von Willebrand Disease Flashcards
What is the role of vWF in hemostasis ?
.
- mediates platelet adhesion to the endothelium
- binds to GPIb on the platelet surface
- also binds to the subendothelium
- also a protective carrier of Factor VIII
Why are factor VIII levels often
decreased in vWD ?
- because the half life of Factor VIII is shortened when it is not bound to vWF in the plasma
*2 hours when not bound; 8+ hours when bound
What is the biology of vWF ?
- synthesized in endothelial cells and megakaryocytes
- secreted into plasma
- also present within platelet granules
- large protein
- cleaved by ADAMTS13
Does circulating vWF bind to platelets randomly?
- no the forms in plasma do not readily bind to platelets
- must undergo a conformational change to open up the GPIb binding site
- this is induced by sheer stress or binding to extracellular matrix proteins
- IMP: conformational change also happens in response to Ristocetin
What are the most common bleeding
symptoms in vWD ?
- bleeding is variable but rarely fatal
- most common symptoms are:
- epistaxis
- easy bruising
- bleeding after dental extractions
- menorrhagia
- trauma or surgery, gingival bleeding
- post-partum bleeding
- GI bleeding may also occur
- hemarthrosis is UNCOMMON and rarely fatal
What are the three types of
vWD ?
- Type 1 - mild to moderate bleeding disorder
- Type 2 - can be severe but often mild to moderate
- Type 3- severe bleeding disorder
What are the findings in Type I
vWD ?
- most common form (70-80% of cases)
- partial quantitative deficiency of vWF
- functional quality is ok
What are the findings in
Type II vWD ?
- qualitative deficiencies with functional abnormalities
- sometimes the quantity is also reduced
- usually accounts for 20-30% of cases
- subdivided into 4 categories
What are the findings of type 3 vWD ?
- it is rare
- quantitative deficiency of vWF so severe that it is undetectable
What is characteristic of Type 2A and 2B vWD ?
- characterized by a loss of high molecular weight multimers of vWF
- IMP:
- the highest molecular weight multimers have more hemostatic function than the LMW
- therefore the overall function in comparison to quantity is reduced
- activity < antigen
What is the mechanism for loss of HMW
multimers in type 2A vWD ?
- some mutations cause defective assembly and secretion of the multimers
- other mutations lead to normal secretion of multimers but they are proteolyzed at an increased rate
What do mutations in type 2B vWD lead to ?
- increased binding of vWF to GPIb (platelet vWF receptor)
- platelets coated with vWF are cleared from the bloodstream quickly
- loss of HMW multimers and platelets
- platelets coated with vWF are cleared from the bloodstream quickly
What is platelet type vWD ?
- pseudo-von WD
- rare disorder
- mutation is located on the platelet GPIb gene
- instead of the VWF gene
- still causes increased binding of vWF to GPIb resulting in similar findings to 2B
What characterizes type 2M ?
- Decreased function despite the presence of normal multimers
- the mutation affects the GPIb binding site on vWF
- impairs the ability of vWF to bind to GPIb
Where are the type 2N WVF mutations located ?
- vWD 2N
- aka Normandy
- located within the factor VIII binding site of vWF
- FVIII and vWF are normally bound together in the circulation
- with binding impaired the 1/2 life of FVIII is shortened
- therefore:
- vWF levels are normal in number
- binding to platelets is normal
- but FVIII levels are decreased
- KEY: that is why this mimics Hemophilia A
What vWD are inherited as autosomal dominant ?
- Type I
- Type 2
- 2A
- 2B
- 2M
Which vWD are inherited in autosomal recessive fashion?
- 2N
- Type 3
What is important to understand about vWF
and FVIII in laboratory testing ?
- both are acute phase reactants
- increase in APR
- therefore looking at Fibrinogen (another APR) helps assess whether the levels may be affected by APR
What other things can affect vWF ?
- pregnancy, estrogen- (increase)
- ABO blood groups
- type O has the lowest amount
- ABO carbohydrate antigens are present on vWF and A and B antigens may have increased survival
- also type O blood vWF is more prone to proteolysis
How does age affect vWF levels ?
- elevated above baseline at birth
- declines to baseline by 6 months
- then increases gradually with age
IMP: so can miss the diagnosis of vWD shortly after birth
What pre-analytic factors can affect vWF ?
- clotted specimens, serum specimens
- cause a loss of large vWF multimers (also lose Factor VIII)
- produces a false type 2 vWD
- whole blood transported in cold temperatures
- decreases vWF and FVIII
- re-warming can sometimes bring the levels back
- improper thawing of frozen specimens
- precipitates out the vWF and Factor VIII
What is the typical vWF panel ?
- ristocetin cofactor
- vWF antigen
- Factor VIII
- PT
- PTT
- CBC
- Fibrinogen
What is the ristocetin cofactor assay
and how does it work ?
- measures ristocetin mediated binding of vWF to platelet GPIb
- it is a measure of vWF function
- one disadvantage of the ristocetin cofactor assay is that the CV is high, which can result in variable results among labs
Note: ristocetin is an antibiotic
What are the different binding sites on the vWF protein?
- N-terminal portion: Factor VIII binding site
- A1-A3 domains: GPIb, Heparin and collagen binding sites
- A1-A3 domains: also the site of ADAMTS13 cleavage site
- C terminal portion: mediates platelet aggregation by binding the GPIIb/IIIA receptor on platelets
How does the vWF antigen assay work?
- measures the quantity of vWF regardless of the quality/function of the protein
- can be measured by ELISA or automated latex assays
How is Factor VIII measured?
- typically a PTT-based clotting assay, which measures Factor VIII activity
If a type 2B vWD is suspected, what additional testing is performed?
- ristocetin induced platelet aggregation
- this is similar to ristocetin cofactor assay except it tests the ability of the patient’s vWF to bind and agglutinate the patient’s platelets where ristocetin cofactor assay tests the ability of the patient’s vWF to agglutinate normal platelets
When are vWF multiyears analyzed?
- if the initial round of testing suggests a type 2 or type 3 vWD
Is the PFA-100 abnormal in vWD?
- yes
- typically in moderate to severe cases but it is not as sensitive in detecting mild cases
