Under normal circumstances, endothelial and underlying smooth muscle (SM) cells create _______ and ________ which have quiescent effects on platelets to keep them from aggregating.
- NO
- PGI2
What prominent organelle is missing in platelets?
Nucleus
Name 2 molecules that are exposed in vascular injury that activate platelets and clotting. Be sure to name any associated molecules.
- Tissue Factor: makes thrombin/fibrin and activates platelets
- Collagen associated with Von Willebrand Factor (VWF); needs to VWF to activate platelets
Name 4 things activated platelets secrete that are involved in activating and recruiting other platelets.
- Ca2+
- VWF
- ADP
- TxA2
2 ways platelets contribute to hemostasis.
- aggregating to clot
- giving phospholipid substrate to generate fibrin in ten-ase and prothombin-ase complex
6 roles of platelets
- hemostasis
- separation of lymphocytes from vasculature
- innate immunity
- cancer progression
- closure of ductus arteriosus
- blockade of retrograde flow into the thoracic duct
Describe the process of platelet aggregation and the key players. Be sure to describe the structure of the “links” between platelets
- TxA2, thrombin, ADP signal via GPCRs (collagen doesn’t use a GPCR) to ultimately increase cytosolic Ca2+ in platelets
- Ca2+ binds cytosolic protein, Talin, which binds cytosolic domain of aIIbB3 (alpha 2, b beta 3) to activate it
- this is an integrin protein that when activated, can bind the bivalent fibrinogen/fibrin from either end to form bridges between activated platelets
Describe for platelets for TxA2
- platelets have phosphatidylcholine (PC) in membranes with arachidonate moiety
- when activated, platelets’ phospholipase A2 turns on and cleaves off this arachidonate
- Arachidonate via the COX-1 enzyme is turned into TxA2
How does aspirin work?
-irreversibly inhibits COX-1 and thus, irreversibly inhibits TxA2 which inhibits platelet aggregation and recruitment and thus, clot formation
Where do platelets come from?
-megakaryocytes in the bone marrow
Describe the process of regulating platelet count. Where is the main cytokine made?
- Thrombopoietin (TPO) is main cytokine regulating platelet count. Its ligand is MPL and is found on platelets and megakaryocytes. When platelet counts decrease, free TPO levels rise and are now able to reach megs in BM and stimulate them to create more platelets
- TPO is made in liver constituitively
What is the normal platelet count and lifespan?
- 150,000 to 400,000/ microliter
- survive about 10 days, but can be shortened in disorders like ITP
Compare and contrast the typical bleeding phenotypes associated with either platelet or coagulation defects.
Platelet defect: petechiae and ecchymoses, epistaxis, menorrhagia, skin and mucus membrane bleeding, “immediate bleeding”
Coagulation defect: deep spreading hematomas, hemarthroses, retroperitoneal bleeding, “delayed bleeding” when an inadequate fibrin clot breaks down prematurely
3 causes and their subtypes of thrombocytopenia.
- decreased production: can be due to decreased megakaryocytes (chemotherapy, drugs like alcohol or chloramphenicol, marrow disorders like aplastic anemia or leukemia) or ineffective production (vitamin B12 and folate deficiencies, marrow disorders like leukemia or pre-leukemia)
- Decreased survival (increased destruction): immune (ITP, collagen-vascular autoimmune diseases like Lupus, Drugs like quinidine, heparin) or non-immune (DIC, Sepsis, TTP, Bypass pumps)
- Increased sequestration: splenomegaly, liver disease (leading to splenomegaly)
3,
What is ITP, what are its clinical features, what causes it?
- Immune or Idiopathic Thrombocytopenic Purpura
- idiopathic and chronic in adults, but acute and often preceded by virus or illness in children; seen petechiae and ecchymoses at low platelet counts; menorrhagia, surgical bleeding, and very rarely see fatal bleeds
- due to anti-platelet antibodies (some can cross placenta) whose antigen is often surface protein of platelet (aIIbB3) that induce antibody-coate platelet RES removal in spleen
What are the physical and lab findings of ITP and give treatment options.
-platelets can be as low as 1,000, but rest of CBC should be normal
-purpura and petechiae common, fatal bleeds less so
-spleen size= normal
Tx: inhibit phagocyte-mediated clearance of ab-covered platelets (steroids, splenectomy, IVIG); decrease antibody production (steroids, Rituximab anti-CD20, other immunosuppressants); impair T and B cell interactions (steroids and other immunosuppressants); Enhance platelet production (TPO mimetics)
Drug-induced thrombocytopenia can be due to increased destruction or decreased production, or both. Give mechanisms for either case.
- decreased production: usually due to drug effects on BM megs (chemotherapy is an ex.)
- increased destruction: typically antibody-mediated and can target platelets or megs (quinidine)
Give the mechanism for immune-mediate drug-induced thrombocytopenia, treatment, and common example.
- can be fatal!! and onset is 7-10 days after starting drug or shorter if had previous exposure; COMMON!
- drug sticks to glycoprotein on platelet surface. Ab recognizes drug/GP complex or neo-epitope in protein that is produced when drug is bound. The ab-covered platelets are removed in spleen or in circulation if ab fixes complement. Platelets can also be activated by ab crosslinking platelet Fc receptors
- end result: thrombocytopenia
- Tx: stop drug
- Common drug: quinidine
4 examples of inherited abnormalities of platelet function
- aIIbB3 deficiency: Glanzmann’s Thrombasthenia (aggregation defect)
- GPIb deficiency: Bernard-Soulier Syndrome (giant floppy discs that dont adhere to collagen)
- alpha granule deficiency: Grey Platelet Syndrome (secretion defect)
- Dense granule deficiency: Hermansky-Pudlak Syndrome (secretion defect)
* **rare, autosomal recessive
What is thrombocytosis? Give 2 categories and examples.
- elevated platelet counts (>450,000)
- acquired (common): often reactive (secondary); post-splenectomy, iron deficiency, inflammation states; usually asymptomatic
- familial (rare): mutations in TPO 5’ UTR leading to better translation and higher TPO levels; mutations in MPL causing G-of-F or reduced levels on platelets
Thrombocythemia: neoplastic thrombocytosis
- often clonal
- JAK2 gain of function mutations and others (downstream kinase of MPL)
- Myeloproliferative disorders
- can be»_space;>1,000,000
-
Morphology of Thrombi10
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Platelets 1+221
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Anti-Coagulant, fibrinolytic, and anti-platelet agents26
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Hereditary thrombophilias8
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Anemia 126
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Iron deficiency22
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Hemodynamic Disorders19
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Inherited bleeding disorders29
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Acquired Disorders of Hemostasis13
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Hemolytic Anemia25
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DNA metabolism, B12, and Folate deficiency25
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Coagulation24
