Use of lepirudin in patients with heparin-induced thrombocytopenia and renal failure requiring hemodialysis

OBJECTIVE: To report two cases of successful lepirudin use in two patients with heparin-induced thrombocytopenia (HIT) and renal failure. CASE SUMMARY: Two patients with renal failure requiring hemodialysis developed HIT syndrome during intravenous heparin therapy. Anticoagulation was necessary to prevent recurrent, acute venous thrombosis in one patient and to prevent arterial thrombosis associated with the use of an intraaortic balloon pump in the second. Intravenous lepirudin was initiated at doses of 0.01 mg/kg/h and 0.005 mg/kg/h, respectively, and titrated based on the activated partial thromboplastin time (aPTT). Steady-state doses were 0.015 mg/kg/h to maintain aPTT values of approximately 60 seconds in one patient, and 0.005-0.008 mg/kg/h to achieve an aPTT of approximately 45 seconds in the other patient. DISCUSSION: Lepirudin is one of few anticoagulants that can be safely used in patients with HIT. Because it is eliminated through the kidneys, great care must be taken when administering lepirudin to patients with renal failure; in fact, its use is currently not recommended in patients requiring hemodialysis. Lepirudin effectively prevented acute thrombosis in both of our patients with documented HIT, with no bleeding complications. We describe how we selected the initial doses and report results of aPTT monitoring. CONCLUSIONS: In patients with renal failure who develop HIT, lepirudin is one available alternative to heparin despite its poor renal elimination pattern and subsequently prolonged half-life.     

Lepirudin in heparin-induced thrombocytopenia and extracorporeal membranous oxygenation

OBJECTIVE: To report a case of intermediate-probability suspected heparin-induced thrombocytopenia (HIT) treated with lepirudin in a patient requiring continuous extracorporeal membranous oxygenation (ECMO). CASE SUMMARY: A 17-year-old girl was admitted with multiple traumatic injuries including severe bilateral pulmonary contusions. Within 48 hours, she developed progressive pulmonary failure despite mechanical ventilation, and was placed on ECMO. Anticoagulation of the ECMO circuit was facilitated by unfractionated heparin (UFH). The platelet count of 116 x 10(3)/mm(3) after initiation of ECMO gradually decreased over 5 days to 44 x 10(3)/mm(3). On ECMO day 5, a highly positive enzyme-linked immunosorbent assay for HIT antibodies was reported, and the UFH infusion was discontinued. Lepirudin was immediately started with a bolus of 0.1 mg/kg, followed by an infusion of 0.12 mg/kg/h, with a target activated partial thromboplastin time (aPTT) ratio approximately 2 times control. The ECMO circuit was maintained without any unexpected bleeding complications or thrombosis for 6 additional days until the patient died secondary to pulmonary failure after ECMO was removed. DISCUSSION: Use of ECMO typically requires continuous infusion of UFH to keep the circuit from clotting. In patients with HIT, alternative anticoagulation using a direct thrombin inhibitor may be warranted. Lepirudin was effectively used to maintain the circuit despite continued presence of heparin molecules impregnated into the ECMO circuit tubing. The aPTT was successfully used to monitor and adjust the lepirudin infusion. CONCLUSIONS: In patients requiring ECMO in the presence of HIT, anticoagulation of the ECMO circuit may be accomplished using a continuous infusion of a direct thrombin inhibitor such as lepirudin.     

Direct thrombin inhibition during percutaneous coronary intervention in patients with heparin-induced thrombocytopenia

Patients with or at risk of heparin-induced thrombocytopenia (HIT) who are undergoing percutaneous coronary intervention (PCI) are at particular risk of thrombosis due to the prothrombotic nature of HIT and the endovascular disruption from PCI. Patients require aggressive anticoagulation during PCI, and alternative, nonheparin anticoagulation is recommended over heparin in patients with acute or previous HIT. Argatroban, bivalirudin, and lepirudin are nonheparin, fast-acting, parenteral direct thrombin inhibitors (DTIs). Multicenter, prospective studies have demonstrated that argatroban and lepirudin each reduce thrombosis in HIT and that argatroban and bivalirudin each provide adequate anticoagulation during PCI in patients with or at risk of HIT. We review current therapeutic practices with direct thrombin inhibitors in patients with or at risk of HIT during PCI, including individuals requiring periprocedural anticoagulation, and the factors influencing the choice of DTI in this setting.     

