A Greinacher

Anaphylactic and Anaphylactoid Reactions Associated With Lepirudin in Patients With Heparin-Induced Thrombocytopenia

Background—Lepirudin (Refludan) is a hirudin derivative. It is a direct thrombin inhibitor obtained by recombinant technology from the medicinal leech and is approved for treatment of heparin-induced thrombocytopenia complicated by thrombosis. Because 3 cases of fatal anaphylaxis possibly associated with use of lepirudin have been reported, we initiated an investigation of putative lepirudin-associated anaphylaxis. Methods and Results—Aided by the manufacturer (Schering AG, Berlin, Germany), we used the lepirudin study databases to identify all patients in whom possible anaphylaxis/severe allergy was recorded from 1994 to September 2002. The 26 possible cases identified were reviewed independently by 2 investigators. After excluding patients with mild skin reactions, reactions likely caused by concomitant medications, poorly documented cases, and reactions that did not correspond temporally with lepirudin use, there remained 9 patients judged to have had severe anaphylaxis in close temporal association with lepirudin. All reactions occurred within minutes of intravenous lepirudin administration, with 4 fatal outcomes (3 acute cardiorespiratory arrests, 1 hypotension-induced myocardial infarction). In these 4 cases, a previous uneventful treatment course with lepirudin was identified (1 to 12 weeks earlier). We recorded high-titer IgG-anti-lepirudin antibodies in an additional patient with anaphylaxis. Because lepirudin has been used in ≈35 000 patients, the risk of anaphylaxis is ≈0.015% (5 of 32 500) on first exposure and 0.16% (4 of 2500) in reexposed patients (7.5% estimated reexposures). Conclusion—Lepirudin can cause fatal anaphylaxis, particularly in patients who are treated within 3 months of a previous exposure. The overall risk/benefit assessment of lepirudin as a treatment for heparin-induced thrombocytopenia remains favorable.

Heparin‐induced thrombocytopenia: a prospective study on the incidence, platelet‐activating capacity and clinical significance of antiplatelet factor 4/heparin antibodies of the IgG, IgM, and IgA classes

Summary.u2002 Introduction:u2002Platelet‐activating antiplatelet factor 4/heparin (anti‐PF4/heparin) antibodies are the major cause of heparin‐induced thrombocytopenia (HIT). However, the relative utility of functional (platelet activation) vs. antigen [enzyme‐immunoassay (EIA)] assays, and the significance of assay discrepancies remain unresolved.Methods:u2002Consecutive patient sera (nu2003=u20031650) referred for diagnostic HIT testing were screened prospectively by both the heparin‐induced platelet activation (HIPA) test and anti‐PF4/heparin EIA – including individual classes (IgG, IgA, IgM) – with clinical correlations studied. Platelet microparticle and annexin‐V‐binding properties of the sera were also investigated.Results:u2002Only 205 (12.4%) sera tested positive in either the HIPA and/or EIA: 95 (46.3%) were positive in both, 109 (53.1%) were only EIA‐positive, and, notably, only one serum was HIPA‐positive/EIA‐negative. Of 185 EIA‐positive sera, only 17.6% had detectable IgM and/or IgA without detectable IgG. Among sera positive for EIA IgG, optical density values were higher when the sera were HIPA‐positive (1.117 vs. 0.768; Pu2003<u20030.0001), with widely overlapping values. Two HIPA‐positive but EIA‐IgG‐negative sera became HIPA‐negative following IgG depletion, suggesting platelet‐activating antibodies against non‐PF4‐dependent antigens. Clinical correlations showed that HIPA‐negative/EIA‐positive patients did not develop thrombosis and had reasons other than HIT to explain thrombocytopenia. IgM/A antibodies did not increase microparticle penetration, but increased annexin‐V binding.Conclusions:u2002The anti‐PF4/heparin EIA has high (∼99%) sensitivity for HIT. However, only about half of EIA‐positive patients are likely to have HIT. Anti‐PF4/heparin antibodies of IgM/A class and non‐PF4‐dependent antigens have only a minor role in HIT.

