These studies suggest that IVIg treatment should be considered in patients with HIT who have severe disease that is refractory to standard therapies.
Heparin-induced thrombocytopenia (HIT) is a dangerous complication of heparin therapy. HIT diagnosis is established by recognizing thrombocytopenia and/or thrombosis in an affected patient and from the results of serological tests such as the platelet factor 4 (PF4)/heparin immunoassay (PF4 ELISA) and serotonin release assay (SRA). Recent studies suggest that HIT antibodies activate platelets by recognizing PF4 in a complex with platelet glycosaminoglycans (and/or polyphosphates) and that an assay based on this principle, the PF4-dependent P-selectin expression assay (PEA), may be even more accurate than the SRA for HIT diagnosis. Here, we demonstrate that the PEA detected pathogenic antibodies before the SRA became positive in two patients with HIT studied serially, in one case even before seropositivity in the PF4 ELISA. In one of the patients treated with plasma exchange, persistent dissociation between the PEA and SRA test results was observed. These results support a role for the PEA in early HIT diagnosis.
Chondroitin sulfate E (CS-E) is a sulfated polysaccharide that contains repeating disaccharides of 4,6-disulfated N -acetylgalactosamine and glucuronic acid residues. Here, we report the enzymatic synthesis of three homogeneous CS-E oligosaccharides, including CS-E heptasaccharide ( CS-E 7-mer ), CS-E tridecasaccharide ( CS-E13-mer ), and CS-E nonadecasaccharide ( CS-E 19-mer ). The anti-inflammatory effect of CS-E 19-mer was investigated in this study. CS-E 19-mer neutralizes the cytotoxic effect of histones in a cell-based assay and in mice. We also demonstrate that CS-E 19-mer treatment improves survival and protects against organ damage in a mouse model of endotoxemia induced by bacterial lipopolysaccharide (LPS). CS-E19-mer directly interacts with circulating histones in the plasma from LPS-challenged mice. CS-E 19-mer does not display anticoagulant activity nor react with heparin-induced thrombocytopenia antibodies isolated from patients. The successful synthesis of CS-E oligosaccharides provides structurally defined carbohydrates for advancing CS-E research and offers a potential therapeutic agent to treat life-threatening systemic inflammation.
BACKGROUND Maternal immunization against low-frequency, platelet (PLT)-specific antigens is being recognized with increasing frequency as a cause of neonatal alloimmune thrombocytopenia (NAIT). STUDY DESIGN AND METHODS Serologic and molecular studies were performed on PLTs and DNA from two families in which an infant was born with severe thrombocytopenia not attributable to maternal immunization against known PLT-specific alloantigens. RESULTS Antibodies reactive only with paternal PLTs were identified in each mother using flow cytometry and solid-phase assays. Unique mutations encoding amino acid substitutions K164T in glycoprotein (GP)IIb (Case 1) and R622W in GPIIIa (Case 2) were identified in paternal DNA and in DNA from the affected infants. Each maternal antibody recognized recombinant GPIIb/IIIa mutated to contain the polymorphisms identified in the corresponding father. None of 100 unselected normal subjects possessed these paternal mutations. CONCLUSIONS Severe NAIT observed in the affected infants was caused by maternal immunization against previously unrecognized, low-frequency antigens created by amino acid substitutions in GPIIb/IIIa (αIIb/β3 integrin). A search should be conducted for novel paternal antigens in cases of apparent NAIT not explained on the basis of maternal-fetal incompatibility for known human PLT antigens.
