Inadequate prophylactic effect of low-molecular weight heparin in critically ill COVID-19 patients.

PURPOSE: The aim of this study was to investigate potential markers of coagulopathy and the effects of thromboprophylaxis with low-molecular-weight heparin (LMWH) on thromboelastography (TEG) and anti-factor Xa in critically ill COVID-19 patients. MATERIAL AND METHODS: We conducted a prospective study in 31 consecutive adult intensive care unit (ICU) patients. TEG with and without heparinase and anti-factor Xa analysis were performed. Standard thromboprophylaxis was given with dalteparin (75-100 IU/kg subcutaneously). RESULTS: Five patients (16%) had symptomatic thromboembolic events. All patients had a maximum amplitude (MA) > 65 mm and 13 (42%) had MA > 72 mm at some point during ICU stay. Anti-factor Xa activity were below the target range in 23% of the patients and above target range in 46% of patients. There was no significant correlation between dalteparin dose and anti-factor Xa activity. CONCLUSIONS: Patients with COVID-19 have hypercoagulability with high MA on TEG. The effect of LMWH on thromboembolic disease, anti-factor Xa activity and TEG was variable and could not be reliably predicted. This indicates that standard prophylactic doses of LMWH may be insufficient. Monitoring coagulation and the LMWH effect is important in patients with COVID-19 but interpreting the results in relation to risk of thromboembolic disease poses difficulties.

Motivational factors for blood donation in first-time donors and repeat donors: a cross-sectional study in West Pomerania.

OBJECTIVES: This study aimed to analyse motivational factors for blood donation in different donor groups. BACKGROUND: As the demographic change will result in a decrease of the population in age groups of blood donors, the risk of blood product shortage increases. METHODS: During a 12-month period, every sixth blood donor presenting at the blood donation centre of the University Hospital was asked to complete a self-administered questionnaire assessing motivational factors for blood donation. Despite the formalised enrolment protocol, frequent donors were over-represented in the study cohort, which was adjusted by weighting donors with different numbers of donations per year in such a way that the distribution of numbers of donations per year was the same in the sample as in the donor population. RESULTS: Of 2443 participants, 14·3% were first-time and 85·3% repeat donors. To "help other people" (>90%) and receiving "medical assessment of my blood values" (63-69%) were the strongest motivational factors in all donor groups. Receiving remuneration (49·2% vs 38·1%) was more important for repeat donors than for first-time donors, whereas it was the opposite for "being taken by a friend to the donor clinic" (47·0% vs 15·5%). A potentially important observation is that 33·9% of frequent donors reported feeling physically better after blood donation compared to infrequent donors (29·5%). CONCLUSION: Identification of motivational factors can lead to the design of targeted motivation campaigns for blood donation. The underlying cause of the perceived well-being after blood donation requires further studies.

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

BACKGROUND AND OBJECTIVES: 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. MATERIALS AND METHODS: First, we investigated contamination by blood (benzidine assay) of the door handles of our blood donor clinic, taking 175 samples 3 h after opening of the donation centre (baseline). We then introduced band-aids to cover the finger prick and started an information campaign using educational flyers to sensitize blood donors and staff to this problem (period-1). Thereafter, the staff was instructed to use the non-dominant hand for blood sampling and mandated to replace any discarded band-aids immediately (period-2). RESULTS: At baseline, 82% of the nurse room door handles showed contamination with blood. This decreased somewhat (10-40%) after period-1, but only after immediate mandatory band-aid replacement on any donor finger without a band-aid (period-2), no further blood contaminations were detected. CONCLUSION: Blood contamination of shared surfaces can occur after finger prick for capillary blood sampling. Application of a band-aid and use of the non-dominant hand for fingertip incision are easy to apply and effective in reducing this iatrogenic health hazard.

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

BACKGROUND: Laboratory 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: Defining 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: Using quantile regression we determined the 97.5th percentile of PF4/heparin-immunoglobulin G (IgG) EIA reactivities in non-heparin-treated individuals [blood donors (n = 935)] and patients before heparin therapy (n = 1207). In patients with suspected HIT, we compared the correlation of EIA-IgG reactivities (Greifswald laboratory; n = 2821) and the heparin-induced platelet activation assay (HIPA) with the correlation of reactivities of another EIA-IgG (McMaster laboratory; n = 1956) with the serotonin-release assay (SRA). RESULTS: PF4/heparin-IgG EIA OD reactivities had a lower OD 97.5th percentile in blood donors compared with patient groups before heparin treatment (P < 0.001). 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 > 0.9) when normalized OD ranges (maximum OD divided by 10) were used instead of absolute OD values. CONCLUSIONS: Results 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.

