STUDY OBJECTIVES We investigated the effects of the direct thrombin inhibitor argatroban, patient demographics, and the platelet count on thrombotic risks in heparin-induced thrombocytopenia (HIT), a serious thrombotic condition, to determine if argatroban provides effective antithrombotic therapy in patients with HIT without increasing bleeding. DESIGN We retrospectively analyzed thrombotic outcomes in 882 HIT patients (697 patients receiving mean argatroban doses of 1.7 to 2.0 mug/kg/min for 5 to 7 days, plus 185 historical control subjects) from previously reported prospective studies. Time-to-event analyses of our primary end point-a thrombotic composite of death due to thrombosis, amputation secondary to HIT-associated thrombosis, or new thrombosis within 37 days-and the individual components were conducted, with hazard ratios estimated for treatment with and without adjustments for patient age, gender, race, weight, and baseline platelet count. MEASUREMENTS AND RESULTS Argatroban, vs control, significantly reduced the thrombotic composite risk (HIT: hazard ratio, 0.33; 95% confidence interval [CI], 0.20 to 0.54, p < 0.001; HIT with thrombosis: hazard ratio, 0.39; 95% CI, 0.25 to 0.62, p < 0.001), regardless of covariate adjustments. More argatroban-treated patients than control subjects remained thrombotic event free during follow-up, regardless of whether baseline thrombosis was absent (91% vs 73%) or present (72% vs 50%). Argatroban significantly reduced new thrombosis (p < 0.001) and death due to thrombosis (p </= 0.001). Major bleeding was similar between groups (6 to 7%, p = 0.74). Thrombotic risks were 2 times greater in nonwhite than in white patients, 1.7 times greater in female than male patients with HIT and thrombosis, and increased with decreasing weight or platelet count. CONCLUSIONS Argatroban, vs control, provides effective antithrombotic therapy in patients with HIT, without increasing bleeding. Patients at higher risk for HIT-associated thrombosis include women, nonwhites, and individuals with current HIT-associated thrombosis, lower body weight, or more severe thrombocytopenia.

Heparin-induced thrombocytopenia (HIT; sometimes known as HIT type II) is a serious, immune system–mediated complication of heparin therapy often resulting in devastating thromboembolic outcomes. Although nomenclature distinctions have been made historically between this condition and the non–immune system–mediated, asymptomatic transient drop in platelet count in some patients receiving heparin (sometimes known as HIT type I), the term “HIT” is now preferably reserved for the immune system–mediated condition.1 An estimated 1 in 100 patients who receive unfractionated heparin for at least 5 days will develop HIT-associated thrombosis.2 The pervasive use of heparins makes HIT one of the most important adverse drug reactions confronting physicians. Heparin is routinely used for thromboprophylaxis or treatment in many clinical settings, including cardiovascular surgery and interventional procedures, acute coronary syndromes, venous thromboembolism, atrial fibrillation, peripheral occlusive disease, dialysis, and extracorporeal circulation. It is among the most frequently prescribed medications in the United States, with >1 trillion units used3 and 12 million patients treated4 annually.Because thrombocytopenia is common in hospitalized patients, occurring in up to 58% of critically ill patients, and can be caused by a variety of factors,5 HIT unfortunately often remains unrecognized. However, consistent with standard clinical practice for life-threatening conditions, HIT should be suspected in a heparin-treated patient who has thrombocytopenia with or without thrombosis. Increased awareness and a high degree of suspicion for HIT are critical to ensure its prompt recognition, diagnosis, and treatment. Advances in understanding the pathophysiology of HIT and its natural history have led to current treatment recommendations—specifically, that heparin must be discontinued immediately and alternative anticoagulation must be initiated.6 Herein we review the pathogenesis, frequency, natural history, diagnosis, and treatment of HIT.Unfractionated heparin is a heterogeneous group of negatively charged, sulfated glycosaminoglycans (molecular weight 3000 to 30 000 Da) from animal …

