Role of COAGULATION in HEMOSTASIS

Role of COAGULATION in HEMOSTASIS.

PLASMA COAGULATION FACTORS (nomenclature). PLASMA FACTOR I FIBRINOGEN PF II PROTHROMBIN III THROMBOPLASTIN (Tissue) IV CALCIUM V LABILE FACTOR PROACCELERIN PLASMA Ac GLOBULIN VI ACCELERIN VII STABLE FACTOR * PF VIIa ( Activated PF VII ) PROCONVERTIN SPCA (Serum Prothrombin Conversion Accelerator) Co- Thromboplastin Autoprothrombin I.

PF VIII ANTIHEMOPHILIC FACTOR (AHF) (PF VIII:C) and (PFVIII:VWF) THROMBOPLASTINOGEN PLATELET CO-FACTOR 1 PLASMA THROMBOPLASTIC FACTOR A ANTIHEMOPHILIC GLOBULIN (AHG) IX PLASMA THROMB0PLASTIN COMPONENT (PTC) CHRISTMAS FACTOR PLATELET COFACTOR II PLASMA THROMBOPLASTIC FACTOR B ANTIPROTHROMBIN II X STUART-PROWER XI PLASMA THROMBOPLASTIN ANTECEDENT (PTA) XII HAGEMAN FACTOR XIII FIBRIN STABILIZING FACTOR (FSF) LAKI LORAND FACTOR - PREKALLIKREIN /FLETCHER FACTOR (PRE-K) - HMWK : CONTACT ACTIVATION COFACTOR /FITZGERALD Factor.

Coagulation factors:. A. Platelet Factors Designated by Arabic numerals to distinguish them from the blood coagulation factors. Platelet factor 1 (Platelet Accelerator) accelerates prothrombin conversion (now thought to be a platelet factor but blood factor V adsorbed on platelets) Platelet factor 2 (thrombin Accelerator) facilitates the interaction of thrombin and fibrinogen hence the fibrinoplastic platelet factor Platelet factor 3 the thromboplastic factor necessary for the generation of plasma thromboplastin this substance is a phospholipid (PL) , probably cephalin, the most important and possibly the only one that is actually an intrinsic component of platelets Platelet factor 4 has antiheparin activity.

The COAGULATION GROUPS: Prothrombin(Vitamin K–Dependent) Group Fibrinogen Group Contact Group Prothrombin Group Prothrombin (Plasma Factor II), factors VII, IX, and X and the regulatory proteins, protein C, protein S, and protein Z are vitamin K–dependent. These are named the prothrombin group because of their structural resemblance to prothrombin. All seven proteins have 10 to 12 glutamic acid units near their amino termini. All except proteins S and Z are serine proteases when activated; S and Z are cofactors. Vitamin K is a quinone found in green leafy vegetables and is produced by the intestinal organisms Bacteroides fragilis and Escherichia coli. Vitamin K catalyzes an essential posttranslational modification of the prothrombin group proteins (:g-carboxylation of amino-terminal glutamic acids. Glutamic acid is modified to g- carboxyglutamic acid when a second carboxyl group is added to the g carbon. With two ionized carboxyl groups, the g- carboxyglutamic acids gain a net negative charge, which enables them to bind ionic calcium. The bound calcium enables the vitamin K–dependent proteins to bind to negatively charged phospholipids to form coagulation complexes) WHICH ARE ESSENTIAL FOR ENZYME AND SUBSTRATE FUNCTIONS IN THE COAGULATION PATHWAYS. ( characteristics of the clotting factors in terms of : site of production, active form, stability, Vit.K dependent?).

THEORIES OF BLOOD COAGULATION. A. Howell’s Theory He proposed the following sequence of events: 1. Prothrombin is inactiviated by antiprothrombin (heparin) 2. Thromboplastin neutralizes antiprothrombin and releases prothrombin 3. Prothrombin and Ca forms thrombin 4. thrombin plus fibrinogen forms fibrin (clot) B. Morawitz Theory His theory was an attempt to explain the observation that tissue extracts ( thromboplastin ) would accelerate the coagulation of blood in the presence of Ca. Stage I : prothrombin + Ca thrombin tissue thromboplastin Stage II : fibrinogen + thrombin fibrin.

