Thromboelastographic evaluation of blood coagulation in the presence of branded and generic enoxaparins.

AIM: Enoxaparin is the most widely used low-molecular-weight heparin (LMWH) in the USA and has been approved for clinical use in multiple indications. Enoxaparin is a complex biological product with multiple known activities relevant to its antithrombotic effects, and variations in different forms of enoxaparin may have important clinical implications. This study aimed to compare the physiological anticoagulant activity of branded and a generic enoxaparin, using thromboelastography (TEG) to evaluate their effect on the dynamic formation of the blood clot as quantitated by interactions between coagulation factors and inhibitors, fibrinogen, platelets and the fibrinolytic system. METHODS: Whole native (no preservative) blood was obtained from 7 healthy volunteers. Samples were immediately mixed with various concentrations of branded or generic enoxaparin and TEG was performed to assess anticoagulant activity. Five different batches of each enoxaparin (branded and generic) were tested. RESULTS: Generic enoxaparin showed more variation in anticoagulation response with a less predictable concentration-dependent and linear response compared with branded enoxaparin. There was also an apparent batch-to-batch variation for generic enoxaparin. The results demonstrated a lower overall anticoagulant effect (P=0.05; no overlap of 95% confidence intervals) with a wider inter-individual variation for generic enoxaparin in comparison with branded enoxaparin. Some individuals responded with a higher than expected anticoagulant response to the given concentration of the generic enoxaparin. CONCLUSION: The findings of this study suggest that other pre-clinical and clinical studies should be done to validate the clinical interchangeability between branded and generic enoxaparin.

Evaluation of a new point of care heparin test for cardiopulmonary bypass: the TAS heparin management test.

Patients undergoing cardiopulmonary bypass (CPB) require anticoagulation with heparin to avoid thrombosis within the bypass circuit. The common method used to monitor the degree of anticoagulation is the activated clotting time (ACT). We evaluated a novel point of care device, the TAS (Pharmanetics, Raleigh, NC, USA) heparin management test (HMT), for its suitability in monitoring anticoagulation during CPB. In vitro analysis showed a dose-response (r2=0.988) of the HMT from 0.078-10.0 U/ml heparin, covering the range of heparin used during cardiac surgery (2-5 U/ml). Fifty randomly selected patients undergoing CPB were studied. Preheparin clotting times for these patients were 143+/-32 s for the HMT and 146+/-18 s for the ACT; 435+/-60 s HMT and 438+/-39 s ACT during CPB; 145+/-50 s HMT and 128+/-14 s ACT post-protamine (r2=0.797). epsilon-Aminocaproic acid treatment for inhibition of fibrinolysis did not affect the HMT. We conclude that the HMT correlates well with the ACT and may be useful for monitoring heparin during CPB. Advantages of the HMT are small sample volume and good sensitivity to heparin.

Methylprednisolone does not benefit patients undergoing coronary artery bypass grafting and early tracheal extubation.

