Drmsaiem HEMOSTASIS Damaged Blood Vessels. On vessel injury Vasoconstriction occurs as a neurogenic response. Injury breaks the smooth endothelial lining,

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HEMOSTASISHEMOSTASIS

Damaged Blood VesselsDamaged Blood Vessels..On vessel injury On vessel injury

VasoconstrictionVasoconstriction occurs as a occurs as a neurogenicneurogenic response. response. Injury Injury breaks the smooth endothelial lining, exposing breaks the smooth endothelial lining, exposing CollagenCollagen that promotes that promotes thrombus formationthrombus formation by by causing the causing the adherence of plateletsadherence of platelets to the area of to the area of injury.injury.

CollagenCollagen exposure also exposure also initiatesinitiates the the contact phase of contact phase of coagulationcoagulation,, which begins a series of biochemical which begins a series of biochemical reactions known as the reactions known as the IntrinsicIntrinsic coagulation-pathway.coagulation-pathway.Tissue Tissue ThromboplastinThromboplastin is release from the is release from the injured injured vesselvessel, which-, which-promotes coagulationpromotes coagulation through a different through a different series of reactions known as the series of reactions known as the ExtrinsicExtrinsic pathway.pathway.

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Vessel wall, Blood flow & Coagulation Vessel wall, Blood flow & Coagulation SubstancesSubstances

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In Case if there is an Endothelial In Case if there is an Endothelial InjuryInjury((BleedingBleeding must be prevented at site of injury) must be prevented at site of injury)

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Flow must be MaintainedFlow must be Maintained

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Primary HemostasisPrimary Hemostasis

Is initiated by the exposure of Is initiated by the exposure of platelets to the sub-platelets to the sub-endothelialendothelial connective tissue components of blood connective tissue components of blood vessels (vessels (collagencollagen, , microfilamientsmicrofilamients, , basement basement membranes).membranes).

If acute injury occurs, the small If acute injury occurs, the small vessels constrictvessels constrict, , and platelets immediately and platelets immediately adhereadhere to the exposed to the exposed surfaces and release surfaces and release ADPADP and and ATPATP. .

Thromboxane A also is released, which promotes Thromboxane A also is released, which promotes further further Vasoconstriction.Vasoconstriction.

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A reversible primaryA reversible primary platelet platelet aggregationaggregation takes takes place during which platelets adhere to one place during which platelets adhere to one another. Platelets also another. Platelets also change shapechange shape, and their , and their organelles become centralizedorganelles become centralized. At this point, . At this point, platelets may platelets may disaggregate disaggregate in the absence of in the absence of further stimulation. However, with continued further stimulation. However, with continued stimulationstimulation, , SecondarySecondary, , irreversibleirreversible, platelet , platelet aggregation naturally occurs. aggregation naturally occurs.

ImportantImportant substances released during substances released during platelet platelet aggregationaggregation include include ADP, ATP, and serotoninADP, ATP, and serotonin. . The The ADP promotesADP promotes secondary platelet secondary platelet aggregation and recruits additional platelets to aggregation and recruits additional platelets to the site of injury. the site of injury. SerotoninSerotonin promotes further promotes further vasoconstriction. vasoconstriction.

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During During aggregationaggregation, , phospholipid phospholipid ((PLPL) becomes ) becomes available on the platelet membrane surface, available on the platelet membrane surface, providing a site for providing a site for fibrin formationfibrin formation and and thrombo-thrombo-genesis genesis (the(the formation of formation of blood clotsblood clots).).

Secondary HemostasisSecondary Hemostasis

The The Intrinsic and ExtrinsicIntrinsic and Extrinsic Coagulation Pathways Coagulation Pathways The The intrinsic systemintrinsic system is activated in is activated in vivovivo by the by the contact of certain coagulation proteins with contact of certain coagulation proteins with subendothelial connective tissue, which sets the subendothelial connective tissue, which sets the secondary hemostatic mechanism into motion.secondary hemostatic mechanism into motion.

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The The extrinsic coagulationextrinsic coagulation pathway, in contrast, is pathway, in contrast, is initiated with the release of initiated with the release of tissue factortissue factor from from injured vessel endothelial cells and sub-injured vessel endothelial cells and sub-endothelium into the vessel lumen.endothelium into the vessel lumen.

