Flashcards in Coagulation Basics Deck (30)
What is hemostasis?
Cessation of blood loss from a damaged vessel
Hemostasis occurs in 4 phases, what are they?
1. Vascular Spasm
2. Platelet plug formation (primary hemostasis)
3. Blood coagulation (Secondary hemostasis)
4. Dissolution of the fibrin clot (tertiary hemostasis)
Following injury to the vessel wall, the initial event is what?
--which is a transient, locally induced phenomenon
Platelets, in healthy endothelium, remain in their unactivated state. What mediators are released in order to inhibit platelet aggregation?
--prostacyclin and nitric oxide are release by healthy endothelium
--inhibit platelet aggregation
Blood vessel injury exposes what?
--collagen, Von Willebrand factor (vWF): these are components of the extra cellular matrix
The platelet plasma membrane contains what collagen receptors?
GPVI and vWF receptors (GPIb)
--binding of the collagen and vWF on the extra cellular matrix to these receptors causes the platelet to adhere to the subendothelium
Binding of the collagen and vWF to the platelet results in platelet activation, leading to the release of the contents of the cells' granules:?
ADP, Ca2+, ATP, serotonin, vWF, and platelet factor 4
--all secreted from platelet granules
What is the action of ADP?
Mediates platelet aggregation
--through receptor P2Y1 which couples to Gq and mobilizes intracellular Ca2+
--through receptor P2Y12 which couples to Gi to inhibit adenylyl cyclase
Activated platelets synthesize and release what?
Thromboxane A2 (TXA2)
--platelet aggregating agonist and vasoconstrictor
--receptor couples to Gq and leads to mobilization of intracellular Ca2+
Activation of platelets is enhanced by the generation of thrombin through the coagulation cascade; thrombin is an important platelet agonist. Thrombin receptors are what?
Protease activated G protein coupled receptors
---activation of thrombin receptors results in activation of PLC and inhibition of adenylyl cyclase
Signaling molecules released by activated platelets activate receptors on the plasma membrane of resting platelets circulating nearby. What happens next in the cascade?
Previously dormant platelets become activated and start to aggregate
Platelet aggregation is mediated primarily by what?
--soluble plasma glycoprotein
Binds simultaneously to GPIIB/IIIa receptors on two separate platelets
--this leads to platelet cross linking and platelet aggregation which leads to clot formation
GPIIb/IIIa does not bind fibrinogen on nonstimulated platelets
Platelet activation converts GPIIb/IIIa from a low affinity fibrinogen receptor to a high affinity receptor
The above cards went through the formation of a platelet plus (primary hemostasis). Now secondary hemostasis is the coagulation cascade. How does blood start to coagulate after primary hemostasis?
Transformation of soluble fibrinogen into insoluble fibrin
Thrombin does what?
Catalyzes the conversion of fibrinogen to fibrin
--which is incorporated into the plug
--this is the last step of the coagulation cascade
Cross-linking of the fibrin strands stabilize the clot and forms the hemostatic plug
The coagulation cascade is a sequence of enzymatic events. The coagulation factors are generally serine proteases. Most plasma coagulation factors circulate as inactive proenzymes, which are synthesized by the liver. These proenzymes are proteolytically cleaved, and thereby activated, by the activated factors that precede them in the cascade
There are two pathways of the coagulation pathway. Describe the intrinsic pathway first
Activated in vitro by factor XII (Hageman factor)
Describe the extrinsic pathway
In vivo is initiated by activation of clotting factor VII by the tissue factor (Thromboplastin)
Both the intrinsic and extrinsic coagulation pathways lead to the activation of what?
--activated factor X cleaves prothrombin (factor II) to thrombin (factor IIa)
--thrombin converts the soluble plasma protein fibrinogen into fibrin
Moving on to Vitamin K, what is the action of this vitamin?
Blood clotting factors II, VII,IX and X
--must undergo a vitamin K dependent post translational modification, which involves the gamma carboxylation of a number of glutamic acid residues
Vitamin K is regenerated from the epoxide by what?
Vitamin K epoxide reductase
Finally after vascular injury, anticoagulant factors are secreted by the endothelium:
Proteins C and S
Tissue Factor Pathway Inhibitor (TFPI)
Tissue Type Plasminogen Activation (t-PA)
How does PGI2 work as an anticoagulant factor?
Increases cAMP levels within platelets
--inhibit platelet activation
Also a vasodilator
--increases cAMP levels in the vascular smooth muscle cells
How does antithrombin III work as an anticoagulant factor?
Inactivates thrombin and other coagulation factors
--by forming a complex with them
How does protein C and S work as a anticoagulant agents?
--vitamin K dependent serine protease that is activated by thrombin
Protein C and S
--degrade factors Va and VIIIa
How does tissue factor pathway inhibitor (TFPI) work as an anticoagulant factor?
Limits the action of tissue factor (TF)
--prevents excessive TF-mediated activation of factors IX and X
Finally how does t-PA work as an anticoagulant factor?
Plasmin proteolytically degrades fibrin
--plasmin is generated by cleavage of plasminogen
The cleavage is catalyzed by tissue plasminogen activator (t-PA)
--which is synthesized and secreted by the endothelium
Finally lets touch briefly on thrombosis, what is thrombosis?
Pathologic extension hemostasis
--formation of a clot called a thrombus
What are three major factors that predispose to thrombus formation?
Abnormal blood flow
--this is known as Virchow's Triad
Venous thrombosis is usually trigged by what?
Blood stasis or inappropriate activation of the coagulation cascade
--clot that is rich is fibrin with fewer platelets than in arterial clots