Flashcards in Platelet Function and Its Defects Deck (20):
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?
-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
-COX1 mediates production of thromboxane A2
-Calcium, signaling enzymes
In general, what are the three As of platelet function?
What are the steps in platelet adhesion?
1. Endothelial injury-->release of vWF
-vWf adheres to subendothelial colllagen
-vWf binds to platelet GP Ib/V/IX
2. Stable binding of platelet GP VI to collagen
-high shear stress in arteries-->conformation change in vWf, leads to better binding to platelet
3. 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?
-collagen binding to GP VI
-vWf binding to Gp1b/v/IX (platelet)
-thrombin (activated by a developing clot)
-CD39 (breaks down ADP)
What are the results of platelet activation?
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.
1. Defective vWF
2. BSS Bernard Soulier Syndrome-absent GP Ib/V/IX
3. Platelet type vWD -defect in GP Ib/V/IX enhanced binding and clearance of vWf
4. Defective collagen or GP VI
What laboratory tests can you use to detect platelet adhesion defects?
1. Bleeding Time, PFA-100
2. Ristocetin Cofactor Assay -enhances vWF interaction with Plt GP Ib/V/IX - detects problems with vWf
3. 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?
1. 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?
-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?
1. 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
2. Cryoprecipitate -donor plasma w/ VIII and vWf (not recommended)
3. Purified vWf:VIII from donors- humane P, alphanate.
-can be used for surgical prophylaxis and active bleeding
4. Anti fibrinolytic agents to help control mucosal bleeding
5. hormones or nasal DDAVP for menorrhagia
Describe Bernard Soulier Syndrome.
-inherited autosomal recessive disorder
-deficiency in Plt GP Ib/V/IX
-smear: mild to moderate thrombocytopenia, large platelets
-RIPA is low
List the defects associated with platelet activation.
1. storage pool defects
a. gray platelet syndrome-Autosomal recessive deficiency of alpha granules-
b. quebec platelet disorder-Autosomal dominant (but rare) proteolysis of alpha granules due to excess platelet plasminogen activator
2. Inherited platelet receptor defects for ADP, collagen, TXA2, epinephrine
3. Inherited defects in cyclooxygenase or arachidonic acid (can’t make TXA2)
4. Inherited defects in intracellular signalling
Describe Glanzmann's thrombasthenia. How is it diagnosed?
-autosomal recessive defect in platelet GP IIb/IIIa
-normal plt count, iron def anemia
Excessive bleeding extremely variable even within same individual and same family (same genotype)
Moderate to severe spontaneous mucous membrane and cutaneous bleeding
Severe bleeding after trauma or surgery
Severe postpartum bleeding
-prolonged BT, absence of aggregation to any agonist except ristocetin
-diagnosis: confirmed by flow cytometry with antibodies to GP IIb/IIIa
What are treatments for Glanzmann's thrombasthenia?
Hormonal treatment in women
Platelet transfusions after trauma or before surgery
Fibrinolytic inhibitors for mucous membrane bleeding
Recombinant factor VIIa