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112 Cards in this Set
- Front
- Back
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What is Primary hemostasis?
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When platelets stop bleeding by forming a white thrombus, without any help from the clotting cascade.
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What molecule is a potent inhibitor of platelet function and keeps them in an inert state? What is it secreted by?
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Prostacyclin - PGI2 - secreted by endothelial cells
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What 4 specific components of the subendothelial matrix are exposed when a vessel wall is injured?
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-vWf
-Collagen -Fibronectin -Laminin |
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What receptor for vWF is on platelets that allows them to adhere to damaged endothelium?
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GPIb-alpha
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What happens when platelets adhere to subendothelial matrix?
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They become activated and release substances in their platelet storage granules
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What are 2 especially important substances in platelet storage granules that are released when platelets are activated?
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-ADP
-TxA2 |
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What is the function of ADP and Thromboxane?
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To activate more platelets to produce a conformation change in GP2b-3alpha
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What is GP2b-3alpha able to do when it undergoes conformational shape change?
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It can bind to fibrinogen.
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What does Fibrinogen do?
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Crosslinks platelets by binding to their gp2b-3a receptors - producing a platelet aggregate
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What is the platelet aggregate composed of platelets and fibrinogen called?
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A white thrombus (thus this is still primary hemostasis)
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What do activated platelets promote?
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The clotting cascade
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What is the result of a platelet plug plus a fibrin network created by clotting cascades?
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A more effective barrier to blood loss.
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Will a person with congenital hypofibrinogenemia bleed uncontrollably?
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No - they still have primary hemostasis which can form platelet plugs, despite the lack of clotting cascade.
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So the 2 important receptors on platelets are:
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-GpIIb-3A (fibrinogen)
-GPIb - vWF receptor |
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What is lack of fibrinogen receptor called?
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Glanzmann thrombasthenia
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What is lack of GPIb called?
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Bernard soulier
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What is lack of vWF called?
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vWD
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How do activated Platelets (by ADP and thromboxane) trigger the clotting cascade?
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By externalizing anionic phospholipids which provide a surface for coag protein complexes
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What 2 reactions are enhanced by the anionic surface of activated phospholipids on platelets?
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-Conversion of Fx X to Xa
-Conversion of Fx II to IIa |
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How much are these reactions enhanced by platelet phospholipid?
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300-1000X faster!
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What cells are platelets derived from?
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Megakaryocytes in the bone marrow
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What 2 factors could inhibit platelet production if deficient?
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-Stem cell factor
-Thrombopoietin |
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What is the main regulator of platelet production? Where is it primarily produced?
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Thrombopoietin - in the liver
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What are the 2 ways that TPO functions?
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-Shunts HSCs into the megakaryocytic pathway
-Speeds up megakaryo maturation and platelet release |
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How is Thrombopoietin itself regulated?
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By negative feedback; when platelets are high, they eat up a lot of TPO; when low they allow TPO to stay and activate more plt production
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What can be given exogenously to increase platelet production?
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Thrombopoietin analogs
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For what condition is thrombocytopenia a major limitation on how it is treated?
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Cancer - low platelets greatly limits the amt of chemotherapy that can be given
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What is the normal platelet lifespan in the circulation?
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~8 days
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What is the minimum number of platelets required for normal hemostasis?
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25-50,000/uL
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What is the normal platelet count?
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140,000-400,000/uL
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What are the 3 main classes of platelet disorders?
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1. Thrombocytosis
2. Functional defects 3. Thrombocytopenia |
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2 causes of thrombocytosis:
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-Reactive
-Primary (essential) |
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How do TPO levels differ in Reactive vs Primary thrombocytosis?
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Reactive: normal-increased
Primary: low-normal |
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What are 5 conditions that cause reactive thrombocytosis?
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1. Chronic blood loss (Fe defic)
2. Chronic inflammatory disease 3. Chronic infections 4. Cancer 5. Post-surgery |
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What causes the most EXTREME form of reactive thrombocytosis?
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Splenectomy
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When after splenectomy do platelet counts return to normal?
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2-4 weeks
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What are 4 conditions that cause Essential Primary Thrombocythemia?
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1. CML
2. PV 3. ET 4. Myelofibrosis |
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And the main difference between these Primary thrombocythemias vs reactive thrombocytosis?
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Primary - not regulated by TPO
Reactive - driven by TPO |
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What is the paradox to how patients with Essential thrombocythemia often present?
