Coagulation factors

GOAGULATION

1. COAGULATION FACTORS 1 Presented by : Dr. Vishal kr. Kandhway

2. Definition 2 Coagulation or clotting is defined as the process in which blood loses its fluidity and becomes a jelly like mass few minutes after it is shed out or collected in a container.

3. 3 Factors involved in blood clotting : Coagulation of blood occurs through a series of reactions due to the activation of group of substances. Substances necessary for clotting are called clotting factors. Thirteen clotting factors are identified

4. Factor Synonyms Half life (hrs) Deficiency syndromes Cause I Fibrinogen 100-150 Afibrinogenemia Premature sep of placenta/congenital II Prothrombin 50-80 Hypo- prothrombinemia Decreased Hepatic synthesis /secondary to Vit K Def III Tissue factor/ Thromboplastin IV Calcium Ion V Proaccelerin / Labile Factor 24 Para hemophillia Congenital COAGULATON NOMENCLATURE :

5. Factor Synonyms Half life(hr) Deficiency syndromes Cause VII S.Prothrombin converter accelerator Stable factor 6 Hypoconvertinemia Congenital VIII Antihemophillic factor AHF-A,VIII:C 12 Hemophillia –A Classical Hemophillia Congenital : X linked IX Christmas Factor AHF-B 24 Hemophillia –B Christmas disease Congenital X Stuart prower factor Auto prothrombin 25-60 Stuart prower factor def Congenital XI Plasma thromboplastin antecedent AHF-C 40-80 PTA def Congenital XII Hageman /contact 50-70 Hageman trait Congenital XIII Fibrin stabilising 150

6. Sequence of clotting mechanism 6 Enzyme Cascade theory : Most of the clotting factors are proteins in the form of enzymes. Normally all the factors are present in the form of inactive proenzyme . These proenzymes must be activated into enzymes to enforce clot formation. It is carried out by a series of proenzyme -enzyme conversion reactions. First one of the series is converted into an active enzyme that activates the 2 nd one, which activates the 3 rd one, this is continued till final active enzyme thrombin is formed. Cascade refers to a process that occurs through a series of steps, each step initializing the next, until the final step is reached.

7. 7 Stages of Blood clotting : Formation of prothrombin activator Conversion of prothrombin into thrombin Conversion of fibrinogen into fibrin.

8. 8 Stage 1 : Formation of prothrombin activator Blood clotting commences with the formation of a substance called prothrombin activator, which converts prothrombin into thrombin.Its formation is initiated by substance produced either within the blood or outside the blood. Thus formation of prothrombin activator occurs through 2 pathways : Intrinsic pathway Extrinsic pathway

9. 9 Intrinsic pathway for the formation of Prothrombin activator : In this pathway the formation of prothrombin activator is initiated by platelets, which are within the blood itself. Sequence of events : During the injury, blood vessel is ruptured. Endothelium is damaged & collagen beneath the endothelium is exposed. When factor XII comes in contact with collagen, it is converted into activated factor XII in the presence of kallikrein & high molecular weight (HMW) kinogen . Activated factor XII converts factor XI into activated factor XI in the presence of HMW kinogen . The activated factor XI activates factor IX in the presence of factor IV(calcium) Activated factor IX activated factor X in the presence of factor VIII & calcium.

10. 10 6) When platelets comes in contact with collagen of damaged blood vessel, it gets activated & releases phospholipids. 7) Now the activated factor X reacts with platelet phospholipid & factor V to form prothrombin activator. This needs the presence of calcium ions. 8 ) Factor V is also activated by positive feedback effect of thrombin.

11. 11 Extrinsic pathway for the formation of Prothrombin activator : In this pathway, the formation of prothrombin activator is initiated by the tissue thromboplastin , which is formed from the injured tissues. Sequence of events : Tissues that are damaged during injury release tissue thromboplastin (factor III). Thromboplastin contain proteins, phospholipid & glycoprotein, which act as proteolytic enzymes. Glycoprotein & phospholipid components of thromboplastin convert factor X into activated factor X in the presence of factor VII. Activated factor X reacts with factor V and phospholipid component of tissue thromboplastin to form prothrombin activator. This reaction requires the presence of calcium ions.

12. 12 2) Stage 2 : Conversion of prothrombin into thrombin Blood clotting is all about thrombin formation. Once thrombin is formed, it definetly leads to clot formation. Sequence of events in stage 2 : 1) Prothrombin activator that is formed in intrinsic & extrinsic pathways, converts prothrombin into thrombin in the presence of calcium(factor IV). 2) Once formed thrombin initiates the formation of more thrombin molecules. The initially formed thrombin activates factor V. Factor V in turn accelerates formation of both extrinsic & intrinsic prothrombin activator, which converts prothrombin in thrombin. This effect of thrombin is called positive feedback effect.

13. 13 Stage 3 : Conversion of fibrinogen into fibrin The final stage of blood clotting involves the conversion of fibrinogen into fibrin by thrombin. Sequence of events in stage 3 : Thrombin converts inactive fibrinogen into activated fibrinogen due to loss of 2 pairs of polypeptides from each fibrinogen molecule. The activated fibrinogen is called fibrin monomer. Fibrin monomer polymerizes with other monomer molecules & form loosly arranged strands of fibrin. Later these loose strands are modified into dense & tight fibrin threads by fibrin stabilizing factor(factor XIII) in the presence of calcium ions. All the tight fibrin threads are aggregated to form a meshwork of stable clot.

