Coagulation Cascade Flashcards by Chum SJM

coagulation is also known as

clotting

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the process by which blood changes from a liquid to a gel, forming a blood clot.

Coagulation

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Coagulation - It potentially results in ________, the cessation of blood loss from a damaged vessel, followed by _______.

hemostasis ; repair

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in coagulation,

cascades in that as _____ became activated, it in turn activated the next enzyme in _____

one enzyme ; sequence

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Coagulation factors/ clotting factors:

glycoproteins synthesized in the liver (monocytes, ECs, and megakaryocytes: produce few amts)

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8: enzymes that circulate in an inactive form

(zymogens)

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bind, stabilize, and enhance the activity of their respective enzymes.

Cofactors

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If zymogen activation is uncontrolled and generalized, the condition is called _______

disseminated intravascular coagulation (DIC)

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ultimate substrate of the coagulation pathway
Large, stable globulin protein (mw 341,000)
Precursor of fibrin (Factor Ia), which forms clot

Fibrinogen (Factor I)

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When fibrinogen is exposed to thrombin, 2 peptides split from the fibrinogen leaving _______

Monomers aggregate together to form ________

fibrin monomer ; polymerized fibrin clot

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___________, whose level increases in inflammation, infection, and other stress conditions

acute phase reactant protein

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Cross-linking of fibrin polymers by factor XIIIa covalently incorporates ________: a plasma protein involved in cell adhesion

fibronectin

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renders the fibrin mesh resistant to fibrinolysis.

a2-antiplasmin

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Stable CHON (mw 63,000)
Converted into thrombin by enzymatic action of thromboplastin in the presence of ionized calcium
Half life is almost 3 days

Factor II (Prothrombin)

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Activated form of prothrombin
Inert precursor in the circulation
Consumed when fibrinogen is converted to fibrin

Factor IIa (Thrombin)

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In factor IIa (thrombin), a unit will coagulate 1 mL of a ________ in 15 seconds at 28 degrees Celsius

standard fibrinogen solution

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initiates aggregation of platelets
considered the key protease of the coagulation pathway
plays a role in coagulation (fibrin), in platelet activation, in coagulation control (binding to thrombomodulin to activate protein C), and in controlling fibrinolysis (activates TAFI)

Factor IIa (thrombin)

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Nonplasma, contains lipoCHON complex from tissues

Tissue Thromboplastin (Factor III)

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Tissue Thromboplastin (Factor III) is high concentration in

Brain, Lung, Vascular Endothelium, Liver, Placenta, Kidneys

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These tissue types are capable of converting prothrombin to thrombin
Transmembrane receptor for factor VIIa

Tissue Thromboplastin (Factor III)

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Necessary for the activation of thromboplastin and conversion of prothrombin to thrombin

Ionized Calcium (Factor IV)

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Labile globulin CHON
Half life is 16 hrs
Consumed during clotting and essential in thromboplastin formation
Both activated by thrombin and then ultimately inactivated by the generation of thrombin

Factor V (Proaccelerin)

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bound thrombin activates protein C, which inactivates Va to Vi

thrombomodulin

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A beta globulin
Activation of tissue thromboplastin and acceleration of the production of thrombin from prothrombin
Reduced by vitamin k antigonists

Factor VII (Proconvertin)

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- produced primarily by hepatocytes, & microvascular ECs in lung and other tissues - activated by thrombin and inactivated by protein C - cofactor to factor IX - circulates bound to VWF

Factor VIII (Antihemophilic Factor)

unstable in plasma

Free factor VIII

During coagulation, thrombin cleaves factor VIII from VWF and activates it. Factor VIIIa binds to activated platelets and forms the _______

intrinsic tenase complex

Males with hemophilia A have diminished _______ but normal _______

factor VIII activity ; VWF levels

deteriorates more rapidly than the other coagulation factors in stored blood

Factor VIII (Antihemophilic Factor)

level drops to approximately 50% after 5 days

thawed component plasma

In factor VIII, Replacement therapy transfused according to the _________ of factor VIII

12-hour half-life

participates in platelet adhesion and transports the factor VIII

VWF

VWF-cleaving protease

ADAMTS-13

In TTP: inherited or acquired defective ADAMTS-13 enzyme activity is associated with the presence of ______

ultralarge VWF

individuals with VWD: diminished ________ levels

factor VIII activity

In factor VIII, _______ individuals have lower levels of VWF than other ABO types

Group O

an acute phase protein, as is factor VIII, and levels increase in ______, _____, ______, and _______.

pregnancy, trauma, infections, and stress.

