Rivaroxaban and apixaban for the treatment of suspected or confirmed heparin-induced thrombocytopenia.

WHAT IS KNOWN AND OBJECTIVE: Heparin-induced thrombocytopenia (HIT) is an adverse hematologic drug reaction that results in thrombocytopenia. This potentially life-threatening event is due to the administration of heparin products, such as unfractionated heparin (UFH) and low-molecular-weight heparin (LMWH). The incidence of HIT occurs in <0.1%-7% of hospitalized patients treated with heparin products, with a risk of thrombosis as high as 50%. In 2018, the American Society of Hematology (ASH) recommended the utilization of direct oral anticoagulants (DOACs) in clinically stable patients at average bleeding risk with HIT. The objective of this study was to evaluate the prescribing patterns of rivaroxaban and apixaban for the treatment of suspected or confirmed HIT. METHODS: This was a retrospective chart review from January 2013 through October 2019 at the University of Chicago Medicine. Twelve patients were identified to have received a DOAC for suspected or confirmed HIT. RESULTS: Rivaroxaban was utilized in seven (58%) patients, six of whom received argatroban prior to starting rivaroxaban. Five (71%) of these patients were started on the recommended dose of rivaroxaban for VTE. Apixaban was utilized in five (42%) patients; four patients were started on argatroban and transitioned to apixaban. One patient was started on the suggested dose of apixaban for VTE. WHAT IS NEW AND CONCLUSION: After starting DOACs for suspected HIT, no patients had new thrombosis during hospitalization. Eight patients (67%) followed up at our institution within 6 months of their discharge date. No subsequent thrombi formation were identified for any of these patients. The results of this study add to the expanding literature regarding the safety and efficacy of DOAC use in HIT, and indicate DOACs are being increasingly utilized for the treatment of confirmed or suspected HIT.

Using Nonheparin Anticoagulant to Treat a Near-Fatal Case With Multiple Venous Thrombotic Lesions During ChAdOx1 nCoV-19 Vaccination-Related Vaccine-Induced Immune Thrombotic Thrombocytopenia.

OBJECTIVES: To describe the successful recovery from multiple and life-threatening venous thrombosis after ChAdOx1 nCoV-19 vaccination. DESIGN: Case report. SETTING: University Hospital. PATIENT: Few days after the first dose of the ChAdOx1 nCoV-19 vaccine, a 21-year-old woman experienced massive thrombosis in the deep and superficial cerebral veins together with seizures, neurologic focal deficit, and thrombocytopenia. In the neurointensive care unit, her condition worsened despite early decompressive craniectomy. She developed bilateral segmental pulmonary embolism, left hepatic, and left external iliac venous thrombosis. INTERVENTION: Argatroban (0.5-2.2 µg/kg/min) and high-dose IV immunoglobulin (1 g/kg/d for 2 consecutive days) were initiated on day 6 after admission. With these therapies, there was a gradual resolution of multiple sites of venous thrombosis, and platelet count returned to normal. The patient left the ICU with full consciousness, expressive aphasia, and right hemiparesis. CONCLUSIONS: This case of vaccine-induced immune thrombotic thrombocytopenia shows that a good outcome can be obtained even with multiple and life-threatening venous thrombotic lesions. Argatroban and high-dose IV immunoglobulin along with management of severe cerebral venous thrombosis played a major role in this epilogue.

Argatroban plus aspirin versus aspirin in acute ischemic stroke.