Enoxaparin vs. unfractionated heparin for anticoagulation during continuous veno-venous hemofiltration: a randomized controlled crossover study

OBJECTIVE: The purpose of this study was to evaluate the efficacy and safety of the low molecular weight heparin enoxaparin as anticoagulant in continuous veno-venous hemofiltration (CVVH) compared with unfractionated heparin. DESIGN: Prospective randomized controlled crossover study. SETTING: Medical and Surgical Intensive Care Unit of a University Hospital. PATIENTS: Forty consecutive adult medical and surgical ICU patients with normal anticoagulation parameters requiring CVVH. INTERVENTION: CVVH was performed with pre-filter fluid replacement at 2500 ml/h and blood flow rates of 180 ml/min. Heparin-treated patients received an initial pre-filter bolus of 30 IU/kg and a maintenance infusion at 7 units/kg h(-1), titrated to achieve a systemic activated partial thromboplastin time (aPTT) of 40-45 s. Enoxaparin-treated patients received an initial pre-filter bolus of 0.15 mg/kg and a maintenance infusion starting at 0.05 mg/kg h(-1), which was subsequently adjusted to maintain systemic anti-factor Xa activity (anti-Xa) at 0.25-0.30 IU/ml. Each patient received both regimens in a crossover design. Maximum treatment duration for each set was 72 h. RESULTS: Patients included had a mean APACHE II score of 22 (10-35). Thirty-seven patients completed both study arms. Mean filter life span was 21.7 h (+/- 16.9 h) for heparin and 30.6 h (+/- 25.3) for enoxaparin (p = 0.017, ANOVA for repeated measures). One major bleeding episode occurred during heparin as well as during enoxaparin treatment. Cost analysis showed average daily costs of 270 and 240 euro for heparin and enoxaparin, respectively. CONCLUSION: Enoxaparin can be safely used for anticoagulation during CVVH resulting in higher filter lifespan compared with unfractionated heparin.     

Lepirudin use in a neonate with heparin-induced thrombocytopenia

OBJECTIVE: To describe a case of heparin-induced thrombocytopenia (HIT) in a premature infant and the doses of danaparoid and lepirudin needed to achieve appropriate therapeutic endpoints. CASE SUMMARY: A 30-week gestational age infant was diagnosed with HIT with heparin antibodies. Danaparoid 2.0-2.4 units/kg/h achieved anti-Xa levels of 0.2-0.4 U/mL, but thrombocytopenia failed to resolve. Lepirudin was started in place of danaparoid. Lepirudin doses of 0.03-0.05 mg/kg/h achieved target activated partial thromboplastin time values of 1.5-2.0 times baseline. DISCUSSION: Dosing information for danaparoid in neonates is limited, and information for lepirudin appears only in German literature at this time. HIT is well documented in newborns, and lepirudin use in these situations is likely to increase. This report provides some guidance for optimal dosing. It also provides some guidance for HIT evaluation in preterm infants, in whom blood volume for laboratory tests is a major issue. CONCLUSIONS: HIT is an important and potentially fatal problem in neonates. Lepirudin may be the drug of choice, especially since danaparoid is now unavailable. Initial lepirudin dosing should not exceed 0.05 mg/kg/h.     

Argatroban and renal replacement therapy in patients with heparin-induced thrombocytopenia