Tissue factorTissue factor, a high-molecular-weight , a high-molecular-weight llipoproteinipoprotein, is , is found in most organs, including found in most organs, including the lungs, kidneys,the lungs, kidneys, liverliver, , brain, placenta, and brain, placenta, and spleen, as well as in large blood vessels such as spleen, as well as in large blood vessels such as the vena cava and aorta.the vena cava and aorta.

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Both the Both the intrinsic and the extrinsic coagulation intrinsic and the extrinsic coagulation pathwayspathways lead to secondary hemostasis, namely, lead to secondary hemostasis, namely, the formation of the the formation of the stable fibrin clotstable fibrin clot. The . The clot clot thus includes both thus includes both fibrinfibrin formed in secondary formed in secondary hemostasis and the hemostasis and the platelet plugplatelet plug formed in formed in primary hemostasis.primary hemostasis.

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Hemostatic Plug FormationHemostatic Plug Formation

Thrombin

AGGREGATION

Fibrin

Hemostaticclot

ClottingPlatelet Aggregation

0 min 10 min5 min

SECONDARY

PRIMARY

COAGULATION

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COAGULATION PROTEINSCOAGULATION PROTEINS

The The intrinsic and extrinsicintrinsic and extrinsic coagulation pathways coagulation pathways are a series of reactions involve coagulation are a series of reactions involve coagulation factors known as factors known as

1- enzyme precursors (1- enzyme precursors (zymogenszymogens) )

2- non-enzymatic (2- non-enzymatic (cofactors)cofactors)

3- calcium (Ca3- calcium (Ca ++ ++))

4- phospholipids (4- phospholipids (PLPL).).

All coagulation factors normally are present in the All coagulation factors normally are present in the plasma, with plasma, with PLPL being provided by being provided by plateletsplatelets..

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The The zymogenszymogens are factors are factors II, VII, IX, X, XI, XIIII, VII, IX, X, XI, XII,, and and prekallikreinprekallikrein

The The cofactorscofactors are factors are factors V, VIIIV, VIII, , tissue factortissue factor, , and high-molecular-weight kininogen (and high-molecular-weight kininogen (HMWKHMWK).).

ZymogensZymogens are substrates that have are substrates that have NONO biologic biologic activityactivity until until converted converted by enzymes to active by enzymes to active enzymes called enzymes called serine proteasesserine proteases, which have , which have exposed, exposed, serine-richserine-rich, active enzyme sites., active enzyme sites.

Serine proteasesSerine proteases selectively hydrolyzed selectively hydrolyzed arginine arginine or lysine-containingor lysine-containing peptide bonds of other peptide bonds of other zymogens, thus converting them to serine zymogens, thus converting them to serine proteases.proteases.

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COAGGULATION FACTORSCOAGGULATION FACTORS

Factor NomenclatureFactor Nomenclature

The nomenclature of coagulation factors covers The nomenclature of coagulation factors covers those referred to by those referred to by Roman numeralsRoman numerals and the and the two factorstwo factors in the in the kinin systemkinin system, , prekallikrein and prekallikrein and HMWKHMWK, which are referred to by , which are referred to by name onlyname only. .

Each factor was assigned a Each factor was assigned a Roman numeralRoman numeral by by the the International Committee in Nomenclature of International Committee in Nomenclature of Blood Coagulation FactorsBlood Coagulation Factors in the in the order of its order of its

discoverydiscovery, not its place in the reaction sequence, not its place in the reaction sequence..

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An important aspect of coagulation factor An important aspect of coagulation factor nomenclature is the “nomenclature is the “aa” that sometimes ” that sometimes accompanies a accompanies a Roman numeralRoman numeral (e.g., factor (e.g., factor XllXllaa). ). It indicates the activated serine protease form of It indicates the activated serine protease form of that factor.that factor.

Tissue factorTissue factor is sometimes referred to as factor is sometimes referred to as factor IIIIII and and calcium ionscalcium ions, as , as factor IVfactor IV. However, . However, tissue and calcium (Catissue and calcium (Ca++++) are the generally ) are the generally accepted terms today.accepted terms today.