Ag is procoagulant Ag as measured by immunological techniques using antibodies for factor VIII:C

Factor VIIIC

Ag is a related factor VII ag that was identified by immunological techniques employing heterologous Ab to VIII/vWF

Factor VIIIR

RCo demonstrates ristocetin cofactor activity, required for aggregation of human platelets induced by the antibiotic ristocetin

Factor VIIIR

synthesize by endothelial cells

Factor VIII/vWF

Forms the final common pathway through which the products of both the intrinsic and extrinsic thromboplastin generating systems merge to form thromboplastin that converts prothrombin to thrombin

Factor X (Stuart Factor)

- A beta globulin - Found in serum - For thromboplastin-generating mechanism - Activated by the contact factor complex and by thrombin

Factor XI (Plasma Thromboplastin antecedent)

Deficiencies of factor XI: __________

Rosenthal syndrome

- Stable factor, consumed in coagulation - Absorption of this factor and kininogen to negatively charged surfaces like glass and subendothelium exposed by blood vessel injury initiates the intrinsic coagulation pathway - Surface absorption alters and partially activates this factor to factor XIIa by exposing an active enzyme site

Factor XII (Hageman Factor)

Produces stable fibrin clot in the presence of ionized Ca

Factor XIII (Fibrin-stabilizing factor)

contact factors AKA _____________

intrinsic accessory pathway proteins

contact factors include

factor XII, high-molecular-weight kininogen (HMWK, Fitzgerald factor), prekallikrein (pre-K, Fletcher factor)

activated by contact with negatively charged foreign surfaces

Contact factors

intrinsic contact factor complex:___________ is a cofactor to factor XIIa and prekallikrein

High-molecular-weight kininogen

mechanism for activating coagulation in conditions where foreign objects such as mechanical heart valves or bacterial membranes and/or high levels of inflammation are present.

Contact Factors

_______ transforms ______, a glycoprotein that circulates bound to _____, into its active form _______, which cleaves HMWK to form ________

Factor XIIa ; pre-K ; HMWK ; kallikrein ; bradykinin

contact factor complex (HMWK:pre-K:FXII) activates ______

factor XI

Function: Required for coagulation factors to bind to phospholipid (formerly known as factor IV) Associated Genetic Disorders: ---

IV Calcium

Function: Co-factor of X with which it forms the prothrombinase complex Associated Genetic Disorders: Activated protein C resistance

V (proaccelerin, labile factor)

Function: Unassigned – old name of Factor Va Associated Genetic Disorders: --

Function: Activates IX, X Associated Genetic Disorders: congenital factor VII deficiency

VII(stable factor, proconvertin)

Function: Co-factor of IX with which it forms the tenase complex Associated Genetic Disorders: Haemophilia A

VIII (Antihemophilic factor A)

Function: Activates X: forms tenase complex with factor VIII Associated Genetic Disorders: Haemophilia B

IX (Antihemophilic factor B or Christmas factor)

Function: Activates II: forms prothrombinasecomplex with factor V Associated Genetic Disorders: Congenital Factor X deficiency

X (Stuart-Prower factor)

Function: Activates IX Associated Genetic Disorders: Haemophilia C

XI(plasma thromboplastin antecedent)

Function: Activates factor XI, VII and prekallikrein Associated Genetic Disorders: Hereditary angioedema type III

XII (Hageman factor)

Function: Crosslinks fibrin Associated Genetic Disorders: Congenital Factor XIIIa/b deficiency

XIII (fibrin-stabilizing factor)

Function: Binds to VIII, mediates platelet adhesion Associated Genetic Disorders:von Willebrand disease

von Willebrand factor

Function: Activates XII and prekallikrein; cleaves HMWK Associated Genetic Disorders: Prekallikrein/Fletcher Factor deficiency

Prekallikrein/ Pre-K (Fletcher factor)

Function: Mediates cell adhesion Associated Genetic Disorders: Glomerulopathy with fibronectin deposits

fibronectin

Vitamin K–Dependent Prothrombin Group

Prothrombin (factor II), factors VII, IX, and X and the regulatory proteins protein C, protein S, and protein Z

________ is a quinone found in green leafy vegetables and is produced by the intestinal organisms Bacteroides fragilis and Escherichia coli.

