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Heparin Induced Thrombocytopenia.ppt
 

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    Heparin Induced Thrombocytopenia.ppt Heparin Induced Thrombocytopenia.ppt Presentation Transcript

    • Heparin-Induced Thrombocytopenia
    • Learning Objectives
      • Understand the etiology and pathogenesis of Heparin-Induced Thrombocytopenia
      • Be able to differentiate the two types of HIT; Type I and Type II.
      • Recognize the signs and symptoms of Heparin-Induced Thrombocytopenia and institute appropriate treatment
      • Gain the knowledge necessary to minimize the occurence heparin-induced thrombocytopenia.
    • Case Question
      • 55 yo Female patient with history of HTN, Osteoarthritis is s/p Right knee replacement POD #6. The primary service noticed a platelet count of 50,000 today (on admission it was 200,000). You suspect HIT, and start Argatroban. You also send serological work-up for HIT. What is the next important step?
    • Case Question
      • A) Immediately start Coumadin with Argatroban
      • B) Lower extremity Doppler
      • C) V/Q scan
      • D) Nothing currently indicated
    • Case Answer
      • A) Immediately start Coumadin with Argatroban
      • B) Lower extremity Doppler
      • C) V/Q scan
      • D) Nothing currently indicated
    • Definition of HIT
      • Heparin-induced thrombocytopenia is an antibody mediated pro-thrombotic disorder.
      • Diagnosis can be difficult.
    • Heparin-Induced Thrombocytopenia HIT Type I HIT Type II
    • Classificaiton of Type I and Type II HIT
      • Type I HIT
      • Non-immune
      • Decrease in platelets is b/w 10-30,000/ml
      • Do not discontinue heparin
      • Type II HIT
      • Focus of this talk
      • Immune
      • Decrease in platelets by 50% or less than 150,000
      • Heparin needs to be stopped
      • Alternative anticoagulation needs to be started
    • Type I HIT
      • Non-immune
      • Platelet drop due to direct effect of heparin on platelet activation
      • Of no clinical consequence
      • Chong BH and Castaldi Pa. Platelet proaggregating effect of heparin: Possible mechanism for non-immune heparin associated thrombocytopenia . Aust N Z J Med 1986.
    • Arepally G and Ortel T. Heparin-Induced Thrombocytopenia. The New England Journal of Medicine.
    • Schematic of HIT ( TYPE II ) immune activation
    • A Theory for Thrombosis
      • Formation of platelet plug
      • HIT antibodies also bind to endothelial cells  endothelial cell injury
      • Blank M, Shoenfeld Y, Tavor S, et al. Anti-platelet factor 4/heparin antibodies from patients with heparin-induced thrombocytopenia provoke direct activation of microvascular endothelial cells. Int Immunol 2002.
      • Occurs in 3% of those treated with unfractionated heparin
      • Type of Heparin used
      • bovine > porcine > low-molecular weight
      • Frequency of HIT
      • Surgical > Medical > Obstetric patients
      Epidemiology of HIT
    • Complications of HIT
      • - Th rombocytopenia (bleeding rarely occurs) by spleen
      • -Platelet activation  binding to endothelial cells 
      • Leading to thrombosis
      • -DIC
      • -Anaphylactic type reactions
      • Thrombotic risk is 30x control.
      • Arepally G and Ortel T. Heparin-Induced Thrombocytopenia. The New England Journal of Medicine.
    • Thrombosis Location
      • Venous or Arterial
      • Retrospective review of 127 patients with confirmed HIT: venous thrombosis occurred in 78 patients, vs 18 patients with arterial thrombosis (61% and 14%)
      • Warkentin TE and Kelton JG. A 14-year study of heparin-induced thrombocytopenia. Am J Medicine 1992; Vol (101): Pg 502.
    • Risk of Thrombosis
      • Same study; those with only thrombocytopenia, had a 30-day thrombotic event was 53%.
      • Warkentin TE and Kelton JG. A 14-year study of heparin-induced thrombocytopenia. Am J Medicine 1992; Vol (101): Pg 502 .
    • Thrombosis from HIT
      • Venous thrombosis and pulmonary embolism
      • Less frequently arterial thrombosis
      • Other: skin, coronary, CNS, adrenal
      • DVT
    • Onset of HIT
      • HIT usually occurs within 5-10 days
      • Delayed-onset HIT occurs up to 2 weeks after treatment with heparin
      • Rapid onset HIT occurs less than 5 days
      • Due to pre-existing antibodies.
