Platelet function and defects Flashcards
1
Q
Platelet granules
A
- Dense bodies (smaller, fewer): ADP, ATP, serotonin, Ca, histamine
- Alpha granules (larger, more): adhesive proteins (fibrinogen, vWF, P-selectin, ect), coagulation factors (V, XI, fibrinogen, PAI1), growth/angiogenesis factors (PDGF, TGF-b, PF4)
- Lysosomal granules
- Granules secreted into canalicular system: contiguous w/ plasma membrane, increases the platelets surface area when activated
2
Q
Platelet receptors
A
- GP=glycoprotein
- GPIb/IX binds vWF
- GPIIb/IIIa binds fibrinogen and vWF
- GPIa/IIa binds collagen
- GP VI binds collagen
- ADP receptors
- PARs bind thrombin
- Thromboxane A2 receptors
- Integrins bind fibrinogen
3
Q
Arachidonic acid metabolism
A
- Platelets utilize phospholipiases to cleave off arachindonic acid from their membranes, then turn it into TxA2 via COX pathway
- TxA2 is platelet activator and vasoconstrictor
- Endothelial cells use the same mechanism to make arachidonic acid but then send it through the prostacyclin synthase pathway to make prostacyclin
- PCL is a vasodilator
4
Q
Platelet procoagulant factors
A
- “Factor III”: translocation of phosphatidyl serine (PS) from inner to outer membrane
- Fibrinogen
- vWF
- Factor V
- Factor XIII
- P-selectin for microparticle fusion
5
Q
Platelet formation
A
- Anucleate fragments of megakaryocytes, diameter of 3 microns, volume of 7fL
- Due to increase in megakaryocytic size and number
- TPO is most important regulator of megakaryocytic development and proliferation
- TPO is mostly synthesized in liver and secreted at fairly constant rate
- At some point a megakaryocytic stops dividing and undergoes endomitosis (repeated cycles of DNA replication w/o cell division) until it is up to 64N
- Then the cell extends proplatelets (pseudopodia) into sinuses in BM and platelets are broken off into the blood (each proplatelet makes 1-2k platelets)
6
Q
TPO
A
- Thrombopoietin binds to MPL receptor on platelets and megakaryocytes
- Levels vary according to platelet and megakaryocytic mass
- TPO production in hepatocytes can be increased by IL6
- # of platelets depends on the size of the meg, which depends on the ploidy of the meg
7
Q
Thrombocytopenia
A
- Usually either secondary to aplastic anemia (decreased production) or increased destruction (autoAbs to platelets)
- Can also be from other causes (ineffective production, sequestering in spleen, dilution)
- In aplastic anemia there is a reduced # of megs, thus a higher level of TPO since there are fewer receptors binding TPO
- In ITP (idiopathic thrombocytopenic purpura, an autoimmune-mediated destruction of platelets), the Abs are mostly targeting the platelets. Thus the megs are still able to bind the TPO
- There will be an increase in TPO production due to low platelet levels, and an increase in megs in response to the TPO. But overall the excess TPO will be bound by the excess megs and the TPO level will look normal (possibly slightly low)
8
Q
Increasing platelet production
A
- There is an increase in platelet production in ITP even though the platelet levels are low (due to Ab-mediated destruction)
- The higher TPO levels lead to a larger # of megs, an increase in the ploidy of megs, and thus an increase in meg size & volume
- It also leads to a decreased maturation time of the megs
- The platelets released are larger, younger, and far more effective than the older platelets
9
Q
Platelet sequestering
A
- Platelet lifespan is 10 days
- 30% of platelets are in the red pulp of the splenic cords (only recover 70% of platelets in normal people)
- In splenectomized pts you can recover 100% of platelets
10
Q
Evaluation of thrombocytopenia
A
- Can be due to decreased production: small platelets, lower # of megs, usually BM problem
- Can be ineffective production: usually associated w/ megaloblastic anemia
- Can be increased destruction: big platelets, increased # of megs, can be immune or non-immune mediated
- Can be redistribution: enlarged spleen due to portal HTN, storage disease, or BM disorder
- Can be dilution: due to many blood transfusions
- Lower limit of platelets is 150K (upper limit: 400K)
11
Q
Pseudothrombocytopenia
A
- Natural Ab in blood binds to platelets at room temp and the platelets aggregate
- Artifact of the blood drawing process, to Dx must do blood smear and look at the thin edges
12
Q
Platelet size
A
- Normal MPV is 7-9fL
- With increased consumption the MPV goes up
- With decreased production the MPV goes down
13
Q
Cytokines on megakaryocyte development
A
- Endomitosis stimulated by TPO, IL3, IL6, IL11
- The cytokines are released during inflammation, thus chronic illness can lead to elevated platelet levels
- During maturation megs begin to express platelet-specific receptors and granules, also platelet mitochondria, membranes, and lysosomes
14
Q
Sources of fibrinogen and vWF
A
- Fibrinogen: majority made in liver (some from platelets)
- vWF: majority made in endothelium (some from platelets)
15
Q
Platelet adhesion
A
- Endothelial injury leads to release of vWF, which adheres to sub endothelial collagen
- The vWF binds to platelets’ GPIb/IX receptor, causing the platelet to “roll”
- This slowing of the platelet leads to stable binding of the subendothelial collagen to the GPVI receptor
- High shear in arteries cause conformational change in vWF to enhance its binding to GPIb/IX (these interactions do not require energy)
- Once GPVI binds to collagen it induces the expression of GPIa/IIa, which also binds to collagen and stabilizes platelet adhesion
