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1 : Hemostasis Coagulation and Platelets Dr Raghib Ahsan Associate Professor of Physiology Diabetic Association Medical College Faridpur PowerPoint® Lecture Slide Presentation prepared by Dr Raghib Ahsan, Associate Professor of Physiology, Diabetic Association Medical College, Faridpur
2 : 13-Apr-11 2 13-Apr-11 2 Hemostasis Hemostasis is the physiological mechanism which causes spontaneous arrest of bleeding Mechanism: Vasoconstriction/Vascular spasm Platelet aggregation & plug formation Coagulation leading to clot formation Clot retraction Eventual growth of fibrous tissue into the blood clot to close the hole in the vessel permanently
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4 : 13-Apr-11 4 Injury to blood vessel & damage of endothelium Exposure of collagen Adherence of platelets to collagen Activation of platelets Secretion of serotonin Vasoconstriction Secretion of ADP & Throboxane A2 Aggregation of platelets Formation of platelet plug Formation of prothrombin activator Blood clotting Stage 1 Stage 2 Stage 3
5 : 13-Apr-11 5 13-Apr-11 5 Vascular Spasm Vascular spasm results from the: Local myogenic contraction of the blood vessels initiated by direct damage to the vascular wall Release of Local autacoid factors from the traumatized tissues and blood platelets, and Nervous reflexes initiated by pain nerve impulses or other sensory impulses that originate from the traumatized vessel or nearby tissues. Release of a vasoconstrictor substance, Thromboxane A2 by the platelets which for the smaller vessels are responsible for much of the vasoconstriction
6 : 13-Apr-11 6 Platelets Platelets are minute discs 1 to 4 micrometers in diameter. They are formed in the bone marrow from megakaryocytes, which are extremely large cells of the hematopoietic series in the marrow The megakaryocytes fragment into the minute platelets either in the bone marrow or soon after entering the blood, especially as they squeeze through capillaries. The normal concentration of platelets in the blood is between 150,000 and 400,000 per microliter (µl). A count below 50,000 is called ‘Critical count’ 13-Apr-11 6
7 : 13-Apr-11 7 Platelets Platelets contain such active factors in Membrane: Cell membrane of the platelets on its surface contain a glycoproteins coat that prevents adherence of platelets to normal endothelium but accelerates adherence to collagen of injured blood vessel The platelet cell membrane also contains large amounts of phospholipids that activate multiple stages in the blood-clotting process These act as precursors of Thromboxane A2 13-Apr-11 7
8 : 13-Apr-11 8 Platelets Platelets contain such active factors in Cytoplasm: Proteins - Actin and Myosin molecules, which are contractile proteins responsible for contraction of platelets Thrombosthenin, help platelets to contract Von Willebrand factor, which help adherence of platelets Fibrin stabilizing factor, a clotting factor Platelet Derived Growth Factor (PDGF), which helps in repair of damaged blood vessels and wound healing Platelet Activating Factor (PAF), which helps in aggregation of platelets during injury of blood vessels 13-Apr-11 8
9 : 13-Apr-11 9 Platelets Platelets contain such active factors in Cytoplasm: Hormonal substances – Adrenaline Serotonin (5HT) Histamine Other chemical substances – Platelet Derived Growth Factor (PDGF), which helps in repair of damaged blood vessels and wound healing Platelet Activating Factor (PAF), which helps in aggregation of platelets during injury of blood vessels 13-Apr-11 9
10 : 13-Apr-11 10 Platelets Platelets contain such active factors as: Residuals of both the endoplasmic reticulum and the Golgi apparatus synthesize various enzymes and especially store large quantities of calcium ions Mitochondria and enzyme systems are capable of forming ADP & ATP Enzyme systems synthesize prostaglandins, which are local hormones that cause many vascular and other local tissue reactions An important protein called fibrin-stabilizing factor A growth factor that causes vascular endothelial cells, vascular smooth muscle cells, and fibroblasts to multiply and grow, thus helps repair damaged vascular walls 13-Apr-11 10
