.g. school, physical education lessons, sport training sessions.

If breakthrough bleeds, dose may need increasing - either frequency or individual doses. The minimum dosage of factor concentrate that prevents breakthrough bleeds should be used. Daily injections can significantly reduce the amount of concentrate required to prevent bleeds and maintain trough factor levels and should be considered in very active older boys or where breakthrough bleeds are occurring on a less frequent prophylactic regimen.

Trough factor levels should be measured at routine clinic visits. In our clinic we will increase dose or frequency of prophylaxis to ensure a target trough of approximately 3 iu/dl.

Half-life studies may be useful if trough factor VIII levels remain <3 unit/dl in the absence of an inhibitor in order to help determine the most appropriate prophylactic regimen if bleeding is not controlled.

Reinforce treatment pathway for bleeds

Consider general health issues
Enquire whether any other concurrent illnesses
Ensure no inappropriate drug treatment
Inhibitor screen, vaccination status - see below

Confirmation of administration
Confirm understanding of treatment guidance – see guidance below
Confirm possession of haemorrhagic states card
Confirm consent for treatment
Confirm received UKHCDO register information leaflet
Update front sheet
Review Haemtrack records

Examination
General examination
Assess chest wall for enlarging veins if Port-a-cath in situ
Joint assessment - best by physiotherapists
Concentrate on joints with previous haemarthroses
Annual joint review by physiotherapists

Physiotherapy input/advice
This will include use of standardised physiotherapy joint score

Social work input/advice

Dental health
Ensure regular attendance at community dentist
Any operative intervention required referral to Leeds Dental Institute

Family screening
See in ‘1.Patient not yet on prophylaxis or receiving ‘on demand’ therapy’

Review frequency

At initial introduction of prophylaxis review in clinic as dictated by inhibitor screening
After 150 Exposure Days review every 6 months or more frequently if breakthrough bleeds

Plan of Care
Each patient and, where appropriate, their carer should discuss and agree their Plan of Care, and should be offered a written record covering at least:

  1. Agreed goals, including life-style goals
  2. Self-management
  3. Planned assessments, therapeutic and/or rehabilitation interventions
  4. Early warning signs of problems, including acute exacerbations, and what to do if these occur
  5. Agreed arrangements with school or other education provider and preparation for adult life (children and young people only)
  6. Planned review date and how to access a review more quickly, if necessary
  7. Who to contact with queries or for advice

The Plan of Care should be communicated to the patient's GP and to relevant other services involved in their care in the standard letter after clinic. This can be included in GP letters copied to parents/ carers/ patients.

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Inhibitor screening

Screening frequency depends on number of previous exposure days (EDs)
(peak inhibitor development occurs after a median of 10 exposure days (3-69))
Plan for screening depends on number of exposure days:
0-20 EDs          screen every 3rd exposure day or every 3 months
20 -150 EDs      screen every 3 months
After 150 EDs inhibitor testing in haemophilia A should continue 1–2 times a year indefinitely.
For haemophilia B, testing after 150 EDs is only required if clinically indicated
Screen with trough FVIII, IX level and inhibitor screen

Previously untreated and minimally treated patients with severe haemophilia A who have received an intensive FVIII exposure for 5 or more exposure days should be closely monitored for inhibitor formation.

An inhibitor test should be performed in all patients with haemophilia A before any change in concentrate and at least twice in the first 6 months after the change or if there is any change in bleeding pattern or response
to factor VIII concentrate.

An inhibitor test should be performed in mild and moderate haemophilia A yearly (if they have been exposed to
FVIII) or after intensive exposure (>=5 EDs) or after surgery.

Patients with mild/moderate haemophilia A and a mutation with high inhibitor prevalence and/or family history
of inhibitors should undergo inhibitor testing after all exposures.

Patients with haemophilia B should be tested after an allergic reaction to replacement therapy before any further
FIX exposure occurs.

