• Bibliometric analysis
• Continuous renal replacement therapy
• Management
• VOSviewer

• Humans
• Bibliometrics
• Continuous Renal Replacement Therapy/methods
• Sepsis/therapy
• COVID-19/therapy
• SARS-CoV-2
• Anticoagulants/therapeutic use
• Renal Replacement Therapy/methods
• Renal Replacement Therapy/trends

• Acute kidney injury
• Continuous renal replacement therapy
• Coronavirus disease 2019
• Cytokine removal

• anticoagulation
• citrate
• continuous renal replacement therapy

• Perioperative medicine
• andexanet alfa
• argatroban
• fibrinogen concentrate
• idarucizumab
• susoctocog alfa
• vonicog alfa.

• Anticoagulation
• Argatroban
• Bleeding complication

• Administration, Oral
• Anticoagulants/adverse effects
• Anticoagulants/therapeutic use
• Arginine/analogs & derivatives
• Cardiovascular Surgical Procedures
• Chondroitin Sulfates/therapeutic use
• Dermatan Sulfate/therapeutic use
• Evidence-Based Medicine
• Fondaparinux/therapeutic use
• Heparin/adverse effects
• Heparin/therapeutic use
• Heparitin Sulfate/therapeutic use
• Hirudins
• Humans
• Peptide Fragments/therapeutic use
• Pipecolic Acids/therapeutic use
• Platelet Count
• Recombinant Proteins/therapeutic use
• Renal Replacement Therapy
• Sulfonamides
• Thrombocytopenia/chemically induced
• Thrombocytopenia/pathology
• Venous Thromboembolism/diagnosis
• Venous Thromboembolism/drug therapy

• R01 HL142122 NHLBI NIH HHS

Argatroban or lepirudin anticoagulation therapy in patients with heparin induced thrombocytopenia (HIT) or HIT suspect is typically monitored using the activated partial thromboplastin time (aPTT). Although aPTT correlates well with plasma levels of argatroban and lepirudin in healthy volunteers, it might not be the method of choice in critically ill patients. However, in-vivo data is lacking for this patient population.

Therefore, we studied in vivo whether ROTEM or global clotting times would provide an alternative for monitoring the anticoagulant intensity effects in critically ill patients.

This study was part of the double-blind randomized trial “Argatroban versus Lepirudin in critically ill patients (ALicia)”, which compared critically ill patients treated with argatroban or lepirudin. Following institutional review board approval and written informed consent, for this sub-study blood of 35 critically ill patients was analysed. Before as well as 12, 24, 48 and 72 h after initiation of argatroban or lepirudin infusion, blood was analysed for aPTT, aPTT ratios, thrombin time (TT), INTEM CT,INTEM CT ratios, EXTEM CT, EXTEM CT ratios and maximum clot firmness (MCF) and correlated with the corresponding plasma concentrations of the direct thrombin inhibitor.

To reach a target aPTT of 1.5 to 2 times baseline, median [IQR] plasma concentrations of 0.35 [0.01–1.2] μg/ml argatroban and 0.17 [0.1–0.32] μg/ml lepirudin were required. For both drugs, there was no significant correlation between aPTT and aPTT ratios and plasma concentrations. INTEM CT, INTEM CT ratios, EXTEM CT, EXTEM CT ratios, TT and TT ratios correlated significantly with plasma concentrations of both drugs. Additionally, agreement between argatroban plasma levels and EXTEM CT and EXTEM CT ratios were superior to agreement between argatroban plasma levels and aPTT in the Bland Altman analysis. MCF remained unchanged during therapy with both drugs.

In critically ill patients, TT and ROTEM parameters may provide better correlation to argatroban and lepirudin plasma concentrations than aPTT.

ClinicalTrials.gov, NCT00798525, registered on 25 Nov 2008

The online version of this article (10.1186/s12871-018-0475-y) contains supplementary material, which is available to authorized users.