OBJECTIVE: We sought to determine whether methylprednisolone, when administered to patients undergoing cardiac surgery, is able to ward off the detrimental hemodynamic and pulmonary alterations associated with cardiopulmonary bypass. METHODS: After institutional review board approval and informed consent was obtained, 90 patients scheduled for elective cardiac surgery were randomized to 1 of 3 groups. Group 30MP patients received 30 mg/kg intravenous methylprednisolone during sternotomy and 30 mg/kg during initiation of cardiopulmonary bypass, group 15MP patients received 15 mg/kg methylprednisolone at the same 2 times, and group NS patients received similar volumes of isotonic sodium chloride solution at the same 2 times. Perioperative care was standardized, and all caregivers were blinded to treatment group. Various hemodynamic and pulmonary measurements were obtained perioperatively, as well as fluid balance, weight, peak postoperative blood glucose level, and tracheal extubation time. RESULTS: Demographic and clinical characteristics of patients and intraoperative data were similar among the 3 groups. Patients receiving methylprednisolone (either dose) exhibited significantly increased cardiac index (P =.0006), significantly decreased systemic vascular resistance (P =.0005), and significantly increased shunt flow (P =.0020) during the immediate postoperative period. All 3 groups exhibited significant increases in alveolar-arterial oxygen gradient (P <.0001), significant decreases in dynamic lung compliance (P <.0001), and significant decreases in static lung compliance (P <.0001) during the immediate postoperative period, with no differences between groups. Perioperative fluid balance and weights were similar between groups. A statistically significant difference in peak postoperative blood glucose level existed (P =.016) among group NS (234 +/- 96 mg/dL), group 15MP (292 +/- 93 mg/dL), and group 30MP (311 +/- 90 mg/dL). In patients extubated within 12 hours of intensive care unit arrival, a statistically significant difference in extubation times existed (P =.025) between group NS (5.7 +/- 2.3 hours), group 15MP (5.9 +/- 2.2 hours), and group 30MP (7.5 +/- 2.7 hours). CONCLUSIONS: Methylprednisolone, as used in this investigation, offers no clinical benefits to patients undergoing elective coronary artery bypass grafting with cardiopulmonary bypass and may in fact be detrimental by initiating postoperative hyperglycemia and possibly hindering early postoperative tracheal extubation for undetermined reasons.

Emerging anticoagulant and thrombolytic drugs.

Since its discovery, heparin has been used intensely as an anticoagulant for several medical and surgical indications. However, efforts are in progress to replace heparin because of its serious complications, such as intraoperative and postoperative bleeding, osteoporosis, alopecia, heparin resistance, heparin rebound, heparin-induced thrombocytopenia (HIT) and thrombosis syndrome (HITTS), and other disadvantages. Significant developments in the field of new anticoagulants have resulted in the evaluation and introduction of low molecular weight heparins (LMWHs) and heparinoids, hirudin, ancrod, synthetic peptides and peptidomimetics. However, despite significant progress in the development of these new anticoagulants, a better or an ideal anticoagulant for cardiovascular patients is not yet available and heparin still continues to amaze both basic scientists and the clinicians. To minimise the adverse effects of heparin, newer approaches to optimise its use in combination with the new anticoagulants may provide better clinical outcome. In our experience, the off-label use of argatroban at a dose of 300 microg/kg iv. bolus followed by 10 microg/kg/minute infusion in combination with aggrastat (a glycoprotein [GP] IIb/IIIa inhibitor) at a dose of 10 microg/kg iv. bolus followed by an infusion of 0.15 microg/kg/minute in patients with HIT undergoing percutaneous coronary interventions resulted in elevation of celite activated clotting time (ACT) to 300 seconds followed by a gradual decline and the ACT remained above 200 seconds even after 200 min of drug administration. A bewildering array of newer anticoagulants now exist, such as LMWHs and heparinoids, indirect or direct thrombin inhibitors, oral thrombin inhibitors, such as melagatran (AstraZeneca) and HC-977 (Mitsubishi Pharmaceuticals), Factor IXa inhibitors, indirect or direct Factor Xa inhibitors, Factor VIIa/tissue factor (TF) pathway inhibitor, newer antiplatelet agents, such as GPIIb/IIIa inhibitors, fibrin specific thrombolytic agent, such as tenecteplase and modulation of the endogenous fibrinolytic activity by thrombin activatable fibrinolytic inhibitor (TAFI), Factor XIIIa inhibitors and PAI-1 inhibitors. The quest for newer anticoagulant, antiplatelet and fibrinolytic agents will continue until ideal agents are found.

Protective ventilation attenuates postoperative pulmonary dysfunction in patients undergoing cardiopulmonary bypass.