OBJECTIVES: Anticoagulant therapy in the acute phase of AIS remains controversial. The aim of this study was to investigate whether argatroban benefited early stroke outcomes compared with antiplatelet treatment. METHODS: We reviewed data from 1,485 patients with AIS hospitalized at Tianjin Union Medical Center (TUMC) between 1 January 2013 and 31 December 2015 from the TUMC registry database. Patients were divided into two groups: an antiplatelet group (aspirin 300 mg daily) and an argatroban group (argatroban 60 mg for 2 days followed by 20 mg daily; or 20 mg daily - both regimens combination with aspirin 100 mg daily). Two primary outcomes, change in NIHSS score (baseline-discharge) and intracerebral hemorrhage, were investigated. RESULTS: No major symptomatic intracerebral hemorrhages were observed in either group. Both groups had significantly decreased NIHSS scores at discharge (Z = -14.617, P < 0.001 and Z = -6.385, P < 0.001, respectively), and there were no significant group differences in NIHSS score change (Z = -1.888, P = 0.059). In the mild stroke subgroup, the argatroban group had a worse NIHSS score at discharge (Z = -6.148, P = 0.002), while the aspirin group had an improved NIHSS score (Z = -4,423, P < 0.001). In the moderate stroke subgroup, both groups had significantly decreased NIHSS scores at discharge (Z = -13.260, P < 0.001 and Z = -7.108, P < 0.001, respectively) and there were no significant group differences in NIHSS score changes (Z = -1.888, P = 0.059). CONCLUSION: Argatroban is effective and safe for the treatment of moderate AIS with similar efficacy to high-dose aspirin in the acute phase of AIS, although no additional benefit on short-term outcome was observed. For patients with mild AIS, argatroban may be inferior to high-dose aspirin.

In vitro effects of a kaolin-coated hemostatic dressing on anticoagulated blood.

BACKGROUND: The use of kaolin-coated dressings has become common and have efficacy in normal patients, but their increased use will inevitably include use on bleeding patients taking anticoagulants. We hypothesize that kaolin coating material (KCM) will improve clotting regardless of anticoagulation medication. METHODS: A prospective study was performed on blood from patients who were on a vitamin K antagonist (VKA), unfractionated heparin (UH), an antiplatelet (AP) agent, a Xa inhibitor (Xa), or a direct thrombin inhibitor (DTI). None were on more than one type of anticoagulation medication. Viscoelastic testing was performed with and without KCM. All p values were adjusted for multiple comparisons. RESULTS: The addition of KCM significantly decreased the time for initial clot formation (CT) in all groups. The mean CT for controls was decreased from 692 to 190.8 s (p < 0.0001). KCM decreased the initial clot formation time by about 1.5 times in those on DTI (p = 0.043) and 2.5 times in those taking AP medication (p < 0.001). The most profound effect was seen in those on UH (no KCM 1,602 s vs. KCM 440 s; p < 0.001), VKA (no KCM 1,152 s vs. 232 s; p < 0.01), and Xa (no KCM 1,342 s vs. 287 s; p < 0.001). Analysis of other clot formation parameters revealed that KCM significantly improved the clot formation kinetics (CFT) only in patients taking Xa (p = 0.03). KCM improved maximum clot strength in patients on Xa inhibitors (p = 0.05). Patients on UH had a larger effect size with an increase in clot strength from 24.35 mm to 43.35 mm whereas those on Xa had an increase of 38.7 mm to 49.85 mm. CONCLUSION: In this in vitro analysis, the addition of KCM to the blood of patients taking any of these anticoagulation medications significantly improved the time to initial clot formation, indicating that kaolin-based hemostatic dressings will be effective in initiating clot formation in patients on anticoagulants. LEVEL OF EVIDENCE: Therapeutic, level IV.

[Intraluminal Thrombus in Internal Carotid Artery Successfully Treated with Adjuvant Anticoagulant Therapy Followed by Carotid Endarterectomy:A Case Report].

BACKGROUND: An intraluminal thrombus in the carotid artery is relatively rare. A high frequency of perioperative symptomatic stroke has been reported in patients undergoing carotid endarterectomy, and no standard therapy has yet been developed. CASE PRESENTATION: A 69-year-old woman, with no history of trauma, presented with ischemic stroke and mild right hemiparesis. Computed tomography and MRI showed an infarction in the left parietal region. A carotid Doppler study showed carotid stenosis on the left side. Further investigation with digital subtraction angiography confirmed significant carotid artery stenosis with an intraluminal thrombus in the left internal carotid artery. She was treated with initial intravenous anticoagulant therapy followed by carotid endarterectomy with thrombus removal 14 days after admission(subacute phase). There was no postoperative complication and she had uneventful course over 3 years of follow-up. CONCLUSION: Initial adjuvant anticoagulant therapy for symptomatic intraluminal thrombus followed by carotid revascularization is an effective surgical strategy. A meticulous surgical procedure is required to perform a carotid endarterectomy in patients with an intraluminal thrombus.

