Bleeding Disorders: Haemophilia & VWD

Question 1

Which is the most common bleeding disorder?

Answer 1

Von Willebrand disease
Haemophilia A
Haemophilia B

Question 2

Describe the function of VWF [3]

Answer 2

• Mediating platelet adhesion to sites of damaged vascular endothelium
• As a bridging molecule for platelet aggregation.
• Indirectly it acts as a carrier for FVIII in its inactive form

Question 3

Describe the three types of VWD [3]

Answer 3

Type 1 involves a partial deficiency of VWF and is the most common and mildest type. ~70-80%
- Functionally normal VWF, but reduced levels
- Autosomal dominant

Type 2 involves the reduced function of VWF
- Normal levels of VWF, but functionally defective
- Autosomal dominant

Type 3 involves a complete deficiency of VWF and is the most rare and severe type
- Autosomal recessive

Question 4

Describe the different types of type 2 VWD [4]

Answer 4

Type 2A:
* VWF multimers not the right size

Type 2B:
* VWF not the right size and too active, leading to shortage of both VWF and platelets.

Type 2M:
* low or absent binding to platelet receptors
* FVIII still binds normally

Type 2N:
* WF has reduced affinity for FVIII, leading to reduced levels.

Question 5

What are the main symptoms of VWD? [6]

Answer 5

Common symptoms:
* menorrhagia
* Frequent or prolonged nosebleeds (53-74%)
* epistaxis
* Excessive bruising (45-50%)
* Prolonged bleeding post surgery (40-47%)
* Bleeding gums (29-34%)

Other serious rarer complications (more commonly seen in VWD type 3) include:
* Haemarthrosis (2-30%)
* Gastrointestinal bleeding (~4%)

Question 6

Which of the following types of VWD Type 2 is most likely to cause thrombocytopenia

Answer 6

Type 2A
Type 2B
Type 2M
Type 2N

Type 2B: VWF not the right size and too active, leading to shortage of both VWF and platelets.

Question 7

Describe what is meant by Activated partial thromboplastin time (APTT) [1]

Describe how this changes in VWD? [1]

Answer 7

The activated partial thromboplastin time (APTT):
- is a measure of the time taken for blood to clot via the intrinsic pathway
- following PT, is that you ‘Play Table Tennis INSIDE’ therefore PTT is INTRINSIC

VWD can cause normal or increased APTT time
- In VWD, VWF is a carrier for FVIII, therefore APTT will only be prolonged if the FVIII level is sufficiently reduced

Question 8

Describe the changes seen in VWD with regards to:

• FBC
• Prothrombin time
• Fibrinogen
• APTT

Answer 8

FBC:
- Normal

Prothrombin time:
- Normal

Fibrinogen:
- Normal

APTT:
- Normal or increased

Question 9

Diagnosis is based on a history of abnormal bleeding, family history, bleeding assessment tools and laboratory investigations. Due to the various underlying causes and types, there is no single von Willebrand disease test.

Describe the typical screen used to detect VWD

Answer 9

FVIII assay
* Typically low but can be normal

VWF antigen (Ag):
* Diagnosis of VWD can be made when VWF levels are < 0.30 IU/ml in the context of a previous mucocutaneous bleeding history
* If levels undetectable= Type 3

VWF activity: Assessed by measuring ristocetin cofactor (RCo) and collagen binding (CB) as ratios of VWF antigen levels
* RCo/Ag and CB/Ag is >0.6 = Type 1
* RCo/Ag or CB/Ag is < 0.6 = Type 2

Question 10

VWF activity is assessed by measuring ristocetin cofactor (RCo) and collagen binding (CB) as ratios of VWF antigen levels.

What RCo/Ag and CB/Ag levels would indicate type 1 or type 2 VWD? [2]

Answer 10

• RCo/Ag and CB/Ag is >0.6 = Type 1
• RCo/Ag or CB/Ag is < 0.6 = Type 2

Question 11

Describe the treaments for VWD [4]

Answer 11

• Desmopressin (first line) (stimulates the release of vWF from endothelial cells.
• Tranexamic acid
• Von Willebrand factor infusion
• Factor VIII plus von Willebrand factor infusion

Question 12

When giving desmopressin, what should you monitor as a trial period at baseline, 30-60 and after 4-6hrs? [3]

Answer 12

A trial should be carried out with VWF antigen, activity and FVIII measured at baseline, 30-60 mins and 4-6 h

Question 13

Describe the treatment algorithm for patient with VWD during an active bleed? [2]

Answer 13

1st line :
* administration of tranexamic acid and desmopressin
* Both can be used as prophylaxis prior to surgery

2nd line:
* if the patient is non responsive to desmopressin, a VWF-FVIII concentrate should be used
* Also used as prophylaxis prior to surgery
* In menorrhagia, hormonal management and use of IUD can be considered

Question 14

State the inheritence patterns of each type of VWD

Answer 14

Type 1:
- Autosomal dominant

Type 2:
- Autosomal dominant

Type 3:
Autosomal recessive

Question 15

Describe the pathophysiology of haemophilia [5]

Answer 15

Deficiency of either Factor VIII or IX interferes with the intrinsic pathway of the coagulation cascade

This leads to a decreased activation of Factor X to Factor Xa, reducing the generation of thrombin

Thrombin is critical for converting fibrinogen to fibrin, a protein that provides the structural integrity of a clot.