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15. 15 Blood Clot : defined as the mass of coagulated blood which contains RBC, WBC & platelets entrapped in fibrin meshwork. RBC & WBC are not necessary for clotting process. However whn clot is formed, these cells are trapped in it along with platelets. The trapped RBC’S are responsible for the red colour of the clot. The external blood clot is called scab. It adheres to the opening of damaged blood vessel & prevents blood loss.

16. 16 Clot Retraction : After the formation, the blood clot starts contracting. And after about 30-45 mins , the straw coloured serum oozes out of the clot. The process involving the contraction of blood clot & oozing of the serum is called clot retraction. Contractile proteins actin , myocin & thrombostenin are responsible for clot retraction.

17. 17 Fibrinolysis : Lysis of blood clot inside the blood vessel is called fibrinolysis . It helps to remove the clot from lumen of the blood vessel by the help of plasmin fibrinolysin .

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19. 19 Fibrinogen (factor I) : Glycoprotein that helps in the formation of blood clots. Fibrinogen molecule is a soluble large & complex glycoprotein that is converted by thrombin into fibrin during blood clot formation. It is synthesized in the liver by hepatocytes . Concentration of fibrinogen in the blood plasmais 200-400 mg/dl. Deficiency can lead to either bleeding or thrombo -embolic complication. Aquired deficiency is found after hemodilution , blood loss in trauma patients & also in sepsis. In patients with fibrinogen deficiency, the correction of bleeding is possible by infusion of FFP, cryoprecipitate or by fibrinogen concentrates.

20. 20 Prothrombin : is produced in the liver & is co- translationally modified in a vit K dependant reaction that converts 10 glutamic acid on prothrombin to gamma carboxy-glutamic acid. In the presence of calcium, the gamma carboxy-glutamic acid residues promote the binding of prothrombin to phospholipid bilayers . Deficiency of vit K or administration of the anti-coagulant ( warfarin ) inhibits the production of gamma carboxy-glutamic acid residues, slowing the activation of the coagulation cascade. Thrombin is produced by the enzymatic cleavage of two sites of prothrombin by activated factor X. The activity of factor X is greatly enhanced by binding to activated factor V, termed the prothrombinase complex.

21. 21 Thromboplastin (factor III) : It is a plasma protein aiding blood coagulation through catalyzing the conversion of prothrombin to thrombin. It is a complex enzyme that is founf in brain, lung & especially in the blood platelets & that function in the conversion of prothrombin to thrombin in the clotting of blood- called also thrombokinase . Thromboplastin is the combination of both phospholipids & tissue factor, both needed in the activation of extrinsic pathway.

22. 22 Bleeding Disorders : Condition characterized by prolong bleeding/clotting time. 3 types : 1) Hemophilia 2) Purpura 3) von Willebrand disease Hemophilia : group of sex-linked inherited disorder characterized by prolong clotting time. However the bleeding time is normal. Affects the males with carrier females. Because of prolonged clotting time even a mild trauma causes excess bleeding which can lead to death. Easy brusing or hemorrhage in muscles & joints are common.

23. 23 Causes : occurs due to lack of formation of prothrombin activator & hence the coagulation time is prolonged. Formation of prothrombin activator is affected due to the deficiency of factor VIII, IX or XI. 3 Types : 1) Hemophilia A or classic hemophilia : due to the deficiency of factor VIII. 2) Hemophilia B or Christmas disease : due to the defeciency of factor IX. 3) Hemophilia C : due to the deficiency of factor XI.

24. 24 Symptoms include : Spontaneous bleeding Prolonged bleeding due to cuts, tooth extraction & surgery. Hemorrhage in GI & Urinary tracts. Bleeding in joints followed by swelling & pain. Appearance of blood in urine. Treatment include replacement of missing clotting factor.

25. 25 2) Purpura : disorder characterized by prolong bleeding time. However the clotting time is normal. Characteristic feature of this disease is spontaneous bleeding under the skin from ruptured capillaries. It causes small tiny hemorrhagic spots in many areas of the body (purple coloured patch like appearence ) Blood also sometimes collect in large areas beneath the skin called ecchymosea .

26. 26 Types & causes : Thrombocytopenic purpura : due to deficiency of platelets(thrombocytopenia). In bone marrow disease platelet production is affected leading to deficiency of platelets. Idiopathic thrombocytopenic purpura : It is believed that platelet count decreases due to development of antibodies against platelets which occurs after blood transfusion. Thrombasthenic purpura : due to structural or functional abnormality of platelets. However platelet count is normal

27. 27 Von- willebrand disease : is a bleeding disorder characterized by excessive bleeding even with a mild injury. It is due to deficiency of von- willebrand factor, which is a protein secreted by endothelium of damaged blood vessels & platelets. This protein is responsible for adherence of platelets to endothelium of blood vessels during hemostasis after an injury. It is also responsible for the survival & maintainance of factor VIII in plasma. It also causes deficiency of factor VIII

28. 28 Tests for Blood clotting : Bleeding time Clotting time Prothrombin time Partial prothrombin time International normalized ratio Thrombin time

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