• Argatroban
• Heparin-induced thrombocytopenia
• Lepirudin
• Maximum clot firmness
• Monitoring
• Rotational thromboelastometry

• acute kidney injury
• bleeding complication
• continuous renal replacement therapy
• heparin
• regional citrate anticoagulation

• Acute Kidney Injury/therapy
• Anticoagulants/administration & dosage
• Anticoagulants/adverse effects
• Citric Acid/administration & dosage
• Citric Acid/adverse effects
• Critical Illness
• Hemorrhage/chemically induced
• Heparin/administration & dosage
• Heparin/adverse effects
• Humans
• Intensive Care Units
• Renal Replacement Therapy/methods
• Thrombocytopenia/chemically induced

• argatroban
• direct thrombin inhibitor
• extracorporeal circulation
• polymer
• surface coating
• thrombogenicity

The aim of this study was to collect data in France in patients with heparin-induced thrombocytopenia who required parenteral anticoagulation and for whom other non-heparin anticoagulant therapies were contraindicated including patients with renal failure, cross-reactivity to danaparoid or at high hemorrhagic risk.

A total of 20 patients, of mean age 72 ± 10 years, were enrolled in this open-label, multicenter clinical study. Exploratory statistical data analysis was performed with descriptive interpretation of intra-individual comparisons using simple univariate statistics.

The diagnosis of HIT was confirmed in 16 subjects by an independent scientific committee. Fourteen patients (70 %) were in an intensive care unit during the course of the study. Patients were treated with argatroban for a mean duration of 8.5 ± 6.1 days. The mean starting dose of argatroban was 0.77 ± 0.45 μg/kg/min. Platelet recovery was rapid.

aPTT and anti-IIa activity assays were used to monitor the dose of argatroban. The mean baseline aPTT value was 45.0 ± 9.8 sec and increased to 78.2 ± 35.8 sec two hours after initiating argatroban. At this time mean argatroban concentration was 0.34 ± 0.16 and 0.61 ± 0.28 μg/ml using ECT and TT measurements, respectively. New and/or extended thromboses were reported in 25 % of patients and major bleedings were documented in 15 %. Six patients died due to their underlying medical condition.

Considering its hepatic elimination and its short half-life, argatroban can be considered as a safe therapeutic option in HIT patients at high hemorrhagic risk and with renal failure, particularly in an ICU setting.

Administration of low molecular weight heparin (LMWH) is recommended for prophylaxis of venous thromboembolism in patients undergoing hip surgery. In this context, heparin-induced thrombocytopenia (HIT) type II is a complication of rare incidence but sometimes fatal outcome.

A 52-year old obese patient undergoing antithrombotic therapy with Enoxaparin after hip surgery presented with a painful, swollen leg and thrombocytopenia on day eight after surgery. Medical history showed previous administration of Enoxaparin without complications 2 years ago. Further diagnostic investigation supplied evidence of multiple thromboembolic events and concomitant compartment syndrome. Administration of Enoxaparin was stopped immediately and treatment with Argatroban was initiated. Diagnosis of HIT was confirmed according to current guidelines. Despite interventional thrombectomy and fasciotomy, amputation of both lower limbs had to be performed due to ongoing necroses. After a 30-days-stay at the intensive care unit because of sepsis, respiratory and renal failure, clinical condition improved and the patient could be transferred for rehabilitation.

HIT II is known as complication of administration of LMWH in the perioperative setting. Diagnosis results from clinical findings and platelet count. Argatroban is recommended as an alternative therapeutic anticoagulant in HIT II. Inflammation and surgical trauma are discussed as priming factors to increase risk of HIT II.

Administration of LMWH may result in HIT II despite prior uneventful drug exposure. Except for immediate diagnosis, only consequent anticoagulation can stop the course of disease. Hence, interdisciplinary awareness is inevitable for early diagnosis and accurate therapy to prevent from a catastrophic clinical course.