Heparin-induced thrombocytopenia (HIT) is a life-threatening, pro-thrombotic, antibody-mediated disorder. To maximize the likelihood of recovery, early and accurate diagnosis is critical. Widely available HIT assays such as the Platelet Factor 4-Heparin ELISAs lack specificity, and the "gold standard" C14-labeled serotonin release assay (SRA) is of limited value for early patient management due to availability only through reference laboratories. Recent studies demonstrate that "pathogenic" HIT antibodies selectively activate PF4-treated platelets and that a technically simpler assay, the PF4-dependent P-selectin Expression Assay (PEA), may provide an option for rapid and conclusive results. Four hundred and nine consecutive adults suspected of HIT were classified as disease-positive, -negative or -indeterminate based upon predefined criteria that combined 4Ts scores and HIT ELISA results. Patients deemed "HIT-indeterminate" were considered disease-negative in the primary analysis and disease-positive in a sensitivity analysis. The ability of PEA and SRA to identify patients judged to have HIT was compared using receiver operating characteristic curve statistics. Using these predefined criteria, the diagnostic accuracy of PEA was high (Area under the curve [AUC] of 0.94; 0.87-1.0, 95% CI) and similar to that of SRA (0.91; 0.82-1.0, 95% CI). In sensitivity analysis, the AUCs of PEA and SRA were also similar at 0.88 (0.78-0.98, 95% CI) and 0.86 (0.77-0.96, 95% CI), respectively. The PEA, a technically simple non-radioactive assay that uses ~20-fold fewer platelets compared to the SRA had high accuracy for diagnosing HIT. Widespread use of the PEA may facilitate timely and more effective management of patients with suspected HIT.
Heparin-induced thrombocytopenia (HIT) is a severe adverse reaction to heparin treatment characterized by antibodies to platelet factor 4 (PF4)-heparin complexes. 1-3 Recent data suggest that therapies currently in use are associated with a significant likelihood of thrombosis, amputation, and death. 4 Several off-label treatments such as IV immunoglobulin G (IVIg), 5,6 direct oral anticoagulants, 7 and therapeutic plasma exchange (TPE) 8-21 are increasingly being used to treat severe or refractory cases. In performing TPE, a portion of the patient's plasma is removed and replaced by an alternative fluid, typically 5% human albumin, and less often, normal plasma. In fact, several studies of TPE in HIT, including the largest report summarizing the experience in 28 patients 21 and a recent article in Blood, 13 used albumin as the sole replacement fluid. Other publications report using mostly albumin and some plasma, 9,11,12,15,18,19 and in 1 study, plasma alone was used. 8 Heterogeneity of patient presentation, differences in treatment schedule, and variability in replacement fluid used in these studies preclude firm conclusions from being drawn concerning the efficacy of specific TPE replacement solutions in treating HIT. 22
Background Twenty-four low frequency platelet antigens (HPAs) have been implicated as immunogens in neonatal alloimmune thrombocytopenia (NAIT). We performed studies to define more fully how often these antigens trigger maternal immunization leading to NAIT. Study design and methods In a Phase 1 study, fathers of selected NAIT cases not resolved by serologic testing but thought to have a high likelihood of NAIT on clinical and serologic grounds were typed for low frequency HPAs (LFHPAs) by DNA sequencing. In a Phase 2 study, high-throughput methods were used to type fathers of 1067 consecutive unresolved NAIT cases for LFHPAs. Mothers of 1338 unresolved cases were also typed to assess the prevalence of LFHPAs in a population racially/ethnically similar to the fathers. Results In Phase 1, LFHPAs were identified in 16 of 244 fathers (6.55%). In Phase 2, LFPAs were found in only 28 of 1067 fathers (2.62%). LFHPAs were identified in 27 of 1338 maternal samples (2.01%). HPA-9bw was by far the most common LFHPA identified in the populations studied and was the only LFHPA that was significantly more common in fathers than in mothers of affected infants (P=0.02). Conclusions Maternal immunization against recognized LFHPAs accounts for only a small fraction of the cases of apparent NAIT not resolved by standard serologic testing. Typing of the fathers of such cases for LFHPAs is likely to be rewarding only when a maternal antibody specific for a paternal platelet glycoprotein is demonstrated and/or there is compelling clinical evidence for NAIT.
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