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

Summary.u2002 Objectives: To assess efficacy and safety of lepirudin in patients with heparin‐induced thrombocytopenia (HIT) in a prospective study (HAT‐3) as well as in a combined analysis of all HAT study data. Patients/methods: Patients with laboratory‐confirmed HIT were treated with lepirudin in three different aPTT‐adjusted dose regimen and during cardiopulmonary bypass (CPB). Endpoints were new thromboembolic complications (TEC), limb amputations, and death and major bleeding. A historical control group (nu2003=u2003120) was used for comparison. Results: After start of lepirudin in 205 patients treated in HAT‐3, the combined endpoint occurred in 43 (21.0%). Thirty (14.6%) patients died, 10 (4.9%) underwent limb amputation, and 11 (5.4%) new TECs occurred. Major bleeding occurred in 40 patients (19.5%) (seven during CPB surgery). Combining all prospective HAT trials (nu2003=u2003403), after start of lepirudin treatment, the combined endpoint occurred in 82 patients (20.3%), with 47 deaths (11.7%), 22 limb amputations (5.5%), 30 new TECs (7.4%), and 71 (17.6%) major bleedings. Compared with the historical control group (log‐rank test), the combined endpoint after start of treatment was reduced (29.7% vs. 52.1%, Pu2003=u20030.0473), primarily because of reduction in new thromboses (11.9% vs. 32.1%, Pu2003=u20030.0008). Mean lepirudin maintenance doses ranged from 0.07 to 0.11u2003mgu2003kg−1u2003h−1. Major bleeding was more frequent in the lepirudin‐treated patients (29.4% vs. 9.1%, Pu2003=u20030.0148). Conclusions: The rate of new TECs in HIT patients is low after start of lepirudin treatment. The rate of major bleeding of 17.6% might be reduced by reducing the starting dose to 0.1u2003mgu2003kg−1u2003h−1.

Early‐onset and persisting thrombocytopenia in post‐cardiac surgery patients is rarely due to heparin‐induced thrombocytopenia, even when antibody tests are positive

See also Gruel Y, Pouplard C. Post‐operative platelet count profile: the most reliable tool for identifying patients with true heparin‐induced thrombocypenia after cardiac surgery. This issue, pp 27–29.

Heparin‐induced thrombocytopenia in patients requiring prolonged intensive care unit treatment after cardiopulmonary bypass

Summary.u2002 Background:u2002The diagnosis of heparin‐induced thrombocytopenia (HIT) is problematic in postcardiac surgery (CS) intensive care unit (ICU) patients, as there are multiple potential explanations for thrombocytopenia and the presence of anti‐platelet factor 4/heparin antibodies is not highly specific for HIT. Two platelet count profiles for HIT – a 40% or greater fall in platelet count beginning on or after day 5 (pattern 1) and persisting thrombocytopenia (<u2003100u2003×u2003109u2003L–1) beyond day 7 (pattern 2) – have been described in post‐CS patients. Methods and results:u2002We examined the platelet count profiles of 329 consecutive post‐CS patients who required ICU treatment beyond 7u2003days. Although 70 patients (21.3%) developed thrombocytopenia (57.1% pattern 1, 42.9% pattern 2), the overall incidence of HIT was only 1.8% [6/329; 95% confidence interval (95% CI) 0.7–3.9%] in these ICU patients, with more HIT patients showing a pattern 2 than a pattern 1 platelet count decrease (four vs. two patients). Notably, pattern 2 patients with HIT also showed a new proportional fall of >u200330% in platelet count between postoperative days 5 and 10. Among the remaining 2242 post‐CS patients without a prolonged ICU stay, only three (0.1%; 95% CI 0.03–0.4%) developed symptomatic HIT (OR 0.07; 95% CI 0.01–0.3; Pu2003=u20030.0002 vs. ICU patients), all presenting with pattern 1. Conclusions:u2002Among post‐CS ICU patients, a postoperative platelet count fall between days 5 and 10 increases diagnostic specificity for HIT, irrespective of whether this platelet count fall occurs after postoperative platelet count recovery (pattern 1) or is superimposed upon persisting postoperative thrombocytopenia (pattern 2). A prospective study is required in order to validate the findings of this retrospective analysis.

