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HEPARIN INDUCED THROMBOCYTOPENIA: HIT HAPPENS Jerrold H. Levy, MD Professor of Anesthesiology Deputy Chair, Research Emory University School of Medicine.

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Presentation on theme: "HEPARIN INDUCED THROMBOCYTOPENIA: HIT HAPPENS Jerrold H. Levy, MD Professor of Anesthesiology Deputy Chair, Research Emory University School of Medicine."— Presentation transcript:

1 HEPARIN INDUCED THROMBOCYTOPENIA: HIT HAPPENS Jerrold H. Levy, MD Professor of Anesthesiology Deputy Chair, Research Emory University School of Medicine Cardiothoracic Anesthesiology and Critical Care Emory Healthcare Atlanta, Georgia

2 Hemostasis Subendothelial matrix Platelets Hemostatic plug Fibrin Endothelial cell RBC WBC

3 COMPONENTS OF HEMOSTASIS Vasculature Coagulation proteins Platelets

4 Adhesion GpIIb/IIIa Stimulation of Platelets GpIIb/IIIa Aggregation ADP Adrenaline Thrombin Platelet GpIb Exposed Collagen Endothelium vWF PAR-1 (Thrombin receptor) PAR-4 GpIIb/IIIa Aggregation GpIIb/IIIa Aggregation Adhesion Aggregation Adhesion ADP Adrenaline Aprotinin

5 HEPARIN Polyanion: (-) charge From cow lung/pig intestine Mixture of 3K to 30K MWt Binds ATIII/inhibits thrombin Inhibits Xa, esp LMWH Reversible with protamine Causes HIT

6 Heparin-induced Thrombocytopenia (HIT) Definition: HIT is a serious immune- mediated syndrome where heparin administration is associated with: –Thrombocytopenia –The generation of heparin-dependent antibodies (typically IgG) –A high risk for thrombosis causing significant morbidity and mortality

7 30%–50% of patients with HIT will have a thrombotic complication within 30 days Warkentin TE Am J Med. 1996;101:502–507 Heparin-induced Thrombocytopenia Clinical Presentation: Following heparin: –Thrombocytopenia observed 5 – 14 days later; or may occur sooner with previous heparin exposure Platelet count <100,000/µL or Platelet count 50% of baseline (pre- heparin value)

8 HIT: Pathophysiology Presence of IgG antibodies that recognize PF4/heparin complexes on platelet surfaces and vascular walls Binding of IgG to PF4/heparin complexes on platelets Antibody activates platelets via the Fc receptor Activated platelets release microparticles with prothrombotic activity

9 Pathophysiology of HIT and Thrombosis

10 Laboratory Testing for HIT TestAdvantagesDisadvantages SRASensitivity >85%Technically demanding, radioisotopes; Low predictive value HIPARapid, availableVariable sensitivity (30% – 80%); Technique-dependent ELISA High sensitivityHigh cost, low specificity, 10% false-negative tests There is no Gold Standard in diagnostic testing; HIT requires a clinical diagnosis

11 SequelaeIncidence Thrombosis30%–50% Amputation20% (arterial thrombosis) Death30% Frequency of Clinical Sequelae in HIT

12 30%–50% of untreated patients with thrombocytopenia progress to thrombosis 4:1 Incidence Ratio Venous to Arterial Arterial Aortic/Ileofemoral Thrombosis Acute Thrombotic Stroke Myocardial Infarction Intraventricular Thrombosis Thrombosis in upper limb, mesenteric, renal and spinal arteries Venous Deep Vein Thrombosis Pulmonary Embolism Cerebral Dural Sinus Thrombosis Adrenal Hemorrhagic Infarction Sites of Thrombotic Complications in HIT: Warkentin TE Am J Med 1996;101:502–507

13 Risk FactorHighest RiskModerate Risk Route/DoseIV useSC use High doseLow dose TypeUFHLMWH SourceBovine heparinPorcine heparin Patient typeSurgicalMedical CABG Orthopedic HIT Has Occurred with All Types of Heparin

14 Clinical Diagnosis of HIT Platelet count drop occurs during or after heparin therapy Platelet count drops to <50% of baseline Platelet count <100,000/ L No other cause of thrombocytopenia identified Clinical diagnosis of HIT Discontinue all types of heparin Assess the risk of thrombosis or If indicated, initiate alternative anticoagulant therapy