    • Recognizing HIT
      • In any patient receiving heparin/LMWH
      • Unexplained thrombocytopenia
      • Thrombosis with thrombocytopenia
      • Necrotic skin lesions at site of heparin skin injection
    • Pre-test probability
      • Multiple causes of thrombocytopenia in medical/surgical patients
      • Potential for false-positives with ELISA
      • The use of the “4 T’s”
    • Pre-test probability
    • Validation of the 4 T’s
      • Among 111 patients with low pre-test probability; one had HIT (0.9%)
      • Intermediate scores: 11.4% with HIT
      • High scores: 34% with HIT
      • Lo GK, Julh D, Warkentin TE, et al. Evaluation of pretest clinical score (4 T’s) for the diagnosis of heparin-induced thrombocytopenia in two clinical settings. J Thromb Haemost 2006.
    • Diagnosis of HIT
      • A decrease in platelet count by 50%, or platelet level less than 150,000.
      • Absence of other causes of thrombocytopenia
      • May be with or without thrombosis
      • Platelet do not drop below 30,000/ml
    • Arepally G and Ortel T. Heparin-Induced Thrombocytopenia. The New England Journal of Medicine.
    • Differential Diagnosis of Thrombocytopenia
      • Drug Induced
        • heparin
        • procainamide
        • diuretics (furosemide)
        • H 2 blockers (cimetidine)
        • thrombolytic therapy
        • GP IIb/IIIa antagonists
      • Mechinical
        • membrane oxygenator
        • intra-aortic balloon pump
      • Pseudothrombocytopenia
        • platelet clumping
        • hemodilution
      • Associated disorders
        • hypersplenism
        • infections/sepsis
        • hypotension and subsequent disseminated intravascular coagulation
      • Other causes
        • chronic idiopathic thrombocytopenia purpura with exacerbation
        • antiphospholipid antibody syndrome
    • HIT without clinical symptoms of thrombosis
      • Silent DVT’s
    • Serologic Studies
      • Immunoassay
      • -ELISA
      • Functional Assays
      • -Serotonin release assay
      • -Heparin-Induced platelet aggregation
    • First Lab Test is Immunoassay
      • ELISA
      • - measures binding of HIT antibodies from patient serum to PF4-heparin complex coated on the wells of the plate.
      • -Sensitivity >97%
      • -Specificity 74-86%
      • -High NPV
      • If high suspicion and with a positive test result; no further diagnositic work-up needed
    • Arepally G and Ortel T. Heparin-Induced Thrombocytopenia. The New England Journal of Medicine.
    • Need for functional assay
      • If positive immunoassay, but intermediate suspicion of HIT
      • Up to 50% of patients after open heart surgery; 10% of medical patients have reactive anti-bodies against heparin-PF4 without HIT
      • Aster RH and Davoren A. Heparin-Induced Thrombocytopenia and Thrombosis. American Journal of Hematology.
    • Functional Assays
      • Heparin-Induced Platelet aggregation
      • -donor platelets mixed with patient serum; measure aggregation with and without heparin
      • -Sensitivity >90%
      • -Specificity 77-100%
    • Functional Assays
      • 14-C Serotonin Release Assay
      • Gold Standard
      • -Donor platelets radio-labaled with 14-C radiocarbon, patient serum added, serotonin quantified
      • -mixed with low and high concentration of heparin
      • -Sensitivity and Specificity >95%
      • -cost, technical demands, not widely available
      • Sheridan D, Carter C, Kelton JG et al. A diagnositic test for heparin-induced thrombocytopenia. Blood 1986.
    • Treatment
      • When clinical criteria are met, start treatment while awaiting laboratory results
      • Increase in platelet count after stopping heparin in the absence of other causes, may be diagnostic in the absence of confirmatory labs
    • Treatment of HIT
      • Stop any heparin treatment, including heparin line flushes or use of heparin coated catheters
      • Platelet transfusions contraindicated
      • LMWH contraindicated due to cross-reactivity
      • Warfarin contraindicated initially
      • Start alternative anti-coagulation, even without any signs of thrombosis
      • -Argatroban
      • -Lepirudin
      • -Fondaparinux  case report of HIT
    • Coumadin not used initially
      • Report of 8 patients with HIT, at which point heparin stopped and Coumadin started
      • Developed venous limb gangrene and full-thickness skin necrosis
      • Warkentin TE, Elavathil LJ, Hayward CP, et al. The pathogenesis of venous limb gangrene associated with heparin-induced thrombocytopenia . Ann Intern Med 1997.
