Coagulation Cascade Flashcards
coagulation is also known as
clotting
the process by which blood changes from a liquid to a gel, forming a blood clot.
Coagulation
Coagulation - It potentially results in ________, the cessation of blood loss from a damaged vessel, followed by _______.
hemostasis ; repair
in coagulation,
cascades in that as _____ became activated, it in turn activated the next enzyme in _____
one enzyme ; sequence
Coagulation factors/ clotting factors:
glycoproteins synthesized in the liver (monocytes, ECs, and megakaryocytes: produce few amts)
8: enzymes that circulate in an inactive form
(zymogens)
bind, stabilize, and enhance the activity of their respective enzymes.
Cofactors
If zymogen activation is uncontrolled and generalized, the condition is called _______
disseminated intravascular coagulation (DIC)
- ultimate substrate of the coagulation pathway
- Large, stable globulin protein (mw 341,000)
- Precursor of fibrin (Factor Ia), which forms clot
Fibrinogen (Factor I)
When fibrinogen is exposed to thrombin, 2 peptides split from the fibrinogen leaving _______
Monomers aggregate together to form ________
fibrin monomer ; polymerized fibrin clot
___________, whose level increases in inflammation, infection, and other stress conditions
acute phase reactant protein
Cross-linking of fibrin polymers by factor XIIIa covalently incorporates ________: a plasma protein involved in cell adhesion
fibronectin
renders the fibrin mesh resistant to fibrinolysis.
a2-antiplasmin
- 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)
- Activated form of prothrombin
- Inert precursor in the circulation
- Consumed when fibrinogen is converted to fibrin
Factor IIa (Thrombin)
In factor IIa (thrombin), a unit will coagulate 1 mL of a ________ in 15 seconds at 28 degrees Celsius
standard fibrinogen solution
- 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)
Nonplasma, contains lipoCHON complex from tissues
Tissue Thromboplastin (Factor III)
Tissue Thromboplastin (Factor III) is high concentration in
Brain, Lung, Vascular Endothelium, Liver, Placenta, Kidneys
- These tissue types are capable of converting prothrombin to thrombin
- Transmembrane receptor for factor VIIa
Tissue Thromboplastin (Factor III)
Necessary for the activation of thromboplastin and conversion of prothrombin to thrombin
Ionized Calcium (Factor IV)
- 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)
bound thrombin activates protein C, which inactivates Va to Vi
thrombomodulin
- A beta globulin
- Activation of tissue thromboplastin and acceleration of the production of thrombin from prothrombin
- Reduced by vitamin k antigonists
Factor VII (Proconvertin)
- 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: –
VI
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
- Extrinsic Tenase
- Intrinsic Tenase
- 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
- Plasminogen Activator Inhibitor 1 (PAI-1)
- a2-Antiplasmin
- 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
