Bleeding Disorders: Haemophilia & VWD Flashcards
Which is the most common bleeding disorder?
Von Willebrand disease
Haemophilia A
Haemophilia B
Describe the function of VWF [3]
- 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
Describe the three types of VWD [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
Describe the different types of type 2 VWD [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.
What are the main symptoms of VWD? [6]
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%)
Which of the following types of VWD Type 2 is most likely to cause thrombocytopenia
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.
Describe what is meant by Activated partial thromboplastin time (APTT) [1]
Describe how this changes in VWD? [1]
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
Describe the changes seen in VWD with regards to:
- FBC
- Prothrombin time
- Fibrinogen
- APTT
FBC:
- Normal
Prothrombin time:
- Normal
Fibrinogen:
- Normal
APTT:
- Normal or increased
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
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
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]
- RCo/Ag and CB/Ag is >0.6 = Type 1
- RCo/Ag or CB/Ag is < 0.6 = Type 2
Describe the treaments for VWD [4]
- Desmopressin (first line) (stimulates the release of vWF from endothelial cells.
- Tranexamic acid
- Von Willebrand factor infusion
- Factor VIII plus von Willebrand factor infusion
When giving desmopressin, what should you monitor as a trial period at baseline, 30-60 and after 4-6hrs? [3]
A trial should be carried out with VWF antigen, activity and FVIII measured at baseline, 30-60 mins and 4-6 h
Describe the treatment algorithm for patient with VWD during an active bleed? [2]
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
State the inheritence patterns of each type of VWD
Type 1:
- Autosomal dominant
Type 2:
- Autosomal dominant
Type 3:
Autosomal recessive
Describe the pathophysiology of haemophilia [5]
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.
Describe the typical presentation of haemophilia A & B
-
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
Which age group does Haemophilia A & B usually present? [1]
present in neonates or early childhood.
Describe how haemophilia can present in neonates [3]
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
What complication can occur from haemophilia induced muscular haemotoma [1]
compartment syndrome from increased pressures
Diagnosis of haemophilia is based on bleeding scores, coagulation factor assays and genetic testing.
Describe the results seen for these [+]
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
Why does APTT increase in haemophilia? [2]
Both factor VIII and IX form part of the intrinsic clotting pathway, so deficiencies affect the APTT reading.
Describe what is meant bya mixing study when investigating haemophilia [1]
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.
Describe the managment of haemophilia A & B [2]
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
How do you prophylactically treat severe haemophilia?
prophylactic factor infusions
How do you manage patients with severe haemophilia before surgery? [2]
Which surgeries is this particularly needed for? [2]
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.
What are the goals of treatment
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.
Describe what is meant by a factor inhibitor [1]
When antibodies develop to the replacement coagulation factors (so have to increase the concentration of coagulation factors adminstered)
What is the inheritance pattern of haemophilia? [1]
X-linked recessive inheritance pattern
Why should factor exposure be initially given in a specialist centre? [1]
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
Describe the inheritance to a son and daughter from a male haemophilia patient and a female haemophilia patient (individually)
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