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They often BLEED despite HIGH platelet counts
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Why do patients with ET bleed?
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Because their platelets are functionally abnormal
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How is Essential thrombocythemia sometimes treated?
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With platelet transfusions!
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What 3 membrane receptors on Platelets help to immobilize them at sites of vascular injury?
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GPIB - vWF receptor
GPIa/IIa - collagen GPVI - collagen |
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And what receptor is activated by binding to collagen/vWF?
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GP2b/3a - fibrinogen receptor
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And what is the result of binding fibrinogen?
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Platelet aggregation
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What are the 2 main tools available for investigating platelet function in the lab?
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1. Bleeding time
2. Platelet aggregation studies |
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What 4 agonists do platelet aggregation studies test the response of platelets to?
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-ADP
-Epi -Collagen -Ristocetin |
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What is the only time that a BT is useful?
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When the plt count is above 100K/uL
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What 2 conditions can cause a prolonged BT?
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-Platelet dysfunction
-vWF deficiency |
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What is an abnormal BT?
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>9 min
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How is platelet aggregation function tested?
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By seeing whether platelets clump upon addition of an agonist - measured as an increase in light transmission
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What are the 2 main genetically determined platelet function disorders?
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1. Bernard soulier (GPIB absence or dysfunction
2. Glanzmann's thrombasthenia (GPIIB3a absence or dysfunction) |
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What platelet aggregation test shows Bernard soulier syndrome?
What morphologic feature can be observe in BSS? |
-Abnormal Ristocetin response
-Large platelets |
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What platelet aggregation test shows Glanzmann's thrombasthenia? What morphology can be observed?
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Abnormal response to ADP, thrombin, collagen, and epi - but normal response to ristocetin
-Normal morphology |
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What disease is often confused with qualitative platelet disorders?
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von Willebrand disease
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How can vWD be distinguished from other platelet dysfunction disease?
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The BT is abnormal, but intrinsic platelet function is just fine. vWF is what's missing
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What is a very common type of platelet disorder?
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Acquired platelet hypofunction
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What are 3 systemic disorders in which platelet hypofunction is commonly seen?
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-Chronic renal disease
-Chronic hepatic disease -Cardiopulmonary bypass |
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What hematologic diseases often have platelet hypofunction?
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-Chronic myeloproliferatives
-Myelodysplasia -Leukemias -Dysproteinemias |
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What are 3 meds known to cause acquired platelet hypofunction?
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-Aspirin
-NSAIDs -Cephalosporins |
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How bad are the bleeding symptoms in acquired plt hypofunction disorders usually?
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Mild
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When do bleeding symptoms in acquired plt hypofunction disorders become a risk?
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-Major surgery
-Anticoagulative therapy |
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What must be avoided for patients with functional platelet disorders?
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Aspirin and NSAIDs
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What does Platelet Hyperfunction mean?
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Platelets have a low activation threshold (all we have to say)
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What happens to the shape of platelets when activated?
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They go from being smooth and discoid to spikey and more spherical
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What are the spikey things on activated platelets?
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Actin polymerizations and anionic phospholipids that flipped from the inner to outer surfaces.
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When is it good to induce an acquired platelet functional defect?
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In patients with hyperfunctional platelets or atherosclerosis
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What is one of the most effective agents to induce a mild but tolerable bleeding risk?
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Aspirin
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What does Aspirin inhibit?
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Conversion of Arachidonic acid into Thromboxane A2 by Cox 1 and Cox 2 enzymes in platelets
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Is the inhibition of Cox1/Cox2 in platelets reversible?
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No - platelets lack nuclei and cannot regenerate the enzymes.
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What else do platelets inhibit?
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Cox-2 in endothelium
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What does Cox-2 in endothelium do?
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Converts Arachidonic acid into Prostacyclin - prevents thrombosis
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What is the major difference about inhibiting Cox 2 in endothelium?
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ECs still have nuclei so the effects are not permanent.
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What selectively inhibits Cox2?
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Vioxx, the pain medication for arthritis
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Why was Vioxx pulled from the market?
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Because it put patients at risk for clotting/thrombosis due to uninhibited activity of TxA2
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What are 4 causes of Thrombocytopenia?
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1. Decreased plt production
2. Increased plt destruction 3. Sequestration of plts in spleen 4. Dilutional thrombocytopenia |
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What are the normal %s of platelets in the circulation? In the spleen?
