Andreas Koster

Treatment and prevention of heparin-induced thrombocytopenia: American College of Chest Physicians Evidence-Based Clinical Practice Guidelines (8th Edition).

This chapter about the recognition, treatment, and prevention of heparin-induced thrombocytopenia (HIT) is part of the Antithrombotic and Thrombolytic Therapy: American College of Chest Physicians Evidence-Based Clinical Practice Guidelines (8th Edition). Grade 1 recommendations are strong and indicate that the benefits do, or do not, outweigh risks, burden, and costs. Grade 2 suggests that individual patient values may lead to different choices. Among the key recommendations in this chapter are the following: For patients receiving heparin in whom the clinician considers the risk of HIT to be > 1.0%, we recommend platelet count monitoring over no platelet count monitoring (Grade 1C). For patients who are receiving heparin or have received heparin within the previous 2 weeks, we recommend investigating for a diagnosis of HIT if the platelet count falls by >/= 50%, and/or a thrombotic event occurs, between days 5 and 14 (inclusive) following initiation of heparin, even if the patient is no longer receiving heparin therapy when thrombosis or thrombocytopenia has occurred (Grade 1C). For patients with strongly suspected (or confirmed) HIT, whether or not complicated by thrombosis, we recommend use of an alternative, nonheparin anticoagulant (danaparoid [Grade 1B], lepirudin [Grade 1C], argatroban [Grade 1C], fondaparinux [Grade 2C], or bivalirudin [Grade 2C]) over the further use of unfractionated heparin (UFH) or low-molecular-weight heparin (LMWH) therapy or initiation/continuation of vitamin K antagonists (VKAs) [Grade 1B]. The guidelines include specific recommendations for nonheparin anticoagulant dosing that differ from the package inserts. For patients with strongly suspected or confirmed HIT, we recommend against the use of vitamin K antagonist (VKA) [coumarin] therapy until after the platelet count has substantially recovered (usually, to at least 150 x 10(9)/L) over starting VKA therapy at a lower platelet count (Grade 1B); that VKA therapy be started only with low maintenance doses (maximum, 5 mg of warfarin or 6 mg of phenprocoumon) over higher initial doses (Grade 1B); and that the nonheparin anticoagulant (eg, lepirudin, argatroban, danaparoid) be continued until the platelet count has reached a stable plateau, the international normalized ratio (INR) has reached the intended target range, and after a minimum overlap of at least 5 days between nonheparin anticoagulation and VKA therapy rather than a shorter overlap (Grade 1B). For patients receiving VKAs at the time of diagnosis of HIT, we recommend use of vitamin K (10 mg po or 5 to 10 mg IV) [Grade 1C].

Hemostatic activation and inflammatory response during cardiopulmonary bypass: impact of heparin management.

Background Cardiac surgery involving cardiopulmonary bypass (CPB) leads to fulminant activation of the hemostatic–inflammatory system. The authors hypothesized that heparin concentration–based anticoagulation management compared with activated clotting time–based heparin management during CPB leads to more effective attenuation of hemostatic activation and inflammatory response. In a randomized prospective study, the authors compared the influence of anticoagulation with a heparin concentration–based system (Hepcon HMS; Medtronic, Minneapolis, MN) to that of activated clotting time–based management on the activation of the hemostatic–inflammatory system during CPB. Methods Two hundred elective patients (100 in each group) undergoing standard cardiac surgery in normothermia were enrolled. No antifibrinolytic agents or aprotinin and no heparin-coated CPB systems were used. Samples were collected after administration of the heparin bolus before initiation of CPB and after conclusion of CPB before protamine infusion. Results There were no differences in the pre-CPB values between both groups. After CPB there were significantly higher concentrations (P < 0.05) for heparin and a significant reduction in thrombin generation (25.2 ± 21.0 SD vs. 34.6 ± 25.1), d-dimers (1.94 ± 1.74 SD vs. 2.58 ± 2.1 SD), and neutrophil elastase (715.5 ± 412 SD vs. 856.8 ± 428 SD), and a trend toward lower &bgr;-thromboglobulin, C5b-9, and soluble P-selectin in the Hepcon HMS group. There were no differences in the post-CPB values for platelet count, adenosine diphosphate–stimulated platelet aggregation, antithrombin III, soluble fibrin, Factor XIIa, or postoperative blood loss. Conclusion Compared with heparin management with the activated clotting time, heparin concentration–based anticoagulation management during CPB leads to a significant reduction of thrombin generation, fibrinolysis, and neutrophil activation, whereas there is no difference in the effect on platelet activation. The generation of fibrin even in the presence of high heparin concentrations most likely has to be attributed to the reduced antithrombin III concentrations or reduced inhibition of clot-bound thrombin. Therefore, in addition to maintenance of higher heparin concentrations, monitoring and substitution of antithrombin III should be considered to ensure more efficient antithrombin activity during CPB.