C. Modern Cascade or Waterfall theory of Breckenridge and Ratnoff -graphically demonstrates the process of intravascular coagulation in vivo -several aspects of this proposed waterfall mechanism should be clarified: 1. Each protein clotting factor shown occurs in plasma in an inactive or precursor form. These inactive proteins are listed on the left side of the waterfall along with their assigned Roman numeral. 2. When clotting is initiated, each clotting factor except fibrinogen is converted to a form possessing enzymatic activity – shown on the right side 3. The activation of each clotting factor occurs in a stepwise sequence with each newly formed enzyme reacting with its specific substrate and converting it to an active enzyme..

A waterfall sequence for intrinsic blood coagulation: vessel injury Hageman factor (Xii) Act. Hageman Factor (PFX11a) Fatty acids in viitro PTA(XI) Act.PTA ( PFXIa ) Ca++ Christmas factor (IX) Act. Christmas factor (PF IXa ) Ca++ Act. AHF AHF(VIII) phospholipid ( PFVIIIa ) Ca++ Stuart Factor(X) Act. Stuart Factor ( PFXa ) phospholipid Proaccelerin(V) Act. Proaccelerin (PF Va ) Prothrombin (II) Thrombin Fibrinogen (I) Fibrin PF XIII, Ca++ Stabilized FIBRIN C. Modern Cascade or Waterfall theory of Breckenridge and Ratnoff : -graphically demonstrates the process of intravascular coagulation in vivo -several aspects of this proposed waterfall mechanism should be clarified: 1. Each protein clotting factor shown occurs in plasma in an inactive or precursor form. These inactive proteins are listed on the left side of the waterfall along with their assigned Roman numeral. 2. When clotting is initiated, each clotting factor except fibrinogen is converted to a form possessing enzymatic activity – shown on the right side 3. The activation of each clotting factor occurs in a stepwise sequence with each newly formed enzyme reacting with its specific substrate and converting it to an active enzyme..

SCHEMATIC REPRESENTATION OF THE PROCESS OF BLOOD COAGULATION.

PHASE III: THROMBOGENESIS Thromboplastin Prothrombin Ca++ Thrombin Plasma Factor V VII Inhibitor: antithrombin X (thrombin) PHASE IV: FIBRIN FORMATION Fibrinogen thrombin FIBRIN *the autocatalyst is thrombin Stabilizer: PF XIII which participates in each of the Inhibitor: 4 phases Fibrinogenolysin FibrinOlysins Fibrinogen Split Products.

Classification of the Major Hemostatic Defects. I. Vascular & Extravascular Defects 1. Atrophy of elastic tissues; e.g. senile purpura (elderly) 2. Vit . C deficiency- loss of vascular integrity characterized by + Tourniquet Test 3. Unusual fragility – susceptibility to trauma on the part of skin. (Cushing’s Syndrome) II. Intravascular Defects: The main defects: 1. defects of the coagulation, & fibrinolytic mechanisms 2. defects on the platelet system 3. acquired defects in which abnormalities may exist in all three systems.

Defects of the coagulation mechanisms 1. defects of thromboplastin formation (PF XII, XI,IX and VIII) 2. defects of second stage of coagulation (PF X,V,VII and II) 3. defects of fibrin formation (PF I, XIII) Defects of the Fibrinolytic mechanisms 1. physiologic changes ..slight elevation of FDP 2. primary fibrinolysis Mixed defects 1. disseminated intravascular coagulation 2. hepatic and gastrointestinal disease 3. circulating anticoagulants , ex. heparin.

Prothrombin Time (PT) Partial Thromboplastin Time (PTT) Extrinsic System Intrinsic System CONTACT Tissue thromboplastin PF XII PF XII a + PF VII & Ca ++ PF XI PF XI a PF IX Ca++ PF IX a PF VIII Ca++ PF VIII a PF-3 PF X Ca++ PF X a PF V PF Va PF-3 PROTHROMBIN THROMBIN FIBRINOGEN FIBRIN MONOMER + Fibrinopeptides A & B Fibrin polymer XIII FIBRIN Ca++.

Thank You! Note: It is highly recommended that one must supplement the discussion with side readings to fill-in certain gaps that one might have considering that the topic is quite complex. Thank you everyone and good day!.