Coagulation and Hemostasis

• Coagulation is also known as clotting.
• Coagulation is a vital bodily process preventing excessive blood loss after injury.
• It is the second stage of hemostasis.

Secondary Hemostasis Role

• Existing coagulation factors interact, creating a fibrin mesh to stop bleeding.
• The coagulation system activates plasma proteins.
• It involves 16 glycoproteins as serine proteases.

Procoagulants activation

• Most coagulation substances exist in an inert form initially.
• These substances must be activated.
• Coagulation factors are numbered by discovery order.
• An activated procoagulant is indicated by "a" after the numeral.

Procoagulant Nomenclature

• Plasma transports at least 16 procoagulants, also known as coagulation or clotting factors.
• Nearly all procoagulants are glycoproteins produced in the liver's hepatocytes.
• 8 clotting factors are enzymes in an inactive form (zymogens).
• Other procoagulants are cofactors, binding and stabilizing their respective enzymes.
• The endpoint of coagulation activation is a localized clot or thrombus which is an abnormal fibrin clot formation.

1958 International Blood Clotting Factors Committee

• Plasma Procoagulants were officially named using Roman Numerals, ordered by initial description/discovery.
• Activation of a procoagulant is indicated by a lowercase "a."
• Both zymogens and cofactors become activated during coagulation.

Coagulation Factors Composition

• Coagulation factors include serine proteases, proteins, and minerals.

Zymogen Aspects

• Zymogens are inactive precursor forms of coagulation factors.
• They circulate in the blood to be activated when required.
• Factors II, VII, IX, X, XI, XII and PK are zymogens.

Serine Proteases Definition

• Serine proteases are a specific enzyme type within coagulation factors.
• Factors IIa, VIIa, IXa, Xa, XIa, XIIa, and Kallikrein are serine proteases.

Cofactors Examples

• Factors V, VIII Tissue Factor and HMWK are cofactors.

Coagulation factors pathways

• Intrinsic pathway factors are XII, XI, IX, and VIII.
• Extrinsic pathway factors are VII.
• Common pathway factors are X, V, II, I, and XIII.
• Prothrombin time (PT) tests the extrinsic and common pathways.
• Activated partial thromboplastin time (APTT) assesses the intrinsic and common pathways.

Synonyms of Clotting Factors

• Factor I: Fibrinogen
• Factor II: Prothrombin is also prethrombin
• Factor III: Tissue Factor is also tissue thromboplastin
• Factor IV: Calcium is also ionized calcium
• Factor V: Proaccelerin is also labile factor or accelerator globulin
• Factor VII: Proconvertin is also stable factor or Serum prothrombin conversion accelerator (SPCA), or Autoprothrombin
• Factor VIII:C: Antihemophilic Factor (AHF) is also antihemophilic globulin (AHG), or Platelet cofactor I
• Factor IX: Plasma Thromboplastin Component (PTC) is also Christmas factor, Antihemophilic factor B, or Platelet cofactor II
• Factor X: Stuart-Prower Factor is also Stuart factor, Prower factor, or Autoprothrombin III
• Factor XI: Plasma Thromboplastin Antecedent is also Antihemophilic factor C
• Factor XII: Hageman Factor is also Glass factor, or Contact Factor
• Factor XIII: Fibrin Stabilizing Factor is also Laki-Lorand factor, Fibrinase, Plasma transglutaminase, or Fibrinoligase
• HMWK: Fitzgerald Factor is also Contact activation cofactor, Williams factor, or Flaujeac Factor
• Prekallikrein: Fletcher Factor

Additional Notes

• Fibrinogen is the most concentrated coagulation factor.
• All coagulation factors, except Factor VIII complex, are produced by the liver.
• Factor VIII complex is a combination of VIII:C and VWF.
• Factors VII and XI can be prematurely activated at cold temperatures.
• Factors V and VIII are labile.

Fibrinogen Information

• Fibrinogen increases approximately 10mg/dL per decade in the elderly (65-79 yrs).
• Prolonged PT and APTT occur when fibrinogen levels are 100mg/dL or less.
• Fibrinogen levels may fall to less than 100mg/dL in end-stage liver disease, which signifies liver failure.

Intrinsic Pathway

• This pathway is activated in-vivo by contact of coagulation proteins with subendothelial tissue.
• It begins with Factor XII absorption on a negatively charged surface (collagen).
• FXI also forms complexes with HMWK on the surface.
• Factor XIIa initiates the intrinsic pathway, fibrinolysis, and the kinin and complement systems.
• IXa - VIIIa - Ca - PL makes up the intrinsic tenase.

Prekallikrein Functions

• It perpetuates FXII production and its own production.
• This initiates the kinin system.
• It initiates the fibrinolytic and complement systems, along with FXIIa.
• Prekallikrein directly activates IX to IXa.

Extrinsic Pathway

• The pathway is initiated with tissue factor release.
• It consists of tissue factor, FVII, and Calcium.
• Tissue factor, a lipoprotein, is released into plasma from cell membranes when there is vascular injury.
• The phospholipid portion of tissue factor activates FVII and FVIIa.
• The FVII-Ca-TF complex on platelet PL converts FX to FXa.

Common Pathway

• Extrinsic activation occurs when VIIa-Ca-TF converts X to Xa on the PL surface.
• Intrinsic activation occurs when the IXa-Ca-VIIIa complex binds with the PL on the platelet surface, activating FX to Xa.
• FVIII must be modified by thrombin to become functional.
• FXa leads to prothrombinase complex, or Xa-Va-Ca+PL, formation.
• Prothrombinase converts prothrombin to thrombin.
• The reactions are completed once fibrinogen is converted to fibrin and is stabilized into a clot.

Thrombin Functions

• Thrombin converts fibrinogen to fibrin.
• It activates Factor XIII to stabilize the fibrin clot.
• Thrombin also activates and modifies Factors V and VIII.

Thrombin Feedback Mechanism

• Low levels of thrombin activates V to Va and VIII to VIIIa, activating XIII to XIIIa, and platelet aggregation,.
• High level of thrombin inhibits Factor V and VIII, initiates fibrinolysis by converting plasminogen to plasmin, and activates Protein C.

Factors & Vitamin K

• Factor I, V, VIII, XIII - are not Vitamin K Dependent
• Factor II, VII, IX, X, Protein C, Protein S - are Vitamin K Dependent

Stages of Coagulation

• Stage 1: Generation of thromboplastin via Intrinsic (XII --> XI --> IX --> VIII), Extrinsic (III --> VII), and Common (X --> V) pathways.
• Stage 2: Conversion of prothrombin to thrombin.
• Stage 3: Conversion of fibrinogen to fibrin clot involving Factor 1 and Fibrin, with Factor XIII stabilizing the fibrin clot.

Problems

• If all clotting factors are functioning normally then PT and APTT are considered normal.

Inhibitors of Coagulation

• Protein C degrades Factor Va and VIIIa.
• Protein S degrades Factor Va and VIIIa.
• Antithrombin III inhibits thrombin and Factors IXa, Xa, XIa, XIIa, kallikrein, and plasmin.
• Heparin Cofactor II inhibits thrombin.
• A2-Macroglobulin forms a complex with thrombin, kallikrein, and plasmin, inhibiting their activities.
• Extrinsic Pathway Inhibitor (EPI)/Lipoprotein Associated Coagulation Inhibitor (LACI) inhibits the VIIa-tissue factor complex.
• C1 Inhibitor inactivates Factor XIIa and kallikrein and also inhibits Factor XIa and plasmin.
• A1-Antitrypsin inhibits thrombin, Xa, and XIa.