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What occurs during Primary Hemostasis?
- Vascular system and platelets are involved by coming in contact with exposed collagen...
- Small blood vessels constrict
- Platelets begin to aggregate
- Platelet receptor sites are exposed
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What is the function of ADP/ATP?
- Promotes platelet aggregation
- Acts as an energy source
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What is the function of Thromboxane A2?
Promotes acitvation, release, and aggregation
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What is the function of serotonin when dealing with platelet function?
Promotes vasoconstriction
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What happens during Secondary Hemostasis?
- Goal is generation of sufficient thrombin to convert fibrinogen to fibrin clot
- Activation of intrinsic, extrinsic, and common coag pathways
- Fibrin clot
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What is included in the fibrin clot?
- Platelet plug formed in the primary hemostasis
- Fibrin formed in secondary hemostasis
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Write down the coag pathway (intrinsic, extrinsic, and common)
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What does the Intrinsic Pathway include?
- XII (Hageman or Contact Factor)
- XI (Plasma thromboplastin)
- Prekallikrein (Fletcher)
- HMWK (Fitzgerald)
- IX (plasma thromboplastin component or Christmas factor)
- VIII (Anti-hemophiliac Factor)
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How does the Extrinsic Pathway work?
Release of tissue factor from injured blood vessel endothelial cells and subendothelium
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What is included in the Extrinsic Pathway?
- III (Tissue Thromboplastin factor)
- VII (Stabile Factor)
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How does the Common Pathway work?
Factor X Activation by either the extrinsic or intrinsic pathway
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What does the Common pathway include?
- X (Stuart-Prower)
- V (Proaccerlerin or labile factor)
- II (Prothrombin)
- I (Fibrinogen)
- XIII (fibrin/clot stabilizing factor)
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What is another name for Factor IV?
Calcium
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What is another name for von Willebrand Factor?
Ristocetin cofactor
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What else are coag factors known as?
Enzyme precursors or zymogens
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What are zymogens?
Zymogens are substrates having no biologic activity until converted by enzymes to active forms called serine proteases
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What are included in the zymogens?
- II (Prothrombin)
- VII (Stabile Factor)
- IX (Christmas Factor)
- X (Stewart Prower Factor)
- XI (Plasma Thromboplastin Antecedent)
- XII (Hageman or Contact Factor)
- Prekallikrein
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What are included in the serine proteases?
- IIa
- VIIa
- IXa
- Xa
- XIa
- XIIa
- Kallikrein
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What is the only substrate in the cascade that does NOT become an activated enzyme?
Fibrinogen
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What coag factors are included in the Contact group and where are they produced?
- Prekallikrein
- HMWK (high molecular weight kininogen)
- XI (Plasma Thromboplastin Antecedent)
- XII (Hageman or Contact Factor)
- Produced in the liver
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What is the function of the Contact group?
- XII and prekallikrein reciprocally activate each other and HMWK is a cofactor for this process
- All play a role in the intrinsic coag activation
- XIIa, kallikrein, and HMWK play a role in the inflammatory response, intrinsic fibrinolytic activation, kinin formation, and activation of the complement system
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What factors are included in the Prothrombin group and where are they produced?
- II (Prothrombin)
- VII (Stabile Factor)
- X (Stewart Prower Factor)
- Produced in the liver
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What is required for synthesis of functional coag factors?
- Vitamin K is required for synthesis of functional factors
- Calcium binding sites are necessary for binding to phospholipid (PF3) surfaces
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Name some causes for synthesis of nonfunctional coag factors
- Vitamin K deficiency
- Antibiotics that kill the intestinal bacterial flora responsible for vitamin K synthesis
- Oral anticoagulants (warfarin/coumadin) that interfere with the metabolism of vitamin K (vitamin K antiagonists)
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What coag factors are included in the fibrinogen group and where are they produced?
- I (Fibrinogen)
- V (Labile Factor)
- VII (Stabile Factor)
- XIII (Fibrin/clot Stabilizing Factor)
- Produced in the liver
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What happens when there is low thrombin levels?
