Incidence Of HIT Research Articles

Incidence of heparin-PF4 complex antibody formation and heparin-induced thrombocytopenia in acute coronary syndrome

A multicenter prospective study on the rate of seroconversion of antibodies to heparin-PF4 complexes (heparin-induced thrombocytopenia [HIT] antibodies) during and after heparin treatment for 4 weeks was carried out in Japanese patients with acute coronary syndrome (ACS). A total of 254 ACS patients treated with heparin were enrolled consecutively from 12 facilities of cardiology. Two patients with preexisting HIT antibodies were excluded from the analysis. The total seroconversion rate for four weeks during and after heparin treatment was 8.7% ( n=22, 95% confidence interval [CI]: 5.9–13.1), including values of 3.2% ( n=8) at the end of heparin infusion and 5.5% ( n=14) at 4 weeks. Among 22 seroconverted patients, four developed HIT and two of the four had the complication of thrombosis. The incidence of HIT was 1.6% ( n=4, 95% CI: 0.04–3.1). The risk for thromboembolic development was higher in the seroconverted patients (odds ratio, 17.4, 95% CI: 5.2–58.4, p<0.0001) than nonconverted patients. An analysis of factors affecting the seroconversion rate was carried out. The seroconversion rate for ACS patients who underwent percutaneous coronary intervention (PCI; n=163) was 12.3%, significantly higher than the 2.3% in patients who did not undergo PCI ( n=89), leading to an odds ratio of 6.1 (95% CI: 1.4–26.7, p=0.009). A significant odds ratio was obtained for each factor affecting the seroconversion: 3.5 (95% CI: 1.3–9.9, p=0.014) for more than 5 days of heparin infusion, 3.0 (95% CI: 1.2–7.6, p=0.035) for a thrombotic history and 2.7 (95% CI: 1.1–6.8, p=0.039) for hyperlipidemia. No other factor, including age or diabetes mellitus, contributed to the seroconversion. Therefore, PCI, duration of heparin treatment and thrombotic history facilitated the seroconversion in ACS patients. PCI patients treated for more than 5 days with heparin showed a maximal seroconversion rate of 18.3% (95% CI: 13.8–22.2). This high rate in PCI patients did not interact with age, type of underlying disease of unstable angina or myocardial infarction or thrombotic history. In conclusion, ACS patients demonstrating seroconversion are at risk of thromboembolic development due to the likelihood of immunomediated endothelial dysfunction. The increase in the rate of seroconversion in ACS patients would be affected by factors such as PCI with mechanical stress, longer duration of heparin treatment, thrombotic history and presence of hyperlipidemia. If PCI is undertaken with heparin anticoagulation for more than 5 days, seroconversion would easily occur, and the seroconverted patients could subsequently suffer from HIT.

Laboratory diagnosis of heparin-induced thrombocytopenia and monitoring of alternative anticoagulants.

The major complication in the therapeutic or prophylactic use of heparin in medical treatment is type II heparin-induced thrombocytopenia (HIT II), a unique form of drug-induced immune-mediated thrombocytopenia. Due to the extensive use of heparin, this side effect is widespread; up to 3% of patients treated with unfractionated heparin (UFH) develop HIT II (69). Clinically, HIT II is characterized by thrombocytopenia which paradoxically is associated with thrombosis (HIT IIinduced thrombosis [HITTS]) (i.e., deep vein thrombosis, pulmonary embolism, and venous gangrene) in about 50% of the cases. In the pathogenesis of HIT II, the formation of platelet factor 4 (PF4)/heparin complexes seems to be the major determinant (2, 3, 20). The binding of PF4 to heparin induces antibody production directed against a neoepitope created by the three-dimensional assembly of PF4 and heparin. Subsequently, PF4/heparin-antibody complexes induce platelet activation, followed by the shedding of platelet microparticles, thrombin generation, and the involvement of endothelial cells (Fig. 1). Remarkably, the incidence of HIT II, HIT II-associated thrombotic complications, and PF4/heparin-antibodies (HIT II antibodies) in patients receiving therapy with UFH is clearly dependent on the clinical setting of the patient. Cardiosurgical patients are at a high risk to develop HIT II antibodies, while orthopedic patients undergoing hip replacement have a high risk for developing thromboembolic complications (Iceberg model [66]). In medical patients the risk for developing HIT II is substantially lower. Comparing low-molecular-weight heparins (LMWH) with UFH, the use of LMWH coincides with a substantially lower risk of HIT II, but this effect holds true only within the same group of patients (77, 78). It is generally accepted that the clinical diagnosis of HIT II should be followed by immediate cessation of heparin therapy and initiation of therapy with alternative anticoagulants. Negative results in the concomitant laboratory testing should not serve as the sole criterion for restarting heparin therapy. In almost every case of HIT II, administration of alternative anticoagulants is essential either to continue prophylactic anticoagulation or to treat and prevent thrombotic complications due to HIT II. Three substances (danaparoid, hirudin, and argatroban) are available. Since these substances have not been compared directly with each other in the treatment of HIT II, criteria such as half-life and/or route of excretion should be considered for selection. This review focuses on (i) the present laboratory methods for diagnosing HIT II, including their principles, time consumption, and significance, and (ii) the alternative anticoagulants, including their characteristics and indications in certain clinical settings.

