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Hemostasis Subendothelial matrix WBC Hemostatic plug Platelets Fibrin Endothelial cell RBC COMPONENTS OF HEMOSTASIS •Vasculature •Coagulation proteins •Platelets Stimulation of Platelets PAR-1 (Thrombin receptor) Thrombin PAR-4 ADP Aggregation Aggregation GpIIb/IIIa GpIIb/IIIa GpIIb/IIIa Adrenaline Platelet Adhesion vWF Endothelium Exposed Collagen 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 Heparin-induced Thrombocytopenia (HIT) Definition: HIT is a serious immunemediated 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 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 (preheparin value) 30%–50% of patients with HIT will have a thrombotic complication within 30 days Warkentin TE Am J Med. 1996;101:502–507 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 Pathophysiology of HIT and Thrombosis Laboratory Testing for HIT Test Advantages Disadvantages SRA Sensitivity >85% Technically demanding, radioisotopes; Low predictive value HIPA Rapid, available Variable sensitivity (30% – 80%); Technique-dependent ELISA High sensitivity High cost, low specificity, 10% false-negative tests There is no Gold Standard in diagnostic testing; HIT requires a clinical diagnosis Frequency of Clinical Sequelae in HIT Sequelae Incidence Thrombosis 30%–50% Amputation 20% (arterial thrombosis) Death 30% Sites of Thrombotic Complications in HIT: Warkentin TE Am J Med 1996;101:502–507 • 30%–50% of untreated patients with thrombocytopenia progress to thrombosis 4:1 Incidence Ratio Venous to Arterial Venous Arterial Deep Vein Thrombosis Pulmonary Embolism Cerebral Dural Sinus Thrombosis Adrenal Hemorrhagic Infarction Aortic/Ileofemoral Thrombosis Acute Thrombotic Stroke Myocardial Infarction Intraventricular Thrombosis Thrombosis in upper limb, mesenteric, renal and spinal arteries HIT Has Occurred with All Types of Heparin Risk Factor Highest Risk Moderate Risk Route/Dose IV use High dose SC use Low dose Type UFH LMWH Source Bovine heparin Porcine heparin Patient type Surgical CABG Orthopedic Medical Clinical Diagnosis of HIT Platelet count drop occurs during or after heparin therapy Platelet count drops to <50% of baseline or 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 If indicated, initiate alternative anticoagulant therapy 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 IV ANTITHROMBINS • Antithrombin • Hirudin: r-lepirudin, Refludan™ • Bivalirudin (Angiomax) • Argatroban • Other agents Levy JH: Novel intravenous antithrombins. Am Heart J 2001;141:1043 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 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 Bivalirudin •20-amino acid peptide with an active sitedirected 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 Arg3-Pro4 bond, resulting in recovery of thrombin active site function. Bivalirudin: 20 amino acid peptide Gly-Pro-Arg-Pro (active site binding region) (Gly)4 C-terminal dodecapeptide (exosite 1-binding region) Specific, reversible binding 2 Thrombin Gly-Pro-Arg-Pro (active-site-binding portion) (Gly)4 C-terminal dodecapeptide (Exosite 1-binding portion) 2 Thrombin 1 1 Bivalirudin Argatroban Indications and Usage Argatroban is a synthetic direct thrombin inhibitor indicated as an anticoagulant for prophylaxis or treatment of thrombosis in patients with heparininduced thrombocytopenia (HIT) 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 clotbound thrombin Argatroban Is Distinct from Indirect Thrombin Inhibitors (UFH, LMWH, and Heparinoids) • Argatroban – Does not interact with or induce heparindependent antibodies – Does not require a cofactor for thrombin inhibitory activity – Active against both free and clot-bound thrombin 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 Pharmacokinetics of Argatroban Infusion in Healthy Volunteers • Short Half-Life –T1/2 = 39 – 51 minutes –Upon discontinuation of therapy, anticoagulant parameters return to baseline within 2 – 4 hours Relationship at Steady-State Between Argatroban Dose, Plasma Argatroban Concentration, and aPTT Mean aPTT (±secs) Plasma Argatroban (µg/mL) 0 0.4 0.8 1.2 1.6 2.0 0 2 4 6 8 10 100 75 50 25 0 Infusion dose (µg/kg/min) 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 Recommended Dosing Guidelines for Argatroban HIT Patients HIT Patients with Renal Impairment Initiate at 0.5 µg/kg/min† Initiate at 2 µg/kg/min No dosage adjustment required Titrate until steady-state aPTT is 1.5–3.0 times baseline value* * HIT Patients with Hepatic Impairment Titrate until steady-state aPTT is 1.5–3.0 times baseline value* 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 Safety Results for Argatroban Argatroban Historical Control† Studies 1 & 2 (n=568) (n=193) Major Hemorrhagic Events* Overall Bleeding Gastrointestinal Genitourinary and hematuria 5.3% 2.3% 0.9% 6.7% 1.6% 0.5% Decrease in Hb/Hct Multisystem hemorrhage and DIC 0.7% 0.5% 0% 1% Limb and BKA Intracranial hemorrhage 0.5% 0% NOTE: Patients may have experienced more than one adverse event 0% 0.5% * 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 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 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 Guidelines for Conversion to Oral Anticoagulant Therapy • All direct thrombin inhibitors, including Argatroban, may increase prothrombin time (PT); this 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) 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 Guidelines for Conversion to Oral Anticoagulant Therapy Initiate warfarin therapy using the expected daily dose of warfarin while maintaining Argatroban infusion.* A loading dose of warfarin should not be used Measure INR daily† If INR is 4.0, continue concomitant therapy If INR is >4.0, stop Argatroban infusion Repeat INR 4-6 hours later If INR is within therapeutic range on warfarin alone, continue warfarin monotherapy * If INR is below the therapeutic range for warfarin alone, resume Argatroban therapy 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. 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 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 Fondaparinux: Targeted mechanism of action Intrinsic pathway 1 2 ATIII Extrinsic pathway 3 ATIII Fondaparinux ATIII Xa Xa II Fibrinogen IIa Fibrin clot Olson ST, et al. J Biol Chem. 1992; 267:12528-12538. 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 Summary • HIT is a relatively common, often underrecognized, 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 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 HeparinInducedThrombocytopenia.com