OBJECTIVE: To ascertain if protective ventilation can attenuate the damaging postoperative pulmonary effects of cardiopulmonary bypass (increases in airway pressure, decreases in lung compliance, and increases in shunt). DESIGN: Prospective, randomized clinical trial. SETTING: Single university hospital. PARTICIPANTS: Twenty-five patients undergoing elective coronary artery bypass graft procedure and early extubation. INTERVENTIONS: Thirteen patients received conventional mechanical ventilation (CV; respiratory rate, 8 breaths/min; tidal volume, 12 mL/kg; fraction of inspired oxygen [FIO2], 1.0; positive end-expiratory pressure [PEEP], +5), and 12 patients received protective mechanical ventilation (PV; respiratory rate, 16 breaths/min; tidal volume, 6 mL/kg; FIO2, 1.0; PEEP, +5). Perioperative anesthetic and surgical management were standardized. Various pulmonary parameters were determined twice perioperatively: 10 minutes after intubation and 60 minutes after arrival in the intensive care unit. MEASUREMENTS AND MAIN RESULTS: The mean postoperative increase in peak airway pressure in group CV was significantly larger than the mean postoperative increase in peak airway pressure in group PV (7.1 v 2.4 cm H2O; p < 0.001). Group CV experienced significant postoperative increases in plateau airway pressure (p = 0.007), but group PV did not (p = 0.644). The mean postoperative decrease in dynamic lung compliance in group CV was significantly larger than the mean postoperative decrease in dynamic lung compliance in group PV (14.9 v 5.5 mL/cm H2O; p = 0.002). Group CV experienced significant postoperative decreases in static lung compliance (p = 0.014), but group PV did not (p = 0.645). Group CV experienced significant postoperative increases in shunt (15.5% to 21.4%; p = 0.021), but group PV did not (18.4% to 21.2%; p = 0.265). CONCLUSIONS: Data indicate that protective ventilation decreases pulmonary damage caused by mechanical ventilation in normal and abnormal lungs. The results of this investigation indicate that protective ventilation may also help attenuate the postoperative pulmonary dysfunction (increases in airway pressure, decreases in lung compliance, and increases in shunt) commonly seen in patients after exposure to cardiopulmonary bypass.

Severe incisional pain and long thoracic nerve injury after port-access minimally invasive mitral valve surgery.

The authors describe the occurrence of severe postoperative pain and long thoracic nerve injury after Port-Access minimally invasive mitral valve surgery. The potential for these events and the impact on postoperative hospitalization and rehabilitation are emphasized.

Port-access minimally invasive cardiac surgery increases surgical complexity, increases operating room time, and facilitates early postoperative hospital discharge.

BACKGROUND: Proposed advantages of port-access cardiac surgery have yet to be substantiated. The authors retrospectively compared patients undergoing port-access cardiac surgery with a matched group undergoing conventional cardiac surgery. METHODS: Forty-six patients who underwent port-access cardiac surgery were matched with 46 who underwent conventional cardiac surgery. Absolute criteria for matching included morning-of-surgery admission, procedure undergone, and care being delivered by one of two surgeons. If possible, matching included care delivered by one of two anesthesiologists. Patients were matched as closely as possible for preoperative demographic and clinical characteristics. RESULTS: All 46 pairs of patients were matched for procedure and admitted the morning of surgery. All 92 operations were performed by one of two surgeons, and 89% were performed by one of two anesthesiologists. Preoperative demographic and clinical characteristics were equivalent between groups. Compared with conventional cardiac surgery, port-access cardiac surgery increased surgical complexity (it almost tripled cardiopulmonary bypass time during coronary artery bypass grafting and increased it almost 40% during mitral valve procedures) and increased total operating room time (P < 0.0001). Port-access cardiac surgery had no beneficial effect on earlier postoperative extubation, decreased incidence of atrial fibrillation, or intensive care unit time, yet it decreased postoperative duration of stay (P = 0.029, all patients), a benefit observed primarily in patients undergoing coronary artery bypass grafting (P = 0.002). CONCLUSIONS: This retrospective analysis revealed that port-access cardiac surgery increases surgical complexity, increases operating room time, has no effect on earlier postoperative extubation or decreased incidence of atrial fibrillation or intensive care unit time, and may facilitate postoperative hospital discharge (primarily in patients undergoing coronary artery bypass grafting). Properly designed prospective investigation is necessary to ascertain whether port-access cardiac surgery truly offers any benefits over conventional cardiac surgery.

