Bleeding & Clotting Disorders I

1. Bleeding & Clotting Disorders I Richard E. Freeman MD 2013

3. Overview • The Players • Factor Deficiencies causing bleeding • Dissolving the Clot • The Clinical Presentation • Other Causes of Bleeding • Hypercoagulability

4. Bleeding Bleeding Diathesis Clotting Hemostasis Coagulation Thrombophilia The Precarious Balance the anticoagulants vs. the procoagulants

5. Hemostasis: • cessation of blood loss from a damaged vessel • Other Terms • bleeding disorders = bleeding diathesis = coagulopathies • diathesis [Gr. Diathenai – to predispose] : A constitutional predisposition to certain diseases or conditions

6. Clots Stop Blood Flow

7. Phases of Clot Formation • VASCULAR INJURY & SPASM constriction of injured blood vessel • injury releases tissue factors, platelets release serotonin (vasoconstrictor), and activates extrinsic pathway • PLATELET PLUG FORMATION collagen in vessel exposed by injury. von Willebrand factor (vWF) needed to bridge platelets and collagen. • Calcium (Ca 2+) needed

8. Phases of Clot Formation • COAGULATION CASCADE INTRINSIC AND EXTRINSIC PATHWAYS formation of cross-linked fibrin polymer clot “fibrin clot” • DISSOLUTION OF CLOT

9. vascular spasm

10. collagen fibers platelet plug platelet plug formation

11. fibrin clot formation

12. The Players

13. Complex Interactions • ALL OF THESE MUST FUNCTION NORMALLY for EFFECTIVE CLOT FORMATION and HEMOSTASIS • Vascular endothelial cells • Platelets • Clotting factor cascade • Blood flow & shear • Antifibrinolysis

14. Blood Content & Hemostasis • Plasma – Unclotted liquid part of blood • 90% Water • 10% Dissolved and suspending particles • Organics: Proteins • albumin 53%-LIVER • globulins 43% • Antibodies-RE SYSTEM • Compliment & Kinin System (Inflamation) • Clotting Factors-LIVER AND ELSEWHERE • Fibrinogen 4% • Inorganics: salts • Blood Cells • RBCs – Erythrocytes • WBCs – Leukocytes • Platelets – Thrombocytes

15. ENDOTHELIAL CELLS

16. Three Layers of the Blood Vessel • Tunica intima:endothelial cells (EC) & subendothelium • Tunica media: • smooth muscles & extracellular matrix • Tunica adventitia:fibroblasts & cellular matrix(loose connective tissue)

17. The Endothelial Cell (EC) • 1. Intact, healthy EC produces and is “teflon” coated with prostacyclin (PGI2) • – RESTING STATE • A vasodilator • Inhibits platelet adhesion • Acts in opposition to the platelet thromboxane A2 • 2. EC coated w/ heparin sulfate which activates anti-thrombin III in plasma & stops thrombosis • 3. Synthesis of Factor VIII – vonWillebrand factor • vWF synthesized in platelets & EC

18. 3 • PLATELETS

20. The Amazing Platelet • 1. Secrete procoagulants which promote clotting • 2. Secrete vasoconstrictors causing vascular spasm in injured blood vessels • 3. as they aggregate they undergo degranulation releasing: • serotonin (vasoconstrictor), • ADP (attractant)-calls for more platelets to help, • thromboxane A2 –(clot promoter) • 4. form temporary platelet plugs to stop bleeding • 5. dissolves blood clots that have outlasted their usefulness • 6. inflammation and remodeling

21. Platelets

22. Life of a Platelet • MEGAKARYOCYTE (“mama” cell) fragmentation in marrow • thrombopoietin (TPO) stimulates production produced in liver, bone marrow & kidney • 1/3 sequestered to the spleen • 2/3 into circulation (150-450,000 per microliter of blood). • LIFE SPAN 7 TO 10 DAYS • (RBCs 90-120 days, WBCs 1 day) • ASA (aspirin) thus effect lasts this long • irreversible acetylation of cyclooxygenase 1

23. Cell Lines

24. Platelet-Chemistry • ACTIN-MYOSIN • Contraction – pulls clot together • SURFACE: GP IIb/IIIa glycoprotein • Important in adhesion and aggregation • DENSE GRANULE: • Calcium, ADP, Serotonin • ALPHA-GRANULE: • Growth factor, fibrinogen, Factor V, vonWillebrand factor (vWF), fibronectin, beta-thromboglobulin, heparin antagonist (PF4), thrombospondin