Efficacy of argatroban in critically ill patients with heparin resistance: a retrospective analysis.

The patients who do not respond even to very high dosages of heparin are assumed to suffer from heparin resistance. The aim of this study was to investigate whether critically ill patients suffering from heparin resistance generally have low antithrombin III (AT) levels, and if the direct thrombin inhibitor argatroban in that case can be an effective option to achieve prophylactic anticoagulation. The study was conducted at the Department for General and Surgical Intensive Care Medicine at the University Hospital Innsbruck. We retrospectively included all patients between 2008 and 2012, who received argatroban because of poor response to high-dosage heparin prophylaxis. The period under observation lasted in total for 9 days, 2 days of anticoagulation with unfractionated heparin (UFH) and 7 days with argatroban. The primary objective was to investigate if after 7 (± 1) hours of switching to argatroban the activated partial thromboplastin time (aPTT) levels were in a prophylactic range of 45 to 55 seconds. Further objectives were to assess the AT level, side effects such as bleeding or thromboembolism, platelet count, correlation between organ function and argatroban dose as well as any need for allogeneic blood products. The study population, consisting of 5 women and 15 men with a mean (± standard deviation, SD) age of 54.6 ± 16.3 years, differed in many clinical aspects. A median (interquartile range) heparin dose of 1,000, 819 to 1,125 IU/h was administered for 2 days and failed in providing a prophylactic anticoagulation measured by the aPTT. The mean aPTT level with heparin treatment was 38.5 seconds (± 4.7) its change within that period was not significant. After switching to argatroban, the mean increase of the aPTT levels in all study patients amounted from 38.5 to 48.3 seconds (p < 0.001). The rise in aPTT clearly reaches sufficient prophylactic anticoagulant levels. The maintenance of prophylactic aPTT levels was achieved over the period of 1 week. There was neither a correlation found between low-AT levels and occurrence of heparin resistance, nor between the simplified acute physiology score II and the administered argatroban dose (r = -0.224, p = 0.342). The results of the present study indicate that argatroban is an effective alternative therapy, especially in critically ill patients, to achieve prophylactic anticoagulation when heparin resistance occurs.

[Anticoagulant efficacy and safety of argatroban for patients undergoing elective percutaneous coronary intervention].

OBJECTIVE: To investigate the anticoagulant efficacy and safety of argatroban for patients undergoing elective percutaneous coronary intervention (PCI). METHODS: A total of 300 consecutive patients with coronary heart disease undergoing elective PCI were enrolled and randomized into heparin group (100 U/kg via artery sheaths, n = 150) and argatroban group (200 µg/kg bolus, followed by 350 µg·kg(-1)·h(-1) i.v. infusion, n = 150). The primary efficacy endpoint was the activated clotting time (ACT) results (10 min and 60 min after anticoagulant administration and at the point at the end of PCI). The additional dosage of heparin or argatroban was given if the ACT value during PCI procedure < 250 s. Activated partial thromboplastin time (APTT) was also measured at pre-procedure, 10 min after anticoagulant injection and 60 min after PCI. The primary safety endpoint was thrombosis and hemorrhagic events during PCI procedure and hospital stay. RESULTS: All patients in the two groups attained the target ACT ( ≥ 250 s), and ACT in heparin group was significantly prolonged [(343.32 ± 44.70) s vs. (289.60 ± 20.88) s, P < 0.01], at 10 min after anticoagulation injection. ACT was similar between the two groups at 60 min after anticoagulation injection [(291.26 ± 46.79) s vs. (288.40 ± 21.61) s, P > 0.05]. The ACT value in argatroban group was similar at 10 min and 60 min after injection (P > 0.05). Supplemental anticoagulant was needed for 13 (8.7%) patients in heparin group and 2 (1.3%) patients in argatroban group because of ACT under 250 s (P < 0.05) . At the end of PCI procedure, ACT in heparin group was significantly shorter than in argatroban group [(247.16 ± 41.38)s vs. (278.65 ± 20.51) s, P < 0.01]. APTT in heparin group was significantly prolonged than in argatroban group not only at 10 min point [(182.16 ± 4.37) s vs. (81.69 ± 21.49) s, P < 0.01] after anticoagulant injection but also at the point of 60 min after PCI procedure[(169.13 ± 6.35)s vs. (56.21 ± 15.68) s, P < 0.01]. There was no thrombus event in two groups and no bleeding event in argatroban group, and there was three bleeding events in heparin group [2.0% (3/150) vs.0, P > 0.05]. CONCLUSION: Argatroban is an effective and safe anticoagulation agent during elective PCI procedure, anticoagulant efficacy and risk of bleeding side effects of argatroban are similar to heparin.

