von Willebrand disease Flashcards
T/F: vWD is the most common inherited bleeding diathesis overall.
True
-Hemophilia A is considered the most common cause of SEVERE hemophila
vWD is a simultaneous impairment of the coagulation cascade and platelet function.
- Coagulation effect?
- Platelet function effect?
- vWF maintains high levels of circulating factor 8 (VIII)
- vWF is operant in the formation of platelet thrombi
Where does synthesis of vWF occur? (2)
- Endothelial cells
- Megakaryocytes
Where in endothelial cells is vWF stored?
Weibel-Palade bodies
Where in megakaryocytes is vWF stored?
alpha granules
vWF is secreted by endothelial cells into underlying basement membrane. What happens when the basement is exposed?
vWF is bound by platelet GPIb
How is GPIb activated?
- In vivo
- In vitro
- In vivo - shear stress
- In vitro - Ristocetin
*vWF is also referred to as ristocetin cofactor
vWF is also secreted into circulation, what breaks it down?
ADAMTS-13
-variably sized multimers, most commonly dimers
What does vWF do in circulation?
Complexes with F8 (VIII) and protects it from degradation
*vWF is sometimes called F8 related antigen
What is the most common type of vWD?
-Second MC
Type I (70%) -Type IIa (10-15%)
Type I vWD severity?
Mild QUANTITATIVE defect
Type I vWD lab findings:
- Platelet count
- PT
- aPTT
- Bleeding time
- PFA-100
Type I vWD lab findings:
- Platelet count - Normal
- PT - Normal
- aPTT - Prolonged
- Bleeding time - Prolonged
- PFA-100 - Prolonged
What are the levels in Type I vWD?
- Factor 8
- vWF Ag
- vWF activity
- Factor 8 - Decreased
- vWF antigen - Decreased
- vWF activity - Decreased
*Ratio of vWF activity to vWF antigen approaches 1 (always >0.7)
Type IIa vWD severity?
Moderate to severe bleeding
Type IIa vWD mutation.
vWF gene on exon 28
-Missense mutation
What is the abnormality in Type IIa vWD?
Absence of large multimers (abnormal multimer pattern)
Prolonged aPTT
What are the levels in Type IIa vWD?
- Factor 8
- vWF Ag
- vWF activity
- Factor 8 - Normal/-
- vWF Ag - Normal/-
- vWF activity - Decreased (Markedly; <50%)
What is the ratio of vWF antigen to vWF activity in Type IIa vWD?
<0.7
Type I vWD:
- Multimer pattern
- Genetics
- Normal
- Unknown genetics
Type IIb vWD mutation.
Gain-of-Function mutation in GPIb binding domain of vWF
What is the abnormality in type IIb vWD?
Decreased large multimers
How is Type IIb vWD unique? (3)
- Enhanced Ristocetin induced platelet aggregation
- DDAVP causes profound thrombocytopenia and bleeding
- Spontaneous binding of vWF to platelets
What must Type IIb vWD be distinguished from?
Platelet type vWD
what is the mutation in Platelet type vWD?
Gain of function mutation in the gene that encodes he platelet GPIb receptor
What are the characteristic lab features for Type IIb and Platelet type vWD?
- Thrombocytopenia
- Decreased HMW Multimers
*Enchanced binding is selective for HMW multimers and results in clearance of both platelets and HMW multimers from the blood
Type IIM vWD is caused by what?
-What does this prevent
Loss of Function in GPIb binding domain
-Prevents binding of vWF to GPIb
How can you distinguish between Type IIa/IIb from IIm vWD?
Type IIM multimer analysis appears normal
*Type IIa/IIb have Decreased Large multimers
Type IIN (Normandy) vWD is caused by what?
Mutation in the domain that binds factor VIII (8)
Type IIN (Normandy) vWD lab findings. -What does this mimic?
Decreased circulating F8
-Mimics Hemophilia A
*distinguished by autosomal inheritance pattern
what is the vWF quantity and function in Type IIN vWD?
vWF quanitity and function are unaffected
What is the most severe type of vWD?
Type III vWD
-virtually NO vWF
What genetics in Type III vWD?
Frameshift mutations, Nonsense mutations, and Deletions in the vWF gene
What are the laboratory findings in Type III vWD?
- Factor 8
- vWF Ag
- vWF activity
- Multimers
- Factor 8 - Low
- vWF Ag - Low
- vWF activity - Low
- Multimers - All sizes decreased/absent
What type of vWD is caused by an abnormal GPIb, leading to increased avidity for vWF?
Pseudo or Platelet type vWD
What ABO blood group has slightly lower vWF levels?
Type O
T/F: Newborns have high vWF activity.
True
-Disease may not be detectable until 1 y/o
What is the Ristocetin cofactor assay (vWF activity assay)?
- Pt plasma is added to formalin fixed normal platelets in the presence of Ristocetin
- Plasma deficient in vWF does not fully aggregate
*normal plasma will cause platelet agglutination
What is the gold standard for classification of vWD?
Gel Electrophoresis
In surgical and acute bleed settings, what is he best monitoring test for patient with vWD?
Factor 8 activity