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Guideline for treatment of synovitis/target joint in paediatric haemophilia

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Parent of patient with severe bleeding disorder treatment guide

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Guidance for Treatment of a Joint or Muscle Bleed

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Guidance for Treatment of a Serious Injury

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Inhibitor management

See protocol : UKHCDO protocol for first line immune tolerance induction (ITI) for children with severe haemophilia A

Children should undergo ITI to eliminate the inhibitor and restore normal clinical responsiveness to FVIII.     
ITI should be started as soon as an inhibitor is confirmed irrespective of the titre.     
A central venous access device should be inserted if required to facilitate uninterrupted ITI.     
First line ITI should be conducted using recombinant FVIII concentrate (unless as part of a clinical trial). This is usually with the product used by the patient at the time of inhibitor development. 

Historic peak inhibitor titre

Regimen

<5 BU

 Start ITI at a dose of 50 IU/kg on alternate days. 
 Escalate the frequency, then dose if necessary, to control haemarthroses and clinically significant breakthrough bleeds, initially using daily treatment and then increasing factor VIII dosage in increments of 50 IU/Kg/day up to 200 IU/kg/day. 
 If the inhibitor titre on this ITI regimen increases above 40 BU, increase dose immediately to 100 IU/kg/day. If the inhibitor titre increases above 200 BU increase the dose immediately to 200 IU/kg/day.     

>5 and <200 BU

 Start ITI at a dose of 100 IU/kg/day.
 Escalate the dose of FVIII, if necessary, to control haemarthroses and clinically significant breakthrough bleeds, by increments of 50 IU/Kg/day up to 200 IU/kg/day.
 If the inhibitor titre rises to >200 BU, increase dose immediately to 200 IU/kg/day.   

>200 BU

 Start ITI at a dose of 200 IU/kg/day. 

The ITI doses should not be interrupted once started because this will compromise the success of ITI.      
The inhibitor titre should be measured weekly after initiation of ITI to define the peak inhibitor titre. A Bethesda assay with Nijmegen modification and no washout period should be used.  
Once peak titre has been defined, the inhibitor titre should be monitored monthly thereafter.  ITI should be continued as long as there is a sustained downward trend in inhibitor titre.  
If there is an upward trend in titre, or inadequate reduction in titre over a 6 month period - defined as a fall in Bethesda titre of less than 20% in a 6 month period - modify the regimen:  

If factor VIII dosage <200 IU/kg/day, increase to this dose. 
If factor VIII dosage 200 IU/kg/day, change to second line regimen (see below).  
    
NOTE: Port a cath infection can cause an increase in inhibitor titre or a poor response to ITI and should be excluded before assuming an inadequate response. 

Monitoring ITI
Dose tapering should not be attempted in poor risk patients (titre at start of ITI >10 BU, peak titre on ITI >200 BU) until the FVIII half-life is greater than 7 hours and dose reduction should then be undertaken cautiously. 
In good risk patients (titre at start of ITI <10 BU, peak titre on ITI <200 BU), when the Bethesda assay after heat treatment (58°C for 60 minutes) is negative for 2 consecutive months continue ITI regimen unchanged but perform the following measurements monthly; 
24 hour trough factor VIII level
In vivo recovery (IVR) (measured with a pre and a 15 minute post sample).  
When 24 hour trough level is >1 IU/dL for 2 consecutive months dose reduction can be initiated;
 
Reduce factor VIII dosage by available vial size increments, but maintain the 24 hour trough factor VIII level >1 IU/dL. If breakthrough bleeds occur, FVIII trough should be maintained at a higher level. 

To help guide dose tapering, the trough FVIII level is proportional to the dose if the half-life remains constant. Therefore if the dose is reduced by 50% the trough will also decrease by about 50%. 

The factor VIII dose should not be reduced by more than 50% at one time and the trough should be measured soon after the reduction to ensure a level above 1 IU/dL is maintained.   
Continue to measure Bethesda titre and 24 hour trough factor VIII level monthly and reduce FVIII dose further if trough is >1 IU/dL.  

Maintain the 24 hour trough >1 IU/dL during dose reduction.
 
