Dr. Shaikh Mujeeb Ahmed Assistant Professor AlMaarefa College HEMOSTASIS HMIM BLOCK 224 Dr. Shaikh Mujeeb Ahmed Assistant Professor AlMaarefa College

Objectives Define hemostasis and explain the mechanisms that help to achieve it. Review the major steps in coagulation. Explain how to prevent coagulation.

Hemostasis Hemostasis refers to the stoppage of bleeding Actions that limit or prevent blood loss include: Blood vessel spasm Platelet plug formation Blood coagulation

Platelets Formed in bone marrow, 150-400,000 /µl Sequestered in spleen (30%) 2-4 m in diameter, life span 8-12 days, no nucleus Active cytoplasm actin + myosin enzyme synthesis + storage of calcium synthesis of prostaglandins dense granules containing ADP, serotonin and ATP a-granules (fibrinogen, PDGF, vWF, fibronectin) fibrin stabilizing factor

Platelets Membrane Receptors: thrombin, ADP, epi, serotonin Adhesion proteins: vWF, fibronectin, collagen, fibrinogen coat of glycoproteins adhesion to injured areas phospholipids activation of intrinsic pathway adenylate cyclase cAMP activate other platelets

Blood Vessel Spasm Blood vessel spasm Triggered by pain receptors, platelet release, or serotonin Smooth muscle in blood vessel contracts

Platelet Plug Formation

Stages of platelet plug formation Platelet adhesion von Willebrand factor (vWF) Platelet activation Ca++ release Pseudopodia Granule discharge Integrin on surface Thromboxane formation (TXA2) Platelet aggregation

Blood Coagulation Blood coagulation Triggered by cellular damage and blood contact with foreign surfaces A blood clot forms This is a: Hemostatic mechanism Causes the formation of a blot clot via a series of reactions which activates the next in a cascade Occurs extrinsically or intrinsically

CLOTTING FACTORS

Clotting Cascade Series of steps involving 12 plasma clotting factors that lead to final conversion of fibrinogen into a stabilized fibrin mesh May be triggered by Intrinsic pathway Involves seven separate steps Set off when factor XII (Hageman factor) is activated by coming into contact with exposed collagen in injured vessel or foreign surface such as glass test tube

Intrinsic Pathway Figure 36-4; Guyton & Hall

Clotting Cascade Extrinsic pathway Requires only 4 steps Requires contact with tissue factors external to the blood Tissue thromboplastic released from traumatized tissue directly activates factor X

Extrinsic Pathway Figure 36-3; Guyton & Hall

Clot Pathways

Clot under microscope

Fate of Blood Clots After a blood clot forms it retracts and pulls the edges of a broken blood vessel together while squeezing the fluid serum from the clot Platelet-derived growth factor stimulates smooth muscle cells and fibroblasts to repair damaged blood vessel walls Plasmin digests the blood clots A thrombus is an abnormal blood clot An embolus is a blood clot moving through the blood vessels

Prevention of Coagulation The smooth lining of blood vessels discourages the accumulation of platelets and clotting factors As a clot forms fibrin absorbs thrombin and prevents the clotting reaction from spreading Anti-thrombin inactivates additional thrombin by binding to it and blocking its action on fibrinogen Some cells such as basophils and mast cells secrete heparin (an anticoagulant)

Clinical Application

Abnormal Blood Clotting Thrombus Abnormal intravasculaar clot attached to a vessel wall Emboli Freely floating clots Factors that can cause thromboembolism Roughened vessel surfaces associated with atherosclerosis Imbalances in the clotting-anticlotting systems Slow-moving blood Occasionally triggered by release of tissue thromboplastin into blood from large amounts of traumatized tissue Hemophilia Excessive bleeding caused by deficiency of one of the factors in the clotting cascade

Coagulation Defects I. Vitamin C deficiency lack of stable collagen (elderly, alcoholics) II. Hepatic failure almost all clotting factors are made in the liver III. Vitamin K deficiency required for II (prothrombin), VII, IX, and X fat malabsorption due to lack of bile secretion IV. Hemophilia Factor VIII (hemophilia A 1/10,000), Factor IX (hemophilia B 1/100,000) chromosome X

Coagulation Defects Coagulation Defects V. Thrombocytopenia bleeding small capillaries and blood vessels mucosal, skin low number of platelets ITP- autoimmune (common)

Hemophilia Hemophilia A is classic hemophilia (a disease referring to the inability to clot blood). It is an X-linked disorder resulting from a deficiency in factor VIII, Individuals with deficiencies in factor VIII suffer Joint and muscle hemorrhage, Easy bruising and Prolonged bleeding from wounds. Treatment of hemophilia A is accomplished by infusion of factor VIII concentrates prepared from either human plasma or by recombinant DNA technology.

Male suffer from disease. HEMOPHILIA It’s a X linked disease Females are carriers Male suffer from disease.

Hemophilia B Hemophilia B results from deficiencies in factor IX.

Antihemostatic Drugs Heparin Potentiates antithrombin III. Antithrombin III inactivates various coagulation factors including thrombin Used in prevention of Deep vein thrombosis (DVT) & Pulmonary embolism (PE) During heart surgery & hemodialysis

Antihemostatic Drugs Aspirin is an important inhibitor of platelet activation. By virtue of inhibiting the activity of cyclooxygenase (COX), aspirin reduces the production of TXA2 by platelets. Aspirin also reduces endothelial cell production of prostacyclin (PGI2), an inhibitor of platelet aggregation and a vasodilator. 

Antihemostatic Drugs The drug clopidogrel: Plavix is an irreversible inhibitor of the ADP receptor on platelet membranes. When ADP binds to platelets they are activated and aggregate leading to amplification of the coagulation response, thus Plavix interferes with this process. 

Antihemostatic Drugs The plasminogen activators also are useful for controlling coagulation. tPA is highly selective for the degradation of fibrin in clots. Used particular during the short period following myocardial infarct. Streptokinase (an enzyme from the Streptococcibacterium) is another plasminogen activator

TESTS PLATELET DISORDER COAGULATION DISORDERS Bleeding time – 2-6 min. Increased in thrombocytopenia COAGULATION DISORDERS Clotting time – 5-11 min. Increased in hemophilia Partial thromboplastin time (PTT) For intrinsic & common pathway Normally less than 45 sec. Prothrombin time (PT) For extrinsic & common pathway

SUMMARY