15 THROMBOCYTOPENIA AND HIT: KEY POINTS 50% decrease in platelets is significant Appears day 5-8 of treatment, but earlier suggestes pre-existing heparin antibodies (three months). Consider other causes: sepsis, DIC, autoimmune, and other medications. MOA: PF4/heparin epitope

16 IV ANTITHROMBINS Antithrombin Hirudin: r-lepirudin, Refludan Bivalirudin (Angiomax) Argatroban Other agents Levy JH: Novel intravenous antithrombins. Am Heart J 2001;141:1043

17 RECOMBINANT HIRUDIN (LEPIRUDIN, REFLUDAN) 65 amino acid peptide with potential antigenicity Direct, IRREVERSIBLE thrombin inhibitor, most potent. Rapid onset IV bolus; efficacy in HIT; short half life (PK) but accumulates in renal failure, NOT reversible, and can cause anaphylaxis. Approved in US 1998

18 ARGATROBAN Direct thrombin inhibitor Rapid anticoagulation following IV bolus; efficacy in HIT suggested; short half-life; does not accumulate in renal failure Accumulates in hepatic failure; effect on INR complicates monitoring during overlap with warfarin; no antidote FDA approved 2002

19 Bivalirudin 20-amino acid peptide with an active site- directed peptide, D-Phe-Pro-Arg-Pro, linked via a tetraglycine spacer to a dodecapeptide analogue of the carboxy-terminal of hirudin. Binds directly/reversibly to both the active catalytic site and anion-binding exosite 1 of both circulating and clot-bound thrombin. Thrombin slowly cleaves the bivalirudin - Arg 3 -Pro 4 bond, resulting in recovery of thrombin active site function.

20 Bivalirudin: 20 amino acid peptide Gly-Pro-Arg-Pro (active site binding region) (Gly) 4 C-terminal dodecapeptide (exosite 1-binding region)

21 Specific, reversible binding (Gly) 4 C-terminal dodecapeptide (Exosite 1-binding portion) 2 1 Thrombin 2 1 Bivalirudin Gly-Pro-Arg-Pro (active-site-binding portion)

22 Argatroban Indications and Usage Argatroban is a synthetic direct thrombin inhibitor indicated as an anticoagulant for prophylaxis or treatment of thrombosis in patients with heparin- induced thrombocytopenia (HIT)

23 Mechanism of Action for Argatroban Directly inhibits all procoagulant and prothrombotic actions of thrombin Reversibly binds to the thrombin catalytic site Active against both free and clot- bound thrombin

24 Argatroban Is Distinct from Indirect Thrombin Inhibitors (UFH, LMWH, and Heparinoids) Argatroban –Does not interact with or induce heparin- dependent antibodies –Does not require a cofactor for thrombin inhibitory activity –Active against both free and clot-bound thrombin

25 Pharmacokinetics of Argatroban Infusion in Healthy Volunteers Rapid Onset of Action –Anticoagulant effects are produced immediately upon infusion –Steady-state levels are reached within 1 – 3 hours –Steady-state levels are maintained until dosage is adjusted or infusion is discontinued

26 Pharmacokinetics of Argatroban Infusion in Healthy Volunteers Short Half-Life –T 1/2 = 39 – 51 minutes –Upon discontinuation of therapy, anticoagulant parameters return to baseline within 2 – 4 hours

27 Relationship at Steady-State Between Argatroban Dose, Plasma Argatroban Concentration, and aPTT 0 25 50 75 Mean aPTT (±secs) 100 0486210 Infusion dose (µg/kg/min) Plasma Argatroban (µg/mL)

28 Special Populations In healthy subjects, the pharmacokinetics and pharmacodynamics of Argatroban were NOT affected by renal impairment, age, or gender Dosage adjustment is NOT necessary in renally impaired patients Hepatic impairment decreases Argatroban clearance; therefore, the dosage must be reduced for hepatically impaired patients

29 Recommended Dosing Guidelines for Argatroban HIT Patients HIT Patients with Renal Impairment HIT Patients with Hepatic Impairment * Not to exceed a dose of 10 µg/kg/min or aPTT of 100 seconds Due to approximate 4-fold decrease in Argatroban clearance relative to those with normal hepatic function Initiate at 2 µg/kg/min Titrate until steady-state aPTT is 1.5–3.0 times baseline value* No dosage adjustment required Initiate at 0.5 µg/kg/min Titrate until steady-state aPTT is 1.5–3.0 times baseline value*