If the Bethesda titre becomes positive, the 24 hour trough factor VIII level is <1 IU/dL, or a breakthrough bleed occurs, reintroduce the previous factor VIII dosage. 

When the factor VIII dose has been reduced to 50 IU/Kg/day and the 24 hour trough factor VIII level is >1 IU/dl, either continue daily infusions or switch to alternate day treatment. (Alternate day treatment is likely to require an increase in total factor VIII dose to maintain a 48 hour trough factor VIII level of > 1 IU/dl and pharmacokinetic studies will be helpful to plan the change in regimen). 

Continue to reduce factor VIII dose to maintain a 24 or 48 hour trough factor VIII level of > 1IU/dl and to prevent breakthrough bleeds.  

If there is an inadequate sustained downward trend in the inhibitor titre (see section 5), consider alternative strategies;

Options include FVIII dose increase, the introduction of plasma derived FVIII with a high vWF content (pdFVIII) or immunosuppression with rituximab.  

Timelines for second-line therapy 
If there is no sustained downward trend after 6 months* of first line ITI, escalate to full dose (200 IU/kg/day)

If there is no sustained downward trend after 6 months* of full dose ITI (200 IU/kg/day), change to pd FVIII or immunosuppression for a further 6 months* 

NB; pd FVIII and and immunosuppression may be undertaken simultaneously or sequentially. If used sequentially and there is no downward trend after 6 months* with the 1st choice intervention, consider adding the alternate intervention with a further 6 months observation. 

If there is no sustained downward trend after 6 months of pd FVIII and immunosuppression and FVIII cannot be used to prevent and treat bleeds the ITI should be stopped. 

The final decision regarding cessation of ITI can be referred to a UKHCDO expert panel via the Inhibitor Working party Chairperson if uncertainty remains about interpreting response to 2nd line ITI strategies and/or future treatment planning with either FVIII concentrate or bypassing agents.

Novel agents are being introduced which do not contain factor VIII. One such agent is Emicizumab which is currently restricted for use in patients with haemophilia A and inhibitors. It is a therapeutic bispecific monoclonal antibody that restores the haemostatic process by bridging FIXa and FX, allowing the coagulation cascade to continue. Detailed instructions on use will be included in the patients’ notes and PPM +. Always consult the haemophilia consultant on call for advice about its use. NEVER administer FEIBA in conjunction with this drug.

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Vaccination policy

Vaccination policy

Recipients of recombinant factor concentrate do not need specific vaccinations as the risk of viral transmission is assumed negligible

Primary vaccination policy for patients receiving plasma derived products

Check Hepatitis A, B, C serology at diagnosis
If no previous exposure vaccinate with Twinrix after age 1 year (combined hep A and B, licensed for use at age >1 year)
Check viral serology 1-2 months after final vaccination

Follow-up

Recipients of plasma derived factor concentrate

Hepatitis A
Assess post vaccination titres, revaccinate after 10 years with a booster

Hepatitis B
Check anti-HBs levels after vaccination and ensure >10 miu/ml.
If responded and patients not receiving plasma then administer booster 5 years later, no further Rx and no further testing required.
Check anti-HBc annually to check for infection if plasma products received

Consider immunisation of parents/carers if plasma derived products used

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Procedures – preparation

Procedures

Surgery

Always check inhibitor beforehand, ideally within 1 week of planned surgery
Write written protocol for laboratory, ward, notes, regional network and on call consultant
Consider continuous infusion

Port-a-cath insertion

See protocol template (see below)
Discuss complications of infection, dislodgement, skin breakdown, thrombosis need for replacement on occasions.
Remove when peripheral access achieved

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Protocol for insertion of Port-a-cath

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Transition to Adult Services and Preparation for Adult Life

Transition is ‘the purposeful planned movement of adolescents and young adults with chronic physical and medical conditions from child-centred to adult-oriented health care systems.’

The importance of transitional care has been highlighted in the Children’s National Service Framework Hospital Standards, Improving the transition of young children with long term conditions to adult health services and the intercollegiate report, Bridging the gaps: health care for adolescents. This includes a requirement for children and adult services to take the needs of this group of patients into consideration when planning and developing services.

