Disorders of Hemostasis

1. Disorders of Hemostasis • Objectives: • To learn the hypercoagulability states as one type of hemostatic disorders in relation to the increased in platelet function and clotting activity; • To understand the mechanisms of bleeding disorders in relation to platelet defects, coagulation defects, disseminated intravascular coagulation and vascular disorders

2. Disorders of Hemostasis • Expected Learning Outcomes: • After learning this topic, students: • are able to describe the pathogenesis of hypercoagulation states which are originated from the changes in platelet function and clotting activity; • can explain the mechanisms and pathophysiology of bleeding disorders due to platelet defects, coagulation defects, disseminated intravascular coagulation and vascular disorder

3. Brief Review of Mechanisms of Hemostasis Steps in Hemostasis

4. Brief Review of Mechanisms of Hemostasis Steps of Coagulation C

5. Brief Review of Mechanisms of Hemostasis Intrinsic and Extrinsic Coagulation Pathways

6. Brief Review of Mechanisms of Hemostasis Fibrinolytic System

7. Hypercoagulability States • Conditions of increased platelet function and accelerated activity of coagulation system • Predisposition to thrombosis • 1. Increased Platelet Function • Results in platelet adhesion, formation of platelet clots, disruption of blood flow • Caused by disturbances in blood flow (e.g. atherosclerotic plaques), leading to endothelial damage and platelet adherence to vessel wall  release growth factors  proliferation of smooth muscles  risk of atherosclerosis

8. Hypercoagulability States • 1. Increased Platelet Function (cont’d) • Other causes of vessel damages: smoking, elevated levels of blood lipids and cholesterol, hemodynamic stress, diabetes mellitus • also followed by platelet adherence and eventually causes thrombosis • More severe in thrombocytosis (elevated platelet count); can happen in malignancies and after splenectomy

9. Hypercoagulability States • 2. Increased Clotting Activity • Thrombus formed by activation of coagulation system • Primary (genetic) and secondary (acquired) disorders which increase procoagulation factors or decrease anticoagulation factors • Inherited disorders • Mutations in factor V and anticoagulant genes (antithrombin III, protein C, protein S) • Mutated factor Va  failed to be inactivated by protein C  loss of antithrombotic counterregulatory mechanism  predisposed to venous thrombosis

10. Hypercoagulability States • 2. Increased Clotting Activity (cont’d) • Acquired disorders • Involve stasis (due to prolonged immobilization), myocardial infarction, cancer, hyperestrogenic states, autoimmune disorder, smoking and obesity • Stasis causes accumulation of activated clotting factors, platelets and inhibition of their interactions to inhibitors  venous thrombosis •  clotting factors during pregnancy  venous thrombosis predisposed by immediate postpartum •  estrogen level (contraceptives) causes  hepatic synthesis of coagulation factors and  synthesis of antithrombin III • Tissue factors from cancer cells contribute to thrombosis

11. Hypercoagulability States • 2. Increased Clotting Activity (cont’d) • Acquired disorders (cont’d) • Antiphospholipid syndrome – an autoimmune hypercoagulability disorder with antiphospholipid antibodies • Manifestation: • Venous and arterial thrombosis affecting multiple organs (e.g. pulmonary emboli, transient ischemic attacks or stokes) • Recurrent fetal loss – thrombosis of placental vessels • High risk to have pregnancy-associated hypertension and uteroplacental insufficiency

12. Hypercoagulability States • 2. Increased Clotting Activity (cont’d) • Antiphospholipid disorders (cont’d) • Molecular mechanisms - antiphospholipid antibodies directly interfere with coagulation cascade  hypercoagulability • Targets of inhibition: activated protein C, antithrombin pathway, fibrinolysis • Target of activation: endothelial cells  cytokines released  promote coagulation and platelet aggregation • Other factors involved before showing clinical manifestations: traumatic injury to vascular bed, infection leading to endothelial cell activation

13. 13 / 26 Bleeding Disorders • Caused by platelet defects, coagulation defects and vascular integrity • 1. Platelet Defects • Decreased in no. circulating platelets • Depletion of platelets: 10,000-20,000/ml (normal range: 150,000 – 400,000/ml) • Petechiae and purpura found on limbs; bleeding in small vessels • Bleeding from mucous membrane of nose, mouth, GI tract vagina, intracranial vessels

14. Bleeding Disorders • 1. Platelet Defects (cont’d) • Thrombocytopenia • Platelet count < 100,000/ml • Can be caused by: •  production of platelet in bone marrow - due to aplastic anemia, replacement by malignant cells, HIV infection (suppresses megakaryocytes production), radiotherapy •  pooling of platelets in spleen with splenomegaly (due to cirrhosis and lymphoma) •  platelet survival due to antiplatelet antibodies – blood transfusion, pregnancy; target against platelet membrane glycoproteins

