Term
| Describe the basic developmental trajectory of platelets. |
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Definition
Platelets form in the bone marrow and "bud" from megakaryocytes (derived from MEP from MPC) under the influence of thrombopoietin (TPO)
live 8-12 days and 1/3 of "platelet mass" temporarily resides in spleen |
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Term
| What are the basic components of a platelet? |
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Definition
4 um, discoid-shaped structures that contain
1) Alpha granules (high MW proteins)
- PDGF (fibroblast/smooth muscle mitogen for wound healing and atherosclerosis)
- Platelet factor 4 (anti-heparin)
2) Dense granules (low MW proteins)
- Adenosine, calcium, serotonin recruit additional platelets and form hemostatic plug.
3) Lysosomes (acid hydrolases)
- vWf, fibrinogen, thrombospondin and fibrnective bind platelets to eachother in subendothelial matrix |
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Term
| How are platelets activated during blood vessel injury? |
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Definition
1) Activation- Circulating platelets adhere to sub-endothelial matrix
- GP Ib-IX binds vWF
- GP Ia-IIa binds collagen
2) Aggregation- GP IIb-IIIa undergoes conformation change and binds Fibrinogen
- Fibrinogen binds other platelets
3) Platelets change from compact discs into spheres with pseudopods
- Phospholipases are activated (kinases..calcium...granular secretion)
- Arachadonic acid is released, leading to formation of TXA2
4) Membrane phospholipids rearrange into tiny vesicles that are shed (Micro particles)
- particles contain "Prothrombin Activator Complex" (phospholipid, calcium, factor Va, factor Xa), which accelerates conversion of prothrombin to thrombin (clotting cascade) |
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Term
| How do platelets activate the immune system during thrombus formation? |
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Definition
1) Express P-selectin on their membrane surfaces following alpha granule fusion (PDGF, PF4)
2) Leukocytes express mucin PSGL-1 ligand for P-selectin, allowing them to adhere to platelets on the vascular wall.
3) Leukocytes provide Tissue Factor (TF), which promotes thrombus formation. |
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Term
| What is the net result of platelet pro-cagulant activity? |
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Definition
1) Phospholipid microparticles provide phospholipid and Granular secretions supply calcium for "prothrombin activator complex" (which also contains factor Va and factor Xa)
2) Activated thrombin acts on fibrinogen to form a fibrin meshwork, which stabalizes the platelet plug |
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Term
| What are the common physical and laboratory findings associated with platelet disorders? |
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Definition
1) Petechia, Purpura, Echymosis, Oral bleeding, Epistaxis (nose bleeding)
2) In patients with normal platelet counts, "Closure Time" aggregation/adhesion studies are useful
- measures time for Epi or ADP to activate platelets and "plug" small diameter collagen -coated channel.
**Aggregation/photometric studies are also useful** |
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Term
Describe the pathophysiology of each of the following congenital, qualitative defects of platelet function.
1) Glanzmann's thrombasthenia
2) Bernard-Soulier syndrome
3) Storage pool deficiency
4) Gray platelet syndrome |
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Definition
All may lead to bleeding risk!
1) Defect in gp IIb-IIIa (fibrinogen receptor) prevents aggregation.
2) Defect in gp 1b-IX (vWf receptor) prevents adhesion
3) Dense body deficiency (adenosine, calcium, 5-HT) prevents hemostatic plug formation
4) Alpha granule deficiency (PDGF and PF4/anti-heparin) |
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Term
Which of the following does not carry a significant bleeding risk?
1) Acetylsalicylic acid
2) Ticaricillin
3) Fish oil
4) Ibuprofin
5) Renal failure |
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Definition
Acquired defects of platelet function
4: Ibuprofin reversibly inhibits platelet COX, thus very transiently influences thromboxane synthesis.
1) Aspirin irreversibly inhibits COX and prevents TXA2 synthesis
2) PCN antibiotic that alters platelet function
3) Competes with AA for COX-1, interfereing with TXA2 synthesis |
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Term
| How are Thienopyridine derivatives and anti-IIb-IIIa receptor blockers used clinically? |
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Definition
| Inhibit coagulation by preventing platelet aggregation. |
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Term
| Which quantitative platelet disorders produce bleeding and thrombosis, respectively? |
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Definition
Thrombocytopenia can cause either bleeding (simple platelet deficiency) or thrombosis (platelet/coagulation system activation)
1) Thrombosis
- DIC (thrombic potent platelet agonist)
- Sepsis (endotoxin aggregates platelets) |
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Term
| What are the 4 major causes of decreased platelet production? |
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Definition
All show decreased/abnormal megakaryoctyes in bone marrow (vs. destructive causes which show megakaryocyte hyperplasia)
1) Primary disorder (aplastic anemia or impaired thrombopoiesis)
2) Chemical/toxic injury to bone marrow (chemo)
3) Marrow infiltration (leukemia, cancer, marrow fibrosis)
4) Infection |
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Term
| What are the primary causes of TP due to platelet destruction? |
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Definition
Look for megakaryocytic hyperplasia in bone marrow
1) Non-immune
- DIC
- Sepsis
2) Immune (ITP)
- Acute (kids <8) is preceded by viral illness, with abrupt onset bruising, bleeding from nasal/oral mucosa (self limited in 2-6 weeks)
- Chronic (young females 20-40) has insidious onset bruising with h/x of easy bruising several months prior (Handled with steroids, IVIG and Splenectomy in long term) |
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Term
| Why does splenomegaly often cause thrombocytopenia? |
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Definition
| 1/3 of circulating platelets pass through spleen and can thus be damaged in the case of splenic congestion |
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Term
| What is the basic pathophysiology of immune TP? |
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Definition
Can be acute (<8 years old) or chronic (females 20-40), with chronic requiring treatment with
- steroids (impair phagocytosis)
- IVIG (binds Fc receptors and prevents adherence)
- Splenectomy.
1) Anti-platelet autoantibodies bind surface antigens and are recognized by splenic macrophage Fc receptors
2) Phagocytosis and destruction occur, and are potentiated by complement activation. |
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Term
| What is the basic pathophysiology/treatment of TTP? |
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Definition
1) Path
-Abnormal proteolysis of vWF due to deficiency of MMP called "ADAMTS-13"
- Without appropriate cleavage, ultra-large (ULvWF) molecule causes increased platelet adhesion and produces MAHA
- Cause micro-arterial occlusions with platelets and vWF (vs. fibrin in the cause of DIC)
**Diagnose by measuring ADAMST-13**
2) Treat with plasmapheresis/exchange |
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Term
| What are the basic clinical manifestations of TTP? |
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Definition
5 things, but really only need thrombocytopenia in presence of MAHA to consider.
1) TP
2) MAHA
3) Something CNS
4) Something Renal (more dominant in HUS)
5) Fever |
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