Concept: Heparin-induced thrombocytopenia
The diagnostic work-up for heparin induced thrombocytopenia (HIT) can take several days. Consequently patients may be speculatively switched onto replacement anticoagulant therapy before a diagnosis is confirmed. On-demand immunoassay diagnostic testing enables timely treatment decisions, based on test results.
Heparin-induced thrombocytopenia (HIT) is an immune-mediated complication of heparin therapy. Our objective was (i) to compare various laboratory assays for HIT against clinical probability (4-T score) and C-serotonin release assay (SRA), which was the composite gold standard and (ii) to determine the incidence of HIT in the ICU.
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.
The aim of this study was to collect data in France in patients with heparin-induced thrombocytopenia who required parenteral anticoagulation and for whom other non-heparin anticoagulant therapies were contraindicated including patients with renal failure, cross-reactivity to danaparoid or at high hemorrhagic risk.
- American journal of respiratory cell and molecular biology
- Published about 4 years ago
Platelets and neutrophils contribute to the development of acute lung injury (ALI). However, the mechanism by which platelets make this contribution is incompletely understood. We asked whether the two most abundant platelet chemokines, CXCL7, which induces neutrophil chemotaxis and activation, and CXCL4, which does neither, mediate ALI through complementary pathogenic pathways.
The aim of this study was to investigate whether the 2 tirofiban formulations tested in the early and late phases of the PRISM (Platelet Receptor Inhibitor in Ischemic Syndrome Management) trial might differ with respect to risk for thrombocytopenia and clinical outcomes compared with unfractionated heparin (UFH).
Key Clinical Points Heparin-Induced Thrombocytopenia Heparin-induced thrombocytopenia (HIT) is characterized by a decrease in the platelet count of more than 50% from the highest platelet count value after the start of heparin, an onset 5 to 10 days after the start of heparin, hypercoagulability, and the presence of heparin-dependent, platelet-activating IgG antibodies. Use of a scoring system that takes into account the timing and magnitude of the platelet count fall, new thrombosis, and the likelihood of other reasons for thrombocytopenia is helpful in assessing the pretest probability of HIT. Delayed-onset HIT develops after the cessation of heparin, and spontaneous or autoimmune HIT develops in the absence of heparin exposure. Platelet factor 4-heparin antibody tests should be ordered only if clinical features reasonably suggest HIT. These tests have a high negative predictive value but a low positive predictive value. Treatment of acute HIT requires the cessation of heparin and the initiation of therapeutic-dose anticoagulation with an alternative agent (argatroban, danaparoid, fondaparinux, or bivalirudin). Warfarin should be avoided in patients with acute HIT.
Heparin-induced thrombocytopenia (HIT) is an autoimmune thrombotic disorder caused by immune complexes containing platelet factor 4 (PF4), antibodies to PF4 and heparin or cellular glycosaminoglycans (GAGs). Here we solve the crystal structures of the: (1) PF4 tetramer/fondaparinux complex, (2) PF4 tetramer/KKO-Fab complex (a murine monoclonal HIT-like antibody) and (3) PF4 monomer/RTO-Fab complex (a non-HIT anti-PF4 monoclonal antibody). Fondaparinux binds to the ‘closed’ end of the PF4 tetramer and stabilizes its conformation. This interaction in turn stabilizes the epitope for KKO on the ‘open’ end of the tetramer. Fondaparinux and KKO thereby collaborate to ‘stabilize’ the ternary pathogenic immune complex. Binding of RTO to PF4 monomers prevents PF4 tetramerization and inhibits KKO and human HIT IgG-induced platelet activation and platelet aggregation in vitro, and thrombus progression in vivo. The atomic structures provide a basis to develop new diagnostics and non-anticoagulant therapeutics for HIT.
Thrombocytopenia is a significant complication of chemotherapy and radiation therapy. Platelet factor 4 (PF4; CXCL4) is a negative paracrine of megakaryopoiesis. We have shown that PF4 levels are inversely related to steady-state platelet counts, and to the duration and severity of chemotherapy- and radiation-induced thrombocytopenia (CIT and RIT, respectively). Murine studies suggest that blocking the effect of PF4 improves megakaryopoiesis, raising nadir platelet counts and shortening the time to platelet count recovery. We examined the ability of 2-O, 3-O desulfated heparin (ODSH), a heparin variant with little anticoagulant effects, to neutralize PF4’s effects on megakaryopoiesis. Using megakaryocyte colony assays and liquid cultures, we show that ODSH restored megakaryocyte proliferation in PF4-treatedCxcl4-/-murine and human CD34+-derived megakaryocyte cultures (17.4% megakaryocyte colonies,P< .01 compared with PF4). In murine CIT and RIT models, ODSH, started 24 hours after injury, was examined for the effect on hematopoietic recovery demonstrating higher platelet count nadirs (9% ± 5% treated vs 4% ± 4% control) and significantly improved survival in treated animals (73% treated vs 36% control survival). Treatment with ODSH was able to reduce intramedullary free PF4 concentrations by immunohistochemical analysis. In summary, ODSH mitigated CIT and RIT in mice by neutralizing the intramedullary negative paracrine PF4. ODSH, already in clinical trials in humans as an adjuvant to chemotherapy, may be an important, clinically relevant therapeutic for CIT and RIT.
Argatroban or lepirudin anticoagulation therapy in patients with heparin induced thrombocytopenia (HIT) or HIT suspect is typically monitored using the activated partial thromboplastin time (aPTT). Although aPTT correlates well with plasma levels of argatroban and lepirudin in healthy volunteers, it might not be the method of choice in critically ill patients. However, in-vivo data is lacking for this patient population. Therefore, we studied in vivo whether ROTEM or global clotting times would provide an alternative for monitoring the anticoagulant intensity effects in critically ill patients.