Heparin-induced thrombocytopenia: towards standardization of platelet factor 4/heparin antigen tests

Summary.u2002 Background:u2002Laboratory confirmation of heparin‐induced thrombocytopenia (HIT) is based on detection of heparin‐dependent platelet‐activating antibodies. Platelet factor 4 (PF4)/heparin enzyme‐immunoassays (EIA) are a widely available surrogate for platelet‐activating antibodies. Objective:u2002Defining the optical density (OD) reactivity profiles of a PF4/heparin EIA in reference subject and patient populations and the correlation of the EIA results (expressed in OD units) with the prevalence of platelet‐activating antibodies. Patients/methods:u2002Using quantile regression we determined the 97.5th percentile of PF4/heparin‐immunoglobulin G (IgG) EIA reactivities in non‐heparin‐treated individuals [blood donors (nu2003=u2003935)] and patients before heparin therapy (nu2003=u20031207). In patients with suspected HIT, we compared the correlation of EIA‐IgG reactivities (Greifswald laboratory; nu2003=u20032821) and the heparin‐induced platelet activation assay (HIPA) with the correlation of reactivities of another EIA‐IgG (McMaster laboratory; nu2003=u20031956) with the serotonin‐release assay (SRA). Results:u2002PF4/heparin‐IgG EIA OD reactivities had a lower OD 97.5th percentile in blood donors compared with patient groups before heparin treatment (Pu2003<u20030.001). The percentage of sera testing positive in the functional assays strongly correlated with PF4/heparin‐IgG EIA OD reactivities in both laboratories with very similar results (correlation coefficient >u20030.9) when normalized OD ranges (maximum OD divided by 10) were used instead of absolute OD values. Conclusions:u2002Results of PF4/heparin‐IgG EIA should not be reported as only positive or negative as there is no single acceptable cut‐off value. Instead, reporting PF4/heparin‐IgG EIA OD results in ranges allows for risk‐stratified prediction for presence of platelet‐activating antibodies. Use of normalized OD ranges permits a standardized approach for inter‐laboratory comparisons.

IgG classification of anti‐PF4/heparin antibodies to identify patients with heparin‐induced thrombocytopenia during mechanical circulatory support

Summary.u2002 Commercial immunoassays frequently detect anti‐PF4/heparin antibodies during mechanical circulatory support (MCS), but only a small minority of patients develops heparin‐induced thrombocytopenia (HIT). Whereas platelet functional tests can distinguish between platelet‐activating and non‐platelet‐activating antibodies, commercial PF4‐dependent immunoassays do not. Between 2003 and 2004, 113 patients were placed on MCS. Blood samples were obtained on postimplant day 5–7 for analyses by antibody assays and the functional heparin‐induced platelet activation (HIPA) assay. Three distinct groups of patient sera were identified: platelet‐activating anti‐PF4/heparin antibodies (nu2003=u200310), non‐platelet‐activating anti‐PF4/heparin antibodies (nu2003=u200353), and anti‐PF4/heparin antibody negative (nu2003=u200350). Patients with platelet‐activating antibodies had the highest risk for thromboembolic events (Pu2003<u20030.005), whereas those with non‐platelet‐activating antibodies did not differ from antibody negative patients (Pu2003= 0.369). The enzyme‐immunoassay and column agglutination assays, which cover all immunoglobulin classes, demonstrated adequate sensitivity and negative predictive value; yet, both lacked specificity with respect to the platelet‐activating antibodies. If all antibody positive patients were further classified by an IgG‐specific anti‐PF4/heparin enzyme‐immuno assay, specificity for platelet‐activating antibodies increased. Whereas IgG‐specific optical density (OD) values below 1.0 were likely for non‐platelet‐activating anti‐PF4/heparin antibodies, higher values were progressively predictive for pathogenic platelet activation. The probability of the development of clinical HIT also increased steeply. In conclusion, platelet‐activating anti‐PF4/heparin antibodies are relatively common (about 9%) in patients on MCS and are associated with significantly higher thrombotic event rates. Low IgG‐specific OD values (<u20031.0) in the enzyme‐immunoassay indicate low likelihood for the presence of platelet‐activating antibodies. These results justify further validation so that anticoagulation during MCS becomes safer and adequate.

