4.7 Bleeding due to haemophilia and vwf disease

Question 1

Haemophilia is a congenital deficiency in either_________________
• Haemophilia B is less common than haemophilia A, but are clinically indistinguishable
• Both are lifelong disorders (both genes for factors VIII and IX are found on the __________________ → females are usually asymptomatic carriers; males are sufferers)
• Factors VIII and IX are both part of the intrinsic pathway, so patients present with a prolonged APTT but normal PT

The bleeding pattern in a patient with haemophilia are as follows, as secondary haemostasis is affected, so the bleeding is generally delayed:
• ______________is common, while nosebleeds are rare
• Superficial cuts do not bleed
• Spontaneous bleeding is deep in muscles and joints
• Bleeding after trauma may be delayed and prolonged
• Bleeding frequently restarts after stopping

Manifestation

• Haemarthrosis (most common): ____________ and chronic pain
• Soft tissue haematomas (e.g. muscle): Muscle atrophy, shortened tendons
• Other sites of bleeding: Urinary tract, CNS, neck (may be life-threatening)
• Prolonged bleeding after surgery or dental extraction

Answer 1

factor VIII (A) or factor IX (B);

X chromosome

Bruising ;

Fixed joint abnormalities

Question 2

[ Treatment of haemophilia]
Factor VIII is found in plasma, cryoprecipitate and factor concentrates, and recombinant forms of factor VIII and IX are also available for treatment:
• Main choice of treatment: recombinant factor VIII or factor IX (transfusion of plasma, cryoprecipitate, factor concentrates lead to many transfusion-related complications)
• Treatment may be done on demand (acute bleeds) or regular prophylaxis (prevention):
o Factor VIII and IX have different half-lives, with factor IX lasting twice as long in the circulation (____________ for level of factor VIII to reach 50% compared to ________ for factor IX) → affects prophylactic dosing schedules •

Other haemostatic treatments: DDAVP (____– haemophilia A), TXA and ________ (for minor wounds/surgery)
o DDAVP causes temporary increase in factor VIII levels (short-lived effects; giving repeated doses is associated with lowered efficiency)

The main complication with the management of haemophilia currently is the development of antibodies against the treatment:
• Patients who are treated with factor VIII can develop anti-factor VIII antibodies, which makes treatment very complicated

Answer 2

12 hours;

24 hours;

desmopressin ;

fibrin glue

Question 3

WILLEBRAND DISEASE
von Willebrand disease is another congenital bleeding disorder and may either be autosomal dominant or recessive depending on the disease subtype:
• Most common inherited bleeding disorder (1 in 10000) which presents as a mild to moderate disorder with __________ (e.g. menorrhagia, nosebleeds etc.)
• Failure of primary haemostasis (where platelets stick to endothelial collagen directly and also via vWF)
• Males and females are equally affected since it has autosomal inherited
• Associated with clinical symptoms if vWF levels are ≤ 30%

Type 1 : Partial quantitative deficiency (reduced amount of protein)
- Reduced vWF multimers

Type 2*: Qualitative deficiency (abnormal protein which does not work so well)

• *Type 2 von Willebrand disease can be classified further, but tests to differentiate between Type 2A and 2B (e.g. RIPA) are only done in specialised laboratories.
• _____________ are absent

Type 3: Total quantitative deficiency (absent protein)
- Absent vWF multimers

vWF carries factor VIII in circulation and helps to protect it from degradation, so while the basic coagulation screen may be normal, factor VIII levels may be low and APTT is prolonged:
• Not reliable measure as many patients with von Willebrand disease still have normal APTT, and bleeding time and PFA may be prolonged (also not accurate)
• Initial laboratory tests: vWF antigen and activity levels (important to obtain 2 concordant sets of results as there are several factors like ________________ which can artificially elevate vWF antigen levels)
• Diagnosis: von Willebrand disease is diagnosed if the _______________, and patients with a primary haemostatic disorder with low vWF antigen levels (30 – 50%) are at risk

Answer 3

mucocutaneous bleeding;

Large multimers;

exercise, stress, needle phobia, combined contraceptive pill and pregnancy;

vWF antigen levels are < 30%

Question 4

The von Willebrand activity level can be measured by _____________________ (ideally both tests should be done):
• Ratio of function to antigen should be _____________ before a diagnosis of Type 2 von Willebrand disease can

If the patient presents with low vWF antigen and activity as well as ratio of function to antigen < 0.6, they can be diagnosed with Type 2 von Willebrand disease:
• If platelet count is also low, a _____________ should be ordered → if increased, patient is diagnosed with Type 2B vWD

There are 3 approaches to the treatment of von Willebrand disease:

1. Increase release of vWF with ____________
2. Replace vWF with plasma-derived viral-inactivated concentrates (e.g. haemate P)
3. Promote haemostasis using antifibrinolytic drugs (e.g. TXA)

Answer 4

ristocetin cofactor activity (Ricof) or collagen binding assay;

< 0.6;

ristocetin-induced platelet agglutination (RIPA) test;

DDAVP (desmopressin);

Question 5

Desmopressin (DDAVP)
Vasopressin derivative which may cause the release of endogenous stores of vWF from the endothelium:
• Does not increase synthesis of vWF, but rather release of pre-made vWF (2 – 5 fold increase in vWF) → only useful in mild disorders
• Many patients with ___________ will respond to DDAVP
• Important to remind the patient not to drink too much as DDAVP is also an ___________ (cause water retention)

Answer 5

Type 1 vWD;

antidiuretic

Question 6

Tranexamic acid (TXA)
Inhibits fibrinolysis and is widely distributed in the body (crosses placenta):
• Low concentrations can also be found in_____________, so it needs to be used with caution
• Useful adjunctive therapy to reduce risk of bleeding
• Given IV (0.5g tds), oral (1.5g tds), mouthwash (1g 10ml 5% qds)

Answer 6

breast milk

Question 7

Factor concentrates
- Used in patients who do not respond to DDAVP/TXA (e.g. Type 2 vWD) as increasing production of dysfunctional vWF is not helpful:
• Factor concentrates (e.g. __________) containing vWF can be given (may also increase _________)

Answer 7

haemate P;

factor VIII