BACKGROUND: Argatroban, a direct thrombin inhibitor, is an effective anticoagulant for patients who have heparin-induced thrombocytopenia (HIT). Anticoagulation is usually required for renal replacement therapy (RRT). OBJECTIVE: To prospectively evaluate the pharmacokinetics, pharmacodynamics, and safety of argatroban during RRT in hospitalized patients with or at risk for HIT. METHODS: Five patients with known or suspected HIT underwent hemodialysis (n = 4) or continuous venovenous hemofiltration (CVVH, n = 1), while receiving a continuous infusion of argatroban 0.5-2 microg/kg/min. Activated partial thromboplastin times (aPTTs), activated clotting times (ACTs), argatroban concentrations (plasma, dialysate, CVVH effluent), and safety were assessed before, during, and after a 4-hour session of RRT. Systemic and dialytic argatroban clearances were calculated. RESULTS: Among the 4 hemodialysis patients, aPTT, ACT, and plasma argatroban concentrations remained stable during RRT, with respective mean +/- SD values of 74.3 +/- 34.2 seconds, 198 +/- 23 seconds, and 499 +/- 353 ng/mL before RRT, and 70.6 +/- 21.4 seconds, 181 +/- 12 seconds, and 453 +/- 295 ng/mL 2 hours after starting RRT (p values NS). Systemic clearance was 17.7 +/- 12.8 L/h before hemodialysis and 17.0 +/- 9.5 L/h during hemodialysis (n = 2). The dialyzer clearance (dialysate recovery method) was 1.5 +/- 0.4 L/h (n = 4). Generally similar responses occurred in the CVVH patient: systemic argatroban clearance was 4.8 L/h before CVVH and 4 L/h during CVVH. The hemofilter argatroban clearance was 0.9 L/h. No bleeding or thrombosis occurred. CONCLUSIONS: Argatroban provides effective alternative anticoagulation in patients with or at risk for HIT during RRT. Argatroban clearance by high-flux membranes during hemodialysis and CVVH is clinically insignificant, necessitating no dose adjustment.     

Lepirudin for therapeutic use in heparin-induced thrombocytopenia

Heparin-induced thrombocytopenia (HIT) type II is an antibody mediated severe adverse event to heparin with a paradoxical decrease of platelet count and an increased risk for thromboembolic complications. The antibodies are directed against a neoepitop of platelet factor 4 after its binding to heparin. The incidence of HIT type II is lower with low-molecular-weight heparin compared to unfractionated heparin and lower in not operated patients compared to those after major surgery. In patients with HIT type II alternative anticoagulation has to be performed immediately due to the high thrombogenicity of the antibodies. The recombinant hirudin lepirudin (Refludan) is the anticoagulant drug of choice. A long-term anticoagulation has to be performed depending on the concomitant risk factors, intravenous administration followed by subcutaneous lepirudin overlapping with vitamin K antagonists.     

Anticoagulation with prostaglandins and unfractionated heparin during continuous venovenous haemofiltration: a randomized controlled trial

BACKGROUND: The objective of this prospective, randomized, controlled clinical study was to compare efficacy, safety, and costs of fixed-dose prostaglandins with adjusted-dose unfractionated heparin as anticoagulants for continuous venovenous haemofiltration. PATIENTS AND METHODS: Perioperative critically ill patients requiring continuous haemofiltration for acute renal failure received unfractionated heparin anticoagulation titrated to achieve an activated clotting time in the extracorporeal system of > 120 s. Patients were randomly assigned to receive a test infusion containing either prostaglandin I2 (5 ng/kg/min; group I; n = 15; 75 filters), prostaglandin E1 (5 ng/kg/min; group E; n = 18; 72 filters), or placebo (group H; n = 17; 63 filters). Heparin and test solutions were infused into the extracorporeal circuit before the haemofilter. All AN69-surface hollow fiber filters were primed with normal saline containing 5.000 IU heparin. RESULTS: The primary outcome measure--adequate haemofilter life span > 24 h--was compared by using Cochran's Q test. There was a significant difference in the frequencies of adequate haemofilter life span between the groups (36% group H, 65% group I, 59% group E; P < 0.05 versus group H). There were 6 bleeding episodes in group H, 2 in group E, and only 1 trivial bleeding episode in group I (P < 0.05 versus group H). Daily costs of haemofiltration were 61% higher in group I and 23% higher in group E than in group H (P < 0.05 versus group H). A heparin-sparing effect of prostaglandins was observed. CONCLUSIONS: Fixed-dose prostaglandins I2 and E1 reduced the incidence of haemofilter failure and bleeding when compared with adjusted-dose unfractionated heparin. There was no significant difference between the two prostaglandin groups. The increase in daily costs for haemofiltration treatment under prostaglandins is not clinically relevant.     

Argatroban anticoagulation in patients with heparin-induced thrombocytopenia requiring renal replacement therapy

BACKGROUND: Argatroban, a direct thrombin inhibitor, is used for prophylaxis or treatment of thrombosis in heparin-induced thrombocytopenia (HIT). The recommended initial dose is 2 microg/kg/min (0.5 microg/kg/min in hepatic impairment), adjusted to achieve activated partial thromboplastin time (aPTT) values 1.5-3.0 times baseline. However, few argatroban-treated patients with HIT and renal failure requiring renal replacement therapy (RRT) have been described. OBJECTIVE: To evaluate the safety and efficacy of argatroban anticoagulation during RRT in patients with HIT. METHODS: We retrospectively reviewed records from 47 patients with HIT and renal failure requiring RRT who underwent 50 treatment courses with argatroban. Patients with HIT had received argatroban during prospective, multicenter studies. Outcomes, safety, and dosing information were summarized. RESULTS: In the multicenter experience, no patient died due to thrombosis and 2 (4%) patients developed new thrombosis while on argatroban. No adverse outcomes occurred during argatroban reexposure. Starting doses were typically 2 microg/kg/min in patients without hepatic impairment and <1.5 microg/kg/min in those with hepatic impairment. Median (range) infusion doses were 1.7 (0.2-2.8) and 0.7 (0.1-1.7) microg/kg/min, respectively, with associated median (range) aPTT ratios, relative to baseline, of 2.2 (1.6-3.6) and 2.0 (1.4-4.1), respectively. Major bleeding occurred in 3 (6%) of 50 treatment courses. CONCLUSIONS: Argatroban provides effective anticoagulation upon initial and repeated administration in patients with HIT and renal impairment requiring RRT, with an acceptably low bleeding risk. Current dosing recommendations are adequate for these patients.     

Bivalirudin use in carotid endarterectomy in a patient with heparin-induced thrombocytopenia

OBJECTIVE: To describe the successful use of bivalirudin as the primary procedural anticoagulant in a patient with suspected heparin-induced thrombocytopenia (HIT) undergoing carotid endarterectomy (CEA). CASE SUMMARY: A 73-year-old white man presented for an elective CEA 3 weeks after emergent, on-pump coronary artery bypass grafting. Bivalirudin was used for procedural anticoagulation because of seropositivity for heparin-PF4 antibodies and a clinical history consistent with HIT. The dose was administered as a 0.75 mg/kg bolus and 1.75 mg/kg/h infusion as reported in percutaneous coronary intervention, based on review of the available bivalirudin literature. The dosage was adjusted for the patient's renal dysfunction. The outcome was successful, with the patient discharged home in 8 days without significant complications. DISCUSSION: During active HIT, when thrombocytopenia and heparin-PF4 antibodies are present, heparin therapy must be avoided. In patients with subacute HIT, when platelet counts have recovered but HIT antibodies are still present, it is also prudent to avoid heparin administration. In the case of a patient in whom anticoagulation is necessary but heparin use is contraindicated, a direct thrombin inhibitor, such as bivalirudin, may offer a viable alternative. Bivalirudin is not immunogenic and does not cross-react with the heparin-PF4 antibodies associated with HIT. To our knowledge, as of January 20, 2006, this is the first report of the use of bivalirudin for procedural anticoagulation during CEA in a patient with HIT antibodies and recent exposure to heparin. CONCLUSIONS: Further investigation is warranted to clarify the clinical benefits of bivalirudin for patients undergoing vascular surgery of the carotids, including potential advantages for vulnerable patient populations such as those with diagnosed or suspected HIT as well as those with renal dysfunction.     