11 : 13-Apr-11 11 Platelets Platelet has a half-life in the blood of 8 to 12 days Then it is eliminated from the circulation mainly by the tissue macrophage system. More than one half of the platelets are removed by macrophages in the spleen 13-Apr-11 11
12 : 13-Apr-11 12 Mechanism of the Platelet Plug When platelets come in contact with a damaged vascular surface, especially with collagen fibers in the vascular wall, the platelets themselves immediately change their own characteristics drastically They begin to swell They assume irregular forms with numerous irradiating pseudopods protruding from their surfaces; Their contractile proteins contract forcefully and cause the release of granules that contain multiple active factors They become sticky so that they adhere to collagen in the tissues and to a protein called von Willebrand factor 13-Apr-11 12
13 : 13-Apr-11 13 Mechanism of the Platelet Plug Formation They secrete large quantities of ADP and their enzymes form Thromboxane A2 The ADP and thromboxane in turn act on nearby platelets to activate them as well, and The stickiness of these additional platelets causes them to adhere to the original activated platelets Thus the damaged vascular wall activates successively increasing numbers of platelets that themselves attract more and more additional platelets, thus forming a platelet plug 13-Apr-11 13
14 : 13-Apr-11 14 Mechanism of Blood Coagulation More than a dozen blood coagulation factors are found in the blood and in the tissues that cause or affect blood coagulation Some that promote coagulation, called Procoagulants, and others that inhibit coagulation, called Anticoagulants A balance between these two substances determine whether coagulation will occur or not 13-Apr-11 14
15 : 13-Apr-11 15 Coagulation
16 : 13-Apr-11 16 Clotting factors in blood 13-Apr-11 16
17 : 13-Apr-11 17 Sequence of Clotting ENZYME CASCADE THEORY: Most of the clotting factors are proteins (enzymes) as inactive proenzymes. They must be activated to ensure clot formation It is carried out by series of proenzyme ? enzyme conversion reactions in cascade (a process that occurs through a series of steps, each step initiating the next until the final step is reached) Stages of blood clotting: Formation of Prothrombin activator Conversion of Prothrombin into Thrombin Conversion of Fibrinogen into Fibrin
18 : 13-Apr-11 18 Sequence of Blood Coagulation Coagulation takes place in three essential steps: Rupture of vessel sets in a complex cascade of chemical reactions in blood involving coagulation factors that finally form a complex of activated substances collectively called prothrombin activator The prothrombin activator catalyzes conversion of prothrombin into thrombin The thrombin acts as an enzyme to convert fibrinogen into fibrin fibers that enmesh platelets, blood cells, and plasma to form the clot 13-Apr-11 18 Schema for conversion of prothrombin to thrombin and polymerization of fibrinogen to form fibrin fibers
19 : 13-Apr-11 19 COAGULATION “CASCADE” INTRINSIC(contact)/EXTRINSIC(TissFac) Proenzymes ? Enzymes Prothrombin(II) ? Thrombin(IIa) Fibrinogen(I) ? Fibrin(Ia) Cofactors: Ca++ Phospholipid (from platelet membranes) Vit-K dep. factors: II, VII, IX, X, Prot. S, C, Z
20 : 13-Apr-11 20 Formation of Prothrombin Activator (Stage 1) Blood clotting commences with the formation of a substance called Prothrombin activator Prothrombin activator is formed either within the the blood itself or outside the blood. Thus formation of Prothrombin activator occurs through two pathways: Extrinsic pathway: here, the formation of Prothrombin activator is initiated by the tissue thromboplastin which is formed from the injured tissue Intrinsic pathway: In this, the formation of Prothrombin activator is initiated by platelets, which are within the blood itself 13-Apr-11 20
21 : 13-Apr-11 21 Coagulation Cascade Central to the Coagulation Cascade is the ability to make a clot
22 : 13-Apr-11 22 Coagulation Cascade When blood is bleeding outside the body, something intrinsic needs to tell it to stop
23 : 13-Apr-11 23 Coagulation Cascade When blood is bleeding into the tissue, something in the tissue needs to tell it to stop