[Thrombosis prophylaxis in trauma surgery units in Germany: a survey].

BACKGROUNDnA questionnaire study was conducted to ask trauma surgery centers about thrombosis prophylaxis methods and strategies for the diagnosis and therapy of heparin-induced thrombocytopenia (HIT).nnnMETHODSnQuestionnaires were sent by post to German hospitals with trauma surgery units inquiring about the use of unfractionated heparin (UFH) and low-molecular-weight heparin (LMWH), the duration of medication, and the HIT diagnosis. Questionnaires were evaluated descriptively.nnnRESULTSn314 of 685 questionnaires sent out were evaluable (46%): half were from general hospitals, 96 (31%) from specialized hospitals, and 53 (17%) from tertiary care hospitals (others: 8). In more than 90%, only LMWH was used. The mean duration of pharmacological thrombosis prophylaxis was 16.6+/-10.4 days (inpatient/outpatient). Only 10% adhered to the recommended platelet count controls every 2 days (days 5-14) for early detection of HIT.nnnCONCLUSIONSnWhile pharmacological thrombosis prophylaxis following trauma surgery seems to be generally performed according to guidelines, diagnosis and treatment of HIT need to be systematized.ZusammenfassungHintergrundIn einem Fragebogen-Survey wurden unfallchirurgische Kliniken nach ihrem Thromboseprophylaxeschema sowie zur Diagnose und Therapie der Heparin-induzierten Thrombozytopenie (HIT) befragt.MethodikVersand eines Fragebogens an unfallchirurgisch tätige Einrichtungen mit Fragen zu Behandlungsschwerpunkt, Verwendung unfraktionierter (UFH) und niedermolekularer Heparine (NMH), Dauer der Anwendung und HIT-Diagnostik. Die Auswertung erfolgte deskriptiv.ErgebnisseVon 685 verschickten Fragebögen waren 314 (46%) auswertbar: Die Hälfte stammte aus Krankenhäusern der Grund- und Regelversorgung, 96 (31%) aus Schwerpunktkliniken, 53 (17%) aus Kliniken der Maximalversorgung (übrige: 8). In >90% wurden ausschließlich NMH verwendet. Mittlere Dauer der medikamentösen Thromboseprophylaxe: 16,6±10,4xa0Tage (stationär/poststationär). Nur 10% hielten sich an die empfohlenen 2-täglichen Thrombozytenkontrollen (Tagxa05–14) zur frühzeitigen Erkennung einer HIT.SchlussfolgerungenWährend die medikamentöse Thromboseprophylaxe nach unfallchirurgischen Eingriffen weitgehend leitlinienkonform scheint, besteht Handlungsbedarf für eine Systematisierung der HIT-Diagnostik und Therapie.AbstractBackgroundA questionnaire study was conducted to ask trauma surgery centers about thrombosis prophylaxis methods and strategies for the diagnosis and therapy of heparin-induced thrombocytopenia (HIT).MethodsQuestionnaires were sent by post to German hospitals with trauma surgery units inquiring about the use of unfractionated heparin (UFH) and low-molecular-weight heparin (LMWH), the duration of medication, and the HIT diagnosis. Questionnaires were evaluated descriptively.Results314 of 685 questionnaires sent out were evaluable (46%): half were from general hospitals, 96 (31%) from specialized hospitals, and 53 (17%) from tertiary care hospitals (others: 8). In more than 90%, only LMWH was used. The mean duration of pharmacological thrombosis prophylaxis was 16.6±10.4 days (inpatient/outpatient). Only 10% adhered to the recommended platelet count controls every 2 days (days 5–14) for early detection of HIT.ConclusionsWhile pharmacological thrombosis prophylaxis following trauma surgery seems to be generally performed according to guidelines, diagnosis and treatment of HIT need to be systematized.