Vitamin K

Makes them (Vit. K dependent prothrombin group) unable to participate in coagulation: __________

vitamin K deficiency or in the presence of warfarin/ coumadin

- assembled by the prothrombin grp - Composed of vitamin K–dependent serine protease, cofactor, and Ca2+

3 membrane complexes

what are the 3 membrane complexes

1. Extrinsic Tenase 2. Intrinsic Tenase 3. Prothrombinase

- FVIIa + TF (TF-bearing cells) - Activates FIX and X

Extrinsic tenase

- FIXa + VIIIa (Plt membrane) - Activates factor X much more efficiently than the TF:VIIa complex

Intrinsic tenase

- FXa + CfVa (Plt surface) - converts prothrombin to thrombin

Prothrombinase

Cofactors in Hemostasis tissue factor, factor V, factor VIII, and HMWK: _______

Coagulation cascade

______ : Coagulation control cofactors

Thrombomodulin, protein S, and protein Z

cofactor binds its particular _________. When bound to their cofactors, serine proteases gain _____ and increased _____

serine protease ; stability ; reactivity

- _________ : expressed by vascular ECs thrombin cofactor - _________ activate protein C and thrombin activatable fibrinolysis inhibitor (TAFI)

Thrombomodulin ; thrombomodulin and thrombin

- _______ : a coagulation regulatory protein - ______ : fibrinolysis inhibitor

Protein C TAFI

cofactor to protein C and TFPI

Protein S

cofactor to Z-dependent protease inhibitor (ZPI)

Protein Z

- activated partial thromboplastin time (aPTT): laboratory test that detects the absence of one or more of these factors - Deficiency=prolong test

Intrinsic pathway

Prothrombin time test (PT): test used to measure the integrity of the extrinsic pathway

Extrinsic Pathway

This system on activation by factor XIIa generates bradykinin, so named because of the slow contraction of smooth muscle it induces. First, kallikrein is formed from plasma prekaallikrein by the action of prekallikrein activator which is a fragment of factor XIIa. Kallikrein then acts on high molecular weight kininogen to form bradykinin.

Kinin System

maintain a complex and delicate balance between thrombosis and abnormal bleeding

COAGULATION REGULATORY MECHANISMS

- Kunitz-type serine protease inhibitor - TFPI: Principal regulator - Kunitz-2 binds to and inhibits factor Xa - Kunitz-1 binds to and inhibits VIIa:TF - inhibits coagulation: 1st binding and inactivating Xa, TFPI:Xa complex then binds to TF:VIIa -forming a quaternary complex and preventing further activation of X and IX - Protein S: cofactor of activated protein C and TFPI and enhances factor Xa inhibition

Tissue Factor Pathway Inhibitor (TFPI)

- Triggered by thrombin binds the EC membrane protein thrombomodulin - Revises thrombin’s function from a procoagulant enzyme to an anticoagulant - EC protein C receptor (EPCR):transmembrane protein that binds both protein C and APC adjacent to the thrombomodulin-thrombin complex - Augments the action of thrombin-thrombomodulin at least fivefold in activating protein C to a serine protease - APC dissociates from EPCR and binds its cofactor, free plasma protein S - Stabilized APC-protein S complex hydrolyzes and inactivates factors Va and VIIIa - Protein S: cofactor that binds and stabilizes APC - Chronic acquired or inherited protein C or protein S deficiency or its mutation: may be associated with recurrent venous thromboembolic disease - purpura fulminans: neonates who completely lack protein C

Protein C Regulatory System/protein C anticoagulant system

- Antithrombin (AT): first of the coagulation regulatory proteins to be identified = first to be assayed = binds and neutralizes thrombin (factor IIa) and factors = IXa, Xa, XIa, XIIa, prekallikrein, and plasmin = binds thrombin, forming an inactive thrombin-antithrombin complex (TAT) - Heparin cofactor II: inactivates thrombin - both require heparin for effective anticoagulant activity

Antithrombin and Other Serine Protease Inhibitors (Serpins)

