Normal Platelet Function
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Why do we form clots?
Stop bleeding, prevent pathogens from entering blood stream
Which of the following are involved in normal clotting hemostasis: endothelium, platelets or coagulation proteins?
All of the above
What is the role of the platelet in homeostasis?
Formation of hemostatic plug and provides phospholipid membrane surface for assembly of key coagulation proteins
What three events occur after a vessel injury to stop bleeding?
Vasoconstriction, blood coagulation proteins, platelet activation/aggregation/adhesion
What is the normal lifespan of a platelet?
Up to 10 days
What is the distribution of platelets in the body?
70% in bloodstream, 30% in spleen
True or false: platelets have nuclei
True or false: platelets are divided into 4 zones
What are the 4 zones of the platelet?
Peripheral zone, Sol-Gel zone, Organelle zone, and Membrane system
What are the components of the peripheral zone of a platelet?
- Surface membrane: rich in glycoprotiens for adhesion and aggregation, as well as phospholipids that are a source of thromboxane A2
- Open canalicular system: transports substances in and out of platelets
What are the components of the Sol-Gel zone of the platelet?
Cytoskeleton for retaining and changing shape
What are the components of the organelle zone of the platelet?
Mitochondria and lysosomes, contain granules which store critical signalling compounds.
What are they types of granules found in the organelle zone of the platelet?
- Alpha: adhesive proteins - fibrinogen, vWF, factors V, VIII, XI, XIII, HMWK1, PAI-1
- Delta (dense): ATP and ADP, calcium, histamine, serotonin, and epinephrine
What are the components of the membrane system of platelets?
Calcium store, enzymes for prostaglandin synthesis
What are the 4 things that happen for platelets to become activated?
Adhesion, aggregation, contraction and secretion (contraction and secretion are the steps of platelet activation)
How do platelets adhere to a site of injury?
Triggered by exposure of subendothelial substances, especially collagen. Van willibrand factor binds to collagen and this complex binds to glycoprotein Ib/IX on platelet surface.
What do platelets bind to for aggregation to occur?
Adhere to other platelets via GpIIb/IIIa. This involves vWF and fibrin(ogen)
What is platelet contraction?
Activation of platelet causes shape change from discoid to spheroid.
What do platelets secrete when they are activated? Why does this occur?
Explosive secretion of platelet granular contents due to calcium influx. This makes the platelet plug a tight mass.
How does the platelet plug lead to fibrin formation?
The platelet plug provides surface for assembly of coagulation proteins leading to fibrin formation.
How is thromboxane A2 synthesized?
Arachidonate is released by activated platelets and oxygenated into endoperoxides. These are then converted to thromboxane A2 by thromboxane synthesis.
What is the role of thromboxane A2?
Potent signal for platelet aggregation, vasoconstrictor, increases cytosolic calcium.
How does aspirin (ASA) inhibit platelet aggregation?
It inhibits cyclooxyenase, leading to decreased thromboxane A2 and prostacyclin.
Outline the processes that lead to platelet adhesion.
Tissue injury -> exposure of collagen, fibronectin, vitronectin, laminin, and release of tissue factor. Van Willebrand factor binds to collagen. Ib-alpha on platelet can bind to the vWF-collagen complex. The platelet rolls along this complex until it comes to a halt. Gp6 on the platelet binds collagen, triggering activation of the platelet. GpIIb/IIIa is exposed on the platelet, which can bind additional vWF to allow for aggregation of platelets.
What are some factors that contribute to platelet activation and function?
ADP and calcium
What type of charged phospholipids can be moved to the outside of the platelet membrane to allow for coagulation?
Negatively charged, such as phosphatidylserine.
What factors induce the release of microvesicles from platelets that can coagulate?
Fibrillary collagen (even without thrombin) and fibrin-bound platelets
What is a bleeding time test? What factors can affect the result?
- an in vivo test of coagulation. Limited use in a few circumstances.
- Time required for bleeding to stop after a cut of defined length and depth is made.
- Affected by platelet number and function, subendothelial tissue elasticity, coagulation proteins. Prolonged with van Willebrand factor deficiency and ASA ingestion
True or false: there is a tight correlation between platelet count and bleeding tendency
False - no tight correlation, but a platelet count may still provide diagnostic clues
What is a platelet function test? What is meant by biphasic activation of platelets?
in vitro assay measuring platelet aggregation in response to various stimuli. Stimuli include: ADP, collagen, arachidonic acid, ristocetin, epinephrine. With some stimuli, response can be biphasic: low doses induce primary wave of activation and higher doses induce aggregation plus release of endogenous ADP, producing a secondary wave.
How does a platelet aggregometer work?
Centrifuge blood, platelets are suspended. Put platelet portion in aggregometer and add an agonist (ie. ADP, epinephrine). Stir. The machine has a light source and a photometer that counts the amount of light. With agonist, platelets will undergo shape change and aggregate together, meaning more space between the platelets and a higher reading on the photometer as more light can pass through. If the platelets don't aggregate, transmission will not increase.
What are some causes of thrombocytopenia?
lowered platelet count (uremia, too much ASA and rare genetic disorders), various marrow failure or injury (aplastic anemia, leukemia), sometimes immunologically mediated, destruction of platelets by prosthetic heart valves, common manifestation of AIDS
What are some signs of thrombocytopenia?
- Spontaneous bleeding, prolonged bleeding time
- Bleeding into CNS a concern
What are 2 disorders of platelet function caused by an abnormal platelet receptor?
- Glanzmann's thrombasthenia: GpIIb/IIIa, autosomal recessive, poor platelet plug formation, treated with transfusions
- Bernard-Soulier Syndrome: GpIb alpha/IX, autosomal recessive, large platelets, mild thrombocytopenia, treated with transfusions
What are the 5 possible conditions associated with abnormal storage pools of platelets/granules?
- Gray platelet syndrome: alpha granule, large, gray platelets with light microscopy, abnormal electron microscopy, may respond to DDAVP
- Quebec platelet disorder: abnormal response to epinephrine
- Herman-Pudlak: albinism, dense granules defective, abnormal aggregation with collagen, defective second wave
- Chediak-Higashi: abnormal granules in leukocytes, melanocytes, but not platelets, pyogenic infections, bleeding tendency
- Wiskott-Aldrich: thrombocytopenia, small platelets, X-linked, recurrent infections, Eczema
How to the antiplatlet drugs ASA, clopidogrel and Abciximab work?
- ASA: inhibits cyclooxygenase
- Clopidogrel: blocks ADP receptor
- Abcixibam: antibody, blocks GpIIb/IIIa
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