Antithrombin III<br />
Protein C system<br />Thrombin + thrombomodulin<br />Protein C<br />aProtein C + protein S<br />Cleaves Factor Va and VIII...
Thrombin + thrombomodulin<br />Thrombin-activatable fibrinolysis inhibitor (TAFI)<br />Removes the terminal lysine on the ...
Degradation of the Fibrin Clot<br />Natural part of hemostasis<br />Fibrin fibrils in the clot are dense, dissolution occu...
Plasminogenesis<br />
Plasmin<br />Serine protease formed from plasminogen<br />Plasminogen found in plasma and extracellular space and has high...
Tissue Plasminogen Activator<br />Serine protease released from ECs in response to injury (in response to thrombin and som...
Urokinase<br />Serine protease secreted as pro-urokinase <br />Produced by endothelial cells, fibroblasts, and monocytes/m...
Streptokinase<br />Protein isolated from certain types of streptococci bacteria<br />Potent plasminogen activator<br />Les...
BECAUSE OF THE COMPLEX NATURE OF HEMOSTASIS, POTENTIAL INTERFERENCE IN THE PROCESS CAN OCCUR AT MANY LEVELS.<br />
HEMOSTATIC DEFECTS<br />CONGENITAL<br />Coagulation Factor deficiency<br />Hemophilia<br />von Willebrand’s disease<br />F...
HEMOSTATIC DEFECTS<br />Major surface protein abnormality<br />Glanzmann’s thrombastenia<br />Glycoprotein IIb / IIIa<br /...
HEMOSTATIC DEFECTS<br />ACQUIRED Platelet abnormalities<br />quantitative defects<br />failure of production<br />Bone mar...
Conditions of Excess Bleeding<br />Hemophilia ( inherited sex-linked rec. )<br />Hemophilia A (classic)- deficiency of Fac...
Conditions of Excess Bleeding<br />von Willebrand’s disease<br />Autosomal dominant<br />Low level of vWF<br />CARRIER FOR...
Conditions of Excess Bleeding<br />Thrombocytopenia <br />Most common abnormality of hemostasis in surgical patients<br />...
Conditions of Excess Bleeding<br />Coagulopathy of liver disease<br />Vitamin K deficiency<br />Required by liver for form...
Conditions of Clotting Dysfunction<br />Thromboembolic conditions<br />Can result when endothelial surface is compromised ...
COAGULANTS<br />Thrombosis<br />Inappropriate activation of hemostatic mechanism;<br />Venous –associated with stasis of b...
COAGULANTS<br />Vitamin K<br />Essential for the formation of clotting factors (II, VII, IX and X)<br />Given orally or th...
COAGULANTS<br />Antifibrinolytic Agent<br />Tranexamic acid (Inhibit plasminogen activation),for conditions with bleeding ...
Conditions of Clotting Dysfunction<br />Disseminated intravascular coagulation<br />Clotting activated in widespread areas...
ANTICOAGULATION <br />AND <br />BLEEDING<br />
Prevention of Blood Clotting<br />Critical for clots to dissolve or not form when not needed<br />Endothelial cell surface...
Removal of Thrombin (blocks common pathway)<br />Fibrin – absorbs 85-90% of thrombin by absorption into fibers<br />Anti-t...
Vitamin K cycle (post-translational carboxylation)<br />Factors VII, IX, X and prothrombin<br />
Anticoagulants for Clinical Use<br />Heparin<br />Coumarins<br />Aspirin<br />Cyclooxygenase inhibitor<br />Prevents forma...
Antithrombin III<br />
ANTICOAGULANT<br />Heparin -binds to antithrombin III<br />Combines with anti-thrombin III and increases activity 100-1000...
ANTICOAGULANT<br />Low molecular weight heparin- 4-6 kDa<br />Selective Xa inhibitor<br />More favorable antithrombotic ef...
ANTICOAGULANTS<br />Coumarin derivatives- warfarin,acenocoumarol,phenprocoumon<br />Block coagulation factors(2,7,9,10)<br...
ANTICOAGULATION<br />Antiplatelet Drugs<br />Aspirin<br />Dipyridamole<br />Thienopyridine Derivatives<br />Glycoprotein I...
ANTICOAGULATION<br />Antiplatelet Drugs<br />Aspirin<br />Inhibits cyclooxygenase irreversibly<br />Inhibits TXA2<br />Mai...