30 Safety Results for Argatroban Argatroban Historical Control Studies 1 & 2 (n=568) (n=193) Major Hemorrhagic Events* Overall Bleeding5.3%6.7% Gastrointestinal2.3%1.6% Genitourinary and hematuria0.9%0.5% Decrease in Hb/Hct0.7%0% Multisystem hemorrhage and0.5%1% DIC Limb and BKA0.5%0% Intracranial hemorrhage0%0.5% NOTE: Patients may have experienced more than one adverse event *Defined as overt with a hemoglobin decrease 2 g/dL, that led to a transfusion of 2 units, or that was intracranial, retroperitoneal, or into a major prosthetic joint. Other overt bleeding was considered minor Typical therapy for patients in the historical control group was heparin discontinuation and/or warfarin therapy

31 Safety Results for Argatroban Intracranial bleeding was not observed in ANY of the 568 HIT patients treated with Argatroban –One patient experienced intracranial bleeding 4 days after discontinuation of Argatroban and following therapy with urokinase and oral anticoagulation

32 Re-exposure and Lack of Antibody Formation Plasma from 12 healthy volunteers treated with Argatroban over 6 days showed no evidence of neutralizing antibodies Repeated administration of Argatroban to more than 40 patients was tolerated with no loss of anticoagulant activity No change in the dose was required upon re-exposure for safe/effective anticoagulation

33 Guidelines for Conversion to Oral Anticoagulant Therapy All direct thrombin inhibitors, including Argatroban, may increase prothrombin time (PT); t his must be taken into consideration when converting to warfarin therapy Coadministration of Argatroban and warfarin does produce a combined effect on the laboratory measurement of the International Normalized Ratio (INR)

34 Guidelines for Conversion to Oral Anticoagulant Therapy Concurrent therapy with Argatroban and warfarin does not exert an additive effect on the warfarin mechanism of action (e.g., factor Xa activity) The previously established relationship between INR and bleeding risk is altered during combination therapy –For example, an INR of 4 on cotherapy may not have the same bleeding risk as an INR of 4 on warfarin monotherapy

35 Guidelines for Conversion to Oral Anticoagulant Therapy If INR is below the therapeutic range for warfarin alone, resume Argatroban therapy If INR is >4.0, stop Argatroban infusion Initiate warfarin therapy using the expected daily dose of warfarin while maintaining Argatroban infusion. * A loading dose of warfarin should not be used If INR is within therapeutic range on warfarin alone, continue warfarin monotherapy If INR is 4.0, continue concomitant therapy Repeat INR 4-6 hours later Measure INR daily * For Argatroban infusion at 2 µg/kg/min, the INR on monotherapy may be estimated from the INR on cotherapy. If the dose of Argatroban >2 g/kg/min, temporarily reduce to a dose of 2 g/kg/min 4-6 hours prior to measuring the INR.

36 Additional Benefits of Argatroban Effective anticoagulation, lowering mortality from thrombosis and preventing new thrombosis in patients with HIT An acceptable bleeding risk, comparable with control No dose modification with renal impairment No formation of antibodies to itself Does not interact with or induce heparin-dependent antibodies

37 SYNTHETIC AGENTS Danaparoid (Orgaran): Anti-Xa activity, studied extensively in HIT. For patients with strongly suspected (or confirmed) HIT, whether or not complicated by thrombosis, has Grade 1B recommendation based on ACCP Guidelines ( CHEST 2004; 126:311S–337S). Pentasaccharide (Fondaparinux) a highly selective, indirect inhibitor of activated factor X, is the first of a new class of synthetic antithrombotic agents

38 Olson ST, et al. J Biol Chem. 1992; 267:12528-12538. IIaII FibrinogenFibrin clot Extrinsic pathway Intrinsic pathway 3 ATIII Xa 1 ATIII 2 Fondaparinux Xa Fondaparinux: Targeted mechanism of action

39 THROMBOCYTOPENIA AND HIT: KEY POINTS 50% decrease in platelets is significant Appears day 5-8 of treatment, but earlier suggests pre-existing heparin antibodies (three months). Consider other causes: sepsis, DIC, IABP, autoimmune, other medications. MOA: PF4/heparin epitope

40 Summary HIT is a relatively common, often under- recognized, potentially devastating complication of heparin therapy Diagnosis of HIT is based upon clinical suspicion Treatment of HIT should not rely on laboratory confirmation Untreated patients with HIT are at a high risk of a thromboembolic complication

41 Summary Management of HIT –Discontinue all types of heparin –R/O other potential causes of thrombocytopenia –Assess risk of thrombosis –If indicated, initiate alternative anticoagulant therapy


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