Clinical relevance of intracranial high intensity transient signals in patients following prosthetic aortic valve replacement.

There has been frequent report on transcranially detected microembolic signals (HITS) following cardiac surgery using extracorporeal bypass support. The clinical relevance of HITS, however, has yet to be clarified. The incidence of thromboembolic events is increased following mechanical heart valve replacement. The purpose of this study was to quantify postoperative HITS after implantation of two types of prosthetic aortic valves and to compare both types of mechanical valves with respect to the generation of HITS. In addition, HITS rates were correlated with clinical, echocardiographical and laboratory findings. Forty-two patients following implantation of either a Sorin Biomedica heart valve (n=22, group A) or a Tekna Duromedics mechanical valve (n=20, group B) were examined. A group of ten healthy volunteers served as control. Clinical, echocardiographic, carotid artery duplex and laboratory examinations were performed in all patients. A 60 min bilateral transcranial doppler monitoring of the medial cerebral artery (MCA) was also carried out in order to evaluate cerebral blood flow. In group A 14 of 22 patients were positive for HITS (53%), with an average of 16.4+/-19 HITS/pt.h. In group B 15 of 20 patients were HITS positive (75%) with an average amount of 14.4+/-24 HITS/pt.h. The incidence of HITS was not significantly different between the two groups. No correlation was seen between the HITS-rate/h and neurological findings, duplex sonographic results, mechanical valve size and anticoagulation regimen (P>0.05). However, a negative correlation was observed between patient age and HITS-rate (P=0.02) as well as between the NYHA degree and HITS-rate (P=0.018). The HITS-rate also correlated with postoperative time (P=0.042). No HITS were detected in the control group. HITS do not correlate with the individual clinical status and, thus, cannot predict the occurrence of neurological deficits in patients following mechanical aortic valve implantation.

Complications during Inpatient Thrombosis Prophylaxis – Experience from 40 Patients with Heparin-Induced Thrombocytopenia Type II (HIT II)

Heparin-induced thrombocytopenia Type II (HIT II) is based on a hypersensitivity to heparin and results in serious thromboembolic complications with a lethality of up to 23%. Due to its various manifestations – with or without thrombosis and/or a reduced number of thrombocytes –, a reliable diagnosis proves difficult and can only be made by a combination of clinical signs, thrombocytic behavior and antibody screening. From January 1993 to March 2000, 40 cases of HIT II were observed amongst a total of 25,331 patients presenting at 2 surgical clinics, one of which being specialized in emergency surgery. These patients were analyzed according to clinical and laboratory parameters, at first in retrospect and from 1995 prospectively. In 96.8%, thrombosis prophylaxis was done with unfractionated heparin (incidence of HIT II, 0.16%) and in 3.2% using low molecular weight heparin (incidence, 0%). All HIT II cases occurred following treatment with unfractionated heparin (in 40% subcutaneous, in 47.5% combined subcutaneous/intravenous, and in 12.5% intravenous administration). A positive result in the antibody (AB) tests was obtained on average on day 15.4 (10 to 27) SD±3.91. For AB testing, the HIPA and/or ELISA test or the agglutination test were used. Average age of the 27 female and 13 male patients was 62.8 SD±15.47 years (27 to 85). HIT II was diagnosed in 24 patients (60%) following an accident (group I) and in 16 patients (40%) after endoprosthetic joint replacement (group II). Group I was subdivided into patients suffering from single trauma (14 patients, 58.3%), multiple injury (6 patients, 25%) with an average ISS of 9.7 (4 to 15), and polytrauma (4 patients, 16.7%) with an average ISS of 24.4 (20 to 36). All accident patients sustained injury to at least 1 joint. A marked reduction in the number of thrombocytes was observed in 80%, a reduction < 50% in 10%. 10% showed no reduction or even an increase. Primary thromboembolic complications were clinically manifest – partly overlapping – on average on day 13.6 (11 to 21) SD±3.63, the complications being venous thromboses (42.5%), pulmonary emboli (35%), arterial thromboses (27.5%), and mesenteric artery thromboses (10%). Amputation was necessary in 7.5%, death occurred in 10% of the patients.