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Chapter 31 Antithrombotic therapy

Chapter 31 Antithrombotic therapy. August 8, 2005. Heparin induced thrombocytopenia (HIT). Characterized by formation of antibodies against the heparin-platelet factor 4 complex, type II

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Chapter 31 Antithrombotic therapy

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  1. Chapter 31 Antithrombotic therapy August 8, 2005

  2. Heparin induced thrombocytopenia (HIT) • Characterized by formation of antibodies against the heparin-platelet factor 4 complex, type II • Type I due to direct effect of heparin on platelet activation, occurs within the first two days and often normalizes with continued heparin administration

  3. HIT incidence • Frequency of 0.3 to 3% in patients exposed to heparin for more than 4 days • One randomized study of heparin vs LMWH for hip surgery prophylaxis HIT incidence was 2.7% vs 0% for those on LMWH • SQ unfractionated heparin had an incidence of 0.8% for HIT with 598 consecutive medical patients • Amount required can be as small as 250u from heparin flushes or heparin coated catheters

  4. HIT pathophysiology • IgG and IgM antibodies provoked not by heparin alone but complex of heparin and platelet factor 4 • Heparin-PF4-antibody complex binds to platelet surface and leads to platelet activation that further releases PF4 causing a positive feedback loop • Activated platelets aggregate and are removed prematurely from circulation leading to thrombocytopenia and frequently thrombosis

  5. HIT clinical presentation • Typically occurs 4 to 10 days after initiation of heparin • Earlier onset seen in patients treated with heparin in preceeding 3 to 4 months • Thrombocytopenia is rarely severe with platelet counts over 20k, median platelet count nadir of 60k • Spontaneous bleeding is unusual • Delayed onset HIT • Can occur after heparin has been withdrawn, avg 9 days later, patients have high titer platelet activating antibodies in one study of 12 patients • 14 patients avg time 14 days (9 to 40 days), 11 patients readmitted and treated with heparin resulting in thrombocytopenia and clinical deterioration and death in 3 patients • Criteria for delayed onset HIT, 1 exposure to heparin with benign hospital course, 2 representation with venous and/or arterial thrombosis, 3 positive serological tests for heparin-induced antibodies

  6. HIT thrombosis • 89% of 9 patients with HIT developed thrombosis (7 venous and 1 arterial) after hip surgery • Retrospective review of 127 with HIT, 78 (61%) patients venous thrombosis and 18 (14%) patients arterial thrombosis, P/E manifested occurred in 25% of these patients, patient with isolated thrombocytopenia had a 30 day risk of thrombosis of 53%

  7. HIT diagnostic testing • Clinical diagnosis • Unexplained thrombocytopenia, thrombosis associated with thrombocytopenia, or normal platelet count that has fallen more than 50% • Serotonin release assay • 14C-serotonin release assay is gold standard • Normal donor platelets labeled with C14-serotonin, washed, then patient serum is added along with low and high concentration heparin • Positive test occurs with release of C14-serotonin with therapeutic concentrations of heparin (0.1u/Ml) • Very expensive • Heparin induced platelet aggregation • Very specific (>90%) but with low sensitivity • Solid phase immunoassay • Not a functional assay • Sensitive >91% but not specific as many antibody positive patients do not develop clinical HIT • Best used in conjunction with one of the other tests

  8. HIT thrombosis • Other clinical manifestations • Venous limb gangrene (distal ischemic necrosis followed by DVT) • Cerebral sinus thrombosis • Upper extremity DVT • 260 cases, upper extremity DVT present in 5.4% of cases, all occurred in patients with central venous catheters and at catheter site • Arterial thrombosis • Stroke • MI • Limb ischemia from peripheral artery occlusion • Organ infarction (mesentery, kidney) • Skin necrosis • Similar to warfarin induced skin necrosis but patients not deficient in protein C/S or antithrombin

  9. HIT prevention • Low incidence of heparin dependent IgG antibodies 2.2% vs. 7.8% with use of LMWH • Warfarin should not be given to HIT patients until thrombocytopenia resolves and therapy should be bridged by argatroban or hirudin, LMWH should not be substituted after HIT

  10. HIT treatment • Immediate cessation of all exposure to heparin • Consider direct thrombin inhibitor lepirudin or argatroban to bridge anticoagulation therapy • Warfarin • Start when patient stably anticoagulated with a thrombin specific inhibitor and platelet count increased to 100k • Warfarin therapy alone may increase risk of venous limb gangrene in patients with DVT • High initial doses >= 10 mg should be avoided to minimize transient hypercoagulable state induced by decline in protein C levels • Anticoagulation should be continued for 2 to 3 months

  11. Direct thrombin inhibitors • Hirudin derivative • Lepirudin, renally excreted and monitored using aPTT, initial bolus of 0.4mg/kg followed by infusion of 0.15mg/kg/hr to keep aPTT 1.5 to 2.5 greater than baseline • Lepirudin approved for treatment of HIT • Lepirudin as safe and effective as heparin for unstable angina, adjunct to thrombolytic therapy, prophylaxis and treatment of VTE • Hirulogs • Bivalirudin (angiomax) monitored by ACT to maintain >350 secs • Only direct thrombin inhibitor approved for acute coronary syndromes • Decrease rate of clinically significant bleeding compared to heparin 3.5% vs. 9.3%.