Ancillary approaches to plasminogen activators.

Acute ischemic stroke develops from an interruption in focal cerebral blood flow. In many cases, it is caused by an acute thromboembolism. Although systemic fibrinolytic therapy for acute ischemic stroke has been a significant breakthrough in the management of this disease, additional agents and methods that could improve or restore cerebral flow are necessary. Similarly to findings in acute myocardial infarction, combination pharmacotherapy has the potential to improve current thrombolytic treatment in acute ischemic stroke. In recent years, research efforts were directed toward various combination therapy with pharmacological and nonpharmacological methods. Several trials tested tissue plasminogen activator (t-PA) in combination with antiplateletes and anticoagulants. Combination of t-PA with nonpharmacological agents included sonothrombolysis (amplifying the thrombolytic effect), laser (neuro-recovery), hypothermia (cytoprotection and decreasing brain swelling), and blood flow augmentation (increasing residual flow and recruitment of collateral vessels). This paper will review ongoing clinical trials and safety of these promising combinatory treatments.

Translational success stories: development of direct thrombin inhibitors.

Anticoagulants are the cornerstone of therapy for conditions associated with arterial and venous thrombosis. Direct thrombin inhibitors (DTIs) are anticoagulants that bind to thrombin and block its enzymatic activity. The bivalent parenteral DTIs hirudin and bivalirudin were based on the observation that the salivary extracts of medicinal leeches prevented blood from clotting. Key events that facilitated the subsequent development of small molecule active site inhibitors, such as argatroban, were the observation that fibrinopeptide A had antithrombotic properties and determination of the crystal structure of thrombin. Hirudin and argatroban have found their niche for the treatment of patients with heparin-induced thrombocytopenia, whereas bivalirudin is approved as an alternative to heparin for patients undergoing percutaneous coronary intervention. The development of orally active direct thrombin inhibitors was challenging because of the need to convert water-soluble, poorly absorbable, active site inhibitors into fat-soluble prodrugs that were then transformed back to the active drug after intestinal absorption. Dabigatran etexilate was the first new oral anticoagulant to be approved for long-term anticoagulant treatment in 6 decades. This Review highlights the development of DTIs as a translational success story; an example in which the combination of scientific ingenuity, structure-based design, and rigorous clinical trials has created a new class of anticoagulants that has improved patient care.

High-dose argatroban for treatment of heparin-induced thrombocytopenia with thrombosis: a case report and review of laboratory considerations.

PURPOSE: A case report describing high-dose argatroban for the treatment of heparin-induced thrombocytopenia (HIT) with thrombosis and associated considerations in interpreting laboratory monitoring data are presented. SUMMARY: A 51-year-old woman with an extensive history of coronary artery disease arrived at the emergency department with complaints of chest pain. The patient was admitted, and coronary artery bypass graft surgery was ultimately performed. The patient had a baseline platelet count of 177,000 cells/µL. During hospitalization, the patient received heparin, and her platelet count dropped to 12,000 cells/µL 13 days after the initiation of heparin. The patient developed swelling around a peripherally inserted central catheter and later developed deep vein thrombosis. An argatroban infusion of 2 µg/kg/min was initiated, with a target activated partial thromboplastin time (aPTT) of 40-80 seconds. After 5 days of therapy, the patient had increased swelling in her right arm and an aPTT of 56 seconds. Her goal aPTT was subsequently increased. Six days later, the patient developed a left-lower-extremity DVT despite aPTTs within the goal range. A new aPTT target of >75 seconds was set. The infusion rate was increased to 15.5 µg/kg/min to attain the target aPTT. Results of an in vitro test led to an alternative interpretation of aPTT and International Normalized Ratio values that aided in the monitoring of argatroban during the high-dose infusion. CONCLUSION: A patient with HIT with thrombosis was successfully treated with unusually high dosages of argatroban and may have had serum argatroban concentrations exceeding what has commonly been thought to be the therapeutic range.

