Simvastatin and amlodipine induced thrombocytopenia in the same patient: double trouble and a literature review

What is known and objective: Drug‐induced thrombocytopenia (DITP) may be a fatal adverse reaction to many drugs. It is often misdiagnosed as primary immune thrombocytopenia (ITP), and thus diagnosis can be delayed and patients can be treated inappropriately. Amlodipine a calcium‐channel blocker, and simvastatin, a statin, have very rarely been implicated in DITP. We report on an investigation of the causal relationship of amlodipine and simvastatin with thrombocytopenia occurring in the same patient, and review the literature. Case summary: We present the case of a 78‐year‐old female hypertensive diabetic patient with three successive DITPs. The first attack of acute severe thrombocytopenia occurred after a 2‐week course of amlodipine, and was initially misdiagnosed as ITP. Her platelet count normalized after the amlodipine was discontinued. The second attack followed her restarting simvastatin 3 weeks later. She had stopped it 2 months earlier having previously taken it for over 5 years. Again, she recovered once the simvastatin was discontinued. The third DITP attack occurred when she accidently took a single dose of amlodipine 9 months later. What is new and conclusion: We provide clear evidence of a causal association of amlodipine with thrombocytopenia, and probable evidence of a causal association of simvastatin with thrombocytopenia. This is the first reported case of DITPs occurring with two of the most widely prescribed drugs in the same patient. Many hypertensive patients need to take multiple drugs in order to achieve their treatment goals and this increases their risk of drug‐induced adverse reactions and makes identification of the causal drug (or drugs) extremely difficult.     

Heparin‐associated thrombocytopenia in 24 401 patients with venous thromboembolism: findings from the RIETE Registry1

Summary. Background: Whether the treatment of venous thromboembolism (VTE) with unfractionated heparin (UFH) confers a higher risk of thrombocytopenia than does treatment with low molecular weight heparin (LMWH) remains controversial, and very few data are available from routine clinical practice. Objectives: We assessed the incidence, risk factors and prognosis of heparin‐associated thrombocytopenia (HAT) according to the type of heparin therapy, UFH or LMWH. Patients/Methods: Data were obtained from the international prospective Registro Informatizado de la Enfermedad TromboEmbolica venosa (RIETE), which included 25 369 patients with confirmed VTE until February 2009. Among them, 24 401 patients were treated either with UFH or with LMWH, and had available information about the 6‐month occurrence of confirmed thrombocytopenia, defined as a platelet count ≤ 150 000 mm^–3. Results: One hundred and forty‐one patients receiving UFH and/or LMWH developed thrombocytopenia within a 6‐month period. The incidence of HAT was significantly higher in the UFH group (1.36%, 95% confidence interval [CI] 0.79–2.17) than in the LMWH group (0.54%, 95% CI 0.44–0.64). As compared with LMWH, UFH significantly increased the risk of HAT in female patients (adjusted hazard ratio [HR] 4.90%, 95% CI 2.58–9.31, P = 0.001) but not in male patients (adjusted HR 1.60%, 95% CI 0.64–3.97, P = 0.31); P = 0.027 for comparison. In each gender, the UFH‐associated excess risk was confined to patients with VTE unrelated to cancer. The poor prognosis of patients with thrombocytopenia was not influenced by the type of heparin therapy. Conclusions: In routine clinical practice, treatment of VTE with UFH seems to confer a higher risk of thrombocytopenia than does treatment with LMWH, especially in women and non‐cancerous patients.     

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

Summary. 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.     