PURPOSE:The physical and chemical compatibility of argatroban with abciximab, eptifibatide, or tirofiban during simulated Y-site administration was studied.METHODS:Test solutions of argatroban 1 mg/mL, abciximab 36 microg/mL, eptifibatide 2 mg/mL, and tirofiban 50 microg (as the hydrochloride salt) per milliliter in 5% dextrose injection (D5W) and in 0.9% sodium chloride injection (saline) were prepared in duplicate by using aseptic technique. Argatroban solution was mixed with abciximab, eptifibatide, or tirofiban solution, each at a ratio of 1:1 by volume, and at 4:1 with abciximab solution, 8:1 with tirofiban solution, and 16:1 with eptifibatide solution. Compatibility was evaluated immediately after solution preparation and after storage for four hours at 20-25 degrees C. Physical compatibility was determined with the unaided eye and with a particle counter, and chemical compatibility was measured with high-performance liquid chromatography. The chemical compatibility of argatroban and abciximab was not tested because of the poor stability or recovery of abciximab in the test diluents.RESULTS:Argatroban was physically compatible with abciximab, eptifibatide, and tirofiban in D5W at each ratio tested and in saline at a 1:1 ratio. Argatroban was chemically compatible with eptifibatide and tirofiban. No significant impurities were detected, except for a single impurity in argatroban-eptifibatide 1:1 admixtures.CONCLUSION:At concentrations commonly used in practice, argatroban was physically compatible with abciximab and physically and chemically compatible with eptifibatide and tirofiban for four hours at 20-25 degrees C.

Heparin therapy for any indication, including venous thromboembolism (VTE), can be complicated by heparin-induced thrombocytopenia (HIT). The purpose of this retrospective study was to characterize the clinical experience of patients in whom HIT complicated heparin therapy for VTE and who were switched to argatroban therapy. From the previously reported prospective, multicenter, historical-controlled Argatroban-911 and Argatroban-915 studies of argatroban therapy in HIT, we identified all patients who developed HIT while on heparin therapy for pulmonary embolism and/or deep venous thrombosis and in whom heparin was discontinued and argatroban therapy initiated. The primary study end point was a composite of death, amputation, or new thrombosis within 37 days of argatroban initiation; we also evaluated a 37-day composite end point of thrombosis-associated events, including death due to thrombosis, amputation secondary to HIT, or new thrombosis. A total of 145 patients with VTE and HIT were included in our analysis. During heparin therapy before HIT was diagnosed, platelet counts decreased from daily mean values greater than 175x109/L to a mean±SD nadir of 78±67x109/L over the course of 5 days, and new thrombosis developed in 75 (52%) patients. After heparin was discontinued, patients received argatroban (mean dose 2.1±1.2 mcg/kg/min) for 6.8±4.3 days achieving mean activated partial thromboplastin times during therapy of 63±12 s. By day 6 of argatroban therapy, the mean platelet count had risen to >150x109/L. The primary end point occurred in 41 (28.3%) patients, and the thrombotic composite in 23 (15.9%) patients (Table 1). Seventeen (11.7%) patients, including 12 who had also experienced thrombosis while on heparin, developed new thrombosis after argatroban initiation, typically on the day argatroban was discontinued or later (n=10). Death due to thrombosis occurred in only 1 (0.7%) patient. Seven (4.8%) patients experienced major bleeding. We conclude that in heparin-treated patients with VTE, HIT-associated thrombosis often occurs before HIT is recognized, emphasizing the importance of platelet count monitoring and a high degree of suspicion for HIT in this setting. For VTE patients with HIT, argatroban provides effective anticoagulation, with outcomes comparable with those reported for argatroban-treated patients in whom HIT developed following heparin therapy for any indication. New thrombosis occurring after switching to argatroban therapy more typically occurs in patients with existing HIT-associated thrombosis and at/after argatroban discontinuation.