[Thrombosis prophylaxis in trauma surgery units in Germany: a survey]. / Thromboseprophylaxe in unfallchirurgischen Abteilungen in Deutschland : Eine Umfrage.

BACKGROUND: A 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). METHODS: Questionnaires 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. RESULTS: 314 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. CONCLUSIONS: While pharmacological thrombosis prophylaxis following trauma surgery seems to be generally performed according to guidelines, diagnosis and treatment of HIT need to be systematized.

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.

INTRODUCTION: Platelet-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: Consecutive patient sera (n = 1650) 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: Only 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; P < 0.0001), 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: The anti-PF4/heparin EIA has high ( approximately 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.

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

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 (n = 10), non-platelet-activating anti-PF4/heparin antibodies (n = 53), and anti-PF4/heparin antibody negative (n = 50). Patients with platelet-activating antibodies had the highest risk for thromboembolic events (P < 0.005), whereas those with non-platelet-activating antibodies did not differ from antibody negative patients (P = 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 (< 1.0) 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.

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.

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 (n = 120) 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 (n = 403), 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%, P = 0.0473), primarily because of reduction in new thromboses (11.9% vs. 32.1%, P = 0.0008). Mean lepirudin maintenance doses ranged from 0.07 to 0.11 mg kg(-1) h(-1). Major bleeding was more frequent in the lepirudin-treated patients (29.4% vs. 9.1%, P = 0.0148). 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 0.1 mg kg(-1) h(-1).

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 approximately 35 000 patients, the risk of anaphylaxis is approximately 0.015% (5 of 32 500) on first exposure and 0.16% (4 of 2500) in reexposed patients (7.5% estimated reexposures). CONCLUSIONS: 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.

[Informed consent on heparin-induced thrombocytopenia during thrombosis prophylaxis. A pilot study including 460 patients]. / Aufklärung über die Heparin-induzierte Thrombozytopenie im Rahmen der Thromboseprophylaxe mit Heparin. Pilot-Studie bei 460 unfallchirurgischen Patienten.

BACKGROUND: The practicability and acceptance of written information about heparin thrombosis prophylaxis and the associated risk of heparin-induced thrombocytopenia (HIT) was evaluated in a pilot study. PATIENTS AND METHODS: All patients consecutively admitted to the department of trauma- and reconstructive surgery at the Ernst-Moritz-Arndt-University, Greifswald, Germany, with an indication for heparin thrombosis prophylaxis were give written information about thrombosis prophylaxis and the undesired drug effect HIT. After this, acceptance was evaluated using a standardized questionnaire. Primary endpoint was refusal of heparin for thrombosis prophylaxis, secondary endpoint acceptance and comprehensibility of the information. RESULTS: None of the 460 patients included in the study subsequently refused thrombosis prophylaxis with heparin. The majority welcomed the information and thought it should be given to all patients that are about to be treated with heparin. Only 0.9 % of patients judged comprehensibility of the information to be insufficient. Anticipation of imminent heparin therapy (good/very good in 90 %) and appreciation of the quality of care was not judged to be unacceptable by any patient. CONCLUSIONS: The present study demonstrates that giving information about heparin-induced thrombocytopenia during explanation of the risks and benefits of heparin thrombosis prophylaxis is feasible. This information--given in writing in our pilot study--was judged by patients to be comprehensible and necessary and did not lead to refusal of treatment. Lower incidence of HIT with use of low molecular weight heparins should be considered in the choice of drug for thrombosis prophylaxis.

[Hirudins in the treatment of heparin-induced thrombocytopenia and in thrombosis prophylaxis]. / Hirudine zur Behandlung der heparininduzierten Thrombozytopenie und zur Thromboseprophylaxe.