Direct thrombin and factor Xa inhibitors in children: a quest for new anticoagulants for children.

Venous thrombosis and pulmonary embolism rarely occur in children but are associated with significant morbidity and mortality. Venous thromboembolism (VTE) mostly affects children with severe underlying conditions and multiple risk factors. Newborns and adolescents are at the highest risk. Standard and low molecular weight heparins and vitamin K antagonists are routinely used for the prevention and treatment of VTE. The new anticoagulants, both parenteral such as argatroban, bivalirudin and fondaparinux and oral such as dabigatran and rivaroxaban, have favourable pharmacological properties, all are approved for clinical use in adults and are currently being investigated in children. Argatroban is the only new anticoagulant licensed for use in children so far. The role of these new anticoagulants as alternative anticoagulants for children remains to be defined. This review focuses on the characteristics of VTE in children and reviews current knowledge on the use of the new thrombin and factor Xa inhibitors in this population.

Standardizing the management of heparin-induced thrombocytopenia.

PURPOSE: An evidence-based heparin- induced thrombocytopenia (HIT) treatment protocol to standardize the management of confirmed or suspected HIT was developed. SUMMARY: In a retrospective review of 10 patients with known or suspected HIT over a two-year period, medical records were evaluated for baseline laboratory results, treatment selection, initial dosing and monitoring, discontinuation of heparin, and alternative therapies chosen. Six of 10 patients had antibody-confirmed HIT at admission. Nine patients received alternative anticoagulation therapy with one of two formulary direct thrombin inhibitor (DTI) agents, lepirudin and argatroban; 1 patient was given fondaparinux. Medical record analyses revealed deficiencies in both initial and transitional dose administration and renal function monitoring, order omissions, infusion-related medication errors, and treatments that were unsubstantiated, inappropriate, or lacking in regulatory approval. The new treatment protocol developed to assist physicians, pharmacists, and nurses with HIT management focused primarily on the two agents labeled for HIT, lepirudin and argatroban. The protocol established baseline levels for the selection of anticoagulation therapy as well as guidance in DTI selection, use, and monitoring. Guidelines for initial dosing and continuous infusion rates based on weight and detailed instructions in all aspects of therapy discontinuation (transition) were included. HIT treatments unsupported by data ensuring the efficacy and safety of therapies were excluded. Careful review of the relevant literature led to the inclusion of alternative anticoagulant treatments based on issues of safety, efficacy, cost, and convenience of dose forms. CONCLUSION: A treatment protocol for HIT was developed and implemented in a tertiary care hospital in an effort to improve the management of patients suffering from this complication.

Heparin-induced thrombocytopenia in a pediatric patient receiving extracorporeal support and treated with argatroban.