Bleeding complications with glycoprotein IIb/IIIa inhibitors.

The new class of antiplatelet drugs, the GPIIb/IIIa inhibitors, has proven to be effective in acute coronary syndromes including unstable angina and myocardial infarction as well as adjunct therapy for coronary interventions for preventing morbidity and mortality. As these drugs inhibit the final common pathway of platelet activation, effectively blocking the platelet aggregation response, potential bleeding is a concern with their use. The risk of bleeding has been demonstrated to be higher in patients treated with combination drug therapy (heparin, aspirin, thienopyridines, thrombolytics, oral anticoagulants), when antithrombotic drugs are not given on an individual weight basis and with late removal of vascular access sheaths. The early clinical trials have defined modifications in patient management that have effectively reduced bleeding. Pooled data from the more recent clinical trials, mostly in coronary intervention enrolling over 27,000 patients, show a bleeding rate of 3.6% in the drug group and 2.3% in the placebo group. Although this is acceptable, several unresolved issues remain to be addressed regarding the GPIIb/IIIa inhibitors. Thrombocytopenia occurs infrequently with all GPIIb/IIIa inhibitors but can be severe. The use of these drugs by oral administration presents new challenges with determining optimal dosing, drug-drug interactions and long-term effects. Incorporating point-of-care monitoring may enable better titration of these drugs to avoid bleeding complications. GPIIb/IIIa inhibitors are destined to become a mainstay therapy for cardiovascular treatment and over time these issues should be resolved.

Attempting to maintain normoglycemia during cardiopulmonary bypass with insulin may initiate postoperative hypoglycemia.

UNLABELLED: We attempted to develop an insulin administration protocol that maintains normoglycemia in patients undergoing cardiac surgery and to study the effects of intraoperative blood glucose management on serum levels of creatine phosphokinase isoenzyme BB (CK-BB) and S-100 protein. Twenty nondiabetic patients were randomly allocated to receive either "tight control" of blood glucose with a standardized IV insulin infusion intraoperatively (Group TC) or "no control" of blood glucose intraoperatively (Group NC). Perioperative serum levels of glucose, CK-BB, and S-100 protein were determined in all patients. Group TC patients received 90.0 +/- 49.2 units of insulin, whereas Group NC patients received none. Despite insulin, both Group TC (P = 0.00026) and Group NC (P = 0.00003) experienced similar significant increases in blood glucose levels during hypothermic cardiopulmonary bypass. However, mean blood glucose level upon intensive care unit arrival was significantly decreased in Group TC, compared with Group NC (84.7 +/- 41.0 mg/dL, range 32-137 mg/dL vs 201.4 +/- 67.5 mg/dL, range 82-277 mg/dL, respectively; P = 0.0002). Forty percent of Group TC patients required treatment for postoperative hypoglycemia (blood glucose level <60 mg/dL). Substantial interindividual variability existed in regard to insulin resistance. The investigation was terminated after we realized that normoglycemia was unattainable with the study protocol and that postoperative hypoglycemia was unpredictable. All patients in both groups experienced similar significant increases in postoperative serum levels of CK-BB and S-100 protein. These results indicate that "tight control" of intraoperative blood glucose in nondiabetic patients undergoing cardiac surgery was unattainable with the study protocol and may initiate postoperative hypoglycemia. IMPLICATIONS: The appropriate intraoperative management of hyperglycemia and whether it adversely affects neurologic outcome in patients after cardiac surgery remains controversial. This investigation reveals that attempting to maintain normoglycemia in this setting with insulin may initiate postoperative hypoglycemia.

Intrathecal morphine for coronary artery bypass graft procedure and early extubation revisited.