Effect of lepirudin on the international normalized ratio

BACKGROUND: Many patients receiving direct thrombin inhibitor (DTI) therapy require transition to warfarin. This transition may be complicated by DTI-induced elevations in the international normalized ratio (INR). While the effect of argatroban on the INR has been characterized, data assessing the effect of lepirudin on the INR are limited. OBJECTIVE: To evaluate the effect of lepirudin on the INR. METHODS: Patients receiving lepirudin therapy between January 2000 and May 2001 were identified using the pharmacy database, and a retrospective chart review was conducted. Patients were included for analysis if they had paired activated partial thromboplastin time (aPTT) and INR data while receiving lepirudin monotherapy. RESULTS: Fifty-three paired aPTT and INR data points from 8 patients receiving lepirudin monotherapy were collected. The Organon MDA 180 instrument was used for aPTT and prothrombin time (PT) determination. Organon MDA Platelin L reagent was used for the aPTT and Organon Simplastin L reagent was used for the PT. The international sensitivity index (ISI) of the Simplastin L thromboplastin was 2.0. The mean +/- SD lepirudin dose was 0.05 +/- 0.04 mg/kg/h. Linear regression was used to identify the INRs that correspond to a therapeutic aPTT value of 45-75 seconds (1.5-2.5 times mean laboratory normal of 30 sec). The correlation between aPTT and INR was 0.77. An aPTT of 45-75 seconds with lepirudin correlated to an INR of 1.6-3.2. CONCLUSIONS: Based on laboratory results, when using a thromboplastin with an ISI of 2, lepirudin appears to elevate the INR in the absence of warfarin.     

Lepirudin in patients with heparin-induced thrombocytopenia – results of the third prospective study (HAT-3) and a combined analysis of HAT-1, HAT-2, and HAT-3

OBJECTIVES: To assess efficacy and safety of lepirudin in patients with heparin-induced thrombocytopenia (HIT) in a prospective study (HAT-3) as well as in a combined analysis of all HAT study data. PATIENTS/METHODS: Patients with laboratory-confirmed HIT were treated with lepirudin in three different aPTT-adjusted dose regimen and during cardiopulmonary bypass (CPB). Endpoints were new thromboembolic complications (TEC), limb amputations, and death and major bleeding. A historical control group (n = 120) was used for comparison. RESULTS: After start of lepirudin in 205 patients treated in HAT-3, the combined endpoint occurred in 43 (21.0%). Thirty (14.6%) patients died, 10 (4.9%) underwent limb amputation, and 11 (5.4%) new TECs occurred. Major bleeding occurred in 40 patients (19.5%) (seven during CPB surgery). Combining all prospective HAT trials (n = 403), after start of lepirudin treatment, the combined endpoint occurred in 82 patients (20.3%), with 47 deaths (11.7%), 22 limb amputations (5.5%), 30 new TECs (7.4%), and 71 (17.6%) major bleedings. Compared with the historical control group (log-rank test), the combined endpoint after start of treatment was reduced (29.7% vs. 52.1%, P = 0.0473), primarily because of reduction in new thromboses (11.9% vs. 32.1%, P = 0.0008). Mean lepirudin maintenance doses ranged from 0.07 to 0.11 mg kg(-1) h(-1). Major bleeding was more frequent in the lepirudin-treated patients (29.4% vs. 9.1%, P = 0.0148). CONCLUSIONS: The rate of new TECs in HIT patients is low after start of lepirudin treatment. The rate of major bleeding of 17.6% might be reduced by reducing the starting dose to 0.1 mg kg(-1) h(-1).     

Heparin induced thrombocytopenia: case report with acute thrombotic complications and literature review]

PURPOSE: Review of the frequency, clinical and biological features and treatment of type II heparin-induced thrombocyopenia.METHODS: Case report and literature review.RESULTS: A 65 years old woman received as antithrombotic prophylaxis low molecular weight heparin (LMWH) after prosthetic knee replacement. Day 8, asymptomatic deep vein thrombosis was discovered after systematic echodoppler examination. Curative anticoagulation was started with LMWH. A fall in the platelet count (17 G/L) was noted day 12. Danaparoid was immediately introduced and heparin discontinued. However, day 16 a massive pulmonary embolism occurred which required transfer to an intensive care unit. Danaparoid was changed for lepirudin the same day. It took longer than three weeks for platelet count to return to normal value after heparin discontinuation. The suspicion of heparin-induced thrombocyopenia was confirmed by specific tests.DISCUSSION: HIT type II are rare but life-threatening and thrombosis events are the most frequent complications. The diagnosis is a high probability proved by both clinical and biological patterns. The treatment consists in alternative thrombin inhibitors such as danaparoid and lepirudin. The platelet count usually requires less than ten days to recover normal values after heparin withdrawal. Cases in which the delay to a normal platelet count exceeds 3 weeks have been reported specially after LMWH therapy.CONCLUSION: Type II HIT are rare but life-threatening events can occur. The platelet count check-up during heparin therapy must be systematic.     

