Chapter 31 Antithrombotic therapy - PowerPoint PPT Presentation

Chapter 31 Antithrombotic therapy

August 8, 2005

• 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

• 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

• 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

• 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• Can occur after heparin has been withdrawn, avg 9 days later, patients have high titer platelet activating antibodies in one study of 12 patients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

• 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%

• 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

• 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

• 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

• 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

• 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%.

• 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)

• 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)

• 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%)

• 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

• 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

• 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

• 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

• 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

• 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

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