Approved indications for the recombinant hirudins lepirudin (Refludan(R)) und desirudin (Revasc(R)) are therapy of heparin-induced thrombocytopenia (HIT) and thrombosis prophylaxis following knee or hip replacement surgery. Kidney function dependent pharmacokinetics and their capability of inducing antibodies directed against hirudin are characteristic of this class of drugs. However, close dose-monitoring allows safe and effective use of both compounds. While lepirudin is used widely, besides danaparoid, for treatment of HIT, desirudin has not yet been widely accepted for thrombosis prophylaxis following knee or hip replacement surgery.

[Current recommendations for diagnosis and therapy of heparin-induced thrombocytopenia]. / Diagnose und Therapie der Heparin- induzierten Thrombozytopenie nach Trauma - aktuelle Empfehlungen.

Thrombosis prophylaxis using heparins is mandatory in most trauma patients. However, heparins can induce heparin-induced thrombocytopenia (HIT), the most common and clinically important immune-mediated drug-dependent thrombocytopenia. Affected patients are at risk of developing new thromboembolic complications. HIT has to be considered if platelet counts decrease >50% between day 5-10 of heparin therapy that cannot be explained alternatively or if new thromboses occur in a sufficiently heparinised patient. Immediately changing the anticoagulant to danaparoid or lepirudin is most important. Proof of anti-platelet-factor-4/heparin antibodies secures the diagnosis, usually retrospectively. Diagnosis and therapy are demonstrated in a typical HIT patient. HIT usually occurs in the second week of heparin administration. Heparin-reexposure within 100 days can lead to HIT before day 5. For early recognition of HIT, platelet counts should be monitored regularly. Because of earlier discharge of patients to rehabilitation or outpatient care, the problem of HIT-diagnosis and therapy gains increasing relevance in these sectors.

Drug-induced and drug-dependent immune thrombocytopenias.

Thrombocytopenia is a frequent comorbid condition in many in hospital patients. In some patients, drugs are the cause of low platelet counts. While cytotoxic effects of anti-tumor therapy are the most frequent cause, immune mechanisms should also be considered. This review addresses thrombocytopenias in four groups. Heparin-dependent thrombocytopenia (HIT), by far the most frequent drug-induced immune-mediated type of thrombocytopenia, has a unique pathogenesis and clinical consequences. HIT is a clinicopathological syndrome in which antibodies mostly directed against a multimolecular complex of platelet factor 4 and heparin cause paradoxical thromboembolic complications. The mechanisms through which heparin can enhance thrombin generation are discussed and treatment alternatives for affected patients are presented in detail. It is of primary importance to recognize these patients as early as possible and to substitute heparin with a compatible anticoagulatory drug, such as hirudin, danaparoid or argatroban. Patients seem to benefit from therapeutic doses of alternative treatment rather than from low-dose prophylactic doses. With the increasing use of glycoprotein (GP) IIb/IIIa inhibitors in patients with acute coronary syndromes, thrombocytopenias are increasingly recognized as an adverse effect of these drugs. Up to 4% of treated patients are affected. Most important, pseudothrombocytopenia, a laboratory artefact, is as frequent as real drug-induced thrombocytopenia and must be excluded before changes in treatment are considered. The pathogenesis of these thrombocytopenias is still debated; an immune mechanism involving preformed antibodies is likely. However, since these antibodies are also detectable in a high percentage of normal controls and of patients not developing thrombocytopenia, their impact is still unclear. Patients with real thrombocytopenia are at an increased risk of bleeding; treatment consists of cessation of the GP IIb/IIIa inhibitor and platelet transfusions in cases of severe hemorrhage. Classic immune thrombocytopenia can be induced by some drugs, e.g. gold, which trigger anti-platelet antibodies indistinguishable from platelet autoantibodies found in autoimmune thrombocytopenia. Drug-induced and drug-dependent immune thrombocytopenia is induced by antibodies recognizing an epitope on platelet GP formed after binding of a drug to a platelet glycoprotein. Still unresolved is whether antibody binding is the consequence of a conformational change of the antigen, the antibody, or both. These antibodies typically react with monomorphic epitopes on platelet GP, but only in the presence of the drug or a metabolite. Although several platelet GP have been identified as antibody target (GPIb/IX, GPV, GP IIb/IIIa), antibodies in an individual patient are highly specific for a single GP. Clinically, these patients present with very low platelet counts and acute, sometimes severe, hemorrhage. Treatment is restricted to withdrawal of the drug and symptomatic treatment of bleeding.