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COAGULATION GROUPSCOAGULATION GROUPS

The properties of the coagulation and kinin The properties of the coagulation and kinin factors have similarities that can divide these factors have similarities that can divide these factors easily into factors easily into threethree groups: groups:

1- 1- Contact groupContact group; ; 2- 2- Prothrombin or vitamin K-dependent groupProthrombin or vitamin K-dependent group; ; 3- 3- Fibrinogen groupFibrinogen group. .

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Contact GroupContact Group

PrekallikreinPrekallikrein and and HMWKHMWK of the kinin group along of the kinin group along with factors with factors XIIXII and and XIXI, make up the , make up the contact contact groupgroup. .

The contact group is adsorbed by contact with a The contact group is adsorbed by contact with a negatively charged surface such as negatively charged surface such as collagencollagen or or the the

subendothelium in subendothelium in vivovivo. .

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This contact causes slow conversion of factor This contact causes slow conversion of factor XIIXII to to XIIXIIaa, which initiates both , which initiates both intrinsicintrinsic system system coagulation and coagulation and fibrinolysisfibrinolysis. .

Factor Factor XIIXIIaa, and , and HMWKHMWK together activate factor together activate factor XIXI to to XIXIaa, and convert , and convert prekallikreinprekallikrein to to kallikreinkallikrein. . Kallikrein and HMWK together play a role in Kallikrein and HMWK together play a role in intrinsic coagulation activation, activation of intrinsic coagulation activation, activation of fibrinolysis, kinin formation, and activation of the fibrinolysis, kinin formation, and activation of the complement system.complement system.

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Prothrombin (Vitamin K-Dependent) GroupProthrombin (Vitamin K-Dependent) Group

Contains the vitamin Contains the vitamin K-dependent coagulationK-dependent coagulation factors factors

IIII, , VIIVII, , IX, and XIX, and X. .

These factors are synthesized in the These factors are synthesized in the liverliver in the in the presence of presence of vitamin Kvitamin K, which acts as , which acts as a cofactora cofactor..

Vitamin KVitamin K is fat soluble. It is normally ingested in the is fat soluble. It is normally ingested in the diet and also is manufactured by the gut flora. There diet and also is manufactured by the gut flora. There is no substantial storage of vitamin K in the body.is no substantial storage of vitamin K in the body.

Vitamin K is necessary to Vitamin K is necessary to gamma-carboxylategamma-carboxylate the the pre-formed enzymepre-formed enzyme precursors of factors ( precursors of factors (II, VII, IX, II, VII, IX, and Xand X ) )

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Vitamin K-dependent gamma-carboxylation Vitamin K-dependent gamma-carboxylation reactions may be reactions may be inhibitedinhibited by several by several mechanisms: mechanisms: ((11) ) dietary vitamin K deficiency;dietary vitamin K deficiency;

((22) ) administration of antibiotics that sterilize the administration of antibiotics that sterilize the intestinal tract, where normal flora usually intestinal tract, where normal flora usually synthesize vitamin K;synthesize vitamin K;

((33) ) oral anticoagulantoral anticoagulant therapy, such as with the therapy, such as with the coumarin and warfarin drug, which interferes coumarin and warfarin drug, which interferes with with gamma carboxylationgamma carboxylation. .

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Any of these mechanisms can cause the Any of these mechanisms can cause the formation of formation of non-functional vitamin K-dependentnon-functional vitamin K-dependent coagulation factorscoagulation factors. When such factors are . When such factors are released to the circulation, they released to the circulation, they cannot bind to cannot bind to the platelet the platelet PLPL surface and ultimately surface and ultimately prevent prevent Prothrombin activationProthrombin activation, causing a deficiency in , causing a deficiency in the the coagulation pathwaycoagulation pathway..

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Fibrinogen GroupFibrinogen Group

The The fibrinogen groupfibrinogen group includes includes fibrinogen (fibrinogen (factor factor II) and factor ) and factor V, VIIIV, VIII, and , and XIIIXIII. These have the . These have the highest molecular weights of all factors, are the highest molecular weights of all factors, are the most labilemost labile, are , are consumed in coagulationconsumed in coagulation, and are , and are the only group that act as the only group that act as substrates for the substrates for the fibrinolytic enzyme plasminfibrinolytic enzyme plasmin..