OBJECTIVE: To determine the dose of intrathecal (IT) morphine (along with the intraoperative baseline anesthetic) that provides significant analgesia yet does not delay extubation in the immediate postoperative period in patients undergoing cardiac surgery and early extubation. DESIGN: Prospective, randomized, double-blinded, placebo-controlled clinical study. SETTING: Single university hospital. PARTICIPANTS: Forty patients undergoing elective coronary artery bypass graft procedure and early extubation. INTERVENTIONS: Twenty patients received 10 microg/kg of IT morphine, and 20 patients received IT placebo. Perioperative anesthetic management was standardized and included postoperative patient-controlled morphine analgesia. MAIN RESULTS: Of the patients tracheally extubated during the immediate postoperative period, mean time to extubation was similar in patients who received IT morphine (6.8+/-2.8 h) or IT placebo (6.5+/-3.2 h). Four patients who received IT morphine had extubation substantially delayed because of prolonged ventilatory depression. There was no difference between groups in postoperative patient-controlled morphine analgesia use. CONCLUSION: Even when used in conjunction with an intraoperative baseline anesthetic that allows early extubation, IT morphine (10 microg/kg) was unable to provide substantial postoperative analgesia. The risks of using IT morphine in patients undergoing cardiac surgery and early extubation may outweigh the potential benefits.

Laboratory tests for the diagnosis of heparin-induced thrombocytopenia.

Heparin-induced thrombocytopenia (HIT) is associated with high morbidity and mortality. Because the pathophysiology of this complex disorder has remained unclear, so has the development of supportive diagnostic laboratory assays. The currently available laboratory methods for HIT diagnosis include several platelet function assays: the platelet aggregation assay, platelet aggregation with simultaneous measurement of ATP release (lumi-aggregometry), the serotonin release assay, and flow cytometric assays. ELISA assays, which quantitate anti-heparin/platelet factor 4 antibody titers, have recently become available. Assay characteristics for these assays were studied using sera collected from clinically diagnosed HIT patients with and without thrombosis, normal individuals, various types of hospitalized patients without HIT, heparin or low molecular weight heparin-treated patients without HIT, and patients with platelet-immune disorders other than HIT. The results of our studies suggest that none of the assays can be considered a "gold standard" for the laboratory diagnosis of HIT as many false-negative and false-positive results were obtained. Furthermore, antibodies against the heparin/platelet factor 4 complex, as identified by the current ELISA tests, are not the sole cause of HIT since many patients lacking clinical symptoms associated with HIT exhibited high antibody titers following heparin treatment. An assay using flow cytometry, being developed for HIT testing, will be described. At this time, clinical impression remains important for the diagnosis of HIT.

Comparison of two PF4/heparin ELISA assays for the laboratory diagnosis of heparin-induced thrombocytopenia.

Serum samples from 105 patients with suspected heparin-induced thrombocytopenia (HIT) were evaluated using the 14C-serotonin release assay (SRA), considered the "gold standard" for the diagnosis of HIT, and two enzyme-linked immunosorbent assays (ELISA) that measure anti-platelet factor (PF) 4/heparin antibodies to determine the performance characteristics of the newly available ELISA assays. Relative to the SRA, the sensitivity and specificity of the Asserachrom HPIA assay were 73% and 77%, respectively, in this population of patients. The sensitivity and specificity of the GTI-HAT assay were 60% and 93%, respectively. In serum negative by SRA, GTI-HAT and HPIA detected antibodies in 9% and 25%, respectively. Antibodies were detected by HPIA in 18% of the sera negative by both SRA and GTI-HAT. In a second study, samples evaluated from patients (n = 10) treated for established thrombosis with a low-molecular-weight heparin and who had no decrease in platelet counts, showed a weak antibody titer in 50% of the patients after 12 days of therapy by GTI-HAT, whereas the HPIA identified a strong antibody titer in 75% of the patients after 4 days. These data suggest that the currently available ELISA methods for the detection of anti-PF4/heparin antibodies offer a limited sensitivity and specificity in comparison to SRA. The ELISA assays on their own are thus of limited value for the laboratory diagnosis of HIT. SRA-positive sera do not always have positive antibody titers, and antibodies can be present in SRA-negative sera. Furthermore, these data show that ELISA methods differ in their relative sensitivities and specificities for the detection of anti-PF4/heparin antibodies.

