Inherited bleeding disorders Flashcards
If deficient in XIII, how does one’s PT and aPTT tests show?
-normal since these tests stop at fibrin polymers (before crosslinking)
Deficiencies in all factors except which ones cause bleeding?
-XIII and contact factors (XII, HMWK, Prekallikrein)
If deficient in factor XIII would you expect delayed or immediate bleeding?
-delayed
Give the 4 general categories of inherited defects of platelet function.
- recruitment defects
- secretion defects
- cohesion defects: Glanzmann’s Thromboasthenia
- Adhesion defects: VWD
Glanzmann’s Thrombasthenia: mechanism, clinical manifestation, inheritance.
- fibrinogen receptor deficiency (aIIbB3) resulting in failure of platelet aggregation
- easy bruising, epistaxis, menorrhagia, platelet transfusions before surgery and for bleeds
- autosomal recessive
Functions of Von Willebrand Factor (VWF).
- facilitates platelets adhesion to injured endothelium by acting as accessory molecule to collagen
- binds and carries F VIII in plasma
* *has collagen, platelet and VIII binding sites
Is VWF molecules big or small?
-huge! many multimers held together by disulfide bonds
Where is VWF synthesized? What is the name of the vesicle it is secreted out of?
- megakaryocytes and endothelial cells
- Weibel-Palade Body
If we constantly have VWF in our circulation, how do clots not always form?
- circulating VWF is folded onto itself to physically block platelet binding sites and improper clot formation
- it unfolds and is available when it attaches to collagen and blow flow unravels it
Where are VWF and VIII made?
- VWF: endothelial cells and megs
- VIII: liver, non-hepatocytes
How can VWD lead to hemophilia A?
-VWF is carrier of VIII and greatly prolongs its survival and helping to maintain its levels. Without VWF, VIII doesn’t survive long and its levels may drop
What is ADAMTS13 and what does it do?
- metalloprotease present in plasma
- much of VWF released from WP bodies is in form of potentially dangerous ultra-high molecular weight VWF multimers. ADAMTS13 limited proteolyses some of the largest multimers to a safe size
- responsible in part for characteristic ladder of VWF multimer sizes seen on denaturing SDS agarose gels (non-reducing)
Where is the cleavage site of ADAMTS13 within the VWF gene?
-within A2 domain
TTP: what is it? clinical findings, lab findings, etiology, and treatment.
- prothrombic state
- confusion, strokes, arrhythmias due to platelet-rich microthrombi formation
- MAHA, thrombocytopenia, schistocytes (RBC fragments), renal dysfunction
- autoantibodies to ADAMTS13 leading to persistence of ultra-large VWF multimers and platelet clumping in vivo
- Plasmapheresis to remove Abs, manipulate Ab formation with steroids of rituxan (anti-CD20)
3 types of VWD. Mechanism of type II.
Type I: quantitative reduction of normal VWF
Type II: normal amounts of abnormal VWF; mutations near ADAMTS13 cleavage site that increases sensitivity to proteolysis and results in increased cleavage of normal VWF
Type III: homozygous mutant, making no VWF
