253. Platelet Function, Formation

Question 1

NORMAL PLATELET BIOGENESIS

• what molecule stimulates platelet development
• what is unique about the way platelets develop?
• what is the function of the ____ Demarcation Membrane System?
• what is the role of the different parts of cytoskeleton?

Answer 1

• TPO stim platelet development at every step
• endomitosis: amplification of genetic material without division (2N -> 128N Megakaryocyte)
• Megakaryocyte Demarcation Membrane System: cytoskeleton of MK, reservoir for platelet membrane formation
• Actin-myosin interaction in MK causes proplatelet elaboration and propulsion of MK membrane
• Dynein-microtubule interaction cause proplatelet elongation and transport of granules for platelet function

Question 2

PLATELET PRODUCTION AND LIFESPAN

• what is the lifespan of platelets?
• where are they made?
• where do they go from blood?
• how do platelet kinetics change in thrombocytopenia?
• effect of thrombocytopenia on endothelium
• what mutations can modulate platelet lifespan?

Answer 2

• 8 to 10 days
• made in bone marrow
• leave blood to liver (senescence) or spleen (sequestered)
• thrombocytopenia: decreased survival time due to increased platelet removal
• endothelium thins and develops fenestrations/pores due to thrombocytopenia (role of platelets in endothelium health)
• platelet lifespan altered by intrinsic apoptosis: BCL-2 (pro-survival: knockout = less lifespan); BH3/BAX/BAK (pro-apoptotic: knockout = more lifespan)

Question 3

PLATELET FUNCTION, HEMOSTASIS

• what are the 4 functions of platelets
• what receptors bind vessel during endothelial damage
• what are the key contents in platelet granules
• how is thromboxane synthesized?
• how are additional platelets recruited during thrombus formation?
• how does the lipid bilayer change during platelet activation?

Answer 3

1. Clot formation: adhere to damaged blood vessel, recruit additional platelets, provide a surface for coagulation to occur, clot maturation
2. Provide growth factors for wound repair
3. Endothelial maintenance function
4. Adjuvant immune function

GpIb-IX-V binds vWF-collagen (helps roll onto endothelium)
GpIIbIIIa binds fibrinogen

Dense granules: ADP, ATP, Ca
Alpha granules: PF4, fibrinogen, Factor V, vWF

TxA2: synthesized from arachidonic acid via phospholipase A2, COX pathway

Recruitment: via ADP (platelet degranulation), TxA2 synthesis, Fibrinogen Receptor (GpIIbIIIa) activation and binding

Phospholipids: activation causes increased flippase, floppase, scramblase to express more phosphatidylserine residues on outer membrane (site of coag factor binding)

Question 4

Differences between venous and arterial thromboses

• site
• extension
• factors involved

Answer 4

Arterial

• thrombus at site of turbulence or endothelial injury
• extends retrograde to flow
• platelets, tissue factor, fibrin

Venous

• thrombus at site of stasis
• extends in direction of flow
• RBC, fibrin, few platelets, many leukocytes, NETs, TF, microvesicles (myeloid cells are activated forming neutrophil extracellular traps = NETs)

Question 5

What are 3 tests to assess qualitative platelet defects

Answer 5

1. Platelet function analysis
2. Platelet aggregation studies
   - both use pt platelets, add agonist to look for clumping
3. Platelet flow cytometry - look at receptor defects

Question 6

What are 3 common acquired platelet function defects?

Answer 6

1. Drugs (ASPIRIN, NSAIDs)
2. Uremia - metabolic byproducts inhibit platelet fx
3. Dysproteinemia: liver disease with fibrin degradation products interfere with platelet-fibrinogen binding

Question 7

What are 3 common hereditary platelet function defects?

- give labs and tx for each

Answer 7

1. Bernard-Soulier Syndrome: defective GpIb/IX (vWF receptor) = platelet dysfx
   - variable thrombocytopenia
   - large platelets
   - abnormal ristocetin aggregation, normal with other aggregates (defective vWF receptor)
   - flow cytometry: decreased GpIb/IX complex
   - tx: platelet transfusion (adjunct DDAVP)
2. Glanzmann Thrombasthemia: defective GpIIb/IIIa receptor - platelets cannot bind fibrinogen and aggregate
   - global abnormal aggregation with all agonists except ristocetin
   - flow cytometry: decreased GPIIb/IIIa receptors
   - tx: platelet transfusion (adjunct DDAVP)
3. Dense Granule Storage Pool Disorder: defect in dense granules = less ADP/ATP = less aggregation
   - abnormal platelet aggregation
   - no dense granules on EM