Bleeding and Thrombosis in the Surgical Patient Bronx Veterans Affairs Medical Center Surgery and Gastroenterology Gr

1. Bleeding and Thrombosis in the Surgical PatientBronx Veterans Affairs Medical CenterSurgery and Gastroenterology Grand RoundsOctober 30, 2003 Donald Baril Department of Surgery Mount Sinai School of Medicine

2. Hemostasis Hemostatic response consists of three primary elements: 1) Vasoconstriction 2) Platelet aggregation 3) Clotting cascade

3. Hemostasis Vasoconstriction ? occurs as a result of vessel injury ? limits flow of blood to the area of injury ? enhanced by vasoconstricting elements released from platelets (primarily thromboxane A2) ? reflex sympathetic vasoconstriction may result from pain

4. Hemostasis Platelet aggregation ? platelets are activated by thrombin and aggregate at the site of injury to form a temporary platelet plug ? platelets adhere to damaged endothelium via von Willebrand factor ? bridges GPIb/IX and collagen fibrils ? aggregating platelets release ADP, TXA2 adenosine- 5�-diphosphate, serotonin, phospholipids and other proteins necessary for the coagulation cascade

5. Hemostasis Clotting cascade ? consists of two semi-independent pathways ? intrinsic pathway initiated when contact is made between blood and exposed endothelial tissues (relatively slow: approximately 2-6 minutes) ? extrinsic pathway is triggered by vessel or tissue damage which leads to the exposure of tissue factor (fast: approximately 15 seconds) ? both pathways lead to the activation of prothrombin (factor II) ? final common pathway converts fibrinogen to fibrin

6. Clotting cascade

7. Natural inhibitors of the coagulation cascade ? Thrombomodulin ? Antithrombin III ? Tissue factor pathway inhibitor ? Protein C ? Protein S

8. Natural inhibitors of the coagulation cascade

9. Natural inhibitors of the coagulation cascade Thrombomodulin is a potent inhibitor of thrombin Binds thrombin and inhibits its ability to cleave fibrinogen or active factors V and VII Enhances thrombin�s ability to activate protein C, which degrades factors V and VIII

10. Natural inhibitors of the coagulation cascade Antithrombin III is a large protease inhibitor that inhibits thrombin and factors IXa, Xa, XIa, and XIIa but does not inhibit thrombin within clots ? Heparin accelerates the reaction time of antithrombin III 1000 fold

11. Natural inhibitors of the coagulation cascade ? Tissue factor pathway inhibitor (TFPI) ? Protein with three tandem protease inhibitory domains ? Inhibits Factor Xa and the Factor VIIa-Tissue Factor Complex ? Bound to lipoproteins (LDL, HDL, lipoprotein A) ? Platelets carry about 10% of the TFPI ? Heparin enhances the function of TFPI 2-4 fold.

12. Natural inhibitors of the coagulation cascade ? Protein C and Protein S ? Vitamin K-dependent serine proteases synthesized in the liver ? Circulate as inactive forms (zymogens) ? Protein C ? inhibits the activity of factors Va and VIIIa ? Protein S ? cofactor that potentiates the action of Protein C

13. Eckman et al. Ann Intern Med Vol 138, No 5 Preoperative screening for bleeding risk ? Complete history and physical

14. Preoperative screening for bleeding risk ? Incidence of a significant hereditary deficiency of a coagulation factor is low (1 per 10,000-40,000) ? approximately 1/3 of these are asymptomatic ? Acquired deficiencies of factors should be suspected in the presence of advance hepatic disease, malabsorption, or malnutrition

15. Clinical testing and preoperative screening ? Prothrombin time (PT) ? measure extrinsic and common pathways ? affected by low concentrations of fibrinogen, prothrombin and factors II, V, VII, X ? Activated partial thomboplastin time (aPTT) ? measures intrinsic and common pathways ? deficiencies in all clotting factors except factors VII and XIII may prolong the aPTT

16. Clinical testing and preoperative screening ? PT and aPTT testing involves adding activators, phospholipids, and calcium to plasma and determining the time to clot formation ? Abnormalities result from: ? factor deficiencies in the coagulation cascade ? excess of calcium ? inadequately filled collection tubes ? excessive tourniquet time ? hemolyzed or clotted samples ? prolonged time from sample collection to testing