Experience with over 1000 Implanted Ventricular Assist Devices

Abstract  Purpose: The use of ventricular assist devices (VADs) in patients with chronic end‐stage or acute heart failure has led to improved survival. We present our experience since 1987. Subjects and Methods: Between July 1987 and December 2006, 1026 VADs were implanted in 970 patients. Most of them were men (81.9%). The indications were: cardiomyopathy (n = 708), postcardiotomy heart failure (n = 173), acute myocardial infarction (n = 36), acute graft failure (n = 45), a VAD problem (n = 6), and others (n = 2). Mean age was 46.1 (range 3 days to 78) years. In 50.5% of the patients the VAD implanted was left ventricular, in 47.9% biventricular, and in 1.5% right ventricular. There were 14 different types of VAD. A total artificial heart was implanted in 14 patients. Results: Survival analysis showed higher early mortality (p < 0.05) in the postcardiotomy group (50.9%) than in patients with preoperative profound cardiogenic shock (31.1%) and patients with preoperative end‐stage heart failure without severe shock (28.9%). A total of 270 patients were successfully bridged to heart transplantation (HTx). There were no significant differences in long‐term survival after HTx among patients with and without previous VAD. In 76 patients the device could be explanted after myocardial recovery. In 72 patients the aim of implantation was permanent support. During the study period 114 patients were discharged home. Currently, 54 patients are on a device. Conclusions: VAD implantation may lead to recovery from secondary organ failure. Patients should be considered for VAD implantation before profound, possibly irreversible, cardiogenic shock occurs. In patients with postcardiotomy heart failure, a more efficient algorithm should be developed to improve survival. With increased experience, more VAD patients can participate in out‐patient programs.

Bivalirudin monitored with the ecarin clotting time for anticoagulation during cardiopulmonary bypass.

The problem of heparin-induced thrombocytopenia (HIT) among patients undergoing cardiac surgery is increasingly being appreciated. However, no safe standard anticoagulation strategy has been established for the management of these patients during cardiopulmonary bypass (CPB). Recombinant hirudin (r-

Inflammatory response after implantation of a left ventricular assist device: comparison between the axial flow MicroMed DeBakey VAD and the pulsatile Novacor device.

The implantation of a ventricular assist device (VAD) is associated with a stimulation of the inflammatory system. We compared changes in the inflammatory response after implantation of a pulsatile Novacor left (L) VAD and the axial flow MicroMed DeBakey VAD. Six consecutive patients after implantation of a Novacor LVAD (NC) and six patients after implantation of a MicroMed DeBakey VAD (MD) were included in the investigation. Patients received LVADs for medically non treatable end-stage heart failure. Tumor necrosis factor alpha (TNF), C3a, C5a, interleukin 6 (IL-6), and neutrophil elastase were measured twice a week over a period of 3 months after implantation of the device. All tests were performed with an enzyme-linked immunosorbent assay. There was no significant difference in the clinical course of the two groups. All inflammatory parameters were elevated in both groups during the entire period of the investigation. There was no difference in TNF, polynuclear leukocyte elastase, or C3a levels between the two groups; however, IL-6 (NC: 23.6 ± 37.6 pg/ml vs. MD: 63 ± 114 pg/ml, p < 0.001) and C5a (NC: 708 ± 352 &mgr;g/L vs. MD: 1,745 ± 1,305 &mgr;g/L, p < 0.001) were increased significantly more in patients following implantation of the axial flow MicroMed DeBakey VAD. Compared with the pulsatile Novacor device, the implantation of the axial flow MicroMed DeBakey LVAD seems to be associated with an increased stimulation of one part of the inflammatory system. Further investigations are necessary for evaluation of the pathophysiologic mechanism and clinical implications of these findings.

Anticoagulation during Cardiopulmonary Bypass in Patients with Heparin-induced Thrombocytopenia Type II and Renal Impairment Using Heparin and the Platelet Glycoprotein IIb-IIIa Antagonist Tirofiban