    • Thrombin Inhibitors
    • Thrombin Inhibitors
      • Lepirudin:
      • -direct thrombin inhibitor
      • -goal aPTT of 1.5-2.5x
      • -use another agent if there is renal insufficiency as it is renally excreted
      • -side-effects: bleeding (18%)
      • -anti-dote
    • Thrombin Inhibitors
      • Lepirudin
      • -Lepirudin in 403 patients and 120 controls. Rate outcome of death, amputation, and thrombosis (at 35 days) lower vs control (20.3%, 43%; P value of <0.001).
      • Lubenow N. Eichler P, Lietz T, et al. Lepirudin for prophylaxis of thrombosis in patients with acute isolated heparin - induced thrombocytopenia : an analysis of 3 prospective studies . Blood 2004.
      • Argatroban
      • -direct thrombin inhibitor, interefers at thrombin active site
      • -adjusted to aPTT of 1.5-3x
      • -hepatic clearance so avoid in hepatobiliary disease
      • -side-effect: bleeding (7%), anaphylaxis
      • -anti-dote
      Thrombin Inhibitors
    • Thrombin Inhibitors
      • Argatroban
      • Multicenter study of 722 patients with HIT
      • - outcome of death, amputation, thrombosis at 37 days lower vs control (34-35% vs 43%)
      • - Reduction in new thromboembolic complications (10-14% vs 25%; P value <0.05)
      • Lewis BE, Wallis DE, Leya F, et al. Argatroban anticoagulation in patients with heparin-induced thrombocytopenia. Arch Intern Med 2003.
      • Lewis BE, Wallis DE, Berkowitz SD, et al. Argatroban anticoagulant therapy in patients with heparin-induced thrombocytopenia. Circulation 2001.
    • Thrombin Inhibitors
      • Bivalirudin- not fully investigated for HIT in most settings
    • Synthetic Pentasaccharide
      • Fondaparinux: inhibitor of Xa
      • Case study of Fondaparinux not preventing HIT
      • Alsaleh KA, Al-Nasser SM, Bates SM et al. Delayed-onset HIT caused by low-molecular-weight heparin manifesting during Fondaparinux prophylaxis . Am J Hematol. 2008; Epub ahead of print.
      • Case study associated with episode of HIT, when used as prophylaxis.
      • Warkentin T, Maurer B, Aster R, et al. Heparin-Induced Thrombocytopenia associated with Fondaparinux. The New England Journal of Medicine. Boston: June 2007. Vol 356.
    • Persistent and Worsening Thrombosis despite HIT treatment
      • Can use IVIG, plasma exchange, and aspirin if life-threatening thrombosis are worsening/persistant despite alternative anticoagulation
      • Thrombolysis
      • Thromboembolectomy
    • Course of Treatment HIT without Thrombosis
      • HIT without any thrombosis: continue alternative anticoagulation for at least until platelet count normal
      • Increased risk of thrombosis for 2-4 weeks
      • Coumadin for 1-3 month
      • Studies required
    • Course of Treatment HIT with THROMBOSIS
      • HIT with thrombosis: initiate coumadin once platelet count normal (overlap for 5 days with thrombin inhibitor until INR therapeutic); Continue coumadin for 3-6 months at INR of
      • 2-3.
    • Re-treatment with Heparin in those with prior HIT
      • HIT antibodies (IgG to PF4/heparin) persist 100 days/3 months
      • Use alternative anticoagulation
      • Heparin should still be avoided if possible
      • If heparin is essential (cardio-pulmonary bypass); need to confirm absence of HIT antibodies; and its use should be limited to procedure only
    • As Prophylaxis: UFH vs LMWH
      • In a randomized, double blind clinical trial of 665 patients receiving DVT prophylaxis after hip surgery:
      • 9/332 patients with UHF  HIT
      • None of 333 patients with LMWH
      • 2.7% vs 0%; P value 0.0018
      • Warkentin T, Levine M, Hirsh J, et al. Heparin-Induced Thrombocytopenia in Patients Treated with Low-Molecular-Weight Heparin or Unfractionated Heparin . The New England Journal of Medicine.
    • Other prevention Strategies
      • Limit heparin duration; start Coumadin early in transitioning
      • In someone with history of HIT, heparin should be listed as an allergy
    • Areas of Uncertainty
      • Argatroban vs Lepirudin
      • HIT antibodies are also present in patients that do not have any clinical manifestations. Uncertain why complications occur in some.