INTRODUCTION: Heparin-induced thrombocytopenia (HIT) is rare in the pediatric population, with a majority occurring in the pediatric intensive care unit setting. All reported cases have been associated with the use of unfractionated heparin. Because unfractionated heparin is the anticoagulant of choice for extracorporeal life support, the development of HIT in these patients can be devastating. We report a case of HIT with evidence of small-vessel arterial thromboembolism in a 17-month-old child receiving extracorporeal membrane oxygenation and continuous renal replacement therapy successfully treated with argatroban. CASE: The patient was a 17-month-old boy with severe respiratory failure secondary to asthma and mucus plugging that failed conventional and unconventional ventilation. Venovenous extracorporeal membrane oxygenation was initiated, and within 24 hrs, there was a precipitous decrease in the platelet count, with the development of cutaneous ischemia involving his lower limbs. Heparin-associated antibodies were positive. Argatroban was started, and the child maintained on extracorporeal membrane oxygenation and continuous renal replacement therapy, with resolution of the cutaneous ischemia and rebound of the thrombocytopenia. DISCUSSION: HIT is rare in the pediatric population. Recognition of HIT is vital because withdrawal of heparin is the first and most important therapy. For patients on extracorporeal membrane oxygenation or continuous renal replacement therapy who develop HIT, synthetic thrombin inhibitors (hirulogs) have been reported as an alternative. However, little information on their use in extracorporeal life support has been published, particularly in the pediatric population. CONCLUSION: This report documents a pediatric case of HIT successfully treated with argatroban, allowing continuation of the venovenous extracorporeal membrane oxygenation and continuous renal replacement therapy, with resolution of the thromboembolic ischemia and thrombocytopenia.

Argatroban anticoagulation in patients with acute ischemic stroke (ARGIS-1): a randomized, placebo-controlled safety study.

BACKGROUND AND PURPOSE: Direct thrombin inhibitors, including argatroban, represent an anticoagulant class distinct from heparins. We investigated the safety of 2 levels of argatroban anticoagulation in acute ischemic stroke. METHODS: This multicenter, randomized, double-blinded, placebo-controlled study included 171 patients with acute (< or =12 hours from onset) stroke and National Institutes of Health Stroke Scale (NIHSS) scores of 5 to 22. Patients received continuous intravenous argatroban (100 microg/kg bolus) at 3 microg/kg per minute (n=59) or 1 microg/kg per minute (n=58), respectively, adjusted to target activated partial thromboplastin times (aPTTs) 2.25x and 1.75x baseline or placebo (n=54) for 5 days. The primary outcome was symptomatic intracranial hemorrhage (ICH) at 30 days. RESULTS: Baseline characteristics including neurologic deficits (median NIHSS score 9) were comparable between groups. Argatroban at mean doses of 2.7 and 1.2 microg/kg per minute increased aPTTs significantly (P<0.001), with mean aPTTs at or near target values throughout infusion. Symptomatic ICH was not significantly different between groups (high-dose argatroban, 5.1%; low-dose argatroban, 3.4%; placebo, 0%; P> or =0.18), with 3 events during argatroban infusion and 2 events > or =7 days after stopping infusion. No significant between-group differences occurred in asymptomatic ICH (7 events), major systemic hemorrhage (no event), or 90-day mortality (13.4% overall). CONCLUSIONS: In this first North American randomized, double-blinded, placebo-controlled study of direct thrombin inhibition in acute ischemic stroke, argatroban at each dose evaluated significantly prolonged aPTTs without increasing ICH or major bleeding. These results suggest that argatroban provides safe anticoagulation in acute ischemic stroke, warranting future studies powered to evaluate its efficacy and more precisely estimate event rates.

Successful use of Argatroban as a heparin substitute during cardiopulmonary bypass: heparin-induced thrombocytopenia in a high-risk cardiac surgical patient.

Whereas heparin is the most widely used intravenous anticoagulant in the US for the treatment of thromboembolic disease and is a seminal adjunct to many clinical procedures, its use can cause serious adverse events. Heparin-induced thrombocytopenia (HIT) has emerged as one of the most frequently seen complications of heparin therapy and can be a life-threatening immunohematological challenge for patients requiring cardiopulmonary bypass (CPB) with obligatory heparin exposure. Unfortunately, lack of convenient monitoring techniques and the presence of HIT and other comorbidities in the complex patient frequently limits or precludes the use of most alternatives to heparin anticoagulation during CPB. This case report describes the successful use of the celite activated clotting time and high-dose thrombin time, while using the direct thrombin inhibitor Argatroban as an alternative to heparin anticoagulation during CPB in a high-risk patient presenting with type II HIT, end-stage renal failure, and ischemic cardiomyopathy with ventricular fibrillatory arrest.