Thromboseprophylaxe in unfallchirurgischen Abteilungen in Deutschland

BACKGROUNDnA questionnaire study was conducted to ask trauma surgery centers about thrombosis prophylaxis methods and strategies for the diagnosis and therapy of heparin-induced thrombocytopenia (HIT).nnnMETHODSnQuestionnaires were sent by post to German hospitals with trauma surgery units inquiring about the use of unfractionated heparin (UFH) and low-molecular-weight heparin (LMWH), the duration of medication, and the HIT diagnosis. Questionnaires were evaluated descriptively.nnnRESULTSn314 of 685 questionnaires sent out were evaluable (46%): half were from general hospitals, 96 (31%) from specialized hospitals, and 53 (17%) from tertiary care hospitals (others: 8). In more than 90%, only LMWH was used. The mean duration of pharmacological thrombosis prophylaxis was 16.6+/-10.4 days (inpatient/outpatient). Only 10% adhered to the recommended platelet count controls every 2 days (days 5-14) for early detection of HIT.nnnCONCLUSIONSnWhile pharmacological thrombosis prophylaxis following trauma surgery seems to be generally performed according to guidelines, diagnosis and treatment of HIT need to be systematized.ZusammenfassungHintergrundIn einem Fragebogen-Survey wurden unfallchirurgische Kliniken nach ihrem Thromboseprophylaxeschema sowie zur Diagnose und Therapie der Heparin-induzierten Thrombozytopenie (HIT) befragt.MethodikVersand eines Fragebogens an unfallchirurgisch tätige Einrichtungen mit Fragen zu Behandlungsschwerpunkt, Verwendung unfraktionierter (UFH) und niedermolekularer Heparine (NMH), Dauer der Anwendung und HIT-Diagnostik. Die Auswertung erfolgte deskriptiv.ErgebnisseVon 685 verschickten Fragebögen waren 314 (46%) auswertbar: Die Hälfte stammte aus Krankenhäusern der Grund- und Regelversorgung, 96 (31%) aus Schwerpunktkliniken, 53 (17%) aus Kliniken der Maximalversorgung (übrige: 8). In >90% wurden ausschließlich NMH verwendet. Mittlere Dauer der medikamentösen Thromboseprophylaxe: 16,6±10,4xa0Tage (stationär/poststationär). Nur 10% hielten sich an die empfohlenen 2-täglichen Thrombozytenkontrollen (Tagxa05–14) zur frühzeitigen Erkennung einer HIT.SchlussfolgerungenWährend die medikamentöse Thromboseprophylaxe nach unfallchirurgischen Eingriffen weitgehend leitlinienkonform scheint, besteht Handlungsbedarf für eine Systematisierung der HIT-Diagnostik und Therapie.AbstractBackgroundA questionnaire study was conducted to ask trauma surgery centers about thrombosis prophylaxis methods and strategies for the diagnosis and therapy of heparin-induced thrombocytopenia (HIT).MethodsQuestionnaires were sent by post to German hospitals with trauma surgery units inquiring about the use of unfractionated heparin (UFH) and low-molecular-weight heparin (LMWH), the duration of medication, and the HIT diagnosis. Questionnaires were evaluated descriptively.Results314 of 685 questionnaires sent out were evaluable (46%): half were from general hospitals, 96 (31%) from specialized hospitals, and 53 (17%) from tertiary care hospitals (others: 8). In more than 90%, only LMWH was used. The mean duration of pharmacological thrombosis prophylaxis was 16.6±10.4 days (inpatient/outpatient). Only 10% adhered to the recommended platelet count controls every 2 days (days 5–14) for early detection of HIT.ConclusionsWhile pharmacological thrombosis prophylaxis following trauma surgery seems to be generally performed according to guidelines, diagnosis and treatment of HIT need to be systematized.

Predonation finger lancet punctures: a potential risk factor for interdonor pathogen transmission in the blood donor clinic

Point‐of‐care testing using capillary blood from a finger prick is widely used for predonation haemoglobin testing of blood donors. It is common practice to cover the finger prick with a cotton swab and to instruct the donor to press for few minutes. The finger prick can cause blood contamination of surfaces in contact with the lanced finger, especially door handles, risking infectious disease transmission, particularly if another person touching the contaminated door handle also has a punctured fingertip.