      • Arepally G and Ortel T. Heparin-Induced Thrombocytopenia. The New England Journal of Medicine.
    • Arepally G and Ortel T. Heparin-Induced Thrombocytopenia. The New England Journal of Medicine.
    • References I
      • 1) Arepally G and Ortel T. Heparin-Induced Thrombocytopenia. The New England Journal of Medicine. Boston: Aug, 2006. Vol 344 (8); Pgs 809-819.
      • 2) Warkentin T, Maurer B, Aster R, et al. Heparin-Induced Thrombocytopenia associated with Fondaparinux. The New England Journal of Medicine. Boston: June 2007. Vol 356 (25); Pg 2653.
      • 3) Aster RH and Davoren A. Heparin-Induced Thrombocytopenia and Thrombosis. American Journal of Hematology. 2006. Vol 81; Ppgs 36-44.
      • 4) Warkentin T, Levine M, Hirsh J, et al. Heparin-Induced Thrombocytopenia in Patients Treated with Low-Molecular-Weight Heparin or Unfractionated Heparin . The New England Journal of Medicine. Boston: May 1995. Vol 332 (20); Pgs 1330-1336.
      • 5) Muslimani A, Basma R and Daw H. Immune Heparin-Induced Thrombocytopenia Resulting from Preceding Exposure to Heparin Catheter Flushes.  American Journal of Hematology. 2007. Vol 82; Pgs 652-655.
      • 6) Selleng K, Warkentin T and Greinacher A. Heparin-induced thrombocytopenia in intensive care patients . Critical Care Med 2007. Vol 35 (4); Pgs 1165-1176.
      • 7) Cines D, Rauova L, Arepally G, et al. Heparin-Induced Thrombocytopenia: An autoimmune Disorder Regulated Through Dynamic Autoantigen Assembly/Disassembly . Journal of Clinical Apheresis. 2007. Vol 22; Pgs 31-36.
    • References II
      • 8) Lubenow N. Eichler P, Lietz T, et al. Lepirudin for prophylaxis of thrombosis in patients with acute isolated heparin-induced thrombocytopenia: an analysis of 3 prospective studies . Blood 2004; Vol 104: Pgs 3072-7.
      • 9) Lewis BE, Wallis DE, Leya F, et al. Argatroban anticoagulation in patients with heparin-induced thrombocytopenia. Arch Intern Med 2003; Vol 163: Pgs1849-56.
      • 10) Lewis BE, Wallis DE, Berkowitz SD, et al. Argatroban anticoagulant therapy in patients with heparin-induced thrombocytopenia. Circulation 2001; Vol. 103: Pgs 1838-43.
      • 11) Chong BH and Castaldi Pa. Platelet proaggregating effect of heparin: Possible mechanism for non-immune heparin associated thrombocytopenia . Aust N Z J Med 1986; Vol 16; Pgs 715.
      • 12) Martel N, Lee J and Wells PS. Risk for heparin-induced thrombocytopenia with unfractionated heparin and low-molecular-weight heparin thromboprophylaxis: a metanalysis . Blood 2005; Vol (106); Pg 2710.
    • References III
      • 13) Blank M, Shoenfeld Y, Tavor S, et al. Anti-platelet factor 4/heparin antibodies from patients with heparin-induced thrombocytopenia provoke direct activation of microvascular endothelial cells. Int Immunol 2002; Vol 12: Pg 121.
      • 14) Warkentin TE and Kelton JG. A 14-year study of heparin-induced thrombocytopenia . Am J Medicine 1992; Vol (101): Pg 502.
      • 15) Warkentin TE, Elavathil LJ, Hayward CP, et al. The pathogenesis of venous limb gangrene associated with heparin-induced thrombocytopenia . Ann Intern Med 1997; Vol 127: Pg 804.
      • 16) Sheridan D, Carter C, Kelton JG et al. A diagnositic test for heparin-induced thrombocytopenia. Blood 1986; Vol 67: Pg 27.
      • 17) Lo GK, Julh D, Warkentin TE, et al. Evaluation of pretest clinical score (4 T’s) for the diagnosis of heparin-induced thrombocytopenia in two clinical settings . J Thromb Haemost 2006; Vol 4: 759.
      • 18) Alsaleh KA, Al-Nasser SM, Bates SM et al. Delayed-onset HIT caused by low-molecular-weight heparin manifesting during Fondaparinux prophylaxis . Am J Hematol. 2008; Epub ahead of print.
    • Questions?
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