Coagulation laboratory testing in patients treated with argatroban.

During clinical trials with the thrombin inhibitor argatroban, appropriate methods for drug monitoring were identified. Treated patients presented interesting challenges for coagulation laboratory parameter testing in the presence of argatroban. These issues are reported here. Regarding the monitoring of argatroban, the aPTT and ACT were effectively used clinically for low (0-2.5 microg/mL) or high (1-15 microg/mL) doses of argatroban. However, system (reagent and instrument) differences were noted in the time-to-clot values. A clot-based assay using Ecarin as the activator (ECT, Ecarin clotting time) appeared to be useful for monitoring both low and high drug levels with less interference from other drugs or coagulation defects. Also identified were the chromogenic antithrombin assay that could directly quantify argatroban and an HPLC based assay that could specifically quantify argatroban and its metabolites. With regard to assay interference by argatroban, several important effects were observed. The presence of argatroban synergistically interfered with the INR for those patients treated with oral anticoagulants. However, a chromogenic based method was able to determine factor X levels as a monitor of the oral anticoagulation without effect from argatroban. A similar synergistic response on the aPTT with heparin and argatroban was observed. Patients receiving argatroban evaluated for potential coagulation abnormalities could not be tested with the routine functional (clot based) assays for fibrinogen, factor levels or protein C. Argatroban acted as an inhibitor in these assays, causing a dose-dependent false decrease of fibrinogen and factor levels, and a false increase of protein C. Using a chromogenic assay for protein C, values equal to those obtained by an immunologic assay were achieved. These issues will most likely hold true for all thrombin inhibitors.

Clinical experience with combined treatment of thrombin inhibitors and GPIIb/IIIa inhibitors in patients with HIT.

Despite the use of potent anticoagulants such as r-hirudin and argatroban, the morbidity/mortality of heparin-induced thrombocytopenia (HIT) patients remains high. In the last several months, we have treated three HIT-positive patients with a combined therapy of thrombin inhibitor and GPIIb/IIIa inhibitor when treatment with thrombin inhibitor alone failed to alleviate acute thrombosis. Combination therapies included r-hirudin (Refludan) with tirofiban (Aggrastat) or argatroban (Novastan) with ReoPro. A reduced dose of the thrombin inhibitor with the standard dose of the antiplatelet drug was the dosing regimen used. In all cases, there was no overt bleeding that required intervention and all patients had improved or fully recovered. This first report of the use of GPIIb/IIIa inhibitors with thrombin inhibitors in HIT patients with active thrombosis suggests that this combined therapy may be more effective than thrombin inhibitor treatment alone. The data from these three cases warrant testing of this therapeutic regimen in larger studies to determine optimal dosing strategies.

Hemodynamic effects of methylprednisolone in patients undergoing cardiac operation and early extubation.

BACKGROUND: Whether or not methylprednisolone is beneficial during cardiac operation remains controversial. This study examines the effects of the drug on complement activation and hemodynamics in patients undergoing cardiac operation and early extubation. METHODS: Patients undergoing cardiac operation were randomized to receive either intravenous methylprednisolone (group MP) or intravenous placebo (group NS). Complement 3a (C3a) levels and hemodynamic parameters were obtained perioperatively. Extubation was accomplished at the earliest clinically appropriate time. RESULTS: Both groups exhibited equivalent increases in C3a levels after exposure to bypass. Group MP exhibited increased cardiac index, decreased systemic vascular resistance, and increased shunt flow when compared to group NS. More group MP patients required hemodynamic support and group MP patients had prolonged extubation times. CONCLUSIONS: Methylprednisolone was unable to attenuate complement activation and led to hemodynamic alterations (primarily vasodilation) that may hinder early extubation in patients after cardiac operations.

Semilunar valve switch procedure: autotransplantation of the native aortic valve to the pulmonary position in the Ross procedure.