24 : 13-Apr-11 24 Coagulation Cascade The Coagulation Cascade has two parts One Inside the Body One for inside the body One for outside the Body Both treat slow bleeding
25 : 13-Apr-11 25 Intrinsic Pathway Blood trauma causes (a) activation of Factor XII and (b) release of platelet phospholipids (containing platelet factor 3) Activated Factor XII (XIIa) enzymatically activates Factor XI (XIa) which needs kininogen and is accelerated by prekallikrein Factor XIa enzymatically activates Factor IX to IXa Factor IXa+Factor VIIIa+platelet phospholipids and factor 3 activates Factor X to Xa Factor Xa+Factor V+ platelet or tissue phospholipid form the complex called prothrombin activator The prothrombin activator in turn initiates within seconds the cleavage of prothrombin to form thrombin
26 : 13-Apr-11 26 Extrinsic Pathway Release of tissue factor: Traumatized tissue releases a complex of several factors called tissue factor or tissue thromboplastin Activation of Factor X: Tissue factor further complexes with Factor VII and, in the presence of calcium ions, acts enzymatically on Factor X to form activated Factor X Factor Xa forms prothrombin activator— Factor Xa combines with tissue or platelet phospholipids as well as with Factor V to form the complex called prothrombin activator 13-Apr-11 26
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39 : 13-Apr-11 39 Stage 1 Intrinsic Pathway Extrinsic Pathway Endothelial damage + Collagen exposure Kallikrein HMW Kinogen XII XIIa XI XIa HMW Kinogen IX IXa Calcium X Xa VIII & Calcium Platelets Phospholipid Tissue trauma + Tissue thromboplastin (Glycoprotein+Phospholipiod) Calcium V Prothrombin Thrombin Positive feedback Positive feedback Stage 2 Stage 3 Fibrinogen Fibrinogen a Loose strands of Fibrin Polymerization XIII & Calcium Fibrin tight blood clot Prothrombin activator X Xa VII
40 : 13-Apr-11 40 COAGULATION Schema for conversion of prothrombin to thrombin and polymerization of fibrinogen to form fibrin fibers 40
41 : 13-Apr-11 41 Conversion of Prothrombin to Thrombin First, prothrombin activator is formed as a result of rupture of a blood vessel or as a result of damage to special substances in the blood Second, the prothrombin activator, in the presence of sufficient amounts of ionic Ca++, causes conversion of prothrombin to thrombin Third, the thrombin causes polymerization of fibrinogen molecules into fibrin fibers within another 10 to 15 seconds Platelets also play an important role in the conversion of prothrombin to thrombin because much of the prothrombin first attaches to prothrombin receptors on the platelets already bound to the damaged tissue 13-Apr-11 41
42 : 13-Apr-11 42 Conversion of Fibrinogen to Fibrin— Formation of the Clot Action of Thrombin on Fibrinogen to Form Fibrin: Thrombin is a protein enzyme which acts on fibrinogen to remove four LMW peptides from each molecule of fibrinogen, forming one molecule of fibrin monomer Fibrin monomer automatically polymerize with other fibrin monomer molecules to form fibrin fibers and many fibrin monomer molecules polymerize within seconds into long fibrin fibers that constitute the reticulum of the blood clot In the early stages the resultant clot is weak and can be broken apart with ease. Activated fibrin-stabilizing factor forms covalent bonds between fibrin fibers and gives tremendous strength to the fibrin meshwork 13-Apr-11 42
43 : 13-Apr-11 43 Fibrin Clot How does fibinogen become a net? Multiple polymerizing fibrin strands form “ropes” Together, they form a net
44 : 13-Apr-11 44 Blood Clot - Clot Retraction Blood Clot - The clot is a semisolid mass composed of a meshwork of fibrin fibers running in all directions and entrapping blood cells, platelets, and plasma. The fibrin fibers also adhere to damaged surfaces of blood vessels; therefore, the blood clot becomes adherent to any vascular opening and thereby prevents further blood loss Clot Retraction—Serum: Within a few minutes after a clot is formed, it begins to contract and usually expresses most of the fluid from the clot within 20 to 60 minutes. The fluid expressed is called serum because all its fibrinogen and most of the other clotting factors have been removed 13-Apr-11 44
