Summary. 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 Ô4 T'sÕ, 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%)

Heparin‐induced thrombocytopenia (HIT) is caused by platelet‐activating antibodies that recognize platelet factor 4//heparin (PF4/H) complexes. According to the “iceberg model,” only a subset of anti‐PF4/heparin antibodies of IgG class evincing strong platelet‐activating properties cause clinical HIT. Since many centers rely predominantly on an anti‐PF4/polyanion enzyme‐immunoassay (EIA) to diagnose HIT, we estimated the potential for overdiagnosis when only this single test is available. We examined a database of 100 patients in whom the probability of HIT had been estimated using a clinical scoring system (4Ts), and where patients underwent systematic testing for HIT antibodies using three assays: the platelet serotonin release assay (SRA), an “in‐house” EIA that detects IgG anti‐PF4/heparin antibodies (EIA‐IgG), and a commercial EIA that detects anti‐PF4/polyanion antibodies of all three immunoglobulin classes (EIA‐GTI). Whereas 16 of 100 patients fulfilled a “classic” definition of HIT (intermediate/high probability plus strong platelet‐activating anti‐PF4/heparin IgG antibodies), an additional 16 patients fulfilled a “liberal” definition in which any investigated patient (irrespective of the pretest probability) who had a positive EIA‐GTI was considered to have HIT. The clinical features of these 16 additional patients—including generally weak antibodies and low risk for thrombosis—suggest underlying non‐HIT explanations for thrombocytopenia. Patients with a positive SRA generally corresponded to those with intermediate or high pretest probability of HIT who also had strong EIA‐GTI reactivity (>1.20 OD units). We conclude there is the potential to overdiagnose HIT by ∼100% if any positive EIA is considered to “confirm” the diagnosis of HIT irrespective of the clinical scenario. Am. J. Hematol., 2007. © 2007 Wiley‐Liss, Inc.

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Background: Treatment of poor prognosis metastatic castration-resistant prostate cancer (mCRPC) includes taxane chemotherapy and androgen receptor pathway inhibitors (ARPI). We sought to determine optimal treatment in this setting. Patients and methods: This multicentre, randomised, open-label, phase II trial recruited patients with ARPI-naive mCRPC and poor prognosis features (presence of liver metastases, progression to mCRPC after <12 months of androgen deprivation therapy, or !4 of 6 clinical criteria). Patients were randomly assigned 1 : 1 to receive cabazitaxel plus prednisone (group A) or physician's choice of enzalutamide or abiraterone plus prednisone (group B) at standard doses. Patients could cross over at progression. The primary endpoint was clinical benefit rate for first-line treatment (defined as prostate-specific antigen response !50%, radiographic response, or stable disease !12 weeks). Results: Ninety-five patients were accrued (median follow-up 21.9 months). First-line clinical benefit rate was greater in group A versus group B (80% versus 62%, P ¼ 0.039). Overall survival was not different between groups A and B (median 37.0 versus 15.5 months, hazard ratio (HR) ¼ 0.58, P ¼ 0.073) nor was time to progression (median 5.3 versus 2.8 months, HR ¼ 0.87, P ¼ 0.52). The most common first-line treatment-related grade !3 adverse events were neutropenia (cabazitaxel 32% versus ARPI 0%), diarrhoea (9% versus 0%), infection (9% versus 0%), and fatigue (7% versus 5%). Baseline circulating tumour DNA (ctDNA) fraction above the cohort median and on-treatment ctDNA increase were associated with shorter time to progression (HR ¼ 2.38, P < 0.001; HR ¼ 4.03, P < 0.001). Patients with >30% ctDNA fraction at baseline had markedly shorter overall survival than those with undetectable ctDNA (HR ¼ 38.22, P < 0.001). Conclusions: Cabazitaxel was associated with a higher clinical benefit rate in patients with ARPI-naive poor prognosis mCRPC. ctDNA abundance was prognostic independent of clinical features, and holds promise as a stratification biomarker.