15. Bleeding Disorders • 1. Platelet Defects (cont’d) • Drug-induced Thrombocytopenia • drugs can act as haptens and produce antigen-antibody complex  complement activation  platelet destruction • Rapid fall of platelet counts within few days; platelet counts increased again after drug discontinuation • Idiopathic Thrombocytopenic Purpura (ITP) • An autoimmune disorder  autoantibodies  excess destruction of platelet • Sudden on set of petechiae and purpura • Other manifestations: bleeding of oral mucosa, gums, epistaxis, abnormal menstural bleeding, splenic enlargement

16. Bleeding Disorders • 1. Platelet Defects (cont’d) • Thrombotic Thrombocytopenic Purpura • Combination of thrombocytopenia, hemolytic anemia, renal failure, fever and neurologic abnormalities • Vascular occlusions with thrombi happen in many organs, e.g. heart, brain and kidneys • Erythrocytes may become fragmented when passing through the occluded vessels – hemolytic anemia and jaundice • Manifestations – purpura, petechiae, vaginal bleeding and neurologic symptoms (e.g. headache, seizures)

17. Bleeding Disorders • 1. Platelet Defects (cont’d) • Impaired Platelet Function (Thrombocytopathia) • Associated with inherited disorders of adhesion or specific drugs which impair platelet functions • Aspirin and NSAIDs (nonsteroidal anti-inflammatory drugs) – inhibits platelet cyclooxygenase activity and synthesis of prostagladin TXA2 which is the key molecule for platelet aggregation • Use of aspirin for prevention of arterial thrombi formation, reduce the risk of heart attack and stroke

18. Bleeding Disorders • 2. Coagulation Defects • Resulted from deficiencies or impairment of one or more clotting factors • Large bruises, hematomas, and prolonged bleeding in gastrointestinal tracts, urinary tracts or joint is common • Impaired Synthesis of Coagulation Factors • Coagulation factors, prothrombin and fibrinogen are synthesized by liver; bleeding if liver is defective in such synthesis • Vitamin K dependent for normal activities of coagulation factors – VII, IX, X and prothrombin • Vitamin K – fat soluble (bile salt is required for absorption); synthesized by gut bacteria • Vitamin K deficiency – newborn, antibiotics, liver and gall-bladder disease

19. Bleeding Disorders • 2. Coagulation Defects (cont’d) • Hereditary Disorders • Reported for all clotting factors; but rare • Most common ones: Factor VIII deficiency (hemophilia A; 1:5000) and von Willebrand disease (1:1000) • Factor VIII binds to von Willebrand factor (vWF)  stabilization and prevented from proteolysis in blood • (Platelet adhesion requires vWF produced from endothelial cells of vessels)

20. Bleeding Disorders • 2. Coagulation Defects (cont’d) • Hereditary Disorders (cont’d) • Hemophilia A • X-linked recessive disorder; 30% have no familial link; mutation in factor VIII gene • 90% produce insufficient quantities of factor VIII; 10% produce inactive form of factor VIII • Mild or moderate form – bleeding results from artificial procedures (e.g. dental surgery) or local lesions • Severe form – spontaneous and severe bleeding; common in childhood (bleeding of joints while beginning to walk); death due to intracranial hemorrhage)

21. Bleeding Disorders • 2. Coagulation Defects (cont’d) • Hereditary Disorders (cont’d) • Von Willebrand Disease • Most common type of hereditary bleeding disorder • Deficiency or defective vWF • Reduction in platelet adhesion • Symptoms: bruising, excessive menstrual flow, bleeding from multiple sites

22. Bleeding Disorders • 3. Disseminated Intravascular Coagulation (DIC) • Massive activation of coagulation sequence  systemic formation of fibrin • Reduced level of major anticoagulants • Vessel occlusion by thrombi  tissue ischemia  organ failure • Deletion of coagulation proteins results in severe hemorrhage • Red cells are damaged when passing through vessels partially blocked by thrombus • Manifestations – petechiae, purpura, severe hemorrhage, uncontrolled postpartum bleeding, organ failure, hemolytic anemia

23. Bleeding Disorders • 3. Disseminated Intravascular Coagulation (DIC) (cont’d) • Mechanisms: • Activation of both intrinsic and extrinsic pathways of coagulation * • Examples of initiating factors - trauma, cancers, obstetrical complications with tissue factors released from necrotic placental or fetal tissues, endotoxin released by bacteria causes the release of tissue factors, cytokines released from infection or inflammation

24. Pathophysiology of Disseminated Intravascular Coagulation

25. Bleeding Disorders • 4. Vascular Disorders • Resulted from structurally week vessel walls or vessels damaged by inflammation or infection • Normal platelet counts and platelet factors are normal • Examples of causes: heredity (hemorrhagic telangiectasia; thin and dilated capillaries and arterioles), vitamin C deficiency (poor collagen synthesis; fragile vessel wall), Cushing’s disease (excess cortisol; protein wasting in vessels), aging

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