BACKGROUND:Patients receiving heparin for thromboprophylaxis or treatment may have new or recurrent venous thromboembolism (VTE) if immune-mediated heparin-induced thrombocytopenia (HIT) occurs or for other reasons, eg, if anticoagulation fails. We estimated from the literature how frequently a patient presenting with VTE during or following heparin therapy has HIT-associated VTE.METHODS:A comprehensive, systematic literature search was conducted to identify studies using unfractionated or low-molecular-weight heparin (LMWH) for thromboprophylaxis or treatment in which new or recurrent VTE and serologically confirmed HIT were reported. From extracted study data, the proportion of patients with HIT-associated VTE relative to any VTE was calculated by heparin type and mode of administration.RESULTS:We identified 10 studies, some with multiple arms, that used unfractionated heparin (IV administration, 5 studies; subcutaneous administration, 3 studies) or subcutaneous LMWH (5 studies) and met analysis criteria. Across these studies, 386 of 6,219 heparin-treated patients had VTE, including 32 patients who also had HIT. The frequency of HIT-associated VTE among heparin-treated patients with VTE was comparable between IV and subcutaneous unfractionated heparin therapy (13.2% [17 of 129 patients] vs 12.4% [14 of 113 patients]; odds ratio, 1.07; 95% confidence interval, 0.50 to 2.3; p > 0.99) yet significantly different between unfractionated heparin and LMWH therapy (12.8% [31 of 242 patients] vs 0.7% [1 of 144 patients]; odds ratio, 21.0; 95% confidence interval, 2.8 to 156; p < 0.001).CONCLUSIONS:VTE is associated with HIT infrequently (< 1%) in LMWH-treated patients, yet often (approximately one in eight cases) in unfractionated heparin-treated patients. Physicians should suspect the possibility of HIT if VTE develops during or soon after unfractionated heparin use; if thrombocytopenia is present, alternative anticoagulation should be used until HIT is excluded.

We describe 3 patients who presented to the emergency department (ED) with stroke, deep venous thrombosis, or pulmonary embolism and renal failure after undergoing cardiac surgery 7 to 17 days earlier. Their onset of thrombosis after previous heparin exposure was temporally plausible for complications of heparin-induced thrombocytopenia, an immune-mediated thrombotic disorder triggered by heparin. The patients had normal platelet counts at presentation, yet each had circulating heparin-induced thrombocytopenia antibodies that were ultimately confirmed. Two patients had heparin reexposure in the ED, 1 of whom developed thrombocytopenia with new thrombosis and died. Alternative parenteral anticoagulation prevented further thrombosis in 2 patients. Because heparin use can be catastrophic in patients with heparin-induced thrombocytopenia, physicians should be vigilant in suspecting heparin-induced thrombocytopenia in patients with thrombosis after recent hospitalization or heparin exposure. Alternative anticoagulants are available for these at-risk patients.

INTRODUCTION:Heparin therapy is not recommended for patients with a history of heparin-induced thrombocytopenia (HIT), except in specialized situations, because this treatment can lead to severe reactions including thrombocytopenia and thrombosis. However, the optimal management of patients with a history of HIT requiring acute anticoagulation has not yet been clarified because of the lack of prospective studies. We evaluated the safety and efficacy of argatroban, a direct thrombin inhibitor, as an anticoagulant in patients with a history of HIT needing acute anticoagulation. METHODS:Thirty-six patients with a history of serologically confirmed HIT were treated prospectively with argatroban [median (5th-95th percentile) dose of 2.0 (1.0-4.3) microg/kg/min for 4.0 (0.7-8.4) days]. Prospectively defined endpoints included successful anticoagulation (therapeutic activated partial thromboplastin time), and bleeding, new thromboembolic events, or other adverse effects during therapy or within 30 days following its cessation. RESULTS:All patients required acute anticoagulation with the most common admission diagnoses being deep venous thrombosis or pulmonary embolism (n=13) and chest pain or acute coronary syndrome (n=12). Eleven patients had previously received argatroban therapy for HIT; one patient underwent two treatment courses of argatroban for a history of HIT. The median (5th-95th percentile) time between the past diagnosis of HIT and initiation of argatroban was 7.5 (0.4-114.6) months. All evaluable patients were successfully anticoagulated. No patient had major bleeding, new thromboembolic events, or other adverse effects. There were no adverse events related to reexposure. CONCLUSIONS:Argatroban can provide safe and effective anticoagulation, on initial or repeat exposure, in patients with a history of HIT.

