Platelet Function and Its Defects Flashcards
How are platelets made?
- from megakaryocytic in bone marrow
- undergo endomitosis-repeated cycles of DNA replication without cell division
- Each meg forms 10-20 proplatelets, and each pro platelet gives rise to 1000-2000 mature platelets
What are the contents of a platelet?
Granules
-alpha granules: larger, more
includes: adhesive proteins e.g. fibrinogen, growth factors, coagulation factors
-Dense granules: smaller, fewer
includes platelet agonists i.e. ATP, ADP, Serotonin, Ca2+
-lysosomal granules- minor role
Open Cannicular system (OCS)
-allows internal pathway for release of granules
-increases platelet surface when activated
Cytoplasmic proteins
-COX1 mediates production of thromboxane A2
-cytoskeletal proteins
-Calcium, signaling enzymes
In general, what are the three As of platelet function?
Adhesion
Activation
Aggregation
What are the steps in platelet adhesion?
- Endothelial injury–>release of vWF
- vWf adheres to subendothelial colllagen
- vWf binds to platelet GP Ib/V/IX - Stable binding of platelet GP VI to collagen
- high shear stress in arteries–>conformation change in vWf, leads to better binding to platelet - Platelet expresses GP Ia/IIa, which stabilizes adhesion to exposed collagen
Describe von Willebrand Factor. Where is it made, stored, and how is it broken down?
- made in endothelial cells mainly, some in megakaryocytes
- Stored in Weibel Palade bodies in endothelium and in platelets as large sticky multimers
- Broken down and cleaved by ADAMTS13 into smaller less active forms in circulation
- Its binding domains: GP1b/V/IX, collagen, factor VIII, GPIIB/IIIa, ADAMTS13
What are agonists of platelet activation? What is activation suppressed by?
Agonists: -collagen binding to GP VI -vWf binding to Gp1b/v/IX (platelet) -thrombin (activated by a developing clot) -ADP -Epinephrine Suppressed by: -Endothelial NO -Endothelial Prostacyclin -CD39 (breaks down ADP)
What are the results of platelet activation?
ADP release Platelet shape change Expression of GP IIb/IIIa (increase aggregation) Thromboxane A2 production and release Inhibition of cAMP (platelet antagonist)
How does platelet aggregation occur?
Activated platelets will recruit and activate other platelets
- expression of GP IIb/IIIa - binds fibrinogen and crosslinks platelets
- release ADP, TXA2, fibrinogen
- is surface for thrombin generation by coat proteins–>clot propagation
- phospholipid moved from inner to outer membrane by scramblase–> micro vesicles that are procoag–>thrombin generation
List the disease of platelet adhesion defects.
- Defective vWF
- BSS Bernard Soulier Syndrome-absent GP Ib/V/IX
- Platelet type vWD -defect in GP Ib/V/IX enhanced binding and clearance of vWf
- Defective collagen or GP VI
What laboratory tests can you use to detect platelet adhesion defects?
- Bleeding Time, PFA-100
- Ristocetin Cofactor Assay -enhances vWF interaction with Plt GP Ib/V/IX - detects problems with vWf
- Collagen Binding Assay - measures interaction between vWf and collagen
What are the challenges in diagnosing Von Willebrand’s Disease?
- vWf levels increased by infection, pregnancy, or estrogen intake
- vWf levels decreased in Type O blood groups
- variable clinical expression (bleeding of mucus membranes depends on subtype and heterogeneity)
- bleeding time and PFA-100 lack high sensitivity and specificity
What are the subtypes of von Willebrand’s disease?
Type 1: partial deficiency of vWF
Type 3: complete deficiency of vWF
Type 2: qualitative variants
A: can only make short chains, no high molecular weight multimers
B: same as 2A with increased affinity for plt 1b, slight thrombocytopenia bc binds pot
M: not completely understood
N: decreased affinity for factor VIII, ristocetin factor low, factor VIII low, normal vWF level
What are tests for von Willebrand’s disease?
- vWf: Ag -amt of antigen (normal 50-150IU/dL), low levels of platelets and plasma, increases amt of ristocetin
How id von Willebrand’s disease difference from hemophilia A?
Hemophilia A
- clinical expression: severe, joint bleeding, deep tissue bleeding. SPONTANEOUS bleeding
- inheritance: sex-linked recessive
- bleeding time: normal
- plt agglutination with ristocetin: normal
- factor VIII clotting: decreased and constant
- vWF: Ag: normal
- multimer analysis: normal
von Willebrand’s disease
- clinical expression:mild, mucous membrane bleeding, joint bleeding rare
- inheritance: autosomal dominant usually
- bleeding time: prolonged
- plt agglutination with ristocetin: abnormal
- factor VIII clotting: decreased and variable
- vWF: Ag: decreased
- multimer analysis: decreased
What are treatment options for vWD?
- desmopression (DDAVP) -stimulates endothelial release of vWF
- response of subsequent doses decreases
- can cause hyponatremia b/c is natural antidiuretic, if given with lots of fluid like in a surgery - Cryoprecipitate -donor plasma w/ VIII and vWf (not recommended)
- Purified vWf:VIII from donors- humane P, alphanate.
- can be used for surgical prophylaxis and active bleeding - Anti fibrinolytic agents to help control mucosal bleeding
- hormones or nasal DDAVP for menorrhagia