The HIT Expert Probability (HEP) Score: a novel pre‐test probability model for heparin‐induced thrombocytopenia based on broad expert opinion

Summary. Background: The diagnosis of heparin‐induced thrombocytopenia (HIT) is challenging. Over‐diagnosis and over‐treatment are common. Objectives: To develop a pre‐test clinical scoring model for HIT based on broad expert opinion that may be useful in guiding clinical decisions regarding therapy. Patients/methods: A pre‐test model, the HIT Expert Probability (HEP) Score, was constructed based on the opinions of 26 HIT experts. Fifty patients referred to a reference laboratory for HIT testing comprised the validation cohort. Two hematology trainees scored each patient using the HEP Score and a previously published clinical scoring system (4 T’s). A panel of three independent experts adjudicated the 50 patients and rendered a diagnosis of HIT likely or unlikely. All subjects underwent HIT laboratory testing with a polyspecific HIT ELISA and serotonin release assay (SRA). Results: The HEP Score exhibited significantly greater interobserver agreement [intraclass correlation coefficient: 0.88 (95% CI 0.80–0.93) vs. 0.71 (0.54–0.83)], correlation with the results of HIT laboratory testing and concordance with the diagnosis of the expert panel (area under receiver‐operating curve: 0.91 vs. 0.74, P = 0.017) than the 4 T’s. The model was 100% sensitive and 60% specific for determining the presence of HIT as defined by the expert panel and would have allowed for a 41% reduction in the number of patients receiving a direct thrombin inhibitor (DTI). Conclusion: The HEP Score is the first pre‐test clinical scoring model for HIT based on broad expert opinion, exhibited favorable operating characteristics and may permit clinicians to confidently reduce use of alternative anticoagulants. Prospective multicenter validation is warranted.     

Prospective observational evaluation of the particle immunofiltration anti-platelet factor 4 rapid assay in MICU patients with thrombocytopenia

Introduction

Heparin-induced thrombocytopenia (HIT) results from antibodies to PF4/heparin complexes and clinical diagnosis is difficult. We evaluated the particle immunofiltration anti-platelet factor 4 (PIFA) rapid assay, in conjunction with a clinical risk score, in the diagnosis of HIT.

Methods

We performed a prospective observational study in all patients admitted to the medical intensive care unit (MICU) in a large academic medical center. Patients were screened daily for thrombocytopenia defined as either a platelet count that decreased by at least 33% or an absolute platelet count less than 150,000/μL. Patients with suspected HIT underwent PIFA and ELISA testing for anti-PF4/heparin antibodies. Available residual frozen sera were sent to a reference laboratory for serotonin release assay (SRA) testing.

Results

During the study period, 340 patients were admitted to the MICU, of which 143 patients met criteria for thrombocytopenia. Forty-three patients had no evidence of recent heparin exposure. PIFA and ELISA testing were performed on 100 patients, of which 92 had samples available for SRA analysis. PIFA results were negative in 62, positive in 28 and inconclusive in 2 patients. The 4Ts score showed low to intermediate risk in 57 of the PIFA negative patients. The ELISA results were negative in 86 and positive in 6 patients. SRA testing identified 3 patients with a positive SRA test and 89 patients with a negative result. All patients with a negative PIFA result also had a negative SRA result. In the one patient deemed to have clinical HIT, the pretest probability was high (4Ts score of 6) and the anti-PF4/heparin antibody testing revealed a positive SRA, inconclusive PIFA and a negative ELISA result.

Conclusions

While thrombocytopenia in our population is common, the prevalence of HIT is low. The combination of a low to intermediate pretest probability with a negative PIFA test can rapidly exclude the presence of platelet activating anti-PF4/heparin antibodies and, therefore, HIT as the cause of the thrombocytopenia. Since a positive PIFA result has a low positive predictive value, a positive PIFA is not diagnostic of HIT and additional evaluation is warranted.     

Drug-induced immune thrombocytopenia: pathogenesis, diagnosis, and management

Summary.  Drug-induced immune thrombocytopenia (DITP) can be triggered by a wide range of medications. Although many cases of DITP are mild, some are characterized by life-threatening bleeding symptoms. The pathogenesis of DITP is complex, in that at least six different mechanisms have been proposed by which drug-induced antibodies can promote platelet destruction. It is possible in many cases to identify antibodies that react with platelets in the presence of the sensitizing drug, but the required testing is technically demanding and not widely available. Therefore, a decision on whether to discontinue an implicated medication in a patient suspected of having DITP must be made on clinical grounds. An algorithm is available that can be helpful in assessing the likelihood that a particular drug caused thrombocytopenia, but the most important aspects of patient management are a high index of suspicion and a careful history of drug exposure in an individual who presents with acute, often severe thrombocytopenia of unknown etiology. How drugs induce platelet-reactive antibodies and how, once formed, the antibodies cause platelet destruction following exposure to the drug is poorly understood. Further studies to address these issues and characterize more completely the range of drugs and drug metabolites that can cause DITP are needed.     

Fondaparinux treatment of acute heparin‐induced thrombocytopenia confirmed by the serotonin‐release assay: a 30‐month, 16‐patient case series

See also Greinacher A. Immunogenic but effective: the HIT‐fondaparinux brain puzzler. This issue, pp 2386–8; Goldfarb MJ, Blostein MD. Fondaparinux in acute heparin‐induced thrombocytopenia: a case series. This issue, pp 2501–3. Summary. Background: Fondaparinux is theoretically an attractive agent for the treatment of immune heparin‐induced thrombocytopenia (HIT), a prothrombotic disorder caused by platelet‐activating anti‐platelet factor 4/heparin antibodies. Although reports of the use of fondaparinux for this indication have thus far been favorable, the diagnosis of HIT in most cases was not based on definitive laboratory confirmation of heparin‐dependent, platelet‐activating antibodies. Objectives: To report thrombotic and major bleeding outcomes with fondaparinux in patients with a high likelihood of having acute HIT based on clinical features and a positive result in the confirmatory platelet serotonin‐release assay (SRA), a sensitive and specific test for platelet‐activating HIT antibodies. Methods/Patients: We reviewed consecutive eligible patients with SRA‐positive HIT (mean peak serotonin release, 91% [normal, < 20%]; mean IgG‐specific PF4/heparin enzyme immunoassay result, 2.53 optical density units [normal, < 0.45 units]) in one medical center over a 30‐month period who received fondaparinux for anticoagulation during acute HIT (platelet count, < 150 × 10⁹ L^?1). Where available, plasma samples were used to measure thrombin–antithrombin (TAT) complex levels. Results: Sixteen patients with SRA‐positive HIT received fondaparinux: 14 surgical (11 after cardiac surgery; three after vascular surgery) and two medical (acute stroke). Fifty‐six per cent of patients had HIT‐associated thrombosis at the time of diagnosis. No patient developed new, recurrent or progressive thrombosis; one patient developed a major bleed (calf hematoma). One patient judged to have irreversible tissue necrosis before receiving fondaparinux therapy ultimately required limb amputation. TAT complex levels were reduced within 24 h of starting fondaparinux, and 13 of 13 patients were successfully switched to warfarin. Conclusion: Fondaparinux shows promise for the treatment of patients with SRA‐positive acute HIT.     

Deleterious impact of a generic temozolomide formulation compared with brand-name product on the kinetic of platelet concentration and survival in newly diagnosed glioblastoma

Chemo-induced thrombocytopenia is a limiting toxicity among patients receiving temozolomide (TMZ) as first-line treatment for glioblastoma. We aimed to compare early platelet concentration kinetics, hematological safety profile, and impact on survival following the initiation of either the brand-name or a generic TMZ formulation. A retrospective trial was conducted in patients suffering from newly diagnosed glioblastoma. Patients were treated with TMZ at 75 mg/m² per day during six weeks, concomitantly with radiotherapy. Platelet concentration was collected each week. Primary endpoint was to perform a linear mixed-effect model of platelet concentration kinetic over weeks. A total of 147 patients were included as follows: 96 received the brand-name TMZ, and 51 received a generic TMZ formulation. Exposition to the generic was a significant variable that negatively influenced the platelet kinetics in the radiotherapy and concomitant TMZ phase, P = 0.02. Grade ≥3 chemo-induced thrombocytopenia was more frequent in the generic group: 19.6% [95% CI 8.7-30.5%] vs 3.1% [0-6.6%], P = 0.001. Exposition to the generic formulation of TMZ led to increase early treatment discontinuation due to TMZ-induced thrombocytopenia and was a worsening independent prognostic factor on overall survival: adjusted HR 1.83 [1.21-2.8], P = 0.031. These data suggest that exposition to a generic formulation of TMZ vs the brand-name product is associated with higher early platelet decrease leading to clinically relevant impacts on treatment schedule in glioblastoma. Further prospective trials are needed to confirm these results.     

Heparin-induced thrombocytopenia in the critically ill: Interpreting the 4Ts test in a randomized trial

Background

Thrombocytopenia occurs in 20% to 45% of critically ill medical-surgical patients. The 4Ts heparin-induced thrombocytopenia (HIT) score (with 4 domains: Thrombocytopenia, Timing of thrombocytopenia, Thrombosis and oTher reason[s] for thrombocytopenia) might reliably identify patients at low risk for HIT. Interobserver agreement on 4Ts scoring is uncertain in this setting.

Objective

To evaluate whether a published clinical prediction rule (the “4Ts score”) reliably rules out HIT in “low-risk” intensive care unit (ICU) patients as assessed by research coordinators (who prospectively scored) and 2 adjudicators (who scored retrospectively) during an international heparin thromboprophylaxis trial (PROTECT, NCT00182143).

Methods

Of 3746 medical-surgical ICU patients in PROTECT, 794 met the enrollment criteria for this HIT substudy. Enrollment was predicated on one of the following occurring in ICU: platelets less than 50 × 10⁹/L, platelets decreased to 50% of ICU admission value (if admission value < 100 × 10⁹/L), any venous thrombosis, or if HIT was otherwise clinically suspected. Independently, 4Ts scores were completed in real time by research coordinators blinded to study drug and laboratory HIT results, and retrospectively by 2 adjudicators blinded to study drug, laboratory HIT results, and research coordinators' scores; the adjudicators arrived at consensus in all cases. Of the 763 patients, 474 had a central or local laboratory HIT test performed and had 4Ts scoring by adjudicators; 432 were scored by trained research coordinators. Heparin-induced thrombocytopenia was defined by a centrally performed positive serotonin release assay (SRA).

Results

Of the 474 patients with central adjudication, 407 (85.9%) had a 4Ts score of 3 or lower, conferring a low pretest probability (PTP) of HIT; of these, 6 (1.5% [95% confidence interval, 0.7%-3.2%) had a positive SRA. Fifty-nine (12.4%) had a moderate PTP (4Ts score of 4-5); of these, 4 (6.8%) had a positive SRA. Eight patients had a high PTP (4Ts score of ≥ 6); of these, 1 (12.5%) had a positive SRA. Raw agreement between research coordinators and central adjudication on each domain of the 4Ts score and low, intermediate, and high PTP was good. However, chance-corrected agreement was variable between adjudicators (weighted κ values of 0.31-0.93) and between the adjudicator consensus and research coordinators (weighted κ values of 0.13 and 0.78). Post hoc review of the 6 SRA-positive cases with an adjudicated low PTP demonstrated that their scores would have been increased if the adjudicators had had additional information on heparin exposure prior to ICU admission. In general, the fourth domain of 4Ts (oTher causes of thrombocytopenia) generated the most disagreement.

Conclusions

Real-time 4Ts scoring by research coordinators at the time of testing for HIT was not consistent with 4Ts scores obtained by central adjudicators. The results of this comprehensive HIT testing highlight the need for further research to improve the assessment of PTP scoring of HIT for critically ill patients.     

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. Summary. Background: The high frequency of thrombocytopenia in post‐cardiac surgery patients makes it challenging to diagnose heparin‐induced thrombocytopenia (HIT). Two platelet count profiles are reported as indicating possible HIT in these patients: profile 1 describes a platelet count fall that begins between postoperative days 5 and 10, whereas profile 2 denotes early‐onset thrombocytopenia that persists beyond day 5. Objectives: To examine how these platelet count profiles correlate with antibody status and HIT post‐cardiac surgery. Methods: We prospectively screened 581 cardiac surgery patients for heparin‐dependent antibodies by platelet factor 4 (PF4)–heparin immunoassay and platelet‐activation test, and performed daily platelet counts (until day 10) with 30‐day follow‐up. Results: All three patients with platelet count profile 1 tested positive for platelet‐activating anti‐PF4–heparin IgG antibodies [odds ratio (OR) 521.7, 95% confidence interval (CI) 3.9–34 000, P = 0.002], and were judged to have HIT. In contrast, none of 25 patients with early‐onset and persisting thrombocytopenia (profile 2) was judged to have HIT, including five patients testing positive for platelet‐activating anti‐PF4–heparin IgG antibodies. In these patients, the frequency of heparin‐dependent antibodies did not differ from that in non‐thrombocytopenic controls, either for anti‐PF4–heparin IgG (OR 1.7, 95% CI 0.7–4.1, P = 0.31) or for platelet‐activating antibodies (OR 1.9, 95% CI 0.6–5.7, P = 0.20). Multivariate analysis revealed that type of cardiac surgery, but not HIT antibody status, predicted early‐onset and persisting thrombocytopenia. Together, these findings show that HIT was uncommon in this study population [overall frequency, 3/581 (0.5%), 95% CI 0.1–1.5%]. Conclusions: Thrombocytopenia that begins between 5 and 10 days post‐cardiac surgery is highly predictive for HIT. In contrast, early‐onset and persisting thrombocytopenia is usually caused by non‐HIT factors with coinciding heparin‐dependent antibody seroconversion.     

The utility of pre-test clinical scoring for clinical diagnosis of heparin-induced thrombocytopenia in cardiac surgery patients of a tertiary care centre in north India

Background: Heparin‐induced thrombocytopenia (HIT) should be diagnosed clinically as well as by laboratory assays for timely recognition, prevention and management of complications. Objective: To evaluate the clinical utility of pre‐test clinical scoring system in combination with two immunoassays for the diagnosis of HIT in cardiac surgery patients. Materials and methods: A total of 100 consecutive patients undergoing cardiac surgery were studied. Pre‐test clinical scoring was carried out in patients with thrombocytopenia and further tested by two immunoassays, i.e. Heparin platelet factor 4 (H‐PF4) enzyme‐linked immunosorbent assay (ELISA) and particle gel immunoassay (PaGIA). Results: Of the 100 patients studied, 42 patients developed thrombocytopenia post‐operatively. On pre‐test clinical scoring, low T‐score was observed in 6 patients, intermediate in 28 and high score in 8 patients, whereas 19 patients (45·2%) were positive by H‐PF4 ELISA and 10 (23·8%) by PaGIA for H‐PF4 antibody. The difference in the incidence of clinically significant HIT antibodies in the three categories was statistically significant. A good correlation was also observed with ELISA optical density, T‐scoring and PaGIA. Conclusions: Pre‐test clinical scoring correlates well with the development of H‐PF4 antibodies which are incriminated in the causation of thrombotic complications in patients with HIT. We also propose a protocol for diagnosing patients with clinical suspicion of HIT using pre‐test clinical scoring and immunoassay.     

Differences in platelet function in patients with acute myeloid leukemia and myelodysplasia compared to equally thrombocytopenic patients with immune thrombocytopenia

Summary. Background: Severe thrombocytopenia is a major risk factor for hemorrhage, but platelet function and bleeding risk at low platelet counts are poorly understood, because of the limitations of platelet function testing at very low platelet counts. Objectives: To examine and compare platelet function in severely thrombocytopenic patients with acute myeloid leukemia (AML) or myelodysplasia (MDS) with that in patients with immune thrombocytopenia (ITP). Methods: Whole blood flow cytometric measurement of platelet activation and platelet reactivity to agonists was correlated with the immature platelet fraction (IPF) and bleeding symptoms. Results: Patients with AML/MDS had smaller platelets, lower IPF and substantially lower platelet surface expression of activated glycoprotein (GP)IIb–IIIa and GPIb, both with and without addition of ex vivo ADP or thrombin receptor‐activating peptide, than patients with ITP. In both ITP and AML/MDS patients, increased platelet surface GPIb on circulating platelets and expression of activated GPIIb–IIIa and GPIb on ex vivo activated platelets correlated with a higher IPF. Whereas platelet reactivity was higher for AML/MDS patients with bleeding than for those with no bleeding, platelet reactivity was lower for ITP patients with bleeding than for those with no bleeding. Conclusions: AML/MDS patients have lower in vivo platelet activation and ex vivo platelet reactivity than patients with ITP. The proportion of newly produced platelets correlates with the expression of platelet surface markers of activation. These differences might contribute to differences in bleeding tendency between AML/MDS and ITP patients. This study is the first to define differences in platelet function between AML/MDS patients and ITP patients with equivalent degrees of thrombocytopenia.     

Heparin-induced thrombocytopenia in paediatrics: clinical characteristics,therapy and outcomes

Objective: Reports on heparin-induced thrombocytopenia (HIT) in paediatrics are confined to isolated case reports. The objective was to systematically combine the published data. Design and setting: Cases were identified by MEDLINE search and review of bibliographies. Patients: We included subjects reported with HIT, collecting patient demographics, clinical and laboratory characteristics, therapeutic regimens and outcomes. Measurements and results: Reports on 70 patients were retrieved. In a majority of children, HIT occurred during hospitalisation in a paediatric ICU. In most patients, the typical onset pattern was reported, although rapid-onset-pattern HIT occurred in some. The median platelet-count nadir was 54×10⁹/l; 11% of reported patients had nadirs in the normal range. Clinical symptoms included isolated thrombocytopenia and solitary or combined venous, arterial and intracardiac thromboembolism, sometimes catheter-related. Pulmonary embolism and major bleeding were rarely described. Confirmatory functional or antigenic testing of HIT antibodies showed a similar cumulative sensitivity of about 88%. An unfavourable outcome (death/limb amputation) was reported in 42.1% of patients without therapy and in 18% of patients treated with danaparoid, lepirudin, or argatroban. Conclusions: HIT in children mainly occurs in paediatric intensive care with diagnostic features and outcomes similar to those seen in adults. HIT cannot be ruled out based on normal platelet counts or occurrence after fewer than 5 days of heparin exposure. Children should be presumed to suffer from HIT based on clinical grounds and treated accordingly (immediate heparin withdrawal and alternative anticoagulation). Alternative anticoagulation with danaparoid, lepirudin and argatroban appears to improve outcomes.Electronic Supplementary Material Supplementary material is available in the online version of this article at     

Evaluation of pretest clinical score (4 T''s) for the diagnosis of heparin-induced thrombocytopenia in two clinical settings

BACKGROUND: Heparin-induced thrombocytopenia (HIT) is a prothrombotic adverse drug reaction caused by heparin. As thrombocytopenia is common in hospitalized patients receiving heparin, it would be useful to have a clinical scoring system that could differentiate patients with HIT from those with other reasons for thrombocytopenia. AIM: To compare prospectively the diagnostic utility of a clinical score for HIT in two different clinical settings. METHODS: The pretest clinical scoring system, the '4 T's', was used to classify 100 consecutive patients referred for possible HIT in one hospital (Hamilton General Hospital, HGH) into high, intermediate, and low probability groups. This system was also used to classify likewise 236 patients by clinicians in Germany referring blood for diagnostic testing for HIT in Greifswald (GW). The clinical scores were correlated with the results of laboratory testing for HIT antibodies using the serologic criteria for HIT with high diagnostic specificity. RESULTS: In both centers, patients with low scores were unlikely to test positive for HIT antibodies [HGH: 1/64 (1.6%), GW: 0/55 (0%)]. Patients with intermediate [HGH: 8/28 (28.6%), GW: 11/139 (7.9%)] or high scores [HGH: 8/8 (100%), GW: 9/42 (21.4%)] were more likely to test positive for clinically significant HIT antibodies. The positive predictive value of an intermediate or high clinical score for clinically significant HIT antibodies was higher at one center (HGH). CONCLUSIONS: A low pretest clinical score for HIT seems to be suitable for ruling out HIT in most situations (high-negative predictive value). The implications of an intermediate or high score vary in different clinical settings.     

Variability of anti-PF4/heparin antibody results obtained by the rapid testing system ID-H/PF4-PaGIA

Summary. Background: Recent studies have shown that a low clinical pretest probability may be adequate for excluding heparin‐induced thrombocytopenia. However, for patients with intermediate or high pretest probability, laboratory testing is essential for confirming or refuting the diagnosis. Rapid assessment of anti‐PF4/heparin‐antibodies may assist clinical decision‐making. Objectives: To evaluate the performance of rapid ID‐H/PF4‐PaGIA. In particular, we verified reproducibility of results between plasma and serum specimens, between fresh and frozen samples, and between different ID‐H/PF4‐polymer lots (polystyrene beads coated with heparin/PF4‐complexes). Patients/Methods: The samples studied were 1376 plasma and 914 corresponding serum samples from patients investigated for suspected heparin‐induced thrombocytopenia between January 2000 and October 2008. Anti‐PF4/heparin‐antibodies were assessed by ID‐H/PF4‐PaGIA, commercially available ELISAs and heparin‐induced platelet aggregation test. Results: Among 914 paired plasma/serum samples we noted discordant results (negative vs. low‐titre positive) in nine instances (1%; 95%CI, 0.4–1.6%). Overall, agreement between titres assessed in plasma vs. serum was highly significant (Spearman correlation coefficient, 0.975; P < 0.0001). Forty‐seven samples tested both fresh and after freezing/thawing showed a good agreement, with one discordant positive/negative result (Spearman correlation coefficient, 0.970; P < 0.0001). Among 1376 plasma samples we noted a strikingly variable incidence of false negative results (none – 82%; 95%CI, 66–98%), depending on the employed ID‐H/PF4‐polymer lot. Faulty lots can be recognized by titrating commercial positive controls and stored samples of HIT‐patients. Conclusion: Laboratories performing the assay should implement stringent internal quality controls in order to recognize potentially faulty ID‐H/PF4‐polymer lots, thus avoiding false negative results.     

The costs of heparin‐induced thrombocytopenia: a patient‐based cost of illness analysis

Summary. Background and objectives: Due to the complexity of heparin‐induced thrombocytopenia (HIT), currently available cost analyses are rough estimates. The objectives of this study were quantification of costs involved in HIT and identification of main cost drivers based on a patient‐oriented approach. Methods: Patients diagnosed with HIT (1995–2004, University‐hospital Greifswald, Germany) based on a positive functional assay (HIPA test) were retrieved from the laboratory records and scored (4T‐score) by two medical experts using the patient file. For cost of illness analysis, predefined HIT‐relevant cost parameters (medication costs, prolonged in‐hospital stay, diagnostic and therapeutic interventions, laboratory tests, blood transfusions) were retrieved from the patient files. The data were analysed by linear regression estimates with the log of costs and a gamma regression model. Mean length of stay data of non‐HIT patients were obtained from the German Federal Statistical Office, adjusted for patient characteristics, comorbidities and year of treatment. Hospital costs were provided by the controlling department. Results and conclusions: One hundred and thirty HIT cases with a 4T‐score ≥4 and a positive HIPA test were analyzed. Mean additional costs of a HIT case were 9008 €. The main cost drivers were prolonged in‐hospital stay (70.3%) and costs of alternative anticoagulants (19.7%). HIT was more costly in surgical patients compared with medical patients and in patients with thrombosis. Early start of alternative anticoagulation did not increase HIT costs despite the high medication costs indicating prevention of costly complications. An HIT cost calculator is provided, allowing online calculation of HIT costs based on local cost structures and different currencies.     

Thrombocytopenia due to rivaroxaban: A rare adverse effect

IntroductionRivaroxaban is a novel, oral direct acting anticoagulant (DOAC) that is used for both treatment and prevention of thromboembolic diseases. Due to mechanism of action; most common side effect may be seen with hemorrhage. Here in we reported that a patient with chronic atrial fibrillation presented with thrombocytopenia while taking rivaroxaban.Case reportA 76-year-old female patient with atrial fibrillation was given rivaroxaban, after lack of dose administration of warfarin and gastrointestinal bleeding. In 12th dayweek of treatment, the patient was admitted to emergency department (ED) with oral mucosal bleeding and petechial spots.The patient diagnosed as Drug-induced Thrombocytopenia (DITP)due to rivaroxaban use, after ruled out most possibilities ofITP (immune thrombocytopenic purpura). After rivaroxaban is discontinued, the patient's bleeding complaints regressed,symptoms were completely resolved, and platelet count rapidly increased towards physiological level in days. The patient is currently in the 6th month of follow-up and is has no bleeding.ConclusionTo the best of our knowledge there are only two cases about rivaroxaban induced thrombocytopenia (RIT). In addition to the well-known side effects ofrivaroxaban treatment, it should be kept in mind that thrombocytopenia may also develop.Naranjo adverse drug reaction probability scale calculated as 7 points.(probable cause for the patient's thrombocytopenia)     

The combination of levodopa with levodopa-metabolizing enzyme inhibitors prevents severe fever with thrombocytopenia syndrome virus infection in vitro more effectively than single levodopa

Severe fever with thrombocytopenia syndrome is a hemorrhagic fever caused by a tick-borne infection. The causative agent, Dabie bandavirus, is also called the severe fever with thrombocytopenia syndrome virus (SFTSV). Ogawa et al. (2022) reported that levodopa, an antiparkinsonian drug with an o-dihydroxybenzene backbone, which is important for anti-SFTSV activity, inhibited SFTSV infection. Levodopa is metabolized by dopa decarboxylase (DDC) and catechol-O-methyltransferase (COMT) in vivo. We evaluated the anti-SFTSV efficacy of two DDC inhibitors, benserazide hydrochloride and carbidopa, and two COMT inhibitors, entacapone and nitecapone, which also have an o-dihydroxybenzene backbone. Only DDC inhibitors inhibited SFTSV infection with pretreatment of the virus (half-maximal inhibitory concentration [IC₅₀]: 9.0–23.6 μM), whereas all the drugs inhibited SFTSV infection when infected cells were treated (IC₅₀: 21.3–94.2 μM). Levodopa combined with carbidopa and/or entacapone inhibited SFTSV infection in both conditions: pretreatment of the virus (IC₅₀: 2.9–5.8 μM) and treatment of infected cells (IC₅₀: 10.7–15.4 μM). The IC₅₀ of levodopa in the above-mentioned study for pretreatment of the virus and treatment of infected cells were 4.5 and 21.4 μM, respectively. This suggests that a synergistic effect was observed, especially for treatment of infected cells, although the effect is unclear for pretreatment of the virus. This study demonstrates the anti-SFTSV efficacy of levodopa-metabolizing enzyme inhibitors in vitro. These drugs may increase the time for which the levodopa concentration is maintained in vivo. The combination of levodopa and levodopa-metabolizing enzyme inhibitors might be a candidate for drug repurposing.     

von Willebrand factor activation,granzyme‐B and thrombocytopenia in meningococcal disease

Summary. Background: During invasive meningococcal disease, severe thrombocytopenia is strongly associated with a poor outcome. Objectives: In order to elucidate the pathophysiological mechanism behind the development of thrombocytopenia, we studied the role of von Willebrand factor (VWF) in meningococcal disease. Patients/methods: Thirty‐two children with severe meningococcal disease admitted to our university hospital were included in this study. VWF and related parameters were measured and results were correlated with the development of shock and thrombocytopenia. Results: At admission, all patients had increased levels of (active) VWF and VWF propeptide. The highest VWF propeptide levels were observed in patients with shock, indicating acute endothelial activation. Although VWF propeptide levels in patients with shock, with or without thrombocytopenia, were similar, increased active VWF was significantly lower in patients with thrombocytopenia as compared with patients without thrombocytopenia. ADAMTS13 was moderately decreased. However, the VWF multimeric pattern was minimally increased. We assume that these findings are explained by VWF consumption and perhaps by granzyme B (GrB). In vitro experiments showed that GrB is able to cleave VWF multimers in plasma, whereas GrB was high in patients with shock, who developed thrombocytopenia. Conclusions: Our results demonstrate that consumption of VWF, derived from endothelial cells, could be a key feature of meningococcal disease and primary to the development of thrombocytopenia during shock.