BACKGROUNDHeparin-induced thrombocytopenia (HIT) is an intensely prothrombotic syndrome managed by discontinuation of heparin therapy and substitution of an alternative inhibitor of thrombin. We describe our experience with argatroban, a direct thrombin inhibitor, in patients with HIT or HIT with thrombosis (HITTS).METHODSIn this multicenter, nonrandomized prospective study, 418 patients with HIT were administered intravenous argatroban, 2 micro g/kg per minute, adjusted to maintain the activated partial thromboplastin time at 1.5 to 3 times the baseline value for a mean of 5 to 7 days. Comparisons were made with a historical control cohort (n = 185). The prospectively defined, primary efficacy end point was a composite of all-cause death, all-cause amputation, or new thrombosis in 37 days. Other end points included the components of the composite, death due to thrombosis, increased platelet count, and bleeding.RESULTSIn the HIT arm, the composite end point was significantly reduced in argatroban-treated patients vs controls (28.0% vs 38.8%; P =.04). In the HITTS arm, the composite end point occurred in 41.5% of argatroban-treated patients vs 56.5% of controls (P =.07). By time-to-event analysis of the composite end point, argatroban therapy was significantly better than historical control therapy in HIT (P =.02) and HITTS (P =.008). Argatroban therapy also significantly reduced new thrombosis in HIT and HITTS and death due to thrombosis in HITTS. There were no significant between-group differences in all-cause death or amputation. Platelet counts recovered more rapidly in argatroban-treated patients than in controls. Bleeding rates were similar between groups.CONCLUSIONArgatroban therapy, compared with historical control, improves outcomes, particularly new thrombosis and death due to thrombosis, in patients with heparin-induced thrombocytopenia.

Heparin-induced thrombocytopenia (HIT) is an immune-mediated syndrome that can lead to limb- and life-threatening thrombosis. Argatroban, a small synthetic molecule (Argatroban; GlaxoSmithKline, Philadelphia, PA), and lepirudin, a protein of non-human origin (Refludan; Aventis, Bridgewater, NJ), are direct thrombin inhibitors that have been used successfully for anticoagulant therapy in HIT patients. It has been reported that between 44-74% of lepirudin-treated HIT patients develop drug-specific antibodies that either enhance or suppress the anticoagulant activity of lepirudin. By contrast, there have been no reported patient experiences suggestive of unexpected loss or enhancement of argatroban's anticoagulant effect in clinical trials, including those in HIT patients, or in postmarketing safety surveillance of over 4,800 patients treated in Japan. To confirm the lack of antibodies in argatroban-treated patients with HIT, we examined plasma for anticoagulant-altering activity and reviewed dosing patterns of re-exposed patients. Paired, pre-therapy and post-therapy (> or =7 days) plasma pools exhibited comparable in vitro anticoagulant responses (aPTT and antithrombin activity) to argatroban supplementation. Argatroban at 5 microg/mL similarly prolonged aPTTs of normal plasma pretreated with IgG isolated from pre-therapy versus post-therapy plasma (P>0.6). In trials, mean argatroban doses during initial therapy versus re-exposure were not different among individuals anticoagulated for the treatment or prophylaxis of thrombosis (P=0.60) or during percutaneous coronary interventions (P=0.79), with no discernable pattern of suppression or enhancement of argatroban anticoagulation. Consistent with the lack of reported patient experiences suggestive of unexpected loss or enhancement of argatroban's anticoagulant effect across clinical trials and post-marketing safety surveillance, these data support the lack of anti-argatroban antibodies that affect drug activity in argatroban-treated HIT patients.

The potential for pharmacokinetic interactions between argatroban and warfarin was studied. In a randomized, crossover study, healthy volunteers participated in three treatment periods, each separated by a nine-day washout interval. Drug regimens consisted of a single oral 7.5-mg dose of warfarin, intravenous argatroban infused at a rate of 1.25 micrograms/kg/min for 100 hours, or both. Blood samples were collected at intervals up to 104 hours to determine clearance (CL) and the apparent first-order elimination rate constant (kel) for argatroban and the area under the concentration-versus-time curve (AUC) and maximum concentration (Cmax) for R- and S-warfarin. An interaction was defined as a > 25% difference in the magnitude of the pharmacokinetic values between administration of one drug alone and coadministration with the other agent. Twelve adult subjects were enrolled. The mean CL and lel for argatroban administered alone differed by < 7% from the mean values when the two drugs were coadministered. When warfarin was administered alone, the mean Cmax and AUC of R- and S-warfarin differed from the mean values when the two drugs were coadministered by < 10%. Prothrombin time was prolonged comparably when argatroban was administered alone and with warfarin. No deaths or serious adverse events were reported. No significant pharmacokinetic interactions were detected between i.v. argatroban 1.25 micrograms/kg/min and a single 7.5-mg oral dose of warfarin. Argatroban was well tolerated when administered alone or with warfarin.

