Immune-mediated thrombocytopenia: improving diagnosis and treatment outcomes

Abstract

This thesis investigates immune-mediated thrombocytopenia: the natural history of immune thrombocytopenia (ITP), a novel treatment strategy for ITP, and the diagnosis of heparin-induced thrombocytopenia (HIT).

Retrospective study New international consensus guidelines on the diagnosis of ITP have recently been proposed (Rodeghiero et al, Blood 2009 113:2386-2393). Previous estimates of prevalence and the natural history of ITP may no longer remain relevant. We reviewed 129 patients who met revised criteria for the diagnosis of ITP. 49% of newly diagnosed primary ITP patients did not need treatment at presentation and remained free from grade III/IV bleeding or the need for future treatment. In contrast, patients who required treatment at presentation but were still thrombocytopenic at 1 month, were significantly more likely to remain refractory to medical therapies and experience grade III/IV bleeding.

Prospective study We investigated the use of a novel combination of conventional therapies in ITP given over 4 weeks: 20 patients were enrolled onto phase IIb study of oral dexamethasone 40mg day 1-4, oral cyclosporine 2.5-3mg/kg/daily day 1-28 and intravenous low-dose rituximab 100mg day 7, 14, 21 and 28. There were no therapy-related serious adverse side effects and 6 month response rate was 60%. This study highlights the possibility of achieving an enduring remission for some patients from as little as 4 weeks of therapy.

Diagnosis of HIT study Antibodies against Platelet factor (PF)4/heparin complexes are found in patients who have heparin-induced thrombocytopenia (HIT) and in asymptomatic patients undergoing cardiac surgery. The clinical significance of these antibodies in the latter group remains uncertain. We examined the incidence and time course of anti-PF4/heparin antibodies in patients undergoing cardiac surgery using a commercially available IgG specific ELISA kit in common clinical use. After identifying serum containing anti-PF4/heparin antibodies, we assessed their reactivity against a panel of 16 mutant(m)PF4 proteins and native PF4 (nPF4) purified in-house to determine if any differences exist with clinically pathogenic HIT samples. 24% of cardiac surgery patients are positive on commercial HIT screening versus only 8% by nPF4. We postulate that some patients identified by commercial HIT screening may be cross-reacting to PF4/nucleic acid complexes.