ANTICOAGULATION<br />Antiplatelet Drugs<br />Dipyridamole<br />Phosphodiesterase inhibitor<br />Additive effect to aspirin...
ANTICOAGULATION<br />Antiplatelet Drugs<br />Thienopyridine Derivatives<br />Inhibits ADP-dependent aggregation<br />Orall...
ANTICOAGULATION<br />Antiplatelet Drugs<br />Glycoprotein IIB/IIIA Receptor Antagonists<br />Abciximab – for angioplasty p...
ANTICOAGULATION<br />Thrombolytic agents- plasminogen activators.<br />Recombinant endogenous plasminogen activators(recom...
ANTICOAGULATION<br />Fibrinolytic Drugs<br />Streptokinase<br />Protein extracted from cultures of streptococci <br />Acti...
ANTICOAGULATION<br />Fibrinolytic Drugs<br />Alteplase, Duteplase and Reteplase<br />Recombinant tPA (plasminogen activato...
Tests of hemostasis<br />Primary deficiency/ defect in one component<br />Pharmacologic therapy<br />Anticoagulant/ antipl...
Tests of hemostasis<br />Careful review of patient’s clinical history<br />most important/ initial approach <br />Drug use...
Evaluation of surgical patient<br />Patients history<br />Questions to ask<br />Prolonged bleeding or swelling after bitin...
Four levels of concern<br />Level I 	Hx(-); Sx (m)		no test<br />Level II	Hx(-); Sx (M)		platelet ct<br />							PTT<br />...
Platelet dysfunction<br />Normal 150,000 to 400,000 /ul<br />Clinical signs of thrombocytopenia<br />&lt; 100,000 / ul<br ...
Platelet dysfunction<br />Bleeding time ( BT )<br />Evaluate platelet , vWD and vascular dysfunction<br />Several methods<...
Clotting dysfunction<br />PT reagent contains <br />thromboplastin and calcium + plasma = clot<br />PT measures<br />Facto...
Clotting dysfunction<br />Variations in thromboplastin activity from different sources<br />PT value is adjusted = INR<br ...
Clotting dysfunction<br />aPTT reagent contains <br />Phospholipid substitutes, activator and calcium  + plasma = clot<br ...
HEMOSTASIS<br />RENE PSA MENDOZA, MD, MHSA<br />Associate Professor, Department of Surgery <br />FEU-NRMF Institute of Med...
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Hemostasis Surgury 2

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Hemostasis Surgury 2

  1. 1.
  2. 2. Antithrombin III<br />
  3. 3. Protein C system<br />Thrombin + thrombomodulin<br />Protein C<br />aProtein C + protein S<br />Cleaves Factor Va and VIIIa<br />
  4. 4. Thrombin + thrombomodulin<br />Thrombin-activatable fibrinolysis inhibitor (TAFI)<br />Removes the terminal lysine on the fibrin molecule, renders the clot more susceptible to lysis by plasmin<br />
  5. 5. Degradation of the Fibrin Clot<br />Natural part of hemostasis<br />Fibrin fibrils in the clot are dense, dissolution occurs at “coiled coils” to form oligomers which are digested into smaller units<br />Highly regulated in terms of gene expression<br />Plasmin<br />Tissue plasminogen activator (t-PA)<br />urokinase<br />streptokinase<br />
  6. 6. Plasminogenesis<br />
  7. 7. Plasmin<br />Serine protease formed from plasminogen<br />Plasminogen found in plasma and extracellular space and has high affinity for fibrin<br />Inactive and requires activation to plasmin by urokinase and t-PA <br />Formation of plasmin is highly regulated<br />Cleaves fibrin into degradation products.<br />Circulating plasmin is inhibited by α2-antiplasmin. <br /> Forms complex with plasmin and prevents it from binding to fibrin<br />
  8. 8. Tissue Plasminogen Activator<br />Serine protease released from ECs in response to injury (in response to thrombin and some vasoactive peptides)<br />Chiefly responsible for conversion of plasminogen to plasmin<br />Secretion highly regulated at transcriptional level<br />Major binding is to fibrin clots and extracellular matrix<br />Highly specific ( site of clot formation )<br />Inhibited by plasminogen activator inhibitor-1 (PAI-1)<br />Recombinant protein used clinically to inhibit thrombosis<br />