Study Objective. To evaluate and compare the relationship between dosage and coagulation parameters, as well as safety profiles, of ascending bolus and infusion dosages of argatroban versus heparin in three phase I studies.Design. Two randomized, double‐blind studies compared argatroban and heparin, and one open‐label, dose‐escalation study further evaluated argatroban.Setting. University teaching hospital clinical research unit.Patients. Healthy men (aged 22–62 yrs).Intervention. In the first study, 36 subjects received an argatroban 30‐, 60‐, 120‐, or 240‐μg/kg bolus, or a heparin 30‐, 60‐, 120‐, or 240‐U/kg bolus for three subjects, then amended to 15, 30, 60, or 120 U/kg. In the second study, 37 subjects received argatroban 1.25, 2.5, 5, or 10 μg/kg/minute with or without a 250‐μg/kg bolus, or heparin 0.15, 0.20, 0.25, or 0.30 U/kg/minute with or without a 125‐U/kg bolus. In the third study (open‐label), nine subjects received an argatroban 250‐μg/kg bolus plus an infusion of 15, 20, 30, and 40 μg/kg/minute.Measurements and Main Results. When administered as a bolus dose in the first study, argatroban and heparin both produced dose‐related increases in activated clotting time (ACT) and activated partial thromboplastin time (aPTT) within 10 minutes of administration. Dissipation of anticoagulant effect was approximately 4‐fold faster for argatroban than for heparin. When administered by infusion with or without a bolus in the second study, argatroban, but not heparin, produced predictable dose‐related increases in ACT and aPTT that were generally consistent across both effect measures and modes of administration. Effect steady state was attained by five or more subjects per dosing group receiving argatroban (5–9) but typically two or fewer subjects per group receiving heparin (0–7). Furthermore, upon cessation of infusion, anticoagulant effects dissipated faster for argatroban (effect half‐life 18–41 min) than for heparin (effect half‐life 23–134 min). When argatroban was infused without a bolus, peak and effect steady‐state values for ACT and aPTT generally were attained within 1–3 hours. Data from the second and third studies show that for argatroban dosages up to 40 μg/kg/minute, plasma drug concentrations attained at 4 hours of infusion increased linearly with dose, and weight‐adjusted plasma clearance was dose independent. In all studies, argatroban and heparin were well tolerated.Conclusion. Anticoagulation was more predictable with argatroban than with heparin as measured by ACT and aPTT, with comparable safety profiles.

Study Objective. To determine the pharmacokinetics and pharmacodynamics of argatroban in healthy volunteers and patients with hepatic or renal dysfunction.Design. Prospective, open‐label study (studies 1 and 3); prospective, open‐label, parallel‐group study (study 2).Settings. Two research centers and an inpatient clinic.Subjects. Study 1, healthy volunteers; study 2, healthy volunteers and volunteers with hepatic disease; study 3, volunteers with normal to severely impaired renal function assigned to one of four groups based on creatinine clearance.Intervention. Study 1, argatroban 125‐μg/kg bolus followed by 4‐hour continuous infusion of 2.5 μg/kg/minute; study 2, 4‐hour infusion of 2.5 μg/kg/minute (1.25 μg/kg/minute in one patient with hepatic impairment); study 3, 5‐μg/kg/minute continuous infusion over 4 hours.Measurements and Main Results. Blood samples were obtained to assess plasma argatroban concentration, plasma activated partial thromboplastin time (aPTT), and whole blood activated clotting time (ACT). Study 1: the pharmacokinetic profile was well described by a two‐compartment model with first‐order elimination; effect response and plasma argatroban concentrations were well correlated. Mean ± SD clearance, steady‐state volume of distribution, and half‐life values (40 healthy volunteers) were 4.7 ± 1.1 ml/minute/kg, 179.5 ± 33.0 ml/kg, and 46.2 ± 10.2 minutes, respectively. The only effect of age or gender was the approximately 20% lower clearance in elderly men versus elderly women, which did not translate to clinically or statistically significant differences in pharmacodynamic response. Study 2: in patients with hepatic impairment, area under the concentration versus time curve (AUC) from time zero (t0) to last measurable concentration, AUC from t0 to infinity, maximum concentration, and half‐life of argatroban were increased approximately 2‐to 3‐fold; clearance was one‐fourth that of healthy volunteers. For aPTT and ACT, AUC over time for mean effect and mean maximum effect was higher in these volunteers. Study 3: no significant differences were detected. All four groups had predictable response profiles over time.Conclusion. Argatroban should be easy to monitor and control, with little potential for underdosing or overdosing, regardless of age, gender, or renal function. Dosing precautions are recommended, however, in patients with hepatic dysfunction.