Acute pulmonary thromboembolism induced by prophylactic heparin use and a heparin-coated catheter: a case of heparin-induced thrombocytopenia and thrombosis syndrome.

Heparin-induced thrombocytopenia and thrombosis syndrome (HITTS) is a potentially life-threatening side effect of heparin therapy, triggered by an immune response, and has been reported to be related not only to the therapeutic use of heparin but also to heparin-coated catheters. A 45-year-old woman with intrapelvic malignancy developed an acute pulmonary thromboembolism (PE) after hysterectomy despite prophylactic heparin use. Subsequent large doses of heparin for treatment of the PE exacerbated the thrombocytopenia and, moreover, a large thrombus formed around the heparin-coated central venous catheter. Anti-heparin-platelet factor 4 complex antibody and heparin-induced platelet aggregation assay were positive, so the diagnosis was HITTS, and heparin was replaced by argatroban after carrying out thrombectomy. This therapy was successful, and the patient made favorable progress.

The antithrombotic efficacy of AT-1459, a novel, direct thrombin inhibitor, in rat models of venous and arterial thrombosis.

The antithrombotic efficacy of AT-1459, a novel, direct thrombin inhibitor (Ki = 4.9 nM) was evaluated in rat models of venous thrombosis combined with a bleeding time test and arterial thrombosis. After drugs were given by i. v. bolus injection plus a continuous infusion, the ID50, (a dose that exhibits 50% inhibition of thrombus formation over each vehicle group) values of AT-1459, argatroban, and dalteparin were 0.04 mg/kg plus 0.04 mg/kg/h, 0.1 mg/kg plus 0.4 mg/ kg/h, and 13.0 IU/kg plus 26.0 IU/kg/h, respectively, in the venous thrombosis study. The BT2 (a dose that causes 2-fold prolongation of bleeding time over each vehicle group) values of AT-1459, argatroban, and dalteparin were 0.9 mg/kg plus 0.9 mg/kg/h, 1.0 mg/kg plus 0.6 mg/kg/h, and 345.5 IU/kg plus 691.0 IU/kg/h in the rat tail transection model. The ratios of BT2/ID50 of AT-1459, argatroban, and dalteparin were 22.5, 10.0, and 26.6, respectively. In a rat model of arterial thrombosis induced by topical FeCl2 application, intravenous administration of AT-1459, argatroban, and dalteparin improved the vessel patency significantly (P < 0.01) at 0.6 mg/kg plus 0.6 mg/kg/h, 0.6 mg/kg plus 2.4 mg/kg/h, and 300 IU/kg plus 600 IU/kg/h, respectively. The oral antithrombotic effect of AT-1459 lasted for 6 after administering 30 mg/kg and improved the vessel patency significantly 1 h after administering the same dose in venous and arterial thrombosis models, respectively, with a rapid onset of action. Warfarin also inhibited thrombus weight and improved the vessel patency significantly after oral administration of 0.3 mg/kg for three consecutive days in the same study. The antithrombotic and hemorrhagic effects of all drugs studied were correlated with plasma concentration or clotting times. These results suggest that AT-1459 may be clinically useful as an orally available antithrombotic agent for the prevention of venous and arterial thrombosis.

Clinical application of argatroban as an alternative anticoagulant for extracorporeal circulation.

The authors attempted experimental and clinical use of argatroban as an alternative anticoagulant in left heart bypass with the centrifugal pump, percutaneous cardiopulmonary support (PCPS), and extracorporeal membrane oxygenation (ECMO) to determine if it has complementary effects in preventing thrombus formation without aggravating bleeding tendency. Its reversible binding to thrombin and its short half-life contributed to reduce the risk of excessive blood loss without clot formation within the extracorporeal circulation circuit during thoracic aortic surgery using left heart bypass. PCPS and ECMO were safely performed at doses ranging from 0.5 to 10 micrograms/kg/min to maintain activated clotting time at approximately 200 seconds. Although experimental studies showed argatroban to be advantageous in preserving platelet and fibrinogen, further clinical investigations are necessary.