  9. 9. Urokinase<br />Serine protease secreted as pro-urokinase <br />Produced by endothelial cells, fibroblasts, and monocytes/macrophages<br />Potent plasminogen activator but non-specific<br />secreted as one chain: fragments in urine generated by plasmin<br />Functions to degrade ECM, enabling cells to migrate<br />Half life of only 7 minutes<br />Inhibited by plasminogen activator-2 (PAI-2)<br />synthesis tightly regulated by cytokines and inflammatory mediators<br />Used clinically (e.g. Abbokinase)<br />
  10. 10. Streptokinase<br />Protein isolated from certain types of streptococci bacteria<br />Potent plasminogen activator<br />Less selective than t-PA<br />Can result in circulating plasmin<br />Can produce degradation of fibrinogen as well as fibrin<br />May result in formation of plasmin in excess of that inhibited by α2-antiplasmin and result in bleeding<br />
  11. 11. BECAUSE OF THE COMPLEX NATURE OF HEMOSTASIS, POTENTIAL INTERFERENCE IN THE PROCESS CAN OCCUR AT MANY LEVELS.<br />
  12. 12. HEMOSTATIC DEFECTS<br />CONGENITAL<br />Coagulation Factor deficiency<br />Hemophilia<br />von Willebrand’s disease<br />Factor XI,II, V, X, XIII deficiency<br />Platelet function defects<br />Glanzmann’s thrombastenia<br />Bernard-Soulier syndrome<br />Storage pool disease<br />
  13. 13. HEMOSTATIC DEFECTS<br />Major surface protein abnormality<br />Glanzmann’s thrombastenia<br />Glycoprotein IIb / IIIa<br />Absence of platelet aggregation<br />Bernard-Soulier syndrome<br />Glycoprotein Ib / IX / V<br />Absence of platelet adhesion<br />
  14. 14. HEMOSTATIC DEFECTS<br />ACQUIRED Platelet abnormalities<br />quantitative defects<br />failure of production<br />Bone marrow disorder<br />shortened survival<br />ITP / DIC<br />Sequestration<br />hypersplenism<br />
  15. 15. Conditions of Excess Bleeding<br />Hemophilia ( inherited sex-linked rec. )<br />Hemophilia A (classic)- deficiency of Factor VIII (85%)<br />Hemophilia B – deficiency of Factor IX (15%)<br />Spontaneous bleeding<br />Joints frequently, crippling arthropathies<br />Retroperitoneal hematoma<br />Gastrointestinal/ genitourinary <br />NORMAL PLATELET FUNCTION<br />
  16. 16. Conditions of Excess Bleeding<br />von Willebrand’s disease<br />Autosomal dominant<br />Low level of vWF<br />CARRIER FOR FACTOR VIII<br />NORMAL PLATELET ADHESION<br />ABNORMAL PLATELET FUNCTION<br />Easy bruising and mucosal bleeding<br />Menorrhagia is common<br />
  17. 17. Conditions of Excess Bleeding<br />Thrombocytopenia <br />Most common abnormality of hemostasis in surgical patients<br />Platelets fall from normal 150-400,000 to &lt; 100,000/µl<br />Massive blood loss<br />Heparin induced<br />Impaired platelet function<br />Vit b12 / folic acid def<br />ITP<br />hypersplenism<br />
  18. 18. Conditions of Excess Bleeding<br />Coagulopathy of liver disease<br />Vitamin K deficiency<br />Required by liver for formation of prothrombin and Factors VII, IX, X and protein C<br />Leads to serious bleeding tendencies<br />
  19. 19. Conditions of Clotting Dysfunction<br />Thromboembolic conditions<br />Can result when endothelial surface is compromised or BF is slow<br />Associated with atherosclerosis, infection, or trauma<br />Femoral venous thrombosis<br />When BF is slow (bed ridden, prolonged sitting)<br />Clot grows and large piece can break off<br />Can pass through right side of heart to lodge in pulmonary arteries (pulmonary embolism)<br />If large enough can be fatal<br />
  20. 20. COAGULANTS<br />Thrombosis<br />Inappropriate activation of hemostatic mechanism;<br />Venous –associated with stasis of blood with small platelet component<br />Arterial – associated with artherosclerosis with large platelet component <br />
  21. 21. COAGULANTS<br />Vitamin K<br />Essential for the formation of clotting factors (II, VII, IX and X)<br />Given orally or thru IV (Natural Vit K requires Bile-acid while Menadiol Na Phosphate does not but takes longer to act)<br />USE – bleeding 2o to oral anticoagulants, babies, Vit. K deficiencies<br />