Oral anticoagulants such as warfarin induce depletion of vitamin K-dependent coagulation factors, causing prolongation of the prothrombin time (PT) and the PT-International Normalized Ratio (INR). The available thromboplastins used for measuring the PT vary in their sensitivity to coagulation factor depletion, and each is assigned an International Sensitivity Index (ISI) that is used when calculating the INR. Traditional monitoring of oral anticoagulant therapy using the INR is confounded during concurrent therapy with direct thrombin inhibitors, such as argatroban, that also prolong the INR (1)(2)(3). Although alternative monitoring methods have been suggested for use in this setting (2)(3), guidelines allowing for refined interpretation of the INR would also be useful. To facilitate the development of such guidelines, we have characterized in vitro the differential effects of warfarin and argatroban, as well as the choice of thromboplastin used, on the INR during anticoagulation with both agents. For this study, plasma specimens were obtained from 10 healthy donors (laboratory personnel) and 35 patients on warfarin therapy, in accordance with policies of the institution’s responsible committee. Blood was collected into evacuated tubes (38 g/L sodium citrate), and plasma was prepared by the centrifugation of the blood within 30 min of collection. The only selection criterion for the patient group was that each was on warfarin therapy, and both inpatients and outpatients were included. In addition, four plasma pools (each prepared from at least 10 individuals) were obtained from Harris Laboratories. One plasma pool was from healthy donors, and three pools were from patients on warfarin therapy exhibiting generally similar levels of oral anticoagulation. Plasma specimens were stored at −30 °C for up to 2 weeks and thawed rapidly immediately before testing. The PT of each individual or pooled plasma specimen was determined in the absence and presence of …

The purpose of this study was to establish the effects of clot age and thrombolysis, with either streptokinase or tissue-type plasminogen activator (tPA), on argatroban’s ability to inhibit thrombin. The antithrombotic activity of argatroban has been quantified in fibrin clot permeation and fibrin clot perfusion systems as a function of clot age and composition. Analysis of the argatroban dose-response data with a competitive inhibition model has yielded IC50 values in the low micromolar range. Results obtained in a plasma clot permeation system have also shown that argatroban is a potent inhibitor of clot-bound thrombin, independent of either clot age or the presence of hemostatically active platelets. Treatment of aged plasma clots with either streptokinase or alteplase, at therapeutic levels, increased the available thrombin activity, yet argatroban still inhibited this clot-associated thrombin with IC50 values in the low micromolar range. Scanning electron microscopy/morphometric analyses demonstrated that permeation with argatroban had no significant effects on clot structure. We conclude that argatroban is an effective inhibitor of thrombin bound to aged fibrin clots, in purified systems and in plasma clots, as well as in clots that have been treated with the thrombolytic agents streptokinase and alteplase. © 1998 by The American Society of Hematology.

Because of the unsatisfactory options available for safe and effective antithrombotic therapy, recent, intense research and development efforts have been focused on direct thrombin inhibitors, also known as site-directed thrombin inhibitors. The intravenous agent Novastan (argatroban) is a small-molecule, reversible, direct thrombin inhibitor that is selective for the catalytic site of the thrombin molecule. Argatroban's molecular properties (small molecule; fast, selective, and reversible inhibition of the thrombin catalytic site; and similar in vitro potency for inhibiting both clot-bound and soluble thrombin) offer the potential for significant antithrombotic efficacy with minimal systemic anticoagulant ef fects. Its clinical pharmacologic properties offer the potential for minimal risk of bleeding, very rapid achievement of therapeutic antithrombotic efficacy, predictable dose-response, and rapid restoration of the hemostatic systems to normal upon termination of intravenous infusion. Argatroban is currently approved for clinical use in Japan for the treatment of peripheral arterial occlusive disease. It is in advanced clinical development in North America, South America, and Western Europe for several clinical indications, including (1) adjunctive therapy to thrombolytic agents in the treatment of acute myocardial infarction and (2) antithrombotic therapy for patients with heparin-induced thrombocytopenia and heparin-induced thrombocytopenia and thrombosis syndrome. Key Words: Molecular properties—Novastan (argatroban)—Pharmacology—Thrombin inhibitor.