BACKGROUND: The Ross procedure has gained wide acceptance in young patients with aortic valve disease. The durability of the pulmonary autograft in the aortic position has been proved, with up to 24 years of follow-up. The homograft pulmonary valve, however, has limited longevity. To circumvent this problem we harvested, repaired, and reimplanted the native aortic valve with intact commissures in the pulmonary position in 13 patients undergoing the Ross procedure for aortic insufficiency. METHODS: The cause of aortic insufficiency was rheumatic in 6 patients, congenital in 4, post-aortic valvotomy in 2, and bacterial endocarditis in 1. Patient age ranged from 5 to 45 years (mean, 17+/-9 years). Root replacement technique with coronary artery reimplantation was used. In the first 4 patients, the native aortic valve was sutured into the right ventricular outflow tract, and a polytetrafluorethylene patch was used to reconstruct the main pulmonary artery. In the last 9 patients, the aortic valve and polytetrafluorethylene patch were made into a conduit by another surgeon while the left-sided reconstruction was performed. RESULTS: All patients had marked reduction of left ventricular dilation and good function of the reimplanted native aortic valve, with up to 50 months of follow-up (mean, 29.9+/-14.2 months; range, 12 to 50 months). Two patients died 15 and 26 days, respectively, of a false aneurysm rupture at the distal aortic anastomosis. In the remaining 11 patients, 9 (82%) had mild or absent, and 2 (18%) had mild to moderate, neoaortic valve regurgitation. Similarly, 9 patients (82%) had mild or absent, and 2 (18%) had mild to moderate, neopulmonary valve regurgitation. Mild neopulmonary valve stenosis was present in 6 patients (54%) (mean gradient, 29+/-4 mm Hg; range, 25 to 35 mm Hg). All surviving patients are in functional New York Heart Association functional class I. CONCLUSIONS: We conclude that use of the native aortic valve with the Ross procedure makes the procedure attractive and potentially curative. The diseased aortic valve works well in the pulmonary position because of lower pressure and resistance. The valve leaflets should remain viable and grow in both the pulmonary and aortic positions because they derive nutrition directly from the blood.

Laboratory tests for heparin-induced thrombocytopenia: a multicenter study.

A multicenter clinical trial of the thrombin inhibitor argatroban (Novastan; Texas Biotechnology, Houston, TX; Smith-Kline Beecham Pharmaceuticals, Philadelphia, PA) was recently conducted in patients with heparin-induced thrombocytopenia (HIT) and HIT that had progressed to thrombosis (HITTS). In patients defined by the inclusion/exclusion criteria, the utility of three diagnostic HIT assays was investigated: the platelet aggregation assay, the serotonin release assay (SRA), and the enzyme-linked immunosorbent assay (ELISA) for the antibody to the heparin-platelet factor 4 (H-PF4) complex. Confirmation was made in 26%, 55%, and 64% of the patients, respectively (n = 199 patients; 512 to 606 samples; P < .001 platelet aggregation assay v SRA v ELISA). Patients who progressed to HITTS (n = 98) were more often confirmed than were HIT patients without associated thrombosis (n = 101) (P < .05). Confirmation by platelet aggregation assay and SRA results generally was associated with a higher antibody titer. However, a minimum critical titer could not be identified, because all patterns of positive and negative results by the platelet aggregation assay, SRA, and ELISA were observed, and clinically ill patients had a wide range of antibody titers. Over a 30-day period, the percentage of positive responses did not change. Although multiple testing over several days enhanced the chance of confirmation, this difference was not significant. Combined results of the three assays enhanced the positive response to 83% of the total population (P < .005). These data demonstrate that there is no direct correlation between the positive response of these assays, and that clinically positive HIT patients can be missed by all three assays. With these limitations, the combination of platelet aggregation assay, SRA, and ELISA testing with multiple samples offers the best chance of confirming a positive HIT patient. Caution is advised, however, in interpreting all assay results, as no assay is optimal.