  22. 22. COAGULANTS<br />Antifibrinolytic Agent<br />Tranexamic acid (Inhibit plasminogen activation),for conditions with bleeding or risk of bleeding,life-threatening bleeding following thrombolytic drug administration and hereditary angioedema.<br />Aprotinin-inhibits proteolytic enzymes, used for hyperplasminemia due to fibrinolytic overdose & during cardiac surgery<br />
  23. 23. Conditions of Clotting Dysfunction<br />Disseminated intravascular coagulation<br />Clotting activated in widespread areas<br />Often from severe trauma or shock (endotoxin)<br />Plugging of vessels limits oxygen delivery<br />lethal in ~85% of the cases<br />
  24. 24. ANTICOAGULATION <br />AND <br />BLEEDING<br />
  25. 25. Prevention of Blood Clotting<br />Critical for clots to dissolve or not form when not needed<br />Endothelial cell surface-<br />Most important factor – integrity prevents contact activation of intrinsic clotting system by collagen<br />Charged EC glycocalyx repels platelets and clotting factors<br />Thrombomodulin-EC membrane protein, binds thrombin to slow clotting process. Thrombomodulin-thrombin complex activates a protein C which inactivates Factors V and VIII. <br />
  26. 26. Removal of Thrombin (blocks common pathway)<br />Fibrin – absorbs 85-90% of thrombin by absorption into fibers<br />Anti-thrombin III – binds remaining thrombin <br />Prevention of Blood Clotting<br />
  27. 27. Vitamin K cycle (post-translational carboxylation)<br />Factors VII, IX, X and prothrombin<br />
  28. 28.
  29. 29. Anticoagulants for Clinical Use<br />Heparin<br />Coumarins<br />Aspirin<br />Cyclooxygenase inhibitor<br />Prevents formation of thromboxane A2 and activation of platelets<br />Calcium-deionizing agents<br />Sodium, ammonium and potassium citrate combines with calcium in blood<br />Several factors require calcium for activation<br />Used in test tubes to prevent clotting<br />
  30. 30. Antithrombin III<br />
  31. 31. ANTICOAGULANT<br />Heparin -binds to antithrombin III<br />Combines with anti-thrombin III and increases activity 100-1000X<br />Immediate effect ,half life of 60-90min<br />Monitor by aPTT<br />
  32. 32. ANTICOAGULANT<br />Low molecular weight heparin- 4-6 kDa<br />Selective Xa inhibitor<br />More favorable antithrombotic effect,less bleeding,highly predictable bioavailability<br />Longer half life<br />
  33. 33. ANTICOAGULANTS<br />Coumarin derivatives- warfarin,acenocoumarol,phenprocoumon<br />Block coagulation factors(2,7,9,10)<br />Warfarin decreases formation of Factors VII, IX and X by the liver<br />Competes with vitamin K for reactive sites<br />Restoration after coumarin tx- 3-5 days<br />Prothrombin time <br />INR- corrects the differences of the various thromboplastin activity. INR=1 no anticoagulation<br />
  34. 34. ANTICOAGULATION<br />Antiplatelet Drugs<br />Aspirin<br />Dipyridamole<br />Thienopyridine Derivatives<br />Glycoprotein IIB/IIIA receptor antagonists<br />Other antiplatelet drugs<br />
  35. 35. ANTICOAGULATION<br />Antiplatelet Drugs<br />Aspirin<br />Inhibits cyclooxygenase irreversibly<br />Inhibits TXA2<br />Main drug – acute MI, High-risk for MI, after coronary artery Bypass, after angioplasty, unstable coronary syndromes,TIA and AF if oral anticoagulant is contraindicated<br />
  36. 36. ANTICOAGULATION<br />Antiplatelet Drugs<br />Dipyridamole<br />Phosphodiesterase inhibitor<br />Additive effect to aspirin<br />Less effective than aspirin<br />Headache but no excess risk of bleeding <br />
  37. 37. ANTICOAGULATION<br />Antiplatelet Drugs<br />Thienopyridine Derivatives<br />Inhibits ADP-dependent aggregation<br />Orally given, additive with aspirin<br />Ticlopidine slow onset, unwanted effects-blood dyscrasias (neutropenia)<br />Clopidogrel – same as Ticlopidine except for neutropenia<br />
  38. 38. ANTICOAGULATION<br />Antiplatelet Drugs<br />Glycoprotein IIB/IIIA Receptor Antagonists<br />Abciximab – for angioplasty patient as adjunct to heparin and aspirin, reduces restenosis, Tirofiban – an oligopeptide<br />Abciximab - Risk of bleeding & immunogenicity limits its use<br />They inhibit diverse agonists (e.g. ADP, TXA2 etc. ) <br />
