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Subendothelial matrix

Hemostatic plug

Endothelial cell



•Vasculature •Coagulation proteins •Platelets

Stimulation of Platelets

PAR-1 (Thrombin receptor) PAR-4

Aggregation Aggregation





Exposed Collagen

• 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 SRA Advantages Disadvantages 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

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
IV use High dose
UFH Bovine heparin

Moderate Risk
SC use Low dose
LMWH Porcine heparin

Type Source

Patient type

Surgical CABG Orthopedic


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 If indicated, initiate alternative anticoagulant therapy

• 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

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

• 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

• 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

•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)


C-terminal dodecapeptide (exosite 1-binding region)

Specific, reversible binding

Gly-Pro-Arg-Pro (active-site-binding portion)

2 Thrombin



C-terminal dodecapeptide (Exosite 1-binding portion)

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
Plasma Argatroban (µg/mL)
0 0.4 0.8 1.2 1.6 2.0

Mean aPTT (±secs)





0 2 4 6 8 10

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 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 Renal Impairment

HIT Patients with Hepatic Impairment
Initiate at 0.5 µg/kg/min†

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 5.3% 6.7% Gastrointestinal 2.3% 1.6% Genitourinary and hematuria 0.9% 0.5% Decrease in Hb/Hct 0.7% 0% Multisystem hemorrhage and 0.5% 1% DIC NOTE: Patients may have experienced more than one adverse event * Limb and with a hemoglobin decrease 2 g/dL, that led to a transfusion of 2 units, or that was Defined as overt BKA 0.5% 0% intracranial, retroperitoneal, or into a major prosthetic joint. Other overt bleeding was considered minor Typical therapy for patients in the historical Intracranial hemorrhagecontrol group was heparin discontinuation and/or warfarin therapy 0% 0.5%

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 • Coadministration of Argatroban and warfarin does produce a combined effect on the laboratory measurement of the International Normalized Ratio (INR)

consideration when converting to warfarin therapy

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

• 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 Extrinsic pathway








Fibrin clot

Olson ST, et al. J Biol Chem. 1992; 267:12528-12538.

• 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

• 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


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