nomacopan (rVA576) for Thrombotic Microangiopathies

In patients with AMