chapter 31 antithrombotic therapy august 8, 2005
TRANSCRIPT
Chapter 31 Antithrombotic therapy
Chapter 31 Antithrombotic therapy
August 8, 2005August 8, 2005
Heparin induced thrombocytopenia (HIT)
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
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
HIT incidenceHIT 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
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
HIT pathophysiologyHIT 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
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
HIT clinical presentationHIT 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
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
HIT thrombosisHIT 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%
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%
HIT diagnostic testingHIT 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
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
HIT thrombosisHIT 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
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
HIT preventionHIT 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
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
HIT treatmentHIT 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
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
Direct thrombin inhibitorsDirect 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%.
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%.
Small molecule direct thrombin inhibitors
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)
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)
HIT use of heparin laterHIT 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)
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)
Factor Xa inhibitorsFactor 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%)
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%)
Antiplatelet agentsAntiplatelet 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
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
Antiplatelet agentsAntiplatelet 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
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
Antiplatelet agentsAntiplatelet 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
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
Reversal of anticoagulantsReversal 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
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
Reversal of anticoagulantsReversal 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
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
Reversal of anticoagulantsReversal 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
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
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
Reversal of anticoagulantsReversal 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
Newer anticoagulants No specific antidote for factor Xa
inhibitors Protamine ineffective against direct
thrombin inhibitors Lepirudin and bivalirudin can be
partially cleared by hemodialysis