As a result of inadequate thrombin generation, the conversion of soluble fibrinogen to insoluble fibrin is compromised, rendering the clot fragile and susceptible to premature lysis

Therefore, the platelet plug, lacking the stabilising meshwork of fibrin, fails to halt the bleeding effectively.

Question 16

Describe the typical presentation of haemophilia A & B

Answer 16

• Haemarthrosis (bleeding into a joint)
  Up to 80% of haemorrhages in haemophilia patients
  Muscular haematomas (15% of all hemorrhages in haemophilia patients) - commonly leg muscles (quadriceps, calves)
• Patients can bleed excessively in response to minor trauma
• spontaneous bleeding without any trauma.
• intracranial haemorrhage
• haematomas
• cord bleeding in neonates

Question 17

Which age group does Haemophilia A & B usually present? [1]

Answer 17

present in neonates or early childhood.

Question 18

Describe how haemophilia can present in neonates [3]

Answer 18

Prolonged bleeding after circumcision

Intracranial bleeding (up to 5% of severe cases); can be due to trauma from delivery ie forceps

Prolonged bleeding after heel prick testing

Question 19

What complication can occur from haemophilia induced muscular haemotoma [1]

Answer 19

compartment syndrome from increased pressures

Question 20

Diagnosis of haemophilia is based on bleeding scores, coagulation factor assays and genetic testing.

Describe the results seen for these [+]

Answer 20

Clotting Studies
* Prolonged activated partial thromboplastin time (aPTT)
* Normal bleeding time (BT)
* Normal fibronogen levels
* Normal VWF levels
* A normal prothrombin time (PT) rules out extrinsic and common coagulation pathway pathologies that could present similarly; e.g. liver disease; vitamin k deficiency; DIC
* Reduced factor VII or factor IX activity level for Haem. A & B respectively

Question 21

Why does APTT increase in haemophilia? [2]

Answer 21

Both factor VIII and IX form part of the intrinsic clotting pathway, so deficiencies affect the APTT reading.

Question 22

Describe what is meant bya mixing study when investigating haemophilia [1]

Answer 22

By mixing a haemophilia patient’s blood plasma in a 1:1 ratio with normal plasma, a prolonged APTT should normalise

This is because the normal plasma contains functional clotting factor, so the deficiency can be bypassed.

Question 23

Describe the managment of haemophilia A & B [2]

Answer 23

Desmopressin (DDAVP)
* can be used in acute episodes of mild haemophilia A to promote the function of von Willebrand factor (which in turn promotes factor VIII activity) and only if bleeding persists would coagulation factor concentrates be used.

In more severe disease: replace the missing coagulation factors
* In haemophilia A, coagulation factor VIII needs to be replaced
* in haemophilia B, coagulation factor IX needs to be replaced

Fresh frozen plasma or cryoprecipitate may be needed alongisde factor infusions

Analgesia
- Paracetamol
- Opioids
- avoid the use of aspirin and NSAIDs due to their increased risk of bleeding

Question 24

How do you prophylactically treat severe haemophilia?

Answer 24

prophylactic factor infusions

Question 25

How do you manage patients with severe haemophilia before surgery? [2]

Which surgeries is this particularly needed for? [2]

Answer 25

Patients with severe haemophilia are at high risk of bleeding during and after surgery.

• For this reason, their factor activity should be increased to 50-100% for 2-7 days before surgery, and closer to 100% for surgery on the brain or prostate.
• Tranexamic acid can be considered as this inhibits fibrinolysis without increasing thrombosis risk in healthy individuals.

Question 26

What are the goals of treatment

Answer 26

Goals of treatment are to have coagulation factor levels (CFL) between 30 and 50% of normal. Patients with severe disease generally need 1-3 infusions per week, for a minimum of 45 weeks out of the year.

Question 27

Describe what is meant by a factor inhibitor [1]

Answer 27

When antibodies develop to the replacement coagulation factors (so have to increase the concentration of coagulation factors adminstered)

Question 28

What is the inheritance pattern of haemophilia? [1]

Answer 28

X-linked recessive inheritance pattern

Question 29

Why should factor exposure be initially given in a specialist centre? [1]

Answer 29

The immune response can result in anaphylaxis on exposure to any factor product, so first exposure should always take place in a specialist centre.5

Question 30

Describe the inheritance to a son and daughter from a male haemophilia patient and a female haemophilia patient (individually)

Answer 30

male haemophilia patient
- daughter will be a carrier
- son will be unaffected, as they inherit their father’s normal Y chromosome.

female haemophilia patient
- daughter has 50% chance of being carrier
- son has 50% chance of being carrier