Here at Leeds we follow the “Ready, Steady, Go” programme developed by Southampton University Hospital. This is a generic programme, as many of the problems faced by each sub-speciality group during transition are similar. Through this program we ensure the medical, psychosocial and vocational needs of the young person are being addressed by following a structured, but adaptable, transition plan. A key principle throughout the process is ‘empowering’ the young person to take control of their lives and equipping them with the necessary skills to be able to function independently and confidently in adult services.

The transition programme starts with a “Moving to Adults” information leaflet and a questionnaire which, through a series of structured questions, is designed to establish when the patient is likely to be ready to move to adult services and what needs to be done to get “Ready” for the move to adult services. In due course this is followed up by a questionnaire to assess progress and keep them “Steady” and ensure that they have all the skills to “Go” to adult services at a time which has been mutually agreed by the patient, medical professionals and where appropriate parents.

The programme is facilitated through routine Clinic review and Nurse Led MDT clinic. The idea of transition and the gradual switch of focus from parent to young person should be introduced at an early age, as part of an overview of what parents can expect from clinic reviews. The young person will be encouraged with support to increasingly take responsibility for their own care but have sufficient time to prepare for transfer.

The Moving to Adults Leaflet should be given to the young person when they move from primary to secondary education. Progress should then be assessed at each visit until the patient is ready to move to adult services.

Patients for transition will be discussed in joint paediatric/ adult service MDT meetings so appropriate planning has been undertaken to address any specific needs of an individual patient. At this time a named coordinator for the transfer of care will be allocated. The young person and, where appropriate, their carer forms an essential part in planning the transfer of care so a discussion will be held before transfer to understand their views and needs. At the point of transition to adult services, the clinic review will be facilitated by both adult and paediatric haematologists together with Clinical Nurse Specialist from children’s and adult services.

Before the first appointment with adult services, the patient will attend a “Welcome to adult services” session. This session will include, a tour of the unit (outpatient clinic, day unit, in patients wards); information about how to book or rearrange an appointment, who to contact in an emergency and arrangements for monitoring.

The immediate period after transition is a time of vulnerability and sometimes confusion for the young person who has moved to the adult service. Bespoke attention will be provided by nursing and medical staff in the adult centre during this period.

We aim to transfer care flexibly but around the age of 17 years so that there has been time to establish relationships with the adult centre before possibly leaving home. If patients do leave home they will be provided with advice as to how to registering and communicate with a GP, access emergency and routine care and access support from their Comprehensive Care Centre.

Arrangements should comply with national guidance for Looked After Children - Preparing for independence

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Guidelines for commencing home therapy

Home therapy is a contract between the department, the parents and children. All factor concentrates are potentially dangerous and no family should start home therapy without due consideration to their ability and co-operation. They must also be given adequate time and training to become both confident and competent at the treatment (no matter how long this takes) before they are expected to treat their children at home. Learning home therapy is nearly always a pre requisite for commencing prophylactic treatment.

All patients on home therapy must be reviewed in clinic at least every 4 - 6 months. They must also keep home treatment records so that the severity, frequency and sites of any bleeds can be assessed alongside the success or failure of the prophylactic regime. The recommended platform for this is now the electronic Haemtrack software package.

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Procedure for dispensing home treatment supplies

Supplies can be issued from the Children’s’ Haematology and Oncology Day Unit Monday – Friday between 9am and 5pm. A supply of all factor concentrates is kept in fridges in the haemophilia room.
Parents should request supplies 24hrs in advance.
Check the product and dose that the patient should receive form the front sheet of their notes or the check list in the front of the black product usage file in the Haemophilia Treatment Room.
Match up the bar code on the box of factor concentrate to the bar code on the appropriate sheet in the black product usage file. Record the date, child’s name, date of birth and unit number alongside the bar code.
Please inform Haemophilia Clinical Nurse Specialists at the earliest opportunity

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Ordering and Administering Factor Concentrates

Introduction:
All patients presenting with a bleed must be promptly assessed using the ‘Guidelines for the Management of Haemophilia in Children as guidance. It may then be deemed necessary to treat with a Factor Concentrate product.

