Growth signals, inflammation, and vascular perturbations: mechanistic links between obesity, metabolic syndrome, and cancer.

Nearly 35% of adults and 20% of children in the United States are obese, defined as a body mass index ≥ 30 kg/m(2). Obesity, which is accompanied by metabolic dysregulation often manifesting in the metabolic syndrome, is an established risk factor for many cancers. Within the growth-promoting, proinflammatory environment of the obese state, cross talk between macrophages, adipocytes, and epithelial cells occurs via obesity-associated hormones, cytokines, and other mediators that may enhance cancer risk and progression. This review synthesizes the evidence on key biological mechanisms underlying the obesity-cancer link, with particular emphasis on obesity-associated enhancements in growth factor signaling, inflammation, and vascular integrity processes. These interrelated pathways represent possible mechanistic targets for disrupting the obesity-cancer link.

Etiology and assessment of hypercoagulability with lessons from heparin-induced thrombocytopenia.

Hypercoagulability, or thrombophilia, is a condition associated with an abnormally increased tendency toward blood clotting. Affected individuals are prone to developing venous or arterial thrombosis and often require thromboprophylaxis. Hypercoagulability can be generally classified as either an inherited or acquired condition. Patients with an inherited thrombophilia have genetic variances that alter the quality or quantity of proteins involved with hemostasis. Hypercoagulability may also be acquired and develop as an exaggeration of normal physiologic responses to major tissue injury, or an abnormal response to various prothrombotic clinical factors. Careful assessment for hypercoagulability is important because effective management strategies, often involving anticoagulation, may be available. Heparin-induced thrombocytopenia is an example of an acquired hypercoagulable state that has been well studied and, when recognized, responds to appropriate therapy. In this article, we review the etiology, risks, and assessment of thrombophilia, with emphasis on the clinical lessons learned from heparin-induced thrombocytopenia.

Impact of renal function on argatroban therapy during percutaneous coronary intervention.

Argatroban, a hepatically metabolized direct thrombin inhibitor, is approved for anticoagulation in patients with or at risk of heparin-induced thrombocytopenia (HIT) undergoing percutaneous coronary intervention (PCI). We investigated the effect of renal function on argatroban therapy during PCI. From previous argatroban studies in PCI, we evaluated relationships between estimated creatinine clearance (CrCl) and activated clotting times (ACTs), dosage, and outcomes in 219 patients with or at risk of HIT (HIT group, n = 67) or administered glycoprotein IIb/IIIa inhibition (non-HIT group, n = 152). Patients received an argatroban bolus (350 mcg/kg, HIT group; 250 or 300 mcg/kg, non-HIT group) then 25-30 mcg/kg/min (adjusted to achieve ACTs 300-450 s, HIT group) or 15 mcg/kg/min (target ACTs 275-325 s, non-HIT group), with additional 150-mcg/kg boluses if needed. Of 219 patients, 55 (25%) had CrCl

Heparin-platelet factor 4 antibodies in intensive care patients: an observational seroprevalence study.

Heparin-platelet factor 4 (PF4) antibodies mediate heparin-induced thrombocytopenia (HIT) and, irrespective of thrombocytopenia, are associated with poorer outcomes in some patients. The prevalence of heparin-PF4 antibodies, including platelet-activating ones, in patients in the medical, neurotrauma, or shock-trauma intensive care unit (ICU) remains unclear. In this single-center, observational study, heparin-PF4 antibodies (IgG/A/M) were measured by ELISA in 185 adults (median APACHE II score, 16) admitted to the medical (n = 27), neurotrauma (n = 96), or shock-trauma (n = 62) ICU and after 7 +/- 2 days. Seropositive patients and heparin-treated patients with unexplained, new-onset thrombocytopenia were also tested for platelet-activating antibodies using a serotonin release assay (SRA). Of 185 patients, seropositivity occurred in 20 patients (10.8%; 95% CI 6.7-16.2%) at admission and 54 (29.2%, 95% CI 22.8-36.3%) after 7 days (P < 0.001). Platelet-activating antibodies occurred in 4 seropositive patients at admission and 9 seropositive patients after 7 days (including in 1 patient at each assessment), each without thrombocytopenia or new thrombosis. Of 12 seropositive patients with platelet-activating antibodies, 6 had an ELISA optical density (OD) >1.0. ELISA-positive, SRA-negative, suspected HIT occurred in 1 patient. Heparin-PF4 antibodies are present in 10.8% of medical, neurotrauma, or shock-trauma ICU patients at admission and increase significantly to 29.2% within 7 days. Approximately 17-20% of seropositive ICU patients, often those with an ELISA OD >1.0, have platelet-activating heparin-PF4 antibodies.

Reducing harm associated with anticoagulation: practical considerations of argatroban therapy in heparin-induced thrombocytopenia.

Argatroban is a hepatically metabolized, direct thrombin inhibitor used for prophylaxis or treatment of thrombosis in heparin-induced thrombocytopenia (HIT) and for patients with or at risk of HIT undergoing percutaneous coronary intervention (PCI). The objective of this review is to summarize practical considerations of argatroban therapy in HIT. The US FDA-recommended argatroban dose in HIT is 2 microg/kg/min (reduced in patients with hepatic impairment and in paediatric patients), adjusted to achieve activated partial thromboplastin times (aPTTs) 1.5-3 times baseline (not >100 seconds). Contemporary experiences indicate that reduced doses are also needed in patients with conditions associated with hepatic hypoperfusion, e.g. heart failure, yet are unnecessary for renal dysfunction, adult age, sex, race/ethnicity or obesity. Argatroban 0.5-1.2 microg/kg/min typically supports therapeutic aPTTs. The FDA-recommended dose during PCI is 25 microg/kg/min (350 microg/kg initial bolus), adjusted to achieve activated clotting times (ACTs) of 300-450 sec. For PCI, argatroban has not been investigated in hepatically impaired patients; dose adjustment is unnecessary for adult age, sex, race/ethnicity or obesity, and lesser doses may be adequate with concurrent glycoprotein IIb/IIIa inhibition. Argatroban prolongs the International Normalized Ratio, and published approaches for monitoring the argatroban-to-warfarin transition should be followed. Major bleeding with argatroban is 0-10% in the non-interventional setting and 0-5.8% periprocedurally. Argatroban has no specific antidote, and if excessive anticoagulation occurs, argatroban infusion should be stopped or reduced. Improved familiarity of healthcare professionals with argatroban therapy in HIT, including in special populations and during PCI, may facilitate reduction of harm associated with HIT (e.g. fewer thromboses) or its treatment (e.g. fewer argatroban medication errors).

Dosing patterns and outcomes in African American, Asian, and Hispanic patients with heparin-induced thrombocytopenia treated with argatroban.

We retrospectively evaluated dosing patterns and 37-day outcomes in argatroban-treated African American (n = 52), Asian (n = 13), and Hispanic (n = 14) patients with heparin-induced thrombocytopenia (HIT). The Asians required a lesser median dose (1.0 microg/kg/min) than the other groups (1.9 microg/kg/min, each) to achieve comparable activated partial thromboplastin times (medians: 61-69 s). Durations of therapy were similar (medians: 4.0-5.5 days). New thrombosis occurred in 11 (21%) African Americans, 1 (8%) Asian, and 1 (7%) Hispanic; of these 13 patients, 9 (69%) had baseline HIT-related thrombosis. Amputation occurred in 6 (12%) African Americans and 3 (21%) Hispanics; of these nine patients, 6 (67%) had diabetes. One (2%) African American and 1 (7%) Hispanic died from thrombosis. The composite of death due to thrombosis, amputation due to ischemic complications of HIT, or new thrombosis occurred in 14 (27%) African Americans, 1 (8%) Asian, and 4 (29%) Hispanics. Two (4%) African Americans and none others (0%) had major bleeding. These findings suggest that despite argatroban anticoagulation, African Americans and Hispanics may have worse outcomes in HIT than Asians. In minority patients with adverse HIT outcomes, baseline HIT-related thrombosis or diabetes is often present.

Risk factors for major bleeding in patients with heparin-induced thrombocytopenia treated with argatroban: a retrospective study.

We retrospectively characterized major bleeding events and their risk factors among 269 patients with clinically diagnosed heparin-induced thrombocytopenia (HIT) treated using argatroban (2 microg x kg(-1) x min(-1) initially, adjusted to achieve activated partial thromboplastin times (aPTTs) 1.5-3 times the baseline) in a prospective multicenter study. Patients received a median (range) dose of 1.9 (0.2-9.7) microg x kg(-1) x min(-1) for 5.6 (0.1-61) days. Average aPTTs during therapy were 61.6 (37-183) seconds. Major bleeding, most commonly gastrointestinal, occurred in 19 patients (7.1%) during therapy. Another patient suffered from intracranial hemorrhage 4 days after argatroban cessation. Bleeding was fatal in 2 patients (0.7%); each received multiple anticoagulants and thrombolytic therapy. Major bleeding was more likely to occur in patients with HIT-related thrombosis (odds ratio = 2.9, P = 0.039), pulmonary impairment (odds ratio = 20.3, P < 0.001), or an aPTT >100 seconds (odds ratio = 3.7, P = 0.010). Major bleeding rates associated with average aPTTs of <45, 45-67.5, 67.6-90, and >90 seconds, respectively, were 5.0% (1 of 20 patients), 5.6% (9 of 162 patients), 8.7% (6 of 69 patients), and 22% (4 of 18 patients). No significant effect of patient demographics, other baseline illnesses including hepatic or renal impairment, argatroban dose, or treatment duration was detected on major bleeding. Risk factors for major bleeding in argatroban-treated patients with HIT include baseline HIT-related thrombosis and pulmonary impairment. For minimizing bleeding risk during argatroban therapy for HIT, the aPTT should be routinely monitored and maintained at <90 seconds.

Reduced argatroban doses after coronary artery bypass graft surgery.

BACKGROUND: The Food and Drug Administration-approved argatroban dose for heparin-induced thrombocytopenia (HIT) is 2 microg/kg/min (0.5 microg/kg/min in hepatic impairment), adjusted to achieve activated partial thromboplastin time (aPTT) 1.5-3 times baseline. Recent data suggest that reduced doses are required after cardiovascular surgery. OBJECTIVE: To characterize dosing requirements, aPTTs, factors affecting dosage, and clinical outcomes in patients administered argatroban after coronary artery bypass graft (CABG) surgery. METHODS: Charts of 39 patients who underwent CABG surgery and were administered argatroban postoperatively for laboratory-confirmed HIT (n = 25), antibody-negative suspected HIT (n = 10), or previous HIT requiring anticoagulation (n = 4) were retrospectively reviewed. Patient characteristics, argatroban dosing information, aPTTs (target range 45-90 sec), and outcomes were summarized. Regression analyses explored potential effectors of dosage. RESULTS: Patient features, argatroban dosing patterns, and aPTTs were similar among groups. Many patients had laboratory evidence of some hepatic and/or renal dysfunction (median [range] bilirubin 1.0 [0.3-8.0] mg/dL, creatinine clearance 47 [18-287] mL/min). Overall, median argatroban doses were 0.5 microg/kg/min initially and 0.6 microg/kg/min during therapy (median duration 5.3 days). After argatroban initiation, aPTTs were greater than 90 seconds at first assessment in 4 patients (3 with abnormal hepatic function test results) initially administered 0.5, 1, 2, and 2 microg/kg/min, respectively. Within approximately 16 hours of therapy, 33 (85%) patients achieved consecutive therapeutic aPTTs. No association was detected between mean dose during therapy and preoperative ejection fraction, routine hepatic or renal function test results (other than blood urea nitrogen [BUN]), or surgery type. A clinically insignificant association existed between dose and BUN: there was an approximately 0.15 microg/kg/min dose decrease for each 10 mg/dL BUN increase. One patient developed thrombosis, 1 underwent finger amputation, 7 died (5 after argatroban cessation), and 4 had significant bleeding. CONCLUSIONS: These findings suggest that reduced initial argatroban doses (eg, 0.5 microg/kg/min), adjusted to achieve therapeutic aPTTs, provide rapid, adequate anticoagulation in postoperative CABG patients with presumed or previous HIT. Prospective study of reduced initial dosing in this setting is warranted.

Argatroban therapy in patients with coronary artery disease and heparin-induced thrombocytopenia.

The efficacy of the direct thrombin inhibitor argatroban was investigated in patients who developed heparin-induced thrombocytopenia following heparin therapy for coronary artery disease. The outcome of 121 patients treated with argatroban was compared with that of 26 patients in a historical control (i.e. patients who did not receive direct thrombin inhibition therapy). Argatroban, compared with controls, significantly reduced the 37-day composite of death, amputation or new thrombosis (30 versus 50%, p = 0.043), primarily driven by a significant decrease in new thrombosis (10 versus 31%, p = 0.01), and led to less bleeding (4 versus 15%, p = 0.046). Therefore, in patients with coronary artery disease who develop heparin-induced thrombocytopenia, argatroban provides safe, effective anticoagulation.

Predictors of clinical outcome in patients with heparin-induced thrombocytopenia treated with direct thrombin inhibition.

We aimed to identify predictors of poor outcome in patients with heparin-induced thrombocytopenia, a serious immune-mediated reaction to heparin. All patients were treated with direct thrombin inhibition therapy, as part of two prospective studies. We performed a risk factor analysis of adverse outcomes (defined as death, amputation, new thrombosis, or their composite within a 37-day study period) in 809 patients from two reported prospective studies of the direct thrombin inhibitor argatroban in clinically diagnosed heparin-induced thrombocytopenia. We initially identified from among 14 baseline variables the significant predictors of poor outcome in the first study (304 patients), and then tested our resultant hypothesis in the second, independent study (505 patients), using multivariate analysis. Seven significant predictors were identified in the first study; three were confirmed in the second study. The strongest relationship occurred between the baseline platelet count and the composite of death, amputation, or new thrombosis (P = 0.0001), with the most severely thrombocytopenic patients being at greatest risk. The other significant associations were between renal impairment and death (odds ratio = 2.13, 95% confidence interval = 1.23-3.66, P = 0.007), and between cardiovascular surgery (particularly peripheral vascular surgery) and amputation (odds ratio = 3.39, 95% confidence interval = 1.65-6.95, P = 0.0009). In conclusion, in patients with clinically diagnosed heparin-induced thrombocytopenia, the severity of the baseline thrombocytopenia is the best predictor of death, amputation or thrombotic progression. The identification of higher risk subgroups for poor outcomes, such as patients with more severe thrombocytopenia or a history of renal impairment or peripheral vascular surgery, could allow more targeted therapy.

Argatroban anticoagulation in renal dysfunction: a literature analysis.

BACKGROUND/AIMS: Argatroban, a hepatically metabolized direct thrombin inhibitor, is approved for use in heparin-induced thrombocytopenia (HIT; several countries) and in antithrombin-deficient patients undergoing hemodialysis (Japan). This literature analysis aimed to determine the effects of renal function on argatroban pharmacokinetics, pharmacodynamics, and its therapeutic dose in HIT and to evaluate argatroban dosing and safety during renal replacement therapy (RRT) and in adults with renal dysfunction undergoing surgical or invasive procedures. METHODS: A literature search identified 34 publications (12 prospective studies, 4 retrospective studies, 18 anecdotal reports) that together described 644 argatroban-treated patients (446 with HIT, 82 with antithrombin deficiency) with varying degrees of renal function. Pertinent data were extracted and summarized. RESULTS: In pharmacokinetic studies (40 patients, overall), renal dysfunction exerted little or no clinically significant effects on argatroban pharmacokinetic parameters. For argatroban therapy in HIT, evidence existed that an initial 2 microg/kg/min dose was sometimes excessive; patients with hepatic dysfunction, irrespective of renal function, required reduced initial doses; lesser doses were required in combined hepatic and renal dysfunction than hepatic dysfunction, and for each 30 ml/min decrease in patient creatinine clearance, the therapeutic dose decreased approximately 0.1-0.6 microg/kg/min. Argatroban was well tolerated and enabled RRT with little or no thrombotic or hemorrhagic complications. Experiences with argatroban in renally impaired patients undergoing procedures besides RRT were limited. CONCLUSION: Current literature suggests that argatroban is well tolerated and provides adequate anticoagulation in patients with renal dysfunction or failure, including individuals with HIT or antithrombin deficiency where anticoagulant options are limited.

Heparin-induced thrombocytopenia, a prothrombotic disease.

Heparin-induced thrombocytopenia (HIT) is a serious, yet treatable prothrombotic disease that develops in approximately 0.5% to 5% of heparin-treated patients and dramatically increases their risk of thrombosis (odds ratio, 37). The antibodies that mediate HIT (ie, heparin-platelet factor 4 antibodies) occur more frequently than the overt disease itself, and, even in the absence of thrombocytopenia, are associated with increased thrombotic morbidity and mortality. HIT should be suspected whenever the platelet count drops more than 50% from baseline (or to <150 x 10(9)/L) beginning 5 to 14 days after starting heparin (or sooner if there was prior heparin exposure) or new thrombosis occurs during, or soon after heparin treatment, with other causes excluded. When HIT is strongly suspected, with or without complicating thrombosis, heparins should be discontinued, and a fast-acting, nonheparin alternative anticoagulant such as argatroban should be initiated immediately. With prompt recognition, diagnosis, and treatment of HIT, the clinical outcomes and health economic burdens of this prothrombotic disease are improved significantly.

Argatroban anticoagulation for heparin-induced thrombocytopenia in elderly patients.

BACKGROUND: Argatroban, a direct thrombin inhibitor that has reduced clearance in elderly versus younger volunteers, is used for thromboprophylaxis or treatment in heparin-induced thrombocytopenia (HIT). OBJECTIVE: To evaluate the effect of aging on argatroban therapy, including dosage, anticoagulant responses, clinical outcomes and factors influencing those responses, in elderly patients with HIT or a history of HIT. METHODS: This was a retrospective multicentre database analysis of 118 inpatients treated with argatroban at six medical centres between August 2001 and January 2005. Sixty-two adults aged >/=65 years were administered argatroban for clinically diagnosed HIT (n = 54) or a history of HIT (n = 8). Argatroban infusion was adjusted to achieve activated partial thromboplastin times (aPTTs) 1.5-3 times baseline. All study measures and analyses were prospectively defined. Argatroban dosage patterns, aPTTs and platelet count responses, and 37-day outcomes (death, amputation, new thrombosis, major bleeding) were summarised for patients stratified by age (65-74 years [n = 31]; 75-84 years [n = 26]; >/=85 years [n = 5]) to identify possible age-related trends. Regression analyses explored relationships between dose and patient age, liver function and renal function. Cox proportional hazards models evaluated the effect of age, dose, gender, aPTT and platelet count on the risk of new thrombosis. RESULTS: In each age group, the median argatroban dosage was initially 1.0 microg/kg/min and was generally maintained at or near that dose during therapy (median, 5-7 days). Therapeutic aPTTs occurred within 11.5 hours; the median aPTT during therapy was 54.7 seconds, without obvious trend by age. By regression analysis, the initial and mean argatroban dosages decreased 0.08-0.09 microg/kg/min with each 0.2 mg/dL increase in serum creatinine, but no association was detected between dose and patient age, serum total bilirubin, calculated creatinine clearance or blood urea nitrogen. Platelet counts recovered within 6-7 days of initiating therapy, without apparent trend by age. No patient experienced amputation or major bleeding, and no patient in the oldest group died or had new thrombosis. Overall, 13 (21%) patients died (9 in the 65-74 years group; 1 receiving argatroban) and 5 (8%) had new thrombosis (4 in the 65-74 years group; 2 receiving argatroban), comparing favourably with previously reported rates, irrespective of patient age. By univariate (but not multivariate) analysis, the risk of new thrombosis decreased with increasing argatroban dose (hazard ratio 0.020; 95% CI 0.001, 0.757; p = 0.035). No effect of age or the other covariates considered on thrombotic risk was detected. CONCLUSION: Argatroban at a median initial dosage of 1.0 microg/kg/min, adjusted to achieve median aPTTs of 54.7 seconds during therapy, generally provided safe, adequate anticoagulation across a wide age range in elderly patients with HIT or a history of HIT. In these elderly patients, age was not a significant determinant of argatroban dosage or thrombotic risk. Prospective evaluation of this initial dose of argatroban in the elderly is warranted.

Argatroban therapy in women with heparin-induced thrombocytopenia.

OBJECTIVES: Women have increased risk of developing heparin-induced thrombocytopenia (HIT), a serious, immune-mediated prothrombotic condition, and have a worse prognosis when affected. We compared gender differences for treatment and outcomes in HIT patients administered argatroban therapy. METHODS: From a multicenter retrospective registry of argatroban-treated patients, we identified females (n = 42) and males (n = 50) with clinically diagnosed HIT who were administered argatroban

Reducing thrombotic complications in the perioperative setting: an update on heparin-induced thrombocytopenia.

Heparins are widely used in the perioperative setting. Immune heparin-induced thrombocytopenia (HIT) is a serious, antibody-mediated complication of heparin therapy that occurs in approximately 0.5%-5% of patients treated with heparin for at least 5 days. An extremely prothrombotic disorder, HIT confers significant risks of thrombosis and devastating consequences on affected patients: approximately 38%-76% develop thrombosis, approximately 10% with thrombosis require limb amputation, and approximately 20%-30% die within a month. HIT antibodies are transient and typically disappear within 3 mo. In patients with lingering antibodies, however, re-exposure to heparin can be catastrophic. In the perioperative setting, heightened awareness is important for the prompt recognition, diagnosis, and treatment of HIT. HIT should be considered if the platelet count decreases 50% and/or thrombosis occurs 5-14 days after starting heparin, with other diagnoses excluded. On strong clinical suspicion of HIT, heparin should be discontinued and a parenteral alternative anticoagulant initiated, even before laboratory confirmation of HIT is obtained. Subsequent laboratory test results may help with the decision to continue with nonheparin therapy or switch back to heparin. Heparin avoidance in patients with current or previous HIT is feasible in most clinical situations, except perhaps in cardiovascular surgery. If the surgery cannot be delayed until HIT antibodies have disappeared, intraoperative alternative anticoagulation is recommended.

Argatroban therapy for heparin-induced thrombocytopenia in acutely ill patients.

Heparin-induced thrombocytopenia (HIT) is a prothrombotic, immune-mediated adverse reaction to heparin therapy. To evaluate clinical outcomes and effects of argatroban therapy in acutely ill HIT patients. Retrospective analysis. Hospital in-patient. Acutely ill patients with clinically diagnosed HIT from previous multicenter, historically controlled studies of argatroban therapy in HIT. Argatroban, adjusted to maintain activated partial thromboplastin times 1.5 to 3 times baseline, or historical control therapy (ie, no direct thrombin inhibition). We identified 488 patients who received argatroban (N = 390; mean dose of 1.9 microg/kg/min for a mean 6 days) or historical control therapy (N = 98) for HIT. The primary all-cause composite endpoint of death, amputation, or new thrombosis within 37 days occurred in 133 (34.1%) argatroban-treated patients and 38 (38.8%) controls (P = .41). Argatroban, versus control, significantly reduced the primary thrombosis-related composite endpoint of death because of thrombosis, amputation secondary to ischemic complications of HIT, or new thrombosis (17.7% vs 30.6%, P = .007). Significant reductions also occurred in new thrombosis and death because of thrombosis. Major bleeding was similar between groups (7.7% vs 8.2%; P = .84). Adverse outcomes were more likely to occur in patients who were initially diagnosed with HIT and thrombosis, had undergone cardiac surgery, were not white, or had more severe thrombocytopenia. In acutely ill HIT patients, argatroban, versus historical control, provides effective antithrombotic therapy without increasing major bleeding. Patients with more severe thrombocytopenia or HIT-related thrombosis on HIT diagnosis have a poorer prognosis, emphasizing the importance of prompt recognition/ treatment of HIT in acutely ill patients.

How frequently is venous thromboembolism in heparin-treated patients associated with heparin-induced thrombocytopenia?

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.

Argatroban therapy in heparin-induced thrombocytopenia with hepatic dysfunction.

STUDY OBJECTIVES: We evaluated the dosing requirements in argatroban-treated patients with heparin-induced thrombocytopenia (HIT) and hepatic dysfunction, and compared efficacy and safety outcomes with historical control patients. DESIGN: Retrospective analysis. SETTING: Inpatient setting. PATIENTS: Patients with hepatic dysfunction, defined as total bilirubin > 25.5 micromol/L (1.5 mg/dL), aspartate aminotransferase >100 IU/L, and/or alanine aminotransferase >100 IU/L, were identified from previous multicenter, historical-controlled studies of argatroban therapy in HIT. INTERVENTIONS: Argatroban, adjusted to maintain activated partial thromboplastin times (aPTTs) 1.5 to 3 times baseline in the experimental group, vs no direct thrombin inhibition in the historical control patients. MEASUREMENTS AND RESULTS: The analysis population included 82 argatroban patients and 34 historical control patients with hepatic impairment, of whom approximately 50% in each group had renal dysfunction (defined as a serum creatinine level > 1.3 mg/dL). The argatroban dosage was 1.6 +/- 1.1 microg/kg/min (mean +/- SD) over a mean 5-day course of therapy. Significantly lower doses were used in patients with elevated vs normal total bilirubin levels (0.8 +/- 0.6 microg/kg/min vs 1.7 +/- 0.8 microg/kg/min, p = 0.0063) and in patients with hepatic/renal dysfunction vs hepatic dysfunction alone (1.2 +/- 1.1 microg/kg/min vs 2.0 +/- 1.1 microg/kg/min, p < 0.001). The aPTT 24 h after argatroban initiation was 69 +/- 22 s, with 80% of patients having a therapeutic level of anticoagulation. Thirty-four argatroban-treated patients (41.5%) and 17 control patients (50.0%) experienced the 37-day composite end point of death, amputation, or new thrombosis (p = 0.32). Argatroban significantly reduced new thrombosis (8.5% vs 26.5%, p = 0.012). Major bleeding was similar between treatment groups (4.9% vs 2.9%, p = 0.684). CONCLUSIONS: Hepatic dysfunction affects argatroban dosing, with reduced doses required particularly in patients with serum total bilirubin levels > 25.5 micromol/L (1.5 mg/dL) or combined hepatic/renal dysfunction. Individual mean aPTT-adjusted doses typically remain > or = 0.5 microg/kg/min, supporting the recommendation of 0.5 microg/kg/min as a conservative initial dose for most patients with hepatic impairment. Argatroban, with proper initial dosing and monitoring, can provide safe and effective antithrombotic therapy in patients with HIT and hepatic impairment.

Effects of argatroban therapy, demographic variables, and platelet count on thrombotic risks in heparin-induced thrombocytopenia.

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

Anticoagulation strategies for treatment of ischemic stroke and antiphospholipid syndrome: case report and review of the literature.

A 49-year-old Caucasian man with antiphospholipid syndrome who experienced an ischemic stroke required multidisciplinary decisions regarding acute and long-term care. The patient first received warfarin and unfractionated heparin, followed by low-molecular-weight heparin. However, he developed complications from these drugs (warfarin-induced necrosis and heparin-induced thrombocytopenia), resulting in thigh necrosis and multiple additional cerebral and peripheral infarcts. His condition improved after warfarin and the heparins were discontinued, and a direct thrombin inhibitor, argatroban, was given intravenously for acute treatment. Argatroban is the only anticoagulant known to be safe in patients who experience an acute ischemic stroke in the setting of heparin-induced thrombocytopenia. For long-term anticoagulation, fondaparinux, an indirect, selective factor Xa inhibitor, was given subcutaneously. The patient received intravenous dexamethasone, later changed to azathioprine, for immunomodulatory treatment. He had significant improvement in his neurologic deficits without recurrent events over the next 18 months. Management of anticoagulation therapy in patients with antiphospholipid syndrome is complex and challenging, and therapeutic strategies need to be evaluated further.