17. Assessment of platelet function ? Platelet count ? reproducible, but fails to assess platelet function ? Bleeding time ? highly technician-dependent ? poor screening test for preoperative hemorrhage ? fails to discriminate between those taking ASA and those who are not ? Platelet function analyzer ? quantitative test of platelet function at high sheer rates ? sensitive to impairment of vWF, inhibition of glycoprotein Ib or IIb/IIIa receptors and ASA-induced dysfunction

18. Is preoperative testing useful? ? Houry et al. American Journal of Surgery July 1995 ? Multicenter prospective study of 3242 patients undergoing general surgery procedures ? High-risk patients defined as those with ? easy/excessive bruising ? heavy or prolonged menstrual periods ? epistaxis ? GI/GU bleeding ? prolonged bleeding after cuts/previous surgery ? hemophilia or other inherited hemorrhagic disorder ? renal failure, liver disease, hypersplenism, collagen vascular disease ? purpura, hematomas, jaudince, signs of liver failure on physical exam

19. Is preoperative testing useful? Low-risk patients with normal test results (PT, aPTT, platelet count, and bleeding time) 0.15% of 1951 pts died of bleeding 4.6% had bruising 3.0% had hematomas 0.46% required reoperation to control hemorrhage Low-risk patients with abnormal test results 0 of 340 pts died of bleeding 5.9% had bruising 2.9% had hematomas 0.59% required reoperation to control hemorrhage Houry et al. Am J Surg July 1995

20. Is preoperative testing useful? High-risk patients with normal test results (PT, aPTT, platelet count, and bleeding time) 0 of 779 pts died of bleeding 8.3% had bruising 3.5% had hematomas 1.16% required reoperation to control hemorrhage High-risk patients with abnormal test results 1.16% of 340 pts died of bleeding 10.5% had bruising 6.4% had hematomas 1.16% required reoperation to control hemorrhage Houry et al. Am J Surg July 1995

21. Preoperative screening to assess risk of thrombosis ? Acquired causes of thrombophilia ? cancer ? antiphospholipid antibodies ? nephrotic syndrome ? hyperhomocystinemia ? Heritable causes of thrombophilia ? factor V Leiden mutation ? protein C deficiency ? protein S deficiency ? antithrombin III deficiency

22. Factor V Leiden mutation (activated protein C resistance) ? Inactivation of normal Factor Va occurs through an ordered series of cleavages at arginine residues ? In APC resistance, the arginine at position 506 is substituted with glutamine rendering the Factor Va molecule resistant to cleavage by APC ? Thrombosis occurs because this altered Factor Va still has the same procoagulant activity as normal Factor Va ? Present in 1.25-6% of the U.S. population ? 25-40% of patients with this mutation have a family history of thrombosis ? 7.9 fold increased risk for thrombosis

23. Protein C deficiency ? Congenital deficiency of Protein C ? Causes of acquired deficiency of protein C: ? DVT, PE ? Acute DIC ? Post-operative State ? Severe liver disease ? Malignancy ? Infection ? ARDS ? Hemolytic-uremic syndrome ? Vitamin K Deficiency and/or Warfarin use

24. Protein S deficiency ? Congenital deficiency of protein S ? Type I - Decreased free Protein S, but adequate bound levels. ? Type II - Decreased free and bound Protein S ? 50% will have first thrombotic event before age 25 ? Causes of acquired deficiency of protein C ? DVT/PE. ? warfarin use ? pregnancy, both free and bound Protein S is decreased.

25. Antithrombin III deficiency ? Results from a defect in the synthesis of AT ? May also result from increases consumption of AT: DIC, DVT, PE ? Thrombotic events occur with AT activity at 40-60% of normal

26. Preoperative screening to assess risk of thrombosis Testing for thrombophilia should be performed in patients who have a history of: ? thombotic event before the age of 50 ? recurrent thrombosis ? first-degree relative with thrombotic event before the age of 50

27. Antiplatelet therapy and surgery - Aspirin ? No reported increase in bleeding complications in patients taking aspirin preoperatively undergoing emergent general surgery procedures (Ferraris et al. Surgery, Gynecology, and Obstetircs 1983) ? Cardiac surgery patients on aspirin therapy have been noted to have increased transfusion requirements and higher rates of reoperation for bleeding but with no difference in mortality (Sethi et al. JACC 1990, Goldman et al. Circulation 1998) ? No consensus recommendations for patients undergoing general surgery procedures ? stopping therapy in all patients 7-10 days prior vs. only those with abnormal bleeding times vs. continuing through the perioperative period