BackgroundPatients with heparin-induced thrombocytopenia type II require an alternative to standard heparin anticoagulation. However, in patients with renal impairment, anticoagulation during cardiopulmonary bypass with agents such as danaparoid sodium or r-hirudin are associated with hemorrhage. Anticoagulation with unfractionated heparins combined with prostacyclin, a potent platelet aggregation inhibitor, is associated with severe hypotension. The authors investigated a new concept using unfractionated heparins after platelet inhibition with the short-acting platelet glycoprotein IIb–IIIa antagonist tirofiban. MethodsTen patients with heparin-induced thrombocytopenia type II and renal impairment were enrolled in the investigation. All had heparin-induced thrombocytopenia type II antibodies present as proved by the heparin-induced platelet aggregation assay, the heparin–platelet factor 4 enzyme-linked immunosorbent assay, or both. In all patients, preoperative anticoagulation to an activated partial thromboplastin time of 40–60 s was performed with r-hirudin. Anticoagulation during cardiopulmonary bypass was achieved with a bolus of 400 IU/kg unfractionated heparins after a bolus of tirofiban 10 &mgr;g/kg followed by an infusion of tirofiban at a rate of 0.15 &mgr;g · kg−1 · min−1 until 1 h before conclusion of cardiopulmonary bypass. Additional unfractionated heparins were only administered if activated clotting time decreased below 480 s. Coagulation was monitored by a abciximab-modified TEG® and the adenosine diphosphate–stimulated (20 &mgr;m) platelet aggregometry. D-dimer concentrations, as a marker of venous thromboembolism, were measured before and 12, 24, and 48 h after surgery. Postoperative antithrombotic therapy was started immediately with r-hirudin to anticoagulation to an activated partial thromboplastin time of 40–60 s. ResultsThe postoperative blood loss ranged from 110 to 520 ml. No patient needed reexploration. In no patient was there clinical evidence of thrombosis or embolism in the postoperative period or of a critical increase of the D-dimer concentrations, suggesting venous thromboembolism. Transfusion of platelets was necessary in only two patients. ConclusionsThe protocol is easy to perform and no increased postoperative bleeding and no thromboembolic complications occurred. The combination of unfractionated heparins and tirofiban may be an alternative to other anticoagulation strategies in patients with heparin-induced thrombocytopenia.

Alterations in coagulation after implantation of a pulsatile novacor LVAD and the axial flow micromed DeBakey LVAD

BACKGROUND The MicroMed DeBakey left ventricular assist device (LVAD) is a chamber and valveless axial flow blood pump. We investigated parameters of the coagulation system in patients after implantation of the axial flow LVAD and patients following implantation of a pulsatile Novacor LVAD. METHODS Six consecutive patients of both groups were investigated over a period of 6 weeks after implantation. beta-Thromboglobulin, platelet factor 4, factor XIIa, thrombin/antithrombin complexes, plasmin/alpha2-antiplasmin complexes, and D-Dimer levels were measured. RESULTS With the exception of the plasmin/alpha2-antiplasmin levels in the Novacor group, all parameters were elevated in both groups. The levels of beta-thromboglobulin, platelet factor 4, factor XIIa, and plasmin/alpha2-antiplasmin were significantly increased in the axial flow LVAD group. CONCLUSIONS The axial flow LVAD strongly influences the systems of contact activation and fibrinolysis. The elevation of platelet proteins appears to follow platelet damage. Although no thromboembolic events were observed in both groups, elevation of thrombin/antithrombin complexes provides convincing evidence of an increased activation of the coagulation system and the concomitant risk for the development of thromboembolism.

Results of a consensus meeting on the use of argatroban in patients with heparin-induced thrombocytopenia requiring antithrombotic therapy – A European Perspective

Argatroban has been introduced as an alternative parenteral anticoagulant for HIT-patients in several European countries in 2005. In 2009 a panel of experts discussed their clinical experience with argatroban balancing risks and benefits of argatroban treatment in managing the highly procoagulant status of HIT-patients. This article summarizes the main conclusions of this round table discussion. An ongoing issue is the appropriate dosing of argatroban in special patient groups. Therefore, dosing recommendations for different HIT-patient groups (ICU patients; non-ICU patients, paediatric patients, and for patients undergoing renal replacement therapies) are summarized in this consensus statement. Because of the strong correlation between argatroban dosing requirements and scores used to characterize the severity of illness (APACHE; SAPS, SOFA) suitable dosing nomograms are given. This consensus statement contributes to clinically relevant information on the appropriate use and monitoring of argatroban based on the current literature, and provides additional information from clinical experience. As the two other approved drugs for HIT, danaparoid and lepirudin are either currently not available due to manufacturing problems (danaparoid) or will be withdrawn from the market in 2012 (lepirudin), this report should guide physicians who have limited experience with argatroban how to use this drug safely in patients with HIT.

Heparin-induced thrombocytopenia in patients with ventricular assist devices: are new prevention strategies required?

Heparin-induced thrombocytopenia (HIT) is caused by platelet-activating antiplatelet factor 4/heparin antibodies. However, clinical HIT (thrombocytopenia or thrombosis, or both) develops in only a minority of patients who form antibodies. It is difficult to distinguish HIT from non-HIT thrombocytopenia in patients after ventricular assist device (VAD) implantation. Further, the risks of heparin-induced immunization and clinical HIT approach 65% and 10%, respectively, in this patient population, with a particularly high risk of cerebrovascular ischemia/infarction. Given the apparent high risk of HIT and its complications, and the diagnostic challenges, we suggest that the VAD patient population be evaluated using alternative, nonheparin agents for routine postimplantation anticoagulation.

An assessment of different filter systems for extracorporeal elimination of bivalirudin: an in vitro study

IMPLICATIONS Bivalirudin is a new, direct thrombin inhibitor. We investigated the extracorporeal elimination rate of different hemofilters and one plasmapheresis filter for bivalirudin. Our data show that bivalirudin can be effectively eliminated via hemofiltration and plasmapheresis, although there were significant differences in the elimination rates among the filter systems investigated.