Effect of renal function on the pharmacodynamics of argatroban

BACKGROUND: Argatroban is a direct thrombin inhibitor used to treat heparin-induced thrombocytopenia (HIT). Argatroban is primarily cleared by hepatic mechanisms, with only small amounts of unchanged drug cleared by the kidneys. OBJECTIVE: To assess the effects of renal function on argatroban dose and activated partial thromboplastin time (aPTT). METHODS: Patients treated with argatroban were identified and prospectively screened. Patients with liver dysfunction were excluded from the analysis. Charts and laboratory data were reviewed daily until a therapeutic aPTT was reached or argatroban was discontinued. Data points collected included age, weight, gender, admitting diagnosis, past medical history, indication for anticoagulation, indication for argatroban, initial dose, goal aPTT, titration instructions, liver function tests, serum creatinine (S(cr)), blood urea nitrogen, and estimated creatinine clearance (Cl(cr)). RESULTS: A total of 66 patients were evaluated and 44 met criteria for inclusion. Baseline S(cr) was elevated at 1.5 mg/dL (0.9, 2.3; median 25th, 75th percentile), with an estimated Cl(cr) 40 mL/min/1.73 m(2) (26, 74). The median dose of argatroban to reach the predefined therapeutic range was 1 microg/kg/min (0.68, 2), with a corresponding aPTT of 60 seconds (54, 66). After univariate analysis, Cl(cr) significantly predicted the therapeutic dose (coefficient b +/- SE 0.019 +/- 0.004; r(2) 0.35; p < 0.001). Covariates that predicted dose were the presence of HIT (coefficient b +/- SE -0.61 +/- 0.3; p = 0.045), history of myocardial infarction (coefficient b +/- SE -0.74 +/- 0.3; p = 0.02), and an indication for anticoagulation of deep-vein thrombosis/pulmonary embolism (coefficient b +/- SE 0.69 +/- 0.3; p = 0.03). CONCLUSIONS: Estimated Cl(cr) significantly predicted the dose of argatroban needed to reach a therapeutic aPTT.     

Heparin-induced thrombocytopenia in paediatrics: clinical characteristics,therapy and outcomes

Objective: Reports on heparin-induced thrombocytopenia (HIT) in paediatrics are confined to isolated case reports. The objective was to systematically combine the published data. Design and setting: Cases were identified by MEDLINE search and review of bibliographies. Patients: We included subjects reported with HIT, collecting patient demographics, clinical and laboratory characteristics, therapeutic regimens and outcomes. Measurements and results: Reports on 70 patients were retrieved. In a majority of children, HIT occurred during hospitalisation in a paediatric ICU. In most patients, the typical onset pattern was reported, although rapid-onset-pattern HIT occurred in some. The median platelet-count nadir was 54×10⁹/l; 11% of reported patients had nadirs in the normal range. Clinical symptoms included isolated thrombocytopenia and solitary or combined venous, arterial and intracardiac thromboembolism, sometimes catheter-related. Pulmonary embolism and major bleeding were rarely described. Confirmatory functional or antigenic testing of HIT antibodies showed a similar cumulative sensitivity of about 88%. An unfavourable outcome (death/limb amputation) was reported in 42.1% of patients without therapy and in 18% of patients treated with danaparoid, lepirudin, or argatroban. Conclusions: HIT in children mainly occurs in paediatric intensive care with diagnostic features and outcomes similar to those seen in adults. HIT cannot be ruled out based on normal platelet counts or occurrence after fewer than 5 days of heparin exposure. Children should be presumed to suffer from HIT based on clinical grounds and treated accordingly (immediate heparin withdrawal and alternative anticoagulation). Alternative anticoagulation with danaparoid, lepirudin and argatroban appears to improve outcomes.Electronic Supplementary Material Supplementary material is available in the online version of this article at     

Extensive prolongation of aPTT with argatroban in an elderly patient with improving renal function, normal hepatic enzymes, and metastatic lung cancer

