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Hemostasis/Thrombosis I

Hemostasis/Thrombosis I. Normal Hemostasis/Thrombosis; Assessment of Clotting System. HEMOSTASIS & THROMBOSIS. Platelets Coagulation Cascade Regulation of Coagulation. CIRCULATORY SYSTEM. Low volume, high pressure system Efficient for nutrient delivery to tissues

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Hemostasis/Thrombosis I

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  1. Hemostasis/Thrombosis I Normal Hemostasis/Thrombosis; Assessment of Clotting System

  2. HEMOSTASIS & THROMBOSIS • Platelets • Coagulation Cascade • Regulation of Coagulation

  3. CIRCULATORY SYSTEM • Low volume, high pressure system • Efficient for nutrient delivery to tissues • Prone to leakage 2º to endothelial surface damage • Small volume loss  large decrease in nutrient delivery • Minimal extravasation in critical areas irreparable damage/death of organism

  4. HEMOSTASISPrimary vs. Secondary vs. Tertiary • Primary Hemostasis • Platelet Plug Formation • Dependent on normal platelet number & function • Initial Manifestation of Clot Formation • Secondary Hemostasis • Activation of Clotting Cascade Deposition & Stabilization of Fibrin • Tertiary Hemostasis • Dissolution of Fibrin Clot • Dependent on Plasminogen Activation

  5. HEMOSTATIC DISORDERSSuspicions • Spontaneous bleeding • Prolonged or excessive bleeding afterprocedures or trauma • Simultaneous bleeding from multiple sites

  6. HEMOSTATIC DEFECTS

  7. HEMOSTATIC ABNORMALITIES"Screening Tests" (History) • Dental Extractions • Prior Surgery/Biopsy • Easy bruising • Heavy menses • Deliveries • Blood transfusion

  8. PLATELETS • Anucleate cellular fragments; multiple granules, multiple organelles • Synthesis controlled by IL-6, IL-3, IL-11, & thrombopoietin • Circulate as inactive, non-binding concave discs • On stimulation, undergo major shape change • Develop receptors for clotting factors • Develop ability to bind to each other & subendothelium

  9. RestingPlatelets vWF PlateletAdhesion PLATELET ACTIVATION

  10. II IIa X Xa VIIa-TF Initial Thrombin Formation IIa TR

  11. II IIa X Xa VIIa-TF PLATELET ACTIVATION PlateletActivation

  12. II IIa X Xa VIIa-TF Platelet Release TxA2, ADP, Serotonin, Fibrinogen, Thrombospondin

  13. PLATELET PLUG FORMATION

  14. COAGULATION CASCADEGeneral Features • Zymogens converted to enzymes by limited proteolysis • Complex formation requiring calcium,phospholipid surface, cofactors • Thrombin converts fibrinogen to fibrin monomer • Fibrin monomer crosslinked to fibrin • Forms "glue" for platelet plug

  15. COAGULATION CASCADE

  16. THROMBIN • Serine protease • Cleaves fibrinogen to fibrin • Activates V to Va, VIII to VIIIa • Activates platelets-cleaves thrombin receptor • Activates XIII to XIIIa • In presence of thrombomodulin activates Protein C to APC

  17. COAGULATION CASCADE

  18. VIII VIIIa V Va II IIa X Xa VIIa-TF Platelet Release TxA2, ADP, Serotonin, Fibrinogen, Thrombospondin IX IXa VIIa-TF

  19. Tenase/Prothrombinase complex assembly X Xa II IIa VIIIa/IXa Va/Xa VIIIa R Va R

  20. A A B B FIBRIN FORMATION T F XIIIa

  21. VITAMIN K DEPENDENT CARBOXYLASE • Post-translational modification • Factors II, VII, IX, X; proteins C & S • Converts 1st 7-12 glutamic acids toγ-carboxyglutamic acid • Confers calcium binding and lipid binding on these proteins • Without vitamin K, secrete des- γ-carboxyglutamic acid containing proteins(inactive in coagulation)

  22. COO- COO- COO- CH CH2 O2, CO2 CH2 CH2 NH3+ NH3+ CH CH Vit KCarboxylase COO- COO- Glu γ -CARBOXYGLUTAMIC ACID γ-carboxy Glu

  23. PLATELET FUNCTION STUDIES • Bleeding Time • Platelet Count • Platelet Aggregation Studies

  24. BLEEDING TIME vs. PLATELET COUNT

  25. COAGULATION CASCADE

  26. Clotting Tests • Recalcification times • Blood collected in sodium citrate, a weak calcium chelator • Amount designed to drop calcium concentration to < 1 mM • At that level, blood won’t clot spontaneously • RBC’s & platelets centrifuged off, leaving plasma (unclotted liquid portion of blood)

  27. Prothrombin Time • Mixture of: • 50% patient’s platelet poor plasma • 25% Mixture of Tissue Factor & phospholipid species • 25% Calcium chloride (to bring final calcium concentration to c. 3-5 mM) • Time to clot formation measured

  28. EXTRINSIC PATHWAY ProthrombinTime (PT) FVII TF FVIIa Ca+2 VIIa/TF FX Middle Components Ca+2 FXa Ca+2 T V Va Va/Xa/PL PT Ca+2 T Common Pathway FG F COAGULATION CASCADE

  29. aPTT (activated partial thromboplastin time) • 50% patient’s platelet-poor plasma • 25% mixture of phospholipid & surface active agent (Celite, Kaolin) • 25% Calcium Chloride to bring calcium concentration to 3-5 mM • Time to clot formation measured

  30. INTRINSIC PATHWAY FXII aPTT FXIIa Surface Active Components FXI HMWK FXIa FIX Ca+2 FIXa T Ca+2 VIII VIIIa VIIIa/IXa/PL FX Middle Components Ca+2 FXa Ca+2 T V Va Va/Xa/PL PT Ca+2 T Common Pathway FG F COAGULATION CASCADE

  31. Prekallikrein Kallikrein F XII HMWK F XIIa F XI F XIa COAGULATION CASCADEContact Phase

  32. F VII/TF Ca+2 F VIIa/TF VIIa/TF/PL XIa F IX Ca+2 Ca+2 T VIII VIIIa + F IXa IXa/VIIIa/PL Tenase Complex Ca+2 F X F Xa COAGULATION CASCADEIntermediate Phase

  33. IXa/VIIIa/PL VIIa/TF/PL F X F X Ca+2 Ca+2 V Va + F Xa Xa/Va/PL PT Ca+2 Prothrombinase Complex T Fibrinogen Fibrin monomer COAGULATION CASCADECommon Pathway

  34. CLOTTING ASSAYSSpecific factors/Inhibitors • Deficiency states of every clotting protein described • 50% of any clotting factor will yield normal PT and/or aPTT • Mix 1/2 patient plasma with 1/2 factor deficient plasma; then perform PT and/or aPTT • Factor deficient plasma with missing factor will  prolonged clotting time; all others WNL • If more than one clotting assay prolonged, implies inhibitor to clotting protein

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