28. Antiplatelet therapy and surgery - Clopidogrel ? Known additive effect when clopidogrel is used concurrently with aspirin resulting in greater increase in bleeding time ? Cardiac surgery patients on clopidogrel therapy have been noted to have increased transfusion requirements and higher rates of reoperation for bleeding (Yende et al. Crit Care Med 2001) ? No published data on clopidogrel use in patients undergoing general surgery procedures

29. Chronic anticoagulation and surgery ? Factors to consider: ? risk of thromboembolism in the absence of anticoagulation ? bleeding risk (patient-risk and procedure-risk) ? consequences of intra-op and post-op bleeding ? ability to control bleeding ? duration of post-op bleeding risk ? urgency of surgery

30. Chronic anticoagulation and surgery ? Indications for chronic anticoagulation: ? Mechanical prosthetic heart valves ? greatest risk for thromboembolic event with mitral valve, caged-ball valves ? Atrial fibrillation ? greatest risk for thromboembolic event with history of TIA/stroke, hypertension, impaired LV function, diabetes ? Venous thromboembolism ? highest risk for recurrent disease within the first 1 to 3 months following the initial event

31. Chronic anticoagulation and surgery - Reversing therapy ? Warfarin inhibits vitamin K-dependent ?�carboxylation of factors II, VII, IX, X and proteins C and S ? Procoagulant factors are restored in a pattern proportional to their half-lives and require activity levels of =40% for near normal hemostasis ? Factor VII has a half-life of 4-6 hours ? Factor II has a half-life of 48-96 hours ? approximately 4-5 days are required to reach an INR of 1.4 or less

32. Chronic anticoagulation and surgery - Reversing therapy ? Vitamin K1 (phytonadione): ? fat-soluble vitamin that requires normal pancreatic and small bowel function for absorption of oral form ? 1.5 mg intravenous dose will reverse therapeutic levels of oral anticoagulation within 24-36 hours1,2 ? larger doses associated with anaphylactoid reactions ? 2.5 mg oral dose will have the same effect2 ? Intramuscular injection should be avoided due to risk of hematoma ? Subcutaneous injection should be avoided due to erratic absorption 1. Whitling et al. Arch Intern Med 1998 2. Shields et al. Mayo Clinic Proc 1995

33. Chronic anticoagulation and surgery - Reversing therapy ? Fresh frozen plasma ? required volume is 15-16 ml/kg in a patient who is therapeutic on warfarin ? prothrombin time will begin to prolong in several hours following the administration of FFP due to the short half-life of Factor VII ? major limitation is intravascular volume overload

34. Chronic anticoagulation and surgery - Recommendations ? Minor procedures with low risk of bleeding and easy access to control bleeding need to reduce the anticoagulation dosing to achieve the lower limit of therapeutic range (INR = 2.0-2.5)

35. Chronic anticoagulation and surgery - Recommendations ? Patients on oral anticoagulation for aortic valve prostheses or low-risk atrial fibrillation ? stop oral anticoagulants 3-5 days before surgery ? resume as soon as possible without loading dose

36. Chronic anticoagulation and surgery - Recommendations ? Patients on oral anticoagulation for mitral valve prostheses, high-risk atrial fibrillation, or recent venous thromboembolism (traditional approach) ? cessation of oral anticoagulation ? concurrent anticoagulation with heparin ? cessation of heparin 4-6 hours prior to surgery ? resumption of heparin as soon as possible following surgery

37. Chronic anticoagulation and surgery - Recommendations ? Patients on oral anticoagulation for mitral valve prostheses, high risk atrial fibrillation, or recent venous thromboembolism using bridging therapy with low molecular weight heparin ? initiate therapy once INR below lower limit of therapeutic ? last dose given morning of day prior to procedure ? resume LMWH therapy within 48 hours ? restart oral anticoagulation day following surgery ? options include dalteparin (Fragmin) 100 IU/kg sc bid or enoxaparin (Lovenox) 1 mg/mg sc bid or 1/5 mg/kg sc qd