OBJECTIVE: To report a case of an elderly male with improving renal function and normal hepatic function who sustained an elevated activated partial thromboplastin time (aPTT) after an infusion of argatroban was discontinued. CASE SUMMARY: A 77-year-old white male with a history of heparin-induced thrombocytopenia (HIT) and metastatic lung disease was started on argatroban for treatment of a right upper-extremity deep vein thrombosis (DVT). The infusion was initiated at 2.0 microg/kg/min and was titrated to a goal aPTT of 60-80 seconds. Argatroban was discontinued due to an aPTT elevated to >100 seconds; the aPTT remained elevated for 130 hours after discontinuation of the infusion. DISCUSSION: Argatroban dose reductions in patients with impaired liver and renal function test values have been reported. Elderly subjects may have a prolonged clearance compared with young healthy subjects, although the duration of effect has not been established. As of April 18, 2005, the effect of liver metastasis on argatroban pharmacokinetics in the setting of normal liver function enzyme levels has not been reported. An objective causality assessment using the Naranjo probability scale showed that the prolonged aPTT was probably attributable to argatroban. CONCLUSIONS: Clinicians should exercise caution when initiating argatroban at a dose of 2.0 microg/kg/min in elderly patients with underlying comorbidities, such as metastatic disease and renal impairment, since this may lead to excessive and prolonged anticoagulation and increased risk of bleeding.     

Continuous veno-venous hemofiltration without anticoagulation in high-risk patients

OBJECTIVE: To study the safety and operative efficacy of continuous veno-venous hemofiltration (CVVH) without anticoagulation in patients at high risk of bleeding. DESIGN: Prospective cohort study and comparison to control group. SETTING: Tertiary, multidisciplinary intensive care unit. PATIENTS: Forty hemofiltration circuits in 12 patients with severe acute renal failure (ARF) deemed at high risk of bleeding. Forty control circuits in 14 patients treated with low-dose pre-filter heparin infusion. INTERVENTIONS: CVVH at 21/h of pump-controlled ultrafiltration without anticoagulation or saline flush in patients at high risk of bleeding. Collection of data at the bedside. MEASUREMENTS AND MAIN RESULTS: Mean circuit life was 32 h (95% CI: 20-44.4) in patients receiving CVVH without anticoagulation. Forty-three per cent of filters lasted longer than 30 h. Circuit lifespan did not correlate with international normalized ratio (INR), activated partial thromboplastin time (APTT) or platelet count. There were no bleeding complications and azotemic control was not compromised by lack of circuit anticoagulation with a mean serum urea of 16.0 mmol/l (95% CI: 14.9-18.1) during treatment. A control group of consecutive similarly ill patients not at high risk of bleeding received low-dose pre-filter heparin (mean dose 716 IU; 95% CI: 647-785). Their mean filter life was 19.5 h (95% CI: 14.2-23.8), significantly shorter than in the study patients (p = 0.017). CONCLUSIONS: Critically ill patients at high risk of bleeding who require continuous renal replacement therapy (CRRT) can be safely managed without circuit anticoagulation. This strategy minimizes bleeding risks and is associated with an acceptable filter life. CRRT without anticoagulation should be strongly considered in high-risk patients.     

Use of plasma exchange in patients with heparin-induced thrombocytopenia: a report of two cases and a review of the literature

Heparin-induced thrombocytopenia (HIT), which is characterized by thrombocytopenia and potentially serious thromboses, may develop in patients exposed to heparin anticoagulation. HIT is caused by antibodies to the heparin/platelet factor 4 (PF4) complex. Management of HIT involves discontinuation of heparin and anticoagulation with a nonheparin alternative such as a direct thrombin inhibitor (DTI). This poses a challenge in the management of patients who need to undergo cardiopulmonary bypass surgery (CPB), because CPB requires anticoagulation with heparin and standardized protocols for use of DTIs are not widely available. We report two patients with HIT who underwent successful CPB with heparin anticoagulation following plasma exchange (PE) to reduce heparin/PF4 antibody titers. Case 1 is a 46-year-old male with cardiac amyloidosis who needed urgent placement of a left ventricular assist device. Case 2 is a 34-year-old woman with acute myocarditis who needed placement of a biventricular assist device. Both patients had positive enzyme-linked immunosorbent assay assays for heparin/PF4 antibodies and clinical evidence of HIT before PE. Following PE and subsequent CPB, neither patient had clinical or laboratory evidence of HIT. The literature regarding the use of PE for the treatment of complications of HIT and as prophylaxis before CPB is reviewed.