- ______ : mast cell granules, EC heparan sulfate - ________ :inactivation of thrombin - _________ : inactivates factor Xa

Heparin Unfractionated heparin low-molecular-weight AND pentasaccharide heparins

- ZPI: in the presence of its cofactor, _____, is a potent inhibitor of factor Xa -_____ : vitamin K–dependent plasma glycoprotein - increases the ability of ZPI to inhibit factor Xa - also inhibits factor Xia in the presence of heparin

protein Z Protein Z

- ___________: nonspecific, heparin-binding serpin - inhibits a variety of proteases, including APC, thrombin, factor Xa, factor XIa, and urokinase - can function as an anticoagulant (inhibits thrombin), as a procoagulant (inhibits thrombin-thrombomodulin and APC), or as a fibrinolytic inhibitor

Protein C inhibitor

- The systematic, accelerating hydrolysis of fibrin by bound plasmin - TPA and UPA activate fibrin-bound plasminogen several hours after thrombus formation, degrading fibrin and restoring normal blood flow during vascular repair - Two activators of fibrinolysis: TPA and UPA - released in response to inflammation and coagulation

FIBRINOLYSIS

- Kringles: single-chain protein possessing five glycosylated loops = Enable plasminogen, along with TPA and UPA, to bind - -- fibrin during polymerization - Fibrin bound plasminogen becomes plasmin - Plasmin: digests fibrin polymer = restores blood vessel patency - Free plasmin is capable of digesting plasma fibrinogen, factor V, factor VIII, and fibronectin, causing a potentially fatal primary fibrinolysis = plasma a2-antiplasmin rapidly binds and inactivates any free plasmin

Plasminogen and Plasmin

Plasminogen Activation

TPA - tissue plasminogen activator UPA - urokinase plasminogen activator

hydrolyzes fibrin-bound plasminogen and initiates fibrinolysis by converting plasminogen to plasmin

TPA

- Urinary tract epithelial cells, monocytes, and macrophages: secretor = incorporated into the mix of fibrin-bound plasminogen and TPA at the time of thrombus formation = Does not bind firmly to fibrin

UPA

control of fibrinolysis

1. Plasminogen Activator Inhibitor 1 (PAI-1) 2. a2-Antiplasmin 3. Thrombin-Activatable Fibrinolysis Inhibitor (TAFI)

- principal inhibitor of plasminogen activation - Inactivating TPA and UPA - Platelets store a pool of PAI-1, accounting for more than half of its availability and for its delivery to the fibrin clot - Normal: PAI-1 > TPA - Fibrinolysis: TPA > PAI-1 - PAI-1 deficiency: associated with chronic mild bleeding due to increased fibrinolysis - acute phase reactant - Increased PAI-1 levels correlate with reduced fibrinolytic activity and increased risk of thrombosis

Plasminogen Activator Inhibitor 1 (PAI-1)

- Primary inhibitor of free plasmin - therapeutic lysine analogues (tranexamic acid and e-aminocaproic acid): antifibrinolytic through their affinity for kringles in plasminogen and TPA

a2-Antiplasmin

- activated by the thrombin-thrombomodulin complex - antifibrinolytic enzyme: cleaves exposed carboxy-terminal lysine residues from partially degraded fibrin = preventing the binding of TPA and plasminogen to fibrin = blocks the formation of plasmin - Increased thrombin formation=increased TAFI activation =decreased fibrinolysis

Thrombin-Activatable Fibrinolysis Inhibitor (TAFI)

- Plasmin cleaves fibrin and produces a series of identifiable - fibrin fragments: X, Y, D, E, and D-D - inhibit hemostasis and contribute to hemorrhage by preventing platelet activation and by hindering fibrin polymerization - Fragments X, Y, D, and E: produced by digestion of either fibrin or fibrinogen by plasmin - D-dimer: specific product of digestion of cross-linked fibrin only = marker of thrombosis and fibrinolysis = D-dimer immunoassay is used to identify chronic and acute DIC and to rule out venous thromboembolism

Fibrin Degradation Products and D-Dimer

Fibrin and fibrinogen degradation products (FDP) are protein fragments resulting from the action of plasmin on fibrin and fibrinogen.

Fibrinolysis

Coagulation Cascade Flashcards

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