Personnel:
Front line nursing and medical staff

Equipment:
Factor Concentrate Order Form
Prescription Chart
Factor Concentrate

Procedure:
A doctor or Non-Medical Nurse Prescriber must complete the factor concentrate order sheet. There is a printable template document on EQMS
Specify product, dose and frequency. Ensure that the patients’ details are complete and correct and that the order form is signed.
Check that the correct product has been ordered against information provided on front sheet in the patient’s medical notes. An up to date list of patients receiving regular treatment can also be found in the Haemophilia File on the ‘I’ drive on the ward computers. The Blood Transfusion lab also has a copy.
Phone the Blood Transfusion lab on Ext: 23398 to request order and either fax order form or send via air tube.
Prescribe the factor concentrate on an in-patient prescription chart.
The lab will ring when the concentrate is ready and the ward need to arrange for it to be collected (it is not allowed to be sent via the tube)
When the concentrate arrives, two people – medical or nursing staff should check that the correct concentrate has been supplied before administration. Reconstitute the vial of concentrate following the instructions supplied with each box. Record the batch number or place ‘sticky’ batch label in the patients notes so that products can be traced.
Administer intravenously by slow bolus injection, either peripherally via a butterfly/cannula or via port-a-cath if one in situ.
Provide sling or splint if appropriate to maintain limb in position of maximum comfort
Advise regarding any further doses of concentrate that need to be given at home
Advise patient to rest affected limb whilst painful and then start to remobilize.
If sending the patient home ask them to contact the ward or Children’s Haematology and Oncology Day Unit the next day unless the bleed is completely resolved.
Next morning please notify Dr Richards or Haemophilia Nurse Specialists

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Protocol for flushing of portacaths

Patients on regular prophylaxis
Flush with 5-10 mls 0.9% saline after each use but following saline flush with heparin 100iu/ml 4 mls once weekly
Attempt a pulsating action when flushing
Clamp as flushing last 2 mls

Patients not accessing portacaths regularly
Flush with 5-10 mls 0.9% saline after each use but following saline flush with heparin 100iu/ml 4 mls once monthly
Attempt a pulsating action when flushing
Clamp as flushing last 2 mls

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Management of pregnancy/delivery

Refer to joint obstetric haemophilia clinic via Dr Horn

Care of the infant born to carrier of haemophilia

Ante-natal period

If there is a positive family history of haemophilia, delivery should be in an obstetric unit with an affiliated haemophilia centre which has 24 hour access to coagulation screening and factor assays. Good communication between the haematologist, haematology laboratory, obstetrician and neonatologist is vital.
A written protocol is needed.

Discuss the possible prophylactic role of factor concentrate administration to the infant post delivery with parents. The advantage is the possible reduction of the risk of an intra-cerebral bleed, one of the potential disadvantages is the hypothetical increased risk of inhibitor development.

Ensure availability of appropriate factor concentrate prior to delivery in the appropriate hospital. This should be recombinant factor VIII, third generation, recombinant FIX, or alternative specific coagulation factor ideally of recombinant origin.
(For guidance for rare inherited disorders need specific discussion)

Intra-cranial haemorrhage (ICH)

Incidence of 1-4% of severe/ moderate haemophilia A live births
Intracranial haemorrhage is most commonly subdural
A third of survivors may suffer neurodevelopmental sequelae
There is a risk of severe blood loss in cases of extracranial haemorrhage.

Risk factors for ICH are prolonged labour, abnormally rapid labour, instrumental delivery, bruised head, trauma, preterm delivery, possibly previously affected infant.