Only the factors found in the Only the factors found in the fibrinogen groupfibrinogen group are are found in the found in the plateletsplatelets, specifically in the , specifically in the alpha alpha granulesgranules with with two exceptionstwo exceptions: (: (11) ) factor XIII is factor XIII is found in the general platelet cytoplasm not in found in the general platelet cytoplasm not in alpha granulesalpha granules, and (, and (22) ) factor VIII:C, the factor VIII:C, the coagulant portion of factor VIII, is not found in coagulant portion of factor VIII, is not found in platelets.platelets.

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PHOSPHOLIPIDS CONTRIBUTING TO COAGULATIONPHOSPHOLIPIDS CONTRIBUTING TO COAGULATION

Tissue FactorTissue Factor The existence of a lipoprotein called The existence of a lipoprotein called

Thromboplastin (a complex of two parts, a Thromboplastin (a complex of two parts, a PL PL and a proteinand a protein).).

This substance initiates the This substance initiates the extrinsic coagulationextrinsic coagulation pathway by binding its pathway by binding its PL portion to factor VIIPL portion to factor VII, , converting factor converting factor VII VII to to VIIVIIaa. .

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PHOSPHOLIPIDS CONTRIBUTING TO COAGULATIONPHOSPHOLIPIDS CONTRIBUTING TO COAGULATION

The term The term extrinsicextrinsic was applied to this pathway was applied to this pathway because of the necessity of adding because of the necessity of adding a tissue a tissue extract (PL)extract (PL) to plasma samples in to plasma samples in vitrovitro to to initiate initiate and evaluate this coagulation pathway in the and evaluate this coagulation pathway in the laboratory. laboratory.

The The Prothrombin Time (PT)Prothrombin Time (PT) test which evaluates test which evaluates the the extrinsicextrinsic system, is performed using a system, is performed using a reagent contained (reagent contained (rabbit brain)rabbit brain) or lung tissue or lung tissue ThromboplastinThromboplastin as well as as well as CaCa++++ to activate factor to activate factor VIIVII and initiate the extrinsic pathway. and initiate the extrinsic pathway.

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COAGULATION CASCAEDCOAGULATION CASCAED

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The KININ SystemThe KININ System

Kinins are peptides of low molecular weight Kinins are peptides of low molecular weight composed of a series of amino acids.composed of a series of amino acids.

The kinin system contains factors that are The kinin system contains factors that are activated by the activated by the coagulationcoagulation and and fibrinolyticfibrinolytic systems. systems.

They mediate inflammatory responses, increase They mediate inflammatory responses, increase vascular permeability, cause vasodilatation and vascular permeability, cause vasodilatation and hypotension.hypotension.

Important in the contact activation phase of the Important in the contact activation phase of the intrinsic intrinsic coagulation pathway as in complement coagulation pathway as in complement activation.activation.

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KININ SystemKININ System

The kinin system factors do not have assigned The kinin system factors do not have assigned Roman numerals. They include:Roman numerals. They include:1- prekallikrein1- prekallikrein2- kallikrein2- kallikrein3- kininogen (low and high molecular weight)3- kininogen (low and high molecular weight)

Prekallikrein Prekallikrein circulate in plasma as a complex circulate in plasma as a complex with the cofactor HMWK, and both also are a with the cofactor HMWK, and both also are a part of the contact group.part of the contact group.PrekallikreinPrekallikrein is converted to the serine protease is converted to the serine protease kallikreinkallikrein in the presence of factor in the presence of factor XIIa XIIa and and HMWKHMWK..

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COAGGULATION & The KININ SystemCOAGGULATION & The KININ System

Kallikrein accelerates factor XII activationKallikrein accelerates factor XII activation Also involved in the fibrinolytic system.Also involved in the fibrinolytic system. Kallikrein and activated XIIa form a complex Kallikrein and activated XIIa form a complex

known as the plasminogen activator which known as the plasminogen activator which converts plasminogen to its active form, plasmin.converts plasminogen to its active form, plasmin.

Plasmin is necessary for the degradation of the Plasmin is necessary for the degradation of the fibrin clot (fibrinolysis).fibrin clot (fibrinolysis).

Documents

Drmsaiem HEMOSTASIS Damaged Blood Vessels. On vessel injury Vasoconstriction occurs as a neurogenic response. Injury breaks the smooth endothelial lining,