45 : 13-Apr-11 45 Intravascular Anticoagulants Prevention of blood clotting in the normal vascular system— Endothelial surface factors: the smoothness of the endothelial cell surface, which prevents contact activation of the intrinsic clotting system a layer of glycocalyx on the endothelium (glycocalyx is a mucopolysaccharide adsorbed to the surfaces of the endothelial cells), which repels clotting factors and platelets, thereby preventing activation of clotting; and Thrombomodulin, a protein bound with the endothelial membrane, binds thrombin. The thrombomodulin-thrombin complex also activates a plasma protein, protein C, that acts as an anticoagulant by inactivating activated Factors V and VIII 13-Apr-11 45
46 : 13-Apr-11 46 Activation of Protein C Inactivates Factors Va and VIIIa activates Thrombomodulin Thrombin Protein C Thrombomodulin-Thrombin complex
47 : 13-Apr-11 47 Intravascular Anticoagulants Antithrombin action of fibrin and Antithrombin III – Among the most important anticoagulants in the blood itself are those that remove thrombin from the blood. Important ones are: The fibrin fibers that themselves are formed during the process of clotting. About 85-90% of the thrombin formed from the prothrombin becomes adsorbed to the fibrin fibers as they develop & thus prevents excessive spread of the clot An alpha-globulin called antithrombin III or antithrombin-heparin cofactor. The thrombin that does not adsorb to the fibrin fibers soon combines with antithrombin III which further blocks the effect of the thrombin on the fibrinogen 13-Apr-11 47
48 : 13-Apr-11 48 Intravascular Anticoagulants Continuous flow of blood – The continuous flow of blood in circulation, without stasis, prevents the process of initiation of coagulation process Natural anticoagulant HEPARIN – The heparin molecule is a highly negatively charged conjugated polysaccharide. Itself is not powerful but is a strong anticoagulant when combines with antithrombin III. Secreted by mast cells but also by basophils.
49 : 13-Apr-11 49 Lysis of Blood Clots—Plasmin Fibrinolysis – The lysis of blood clot inside the blood vessel is called fibrinolysis. It helps to remove clot from lumen of blood vessel. This process requires a substance called plasmin or fibrinolysin Plasma proteins contain a globulin called plasminogen (or profibrinolysin) that, when activated, becomes a plasmin or fibrinolysin Action of Plasmin – Plasmin is a proteolytic enzyme and cause lysis of clot by dissolving & digesting fibrin threads Significance of Lysis of clot – In vital organs, blood clot obstructs minute blood vessels leading to infarction. Lysis allows reopening of blood vessels
50 : Anticoagulants Dr Raghib Ahsan
51 : 13-Apr-11 51 Anticoagulants The substances which prevent or postpone coagulation of blood, are called Anticoagulants. Anticoagulants are of 3 types: Anticoagulants used to prevent blood clotting inside the body, i.e. in vivo Anticoagulants used to prevent clotting of blood that is collected from the body, i.e. in vitro Anticoagulants used to prevent blood clotting both in vivo and in vitro Also, a) Natural (Heparin) and, b) Synthetic As drug Used in laboratory
52 : 13-Apr-11 52 HEPARIN Heparin is a naturally occurring anticoagulant in the body, produced by mast cells and basophils which are situated outside blood vessels Heparin is a conjugated polysaccharide Mechanism of action of Heparin: Directly suppresses the activity of thrombin Combines with antithrombin III and removes thrombin from circulation Activates antithrombin III Inactivates IXa, Xa, XIa & XIIa
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54 : 13-Apr-11 54 EDTA EthyleneDiamineTetra Acetic acid (EDTA) is a strong anticoagulant Mechanism of action: EDTA prevents blood clotting by removing calcium from blood Use: Used in laboratory, in lead poisoning
55 : 13-Apr-11 55 Other Anticoagulants Oxalates: Ammonium oxalate, Potassium oxalate MOA: Removes Ca++ from blood by forming insoluble Calcium salts Use: Used as in vitro anticoagulant Citrates: Sodium citrate MOA: Removes Ca++ from blood by forming insoluble Calcium salts Use: Used to store blood in blood bank as Acid Citrate Dextrose (ACD) or Citrate Phosphate Dextrose (CPD)