Glucosamine sulfate does not crossreact with the antibodies of patients with heparin-induced thrombocytopenia.

OBJECTIVE: To assess the crossreactivity of glucosamine sulfate, used for treatment of degenerative joint disease with antibodies induced in heparin-induced thrombocytopenia (HIT). BACKGROUND: HIT is a severe adverse effect of heparin therapy induced by an immunological mechanism. The antibodies in HIT are induced by a complex of heparin and, in most cases, platelet factor 4. Hereby generation of the antigen is not strictly dependent on heparin. Heparin can be substituted by a variety of polysulfated carbohydrates. In vitro and in vivo crossreactivity of HIT antibodies has been demonstrated for a chemically polysulfated chondroitin-like substance (Arteparon, Luitpoldwerke, Munich, Germany), formerly used for chondroprotection. Another drug widely used in the treatment of degenerative joint disease is glucosamine sulfate. Glucosamine is a building block of glycosaminoglycans, of which heparin is the clinically most important. Many patients with degenerative joint disease use glucosamine sulfate. This group is also at the highest risk to develop HIT following joint replacement surgery. METHODS: We examined the interactions of glucosamine sulfate (DONA 200-S, Opfermann, Wiehl, Germany) with platelets and antibodies of patients with HIT in and without the presence of heparin. Sera of 5 HIT patients and platelets of 4 healthy donors were used. The binding of HIT antibodies to PF4/glucosamine sulfate complexes was assessed by an ELISA. RESULTS: HIT antibodies did not activate platelets in the presence of glucosamine sulfate in a serotonin-release assay. Preincubation with glucosamine sulfate did not inhibit platelet activation by HIT antibodies in the presence of heparin (0.2 IU/ml). Antibodies bonded to PF4/heparin but not to PF4/glucosamine sulfate complexes. CONCLUSIONS: In contrast to sulfated glycosaminoglycans, there is no evidence for an immunological crossreactivity of HIT antibodies between heparin and glucosamine sulfate.

Emergency cardiopulmonary bypass in a bilaterally nephrectomized patient with a history of heparin-induced thrombocytopenia: successful reexposure to heparin.

We present a case of emergency coronary artery bypass surgery in a bilaterally nephrectomized patient with a history of heparin-induced thrombocytopenia. The patient was reexposed short term to heparin during cardiopulmonary bypass and did not develop any complications related to heparin-induced thrombocytopenia. Despite intraoperative neutralization of heparin severe bleeding complications occurred, probably resulting from preoperative therapeutic anticoagulation with rhirudin in conjunction with an increased half-life of more than 2 days.

Recombinant hirudin in clinical practice: focus on lepirudin.

Clinical applications for recombinant hirudins have been investigated for the past 10 years. The first indication for which a hirudin-lepirudin-has been approved is treatment of heparin-induced thrombocytopenia (HIT). Also, the recently completed trials for use of lepirudin in unstable angina indicate a potentially new indication. This review describes pharmacology and clinical applications of lepirudin with an emphasis on HIT and unstable angina. An overview of usage of lepirudin in acute coronary syndromes is given, as well as a summary of rare indications for lepirudin, such as extracorporeal circulation, for which comprehensive data are lacking.

Drugs for the prevention and treatment of thrombosis in patients with heparin-induced thrombocytopenia.