• Argatroban
• HIT II
• Heparin induced thrombocytopenia
• LMWH
• Low molecular heparin

Thrombocytopenia is often noted in critically ill patients. While there are many reasons for thrombocytopenia, the use of heparin and its derivatives is increasingly noted to be associated with thrombocytopenia. Heparin induced thrombocytopenia syndrome (HITS) is a distinct entity that is characterised by the occurrence of thrombocytopenia in conjunction with thrombotic manifestations after exposure to unfractionated heparin or low molecular weight heparin. HITS is an immunologic disorder mediated by antibodies to heparin-platelet factor 4 (PF4) complex. HITS is an uncommon cause of thrombocytopenia. Reported incidence of HITS in patients exposed to heparin varies from 0.2% to up to 5%. HITS is rare in ICU populations, with estimates varying from 0.39%-0.48%. It is a complex problem which may cause diagnostic dilemmas and management conundrum. The diagnosis of HITS centers around detection of antibodies against PF4-heparin complexes. Immunoassays performed by most pathology laboratories detect the presence of antibodies, but do not reveal whether the antibodies are pathological. Platelet activation assays demonstrate the presence of clinically relevant antibodies, but only a minority of laboratories conduct them. Several anticoagulants are used in management of HITS. In this review we discuss the incidence, pathogenesis, diagnosis and management of HITS.

• Heparin
• Thrombocytopenia
• Critically ill
• Diagnosis
• Management

Heparin-induced thrombocytopenia (HIT) causes thromboembolic complications which threaten life and limb. Heparin is administered to virtually every critically ill patient as a protective measure against thromboembolism. Argatroban is a promising alternative anticoagulant agent. However, a safe dose which still provides effective thromboembolic prophylaxis without major bleeding still needs to be identified.

Critically ill patients (n = 42) diagnosed with HIT at a tertiary medical center intensive care unit from 2005 to 2010 were included in this retrospective analysis. Patient records were perused for preexisting history of HIT, heparin dosage before HIT, argatroban dosage, number of transfusions required, thromboembolic complications and length of ICU stay (ICU LOS). Patients were allocated to Simplified Acute Physiology Scores above and below 30 (SAPS >30, SAPS <30), respectively. For calculations, patients (n = 19) without previous history of HIT were compared to patients (n = 23) with a history of HIT before initiation of argatroban.

The mean initial argatroban dosage was below 0.4 mcg/kg/min regardless of SAPS score. Maintenance dosage had to be increased in patients with SAPS <30 to 0.54 ± 0.248 mcg/kg/min (p >0.05) to achieve effective anticoagulation. No thromboembolic complications were encountered. Argatroban had to be discontinued temporarily in 16 patients for a total of 57 times due to diagnostic or surgical procedures, supratherapeutic aPTT and bleeding without increasing the number of transfusions. A history of HIT was associated with a shorter ICU LOS and significantly reduced transfusion need when compared to patients with no history of HIT. Cost calculation favour argatroban due to increased transfusion needs during heparin administration and increase ICU LOS.

Argatroban can be used at doses < 0.4 mcg/kg/min without an increase in transfusion requirements and at a reduced overall treatment cost compared to heparin.

• Argatroban
• Assistance circulatoire
• Cardiac surgery
• Chirurgie cardiaque
• Circulatory assistance
• Heparin-induced thrombocytopenia
• Thrombopénie induite par l’héparine