  12. Small molecule direct thrombin inhibitors • Argatroban • Only one FDA approved • Borderline increased risk of MI and lower rates of major bleeding • Hepatically cleared 2ug/kg/min adjusted to maintian aPTT at 1.5 to 3 times baseline, 0.5ug/kg/min for patients with hepatic dysfunction • Ximelagatran • Oral bioavailability of 18 to 24% • Transformed to melagatran • Compared to dalteparin, combination of ximelagatran and melagatran reduced frequency of VTE in ortho patients from 28.2% to 15.1% • Dosing not influenced by age, gender, or weight and does not require monitoring • Ximelagatran vs. warfarin reduced incidence of VTE and death 20.3% vs. 27.6% with total knee replacement patients and no increased risk of bleeding but elevated transaminases were identified 6.4% vs 1.2% (placebo)

  13. HIT use of heparin later • Brief use of heparin during cardiopulmonary bypass has been successful • But consider if alternative anticoagulants are available • Prove that HIT antibodies are not detectable • Restrict use of heparin to operative procedure itself • Use alternative anticoagulant pre/post op (eg, lepirudin, warfarin)

  14. Factor Xa inhibitors • Fondaparinux (arixtra) • Inhibit thrombin generation • Reduced odds of VTE when compared to enoxaparin in major othropedic cases (6.8% vs. 13.7%) but at the cost of increased major bleeding events (2.7% vs. 1.7%) • Patients with acute symptomatic pulmonary embolism no significant difference in recurrent thromboembolism (3.8% vs. 5%) and major bleeding (1.3% and 1.1%)

  15. Antiplatelet agents • Aspirin • Permanently inactivates cyclooxygenase activity of prostaglandin H synthase-1 and 2 • Short half-life but able to completely inhibit platelet thromboxane A2 production • Equally effective in low doses (50 to 100 mg/day) vs. high doses (900-1500 mg/day) • Ticlopidine and clopidogrel • Selectively inhibit ADP-induced platelet aggregation • Ticlopidine effectively reduces mortality in claudicants by 29.1% • Potential side effects include bone marrow suppresion, aplastic anemia, and thrombocytopenic purpura • Clopidogrel six time more potent than ticlopidine and has a better safety profile, at 50 to 100 mg, requires 4 to 7 days to reach steady state, loading doses of 300 mg may result in more rapid effectiveness • Bleeding risk similar to ASA and ASA is more likely to cause GI bleeding

  16. Antiplatelet agents • Clopidogrel • In patients with PVD, recent stroke, or recent MI reduced risk of stroke, MI or vascular death by 23.8% compared to ASA (3.71% compared to 4.86%) • In patients with acute coronary syndromes with ST segment elevation, combination of ASA and clopidrogrel reduced incidence of CV death, non-fatal MI or stroke from 11.4% to 9.3%, this came at the cost of major bleeding from GI and puncture sites • Compared to placebo combination of ASA and clopidogrel found to increase risk of bleeding (24% vs. 42%) without reduction in thrombotic events in patients with PTFE hemodialysis grafts • Abciximab • GP-IIb/IIIa inhibitor (inhibits fibrinogen binding) reduces rate of death, MI, or urgent revascularization in patients undergoing PCI as well as a reduction in 1 year mortality • When used in conjunction with carefully managed heparin and early removal of arterial sheaths, major bleeding rates are similar to the use of heparin alone • May be associated with thrombocytopenia

  17. Antiplatelet agents • Consensus statement that ASA 325 mg/day be started preoperatively for all prosthetic conduits; grafts to the tibial-peroneal arteries; complex reconstructions requiring composite grafts or endarterectomy; and suboptimal bypasses with limited runoff or requiring a compromised conduit • Combination of warfarin and ASA to maintain an INR of 2 to 3 improved three year primary graft patency and limb salvage rate of 74% and 81% respectively compared with 51% and 31% alone

  18. Reversal of anticoagulants • Unfractionated heparin • Protamine 1 mg per 100 units, risks bradycardia and hypotension • Allergic reactions due to previous exposure to protamine containing insulin, vasectomy and fish allergies • LMWH • Protamine less effective due to shorter heparin chains • Normal dosing acutely reverses 42% of factor Xa activity and 92% of anti-factor IIa actvity • Warfarin • Oral vitamin K reduces INR in 24 hrs • Low dose IV doses effective (0.5 to 2.5mg), higher doses (>10mg) associated with temporary warfarin resistance on reintroduction

  19. Reversal of anticoagulants • Warfarin • INR <5 and no bleeding => lowering or omitting a dose • INR >5 and <9 and no bleeding => withhold 1 to 2 doses +/- 1 to 2.5mg of oral vitamin K • INR >9 3 to 5mg of oral vitamin K • For serious bleeding => FFP and slow IV administration of 10mg vitamin K • In preparation for surgery, most patients require 4 days to reach an INR <1.5 after discontinuation of therapy

  20. Reversal of anticoagulants • For VTE, preoperative heparin for INR <2.0 in those with an event within 1 month • Postoperative heparin for those with an event in preceeding 3 months • For cardiogenic thromboembolism, preoperative anticoagulation for those with an event in the preceeding month • For low risk patients (remote >3 month hx of DVT, or atrial fibrillation without stroke) no heparin is indicated • High risk patients (recent DVT, prosthetic mitral valves, or older mechanical valves) warfarin D/C 4 days prior with full bridging heparin anticoagulation when INR <2

  21. 2004;126;204-233 Chest Hylek Jack Ansell, Jack Hirsh, Leon Poller, Henry Bussey, Alan Jacobson and Elaine Seventh ACCP Conference on Antithrombotic and Thrombolytic Therapy The Pharmacology and Management of the Vitamin K Antagonists: The

  22. Reversal of anticoagulants • Newer anticoagulants • No specific antidote for factor Xa inhibitors • Protamine ineffective against direct thrombin inhibitors • Lepirudin and bivalirudin can be partially cleared by hemodialysis

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