Most patients with heparin-induced thrombocytopenia (HIT), a serious adverse effect of heparin mediated by platelet-activating heparin-dependent antibodies, require alternative anticoagulation. This is because HIT is highly prothrombotic and is characterized by markedly increased thrombin generation. Unfractionated heparins seem to induce HIT more often than low molecular weight heparins. There are three anticoagulants for which there is an emerging consensus for their efficacy in management of HIT, and which are currently approved for treatment of HIT in several countries: the recombinant hirudin, lepirudin, a direct thrombin inhibitor; the synthetic direct thrombin inhibitor, argatroban; and the heparinoid, danaparoid sodium, mainly exhibiting antifactor-Xa activity. Recommendations for optimal use of these drugs in HIT are given in this review stressing the need for immediate treatment of patients with HIT without awaiting laboratory diagnosis. Hirudin, the drug for which most data from prospective trials exists, can be safely and effectively used in patients with HIT, its dramatically increased elimination half-life in patients with renal failure being the most important drawback. Argatroban, which is mainly eliminated by the liver, could be used preferentially in such patients with renal impairment. Interference with the international normalized ratio makes oral anticoagulation, which is necessary in many patients with HIT, problematic. Activated partial thromboplastin time is sufficient to monitor lepirudin and argatroban treatment in most cases. Danaparoid sodium, with an antifactor-X activity half-life of about 24 hours seems to be best suited for thrombosis prophylaxis in patients with HIT. In some patients monitoring by determining antifactor-Xa activity is necessary. No antidote is available for any of the drugs discussed, and bleeding complications are the most important adverse effects. In situations such as hemodialysis or cardiopulmonary bypass, not only the characteristics of the drug in use itself, but also availability of monitoring methods play an important role. Adjunctive treatments have not been systematically evaluated and should be used cautiously. Recent data suggest that re-exposure of patients with a history of HIT with heparin, for example during cardiopulmonary bypass, can be well tolerated provided no circulating HIT antibodies are detectable at the time of re-exposure, and heparin is strictly avoided pre- and postoperatively.

Very low platelet counts in post-transfusion purpura falsely diagnosed as heparin-induced thrombocytopenia. Report of four cases and review of literature.

Differential diagnosis between post-transfusion purpura (PTP) and heparin-induced thrombocytopenia (HIT) can be difficult in the initial stages of thrombocytopenia, as the early clinical presentations are often similar. Four patients are described who were suspected clinically of suffering from HIT. All four patients had recent blood transfusions and platelet alloantibodies, thus the diagnosis of PTP was made. One lethal gastrointestinal and one retroperitoneal hemorrhage developed in two of the four patients. Unusually, one patient was male and two different platelet alloantibodies were present in his serum; in another patient platelet alloantibodies and HIT-antibodies were detectable. To arrive at the right diagnosis as quickly as possible is vitally important since treatment, which has to be initiated promptly, is very different for the two syndromes. Thus, we suggest that in patients where HIT is suspected, additional information should be sought. If features consistent with PTP (such as a recent blood transfusion or a marked drop in platelet count to below 15 Gpt/L) are present, we recommend parallel testing for platelet alloantibodies to rule out PTP.

Antihirudin antibodies in patients with heparin-induced thrombocytopenia treated with lepirudin: incidence, effects on aPTT, and clinical relevance.

Hirudin, a potent and specific thrombin inhibitor, is a protein of nonhuman origin and therefore potentially immunogenic. The primary objectives of this investigation were to determine the incidence of antihirudin antibodies (ahir-ab) in patients with heparin-induced thrombocytopenia (HIT) who received lepirudin as parenteral anticoagulation and to determine the incidence of death, limb amputation, new thromboembolic complications (TECs), and major hemorrhage in patients who had ahir-ab, compared with patients who were ahir-ab negative. The investigation used data from 2 prospective multicenter studies with the same study protocol, in which HIT patients received 1 of 4 intravenous lepirudin dosage regimens. The treatment duration was 2 to 10 days. Ahir-ab were determined by a newly developed enzyme-linked immunosorbent assay (ELISA). Eighty-seven of 196 evaluable patients (44.4%) had ahir-ab of the IgG class. Development of ahir-ab was dependent on the duration of treatment (ahir-ab-positive patients 18.6 days vs ahir-ab-negative patients 11.8 days; P =.0001). Fewer ahir-ab-positive than ahir-ab-negative patients died (P =.001). Ahir-ab did not cause an increase in limb amputation (P =.765), new TECs (P >.99), or major bleedings (P =.549). In 23 of 51 (45.1%) evaluable patients in whom ahir-ab developed during treatment with lepirudin ( = 12% of all lepirudin treated patients), the ahir-ab enhanced the anticoagulatory effect of lepirudin. Ahir-ab are frequent in patients treated with lepirudin for more than 5 days. Ahir-ab are the first example for a drug-induced immune response causing enhanced activity of a drug. Therefore, during prolonged treatment with lepirudin, anticoagulatory activity should be monitored daily to avoid bleeding complications.