Heparin-induced thrombocytopenia (HIT) is a rare but potentially severe complication of heparin therapy that is strongly associated with venous and arterial thrombosis (HIT and thrombosis syndrome, HITTS), which requires urgent detection and treatment with a nonheparin anticoagulant. Argatroban, a synthetic direct thrombin inhibitor, is indicated for the treatment and prophylaxis of thrombosis in patients with HIT, including those undergoing percutaneous coronary intervention. Argatroban has a relatively short elimination half-life of approximately 45 minutes, which is predominantly performed via hepatic metabolism. It is derived from L-arginine that selectively and reversibly inhibits thrombin, both clot-bound and free, at the catalytic site. Argatroban anticoagulation has been systematically studied in patients with HIT and HITTS and proved to be a safe and effective agent for this indication. The current review presents the pharmacology of argatroban, data regarding monitoring of the agent, and an overview of the results of the major clinical trials assessing argatroban anticoagulation in HIT patients. Additionally, data from recent clinical trials with argatroban use in more special indications such as in percutaneous coronary intervention, liver dysfunction, renal replacement therapy, and intensive care medicine, are reviewed. The approved initial dosage of argatroban for adults with HIT or HITTS is 2 μg/kg/minute for patients with normal hepatic function and 0.5 μg/kg/minute for patients with hepatic dysfunction. There is evidence that a reduced initial dose may also be advisable for patients with heart failure, multiple organ dysfunction, severe anasarca, or after cardiac surgery. Given this information, argatroban can be effectively used in treating HIT with monitoring of activated partial thromboplastin time.

• HIT
• argatroban
• direct thrombin inhibitor

• Anticoagulants/adverse effects
• Anticoagulants/immunology
• Anticoagulants/therapeutic use
• Autoantibodies/blood
• Autoantibodies/immunology
• Female
• Fibrinolytic Agents/adverse effects
• Fibrinolytic Agents/therapeutic use
• Heparin/adverse effects
• Heparin/immunology
• Heparin/therapeutic use
• Humans
• Male
• Platelet Factor 4/blood
• Platelet Factor 4/immunology
• Practice Guidelines as Topic
• Thrombocytopenia/blood
• Thrombocytopenia/chemically induced
• Thrombocytopenia/drug therapy
• Thrombocytopenia/immunology

• Anticoagulants/adverse effects
• Anticoagulants/therapeutic use
• Blood Coagulation
• Citrates/adverse effects
• Citrates/therapeutic use
• Critical Illness/therapy
• Female
• Humans
• Intensive Care Units
• Male
• Randomized Controlled Trials as Topic
• Renal Replacement Therapy
• Treatment Outcome

Heparin-induced thrombocytopenia (HIT) is a serious, prothrombotic, immune-mediated adverse reaction triggered by heparin therapy. When HIT is diagnosed or suspected, heparins should be discontinued, and an alternative, fast-acting, parenteral, nonheparin anticoagulation such as argatroban should be initiated. Limited and inconsistent data exist about dosing of argatroban in intensive care unit (ICU) patients with critical illnesses.

Retrospective analysis of 12 ICU patients with multiple organ dysfunction syndrome (MODS) treated with argatroban for suspected or diagnosed HIT.

The 12 ICU patients with a mean platelet count of 46,000 ± 30,310 had a mean APACHE II score of 26.7 ± 7.8 on ICU admission and a mean SAPS II score of 61.5 ± 16.3 on the first day of argatroban administration. A mean argatroban starting dose of 0.32 ± 0.25 μg/kg/min (min, 0.04; max, 0.83) was used to achieve activated partial thromboplastin times (aPTTs) >60 sec or aPTTs of 1.5 to 3 times the baseline aPTT. Adjustment to aPTT required dose reduction in six (50%) patients. Patients were treated for a mean of 5.5 ± 3.3 days. The final mean dose in these critically ill patients was 0.24 ± 0.16 μg/kg/min, which is about one eighth of the usually recommended dose and even markedly lower than the previously suggested dose for critically ill ICU patients. In all patients, desired levels of anticoagulation were achieved. The mean argatroban dose was significantly lower in patients with hepatic insufficiency compared with patients without hepatic impairment (0.10 ± 0.06 μg/kg/min versus 0.31 ± 0.14 μg/kg/min; P = 0.026). The mean argatroban dose was significantly correlated with serum bilirubin (r = -0.739; P = 0.006).

ICU Patients with MODS and HIT can be effectively treated with argatroban. A decrease in the initial dosage is mandatory in this patient population. Further studies are needed to investigate argatroban elimination and dosage adjustments for critically ill patients.