  39. 39. ANTICOAGULATION<br />Thrombolytic agents- plasminogen activators.<br />Recombinant endogenous plasminogen activators(recombinant tPA)<br />Streptokinase- exogenous source<br />bleeding<br />
  40. 40. ANTICOAGULATION<br />Fibrinolytic Drugs<br />Streptokinase<br />Protein extracted from cultures of streptococci <br />Activates plasminogen, given IV<br />Additive with aspirin<br />Action blocked by antistreptococcal antibodies<br />Allow 1 year before it can be used again<br />
  41. 41. ANTICOAGULATION<br />Fibrinolytic Drugs<br />Alteplase, Duteplase and Reteplase<br />Recombinant tPA (plasminogen activator)<br />‘Clot-selective’ – fibrin bound plasminogen<br />Not antigenic-substitute for patients w/ ab for streptokinase<br />Reteplase –longer half-life, bolus admn.simple<br />
  42. 42. Tests of hemostasis<br />Primary deficiency/ defect in one component<br />Pharmacologic therapy<br />Anticoagulant/ antiplatelet<br />Comorbid condition<br />Thrombocytopenia<br />Sepsis/ hepatic disease<br />
  43. 43. Tests of hemostasis<br />Careful review of patient’s clinical history<br />most important/ initial approach <br />Drug use<br />Basic laboratory tests<br />Platelet count<br />Prothrombin time ( PT ) or INR<br />Activated partial thromboplastin time ( aPTT )<br />Bleeding time ( BT ) and clotting time ( CT )<br />
  44. 44. Evaluation of surgical patient<br />Patients history<br />Questions to ask<br />Prolonged bleeding or swelling after biting the lip or tongue<br />Bruises without apparent injury<br />Prolonged bleeding after dental extraction<br />Excessive menstrual bleeding<br />Bleeding problems associated with major and minor operations<br />Medical problems receiving a physician’s attention within the past 5 years<br />Medications including aspirin or remedies for headache taken within the past 10 days<br />Relative with a bleeding problem<br />
  45. 45. Four levels of concern<br />Level I Hx(-); Sx (m) no test<br />Level II Hx(-); Sx (M) platelet ct<br /> PTT<br />Level III Hx (suggestive) PT, PTT, BT, CT, pltelet ct<br />Level IV Hx(+) Hematologic consultation<br />
  46. 46. Platelet dysfunction<br />Normal 150,000 to 400,000 /ul<br />Clinical signs of thrombocytopenia<br />&lt; 100,000 / ul<br />Increased bleeding complications in major surgical procedures <br />&lt; 50,00 / ul<br />Increased bleeding complications in minor surgical procedures <br />&lt; 20,000 / ul<br />SPONTANEOUS HEMORRHAGE<br />
  47. 47. Platelet dysfunction<br />Bleeding time ( BT )<br />Evaluate platelet , vWD and vascular dysfunction<br />Several methods<br />Ivy test = 7mins<br />Clotting time ( CT )<br />… + Aspirin use<br />
  48. 48. Clotting dysfunction<br />PT reagent contains <br />thromboplastin and calcium + plasma = clot<br />PT measures<br />Factors I, II, V, X and VII<br />Factor VII extrinsic pathway <br />Abnormal coagulation due to Vit K deficiency<br /> warfarin / coumadin therapy<br />
  49. 49. Clotting dysfunction<br />Variations in thromboplastin activity from different sources<br />PT value is adjusted = INR<br />ISI ( international sensitivity index )<br />Value for each batch of thromboplastin<br />Optimal reagent has as ISI of 1.3 to 1.5<br />INR = ( PTpatient / PTnormal )ISI<br />INR- corrects the differences of the various thromboplastin activity. INR = 1.0 is NORMAL<br />
  50. 50. Clotting dysfunction<br />aPTT reagent contains <br />Phospholipid substitutes, activator and calcium + plasma = clot<br />aPTT measures<br />Factors I, II and V of the common pathway<br />Factors VIII, IX, X and XII<br />intrinsic pathway <br />Heparin therapy<br />
  51. 51. HEMOSTASIS<br />RENE PSA MENDOZA, MD, MHSA<br />Associate Professor, Department of Surgery <br />FEU-NRMF Institute of Medicine <br />
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