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Circulation = 80%
Spleen = 20% |
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What can increase the proportion of platelets in the spleen? What is this condition called?
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Hypersplenism - Distributional thrombocytopenia
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What are 2 conditions associated with Distributional thrombocytopenia?
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-Cirrhosis
-Lymphoid malignancy |
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What causes Dilutional thrombocytopenia?
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Transfusion of whole blood or PRCs which contain no viable platelets - washes out those still in the recipient
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What are 4 conditions that cause thrombocytopenia due to decreased platelet production?
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-Aplastic anemia
-Myelopthisic anemia -Chronic alcohol ingestion -Total body irradiation |
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What procedure can be done to confirma a lack of platelet production?
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Bone marrow biopsy
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What does the presence of adequete numbers of megakaryocytes on a bm aspirate or biopsy tell you?
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That a thrombocytopenia is not the result of inadequete platelet production.
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What are the 2 categories of thrombocytopenia caused by platelet DESTRUCTION?
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1. Nonimmune
2. Immune |
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What is a non-immune thrombocytopenia caused by increased platelet consumption?
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Thrombotic thrombocytopenia purpura
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What are 3 types of Ab-mediated platelet destruction?
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-Drug-induced
-Acute autoimmune -Chronic autoimmune |
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What are 3 universal symptoms seen clinically in TTP?
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1. Severe thrombocytopenia
2. Microangiopathic hemolytic anemia 3. Fluctuating neurologic abnormalities |
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What 2 symptoms are also often seen with TTP?
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-Spiking fever
-Renal failure |
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What age and sex is generally affected most often by TTP?
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Young females
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What 2 morphologic features would be expected on a PBS in TTP?
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-Schistocytes
-Absence of platelets |
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What are the hallmark lesions of TTP?
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Microthrombi
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What are microthrombi?
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NOT true thrombi; just aggregated platelets that occlude small vessels
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What can result from the microvascular occlusions in TTP?
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Neurological damage
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How is TTP treated?
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By plasma exchange therapy
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Is the benefit of Plasma exchange therapy in that it REMOVES something harmful, or ADDS something deficient?
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BOTH!
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IN TTP, what is it that is
-Replaced -Removed |
Replaces ADAMS13 metalloproteinase
Removes autoantibody against ADAMS13 - restores functionality to cleave high MW vWF multimers |
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What is ADAMS13?
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a metalloprotease that normally cleaves the high MW vWF into lower MW multimers
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How do some drugs induce Immune thrombocytopenia?
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By inducing antibodies that cause platelet destruction upon later administration of the drug
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What are 4 drugs that often have the side effect of inducing immune thrombocytopenia?
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-Quinolones
-Quinine -NSAIDs -Antibiotics |
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What is HIT?
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Heparin induced thrombocytopenia
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What is the bad thing that develops in about 10% of the 10% of patients that get thrombocytopenia while on Heparin?
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Arterial/venous thrombosis and thromboembolism leading to death or limb amputation
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What are the antibodies in HIT specific against?
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Heparin-Platelet Fx4 complexes
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What type of heparin is less likely to cause HIT?
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Low molecular weight heparin
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What steps should be taken in treating HIT?
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1. Stop heparin
2. Serologic test for HIT antibody 3. Start alternate anticoagulant |
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What 2 conditions are among the most common of autoimmune disorders? In what age groups are these mostly seen?
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1. Acute Autoimmune TP - kids
2. Chronic AITP - adults |
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When do Acute AITP cases in children often occur?
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Following viral infections
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What patients are affected by Chronic AITP most?
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Adult women
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What is the onset of chronic AITP in women like?
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Insidious, does not follow infection, thrombocytopenia is not always severe
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What is the favored target of autoantibodies in chronic AITP?
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GP2b-3a
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How is AITP treated?
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-Corticosteroids - prednisone
-Splenectomy |
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What can happen to pregnant individuals with AITP?
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Transplacental transfer of the autoantibody to the fetus
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What can develop as a result of transplacental transfer of maternal ALLOantibody?
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Neonatal Alloimmune thrombocytopenia - NATP
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How can NATP occur in a first pregnancy, when we know things like Rh-incompatible transfusion reactions occur in 2nd pregnancies?
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Platelets an cross the placenta early in gestation
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