Labour

Ideally elect for an uncomplicated vaginal delivery, however proceed to early Caesarean section if there is failure to progress.
Avoid scalp electrodes, foetal scalp blood sampling, vacuum extraction, mid-cavity forceps and prolonged labour. Deliver by least traumatic route. Actively manage third stage of labour. Any operative or instrumental delivery should be performed by the most experienced operator.
Minimise genital tract trauma

Delivery

Obtain cord blood sample in citrate anticoagulant for factor VIII, IX level - should be available within 2 hours
Beware maternal contamination
Ring coagulation laboratory 65620 (or switchboard if out of hours) to expect sample
If in doubt check venous sample from infant

Always use age specific normal ranges for interpretation
Infant plasma factor VIII concentrations are at adult levels
Infant plasma factor IX levels are reduced at birth therefore mild haemophilia B cannot be excluded at birth.

The following type of bleeding may occur in an infant with haemophilia:
Ooze/ haematoma after venepuncture or heel prick, intramuscular injections, intra-cranial bleeding or other internal haemorrhage which may be fatal.

Treatment may be administered either prophylactically to prevent severe internal bleeding or as a response to a haemorrhage.

The recovery and half life of factor concentrates in vivo are poorer in neonates compared to older children and adults.

Immediate post partum care

If no concentrate is available use virally inactivated fresh frozen plasma at volume of 15ml/kg
Do not use DDAVP (desmopressin) because of risk of hyponatraemia

At delivery obtain a cord blood sample for coagulation screening and factor VIII assay. The diagnosis should be confirmed by factor assay within the first few hours after delivery. Care should be taken to avoid maternal blood contamination and if there is any uncertainty about the result a venous sample should be obtained from the baby.

Intramuscular vitamin K prophylaxis should be withheld until the results of these investigations are available but if there is likely to be any significant delay oral vitamin K should be administered. If severe factor deficiency is diagnosed further dosing with oral vitamin K should be given according a standard regimen.

Where there is a strong clinical suspicion of intracranial haemorrhage (or other bleeding), recombinant factor VIII concentrate (Advate) should be given immediately and not withheld pending definitive imaging studies.

Factor VIII (Advate) is available from blood bank (tel. 23398). Initial dose: 50 units/kg body weight. Measure Factor VIII level 5 min post infusion to guide dosing (dosing 8 hourly may be necessary) and keep paediatric haemophilia team closely involved.

If treatment needed for acute bleeding during the neonatal period consult coagulation registrar via switchboard in day time or paediatric haematology or oncology consultant out of hours who can then seek further advice if needed. Post-surgical bleeding, post-delivery cephalohaematomas and intra-cranial and extra-cranial bleeding are well documented.

Prophylactic factor VIII administration is not justified in all cases but is appropriate in high risk situations e.g. following instrumental or other potentially traumatic delivery. Other unconfirmed risk factors may include prolonged second stage labour (primigravid >3 h; parous >2 h), delivery of preterm infants and infants born with evidence of superficial cranial bruising, as this may indicate a degree of excessive trauma. Prophylactic dose should be 50 units/kg body weight (3 kg infant needs 150units), repeat dose after 12 hours and one dose on day 2.

Venepuncture should be undertaken for neonatal screening procedures e.g. Guthrie.

Cranial Ultrasound Scan (USS) should be undertaken on day 1 of life and before discharge. Due to the low sensitivity of USS for the detection of subdural bleeding, cranial MRI or CT scan should be undertaken in symptomatic neonates even if an USS is normal. Repeat is indicated on day 5 but clinical assessment is also essential.

Newborn haemophilia carriers or potential carriers should receive routine obstetric and neonatal management.

Paediatric Haemophilia Team: Coagulation Registrar: bleep 4475, Paediatric Haemophilia Specialist Nurse: bleep 07659531362, extension 26863, Paediatric Haematology/Oncology on call (out of hours): via switchboard.

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Information for expectant mothers who may be carriers of a bleeding disorder

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Thrombophilia

Counsel family rather than test.
I feel that if a child is a member of a family who has a clinical diagnosis of thrombophilia then they ought to be considered at increased risk of thrombosis. This analysis will not be influenced significantly by thrombophilia testing. The child has the right to decide if they are tested or not so give them the option when aged 16 years.