25. PLATELET

26. PLATELETS-FOUR MAJOR FUNCTIONS • 1. ADHESION ACTIVATION • 2. AGGREGATION • 3. SECRETION • 4. PROCOAGULANT ACTIVATION

27. 1. ADHESION ACTIVATION: • platelet on subendothelial matrix (surface) • glycoprotein IIb/IIIa surface receptor binds vWF in subendo matrix

28. 2. AGGREGATION: • cohesion of platelets • fibrinogen binds activated glycoprotein IIb/IIIa receptor • Inhibited by • abciximab IV (ReoproR), tirofiban (AggrastatR), eptifibatide (IntegrelinR) all IV; used in angioplasty; often used along with aspirin and heparin* • ADP-receptor involved in GP IIb/IIIa-fibrinogen interaction and possibly also the vWF site • Inhibited by • clopidogrel (PlavixR), ticlopidine (TicilidR) inhibit; both given PO* *all treat and prevent arterial thrombosis

30. 3. SECRETION: • release of plt. granule proteins • ADP, serotonin, adhesive protein (fibronectin, others), Factor V, thromboxane A2 • many growth factors (smooth muscle etc) • may be involved in restenosis post PTCA

31. 4. PROCOAGULANT ACTIVITY: • enhancement of thrombin generation • assembly of the clotting cascade on the platelet surface

32. 4 1 2 3

33. GP-IIb/IIIa Receptor

35. CLOTTING FACTOR CASCADE

37. Coagulation: thecommon pathway • THE OBJECTIVE • is to convert the plasma protein fibrinogen into fibrin, a sticky protein that adheres to the walls of a vessel and also traps additional platelets and RBCs like a spider’s web Factor X

38. Fibrin Polymerization-

39. Coagulation Cascade • TWO reaction pathways (roads) • INTRINSIC PATHWAYuses only clotting factors found inside the blood itself (plasma, platelets) 3- 6 seconds • EXTRINSIC PATHWAY initiated by clotting factors released in damaged vessels (tissue factor or thromboplastin) and perivascular tissues-15 seconds • Roman numerals indicate the order discovered, however some numbers are not used: • Factor IV is Ca++; Factor VI is activated Factor V

40. Extrinsic Pathway Coagulation Cascade Pathways Intrinsic Pathway Common Pathway EXtrinsic = In Tissue INtrinsic = In Blood Common = Yields fibrin CLOT

41. THE INTRINSIC PATHWAY- the reaction amplification cascade

43. Table 18.9

44. PROCOAGULANT “CLOTTING FACTORS” Synthesis • ALL synthesized in the LIVERexcept • von Willebrand Factor in megakaryocytes and endothelial cells • vWF is involved in • PLATELET ACTIVATION • Maintaining normal factor VIII levels

45. Vitamin K • Vitamin K-dependent procoagulants • II (Prothrombin), VII, IX, X • Vitamin K-dependent anticoagulants • Warfarin-dicoumarol (COUMADIN) • Vit K antagonist • Inhibits Vit K epoxide reductase • (recycles oxidized Vit K – after K has been used in carboxylation of clotting factor production)

46. “THE REGULATORS” • PROTEIN C & S • ANTITHROMBIN • TISSUE FACTOR PATHWAY INHIBITOR • PLASMINOGEN->PLASMA • PROSTACYCLIN ( PGI2)

47. PROTEIN C & PROTEIN S Protein C & Protein S • ACTION: inactivates Factor Va and VIIIa • “Natural anticoagulant” – keeps system in balance • Protein C: • vitamin K-dependent serine protease enzyme • Thrombomodulin (on endothelial cell surfaces) and Thrombin stimulate Protein C and when activated by Protein S- inactivates Factor V • .see flow diagram

49. thrombin + thrombomodulin on endothelium turns off clotting cascade by activating Protein C. Protein C w/ Protein S (a cofactor) turn off various Factors

50. Protein C & S deficiency • Spontaneous Thrombosis/thromboemboli • Suspect in young person with DVT/Stroke with significant risk factors • Most will be need Lifelong Anticoagulant therapy