56 : 13-Apr-11 56 Procoagulants Procoagulants are agents which accelerate the process of blood coagulation Thrombin: sprayed upon bleeding surface to arrest bleeding Snake venom: Viper, Cobra contain proteolytic enzymes which enhance blood clotting by activating blood clotting factors Extracts of lungs & thymus Na+ or Ca++ alginate
57 : 13-Apr-11 57 Tests for Clotting Test available to evaluate the process of blood coagulation are: Bleeding time (BT): it is the time interval from oozing of blood after a cut/injury till arrest of bleeding. Normal CT is 1-6 minutes Clotting time (CT): it is the time interval from oozing of blood after a cut/injury till the formation of a clot. Normal CT is 6-10 minutes Prothrombin time: time taken by blood to clot after adding tissue thromboplastin to it. Prothrombin time indicates the total amount prothrombin present in blood. Normal PT is 12 seconds
58 : Applied Physiology Bleeding Disorders Thrombosis
59 : 13-Apr-11 59 Bleeding Disorders These are the diseases or conditions characterized by prolonged BT or CT. Bleeding Disorders are of three types: Hemophilia Purpura von Willebrand disease
60 : 13-Apr-11 60 Hemophilia Hemophilia is a group of sex linked inherited blood disorder featured by prolonged CT. Usually it affects males, females being the carriers Because of prolonged CT, even a mild trauma causes excess bleeding. Easy bruising, and hemorrhage in muscle & joints are common Cause – occurs due to deficiency of factors VIII, IX or XI leading to lack of formation of prothrombin activator. That is why CT is prolonged. These factors are not produced as there is a defect in the gene for these factors on X chromosome
61 : 13-Apr-11 61 Types of Hemophilia Depending upon deficiency of factor involved, hemophilia is classified into three types: Hemophilia A or Classical hemophilia: it is due to deficiency of factor VIII (85%) Hemophilia B or Christmas disease: it is due to deficiency of factor IX (15%) Hemophilia C or Factor XI deficiency: it is due to deficiency of factor XI (very rare)
62 : 13-Apr-11 62 Hemophilia
63 : 13-Apr-11 63 Purpura Purpura is a bleeding disorder characterized by prolonged BT. However, the CT is normal The characteristic feature of this disease is spontaneous bleeding under the skin & mucous membrane (purpuric spots) from ruptured capillaries Blood may also collect in large areas under the skin called ecchymoses Purpura is a bleeding disorder characterized by purple or red colored patchy spots under the skin & mucous membrane from ruptured capillaries Purpura means "purple"
64 : 13-Apr-11 64 Purpura
65 : 13-Apr-11 65 Types of Purpura The Purpura is classified into different types depending upon the causes: Thrombocytopenic purpura – due to deficiency of platelets. Bone marrow disease may cause such deficiency. Normal CT, Prolonged BT Idiopathic thrombocytopenic purpura (ITP) – due to decreased platelet count as a result of antibodies against platelets. Bone marrow disease may cause such deficiency. Normal CT, Prolonged BT Thrombasthenic purpura – due to structural or function abnormalities of platelets but platelet count is normal. Normal CT, normal or prolonged BT but there is defective clot retraction
66 : 13-Apr-11 66 Thrombosis Thrombosis refers to coagulation of blood inside the blood vessels. Causes of thrombosis: Injury to blood vessels Roughened endothelial lining Sluggishness of blood flow Agglutination of RBCs Toxic thrombosis
67 : 13-Apr-11 67 Complications of Thrombosis Thrombus formation – the solid mass of platelets, red cells and/or clot, which obstructs the blood vessel is called thrombus Embolism and embolus – Embolism is the process by which the thrombus or part of thrombus is detached, carried in blood stream and occludes the small blood vessel resulting in arrest of blood flow to any organ or region Ischemia – Insufficient blood supply to an organ or area of body by the obstruction of blood vessels is called Ischemia. This is reversible. Infarction - Tissue death due to loss of blood supply is called Infarction. Occurs by thrombus, embolus or sometimes atherosclerosis
68 : 13-Apr-11 68 Thanks


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