Low thrombin levels activate factors V, VIII, and XIII; and also induce platelet aggregation
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What happens when thrombin levels are high?
Thrombin binds to thrombomodulin on the endothelial cell surface and activates the protein C pathway
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What does activated protein C and its cofactor protein S do?
Inhibit factors V and VIII
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What are the steps for the conversion of fibrinoen to fibrin?
- Fibrinogen alpha and beta fibrinopeptides are cleaved by thrombin, forming soluble fibrin monomers
- Fibrin monomers spontaneously polymerize, forming soluble fibrin polymers - which is the end point for clot based tests
- Clot stabilization occurs, requiring thrombin activation of XIII and calcium
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Where is Factor VIII synthesized?
Liver
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What is Factor VIII composed of?
- VIII:C (antihemophilic factor): the coag portion that acts as a cofactor in the intrinsic coag pathway
- VIII:Ag: the antigenic property of factor VIII
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What are the 2 coag factors that are deficient in Hemophilia A?
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Where is von Willebrand factor (vWF) synthesized?
- Endothelial cells
- Megakaryocytes
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What is the function of vWF:RCo (ristocetin cofactor)?
- Needed for platelet adhesion to collagen in vivo
- Needed for a normal response to ristocetin on aggregation studies in vitro
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What 2 coag factors are deficient in von Willebrand disease?
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What acts as the carrier protein for factor VIII:C?
vWF subunits polymerize to form multimers of varying sizes
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What is the function of the complement system when activated during coagulation and finbrinolysis?
Lysing antibody-coated cells
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How is complement activation regulated?
Regulated by C1 inactivator
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What is included in the kinin system?
- XII (Hageman or Contact Factor)
- XI (Plasma Thromboplastin Antecedent)
- Prekallikrein (Fletcher factor)
- HMWK (Fitzgerald factor)
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What is the function of the kinin system?
- Involved in chemotaxis and pain sensation
- Mediates inflammatory response, promotes vasodilation, and activator of intrinsic coag and complement pathways
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What does the fibrinolytic system do?
- Keeps blood vessels clear
- Important in clot dissolution
- During this process, plasminogen is activated to plasmin
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Where is plasminogen produced?
Liver
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Name the activators that convert plasminogen to plasmin
- Intrinsic activators: XIIa, kallikrein, HMWK
- Extrinsic activators: tissue-type plasminogen activator (t-PA) and urokinase-type plasminogen activator (u-PA)
- Exogenous activators (therapeutic agents): t-PA, streptokinase, urokinase, etc (drugs administered to lyse existing clots)...
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What is not normally found in circluation
Its' precursor is found in circulation
Degrades fibrin clots (fibrinolysis), fibrinogen (fibrinogenolysis), factors V and VIII
Activates complement system
Plasmin
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What regulatory protein:
Produced in the liver
Principal inhibitor of coagulation
Inhibits the serine proteases
Therapeutic heparin enhances the action of this protein
Antithrombin (AT)
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What regulatory protein:
Vitamin K-dependent regulatory proteins
Activated when thrombin binds to thrombomodulin on the endothelial cell surface
Inhibits factors V and VIII to provide negative feedback on the cascade
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What regulatory protein inhibits factor VIIa-tissue factor complex?
Tissue factor pathway inhibitor
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What regulatory protein inhibits thrombin, Xa, kallikrein, and plasmin?
alpha2-Macroglobulin
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What regulatory protein inhibits XIa and inactivates plasmin?
alpha1-Antitrypsin
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What regulatory protein inhibits C1 from the complement cascade, XIIa, XIa, kallikrein, and plasmin?
C1 inhibitor
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What regulatory protein:
Is the principal inhibitor of fibrinolysis
Neutralizes plasmin
alpha2-Antiplasmin
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What regulatory protein:
Important inhibitor of fibrinolysis
Prevents activation of plasminogen by t-PA
Released from endothelial cells upon damage
PAI-1 (plasminogen activator inhibitor-1)
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