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Information leaflet about clinic for parents/ young people

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Provenance

Record: 68
Objective:
Clinical condition:

Bleeding disorders

Target patient group: Children and young adults with inherited bleeding disorders
Target professional group(s): Secondary Care Doctors
Adapted from:

Evidence base

References

Anne De Paepe and Fransiska Malfait
Review
Bleeding and bruising in patients with Ehlers–Danlos syndrome and other collagen vascular disorders
British Journal of Haematology (2004) 127 491 

Khair, Kate & Liesner, Ri
Bruising and bleeding in infants and children – a practical approach.
British Journal of Haematology 133 (221-231.

Pasi KJ, Collins PW, Keeling DM, Brown SA, Cumming AM, Dolan GC, Hay CR, Hill FG, Laffan M, Peake IR.
Management of von Willebrand disease: a guideline from the UK Haemophilia Centre Doctors' Organization.
Haemophilia. 2004 May;10(3):218-31.

Laffan M, Brown SA, Collins PW, Cumming AM, Hill FG, Keeling D, Peake IR, Pasi KJ.
The diagnosis of von Willebrand disease: a guideline from the UK Haemophilia Centre Doctors' Organization.
Haemophilia. 2004 May;10(3):199-217.

Lee CA, Chi C, Pavord SR, Bolton-Maggs PH, Pollard D, Hinchcliffe-Wood A, Kadir RA; UK Haemophilia Centre Doctors' Organization.
The obstetric and gynaecological management of women with inherited bleeding disorders--review with guidelines produced by a taskforce of UK Haemophilia Centre Doctors' Organization.
Haemophilia. 2006 Jul;12(4):301-36

Peter W. Collins, Elizabeth Chalmers, Daniel P. Hart, Ri Liesner, Savita Rangarajan, Kate Talks, Mike Williams and Charles R. Hay (2013)
Diagnosis and treatment of factor VIII and IX inhibitors in congenital haemophilia: (4th edition)
British Journal of Haematology 160, 153–170

Michael Richards, Michael Williams, Elizabeth Chalmers, Ri Liesner, Peter Collins, Vicky Vidler and John Hanley (2010) Writing group: on behalf of the Paediatric Working Party of the United Kingdom Haemophilia Doctors’ Organisation Ltd. A United Kingdom Haemophilia Centre Doctors’ Organization guideline approved by the British Committee for Standards in Haematology: guideline on the use of prophylactic factor VIII concentrate in children and adults with severe haemophilia A  British Journal of Haematology, 149, 498–507

Elizabeth Chalmers, Michael Williams, Janet Brennand, Ri Liesner, Peter Collins and Michael Richards on behalf of the Paediatric Working Party of the United Kingdom Haemophilia Doctors’ Organization Guideline on the management of haemophilia in the fetus and neonate (2011)  British Journal of Haematology, 154, 208–215

Approved By

Trust Clinical Guidelines Group

Document history

LHP version 1.1

Related information

Laboratory contact details

Contact telephone Numbers

Consultant Haematologist

Dr Mike Richards’  secretary (0113) 3928776  or via LGI switchboard
The Haematology Coagulation Registrar and the North and West Yorkshire Haemophilia Network consultant on call can be contacted via switchboard if Dr Richards unavailable

Switchboard Leeds General Infirmary

(0113) 2432799

St James's Coagulation Laboratory
Biomedical Scientists

(0113)  2065620

Blood Bank

Leeds General Infirmary (0113) 3923398
St James University Hospital (0113) 2065559

Haemophilia Clinical Nurse Specialists

Sarah Garside                    (0113) 3926863              Mobile phone: 07717303306   
Ruth Hughes                      (0113) 3926863              Mobile phone: 07876597097

 

Haemophilia Physiotherapists

Anne Penn  (0113) 2068373 pager: 6125
Thuvia Flannery

Clinic: (0113) 3927179
Ward 31: (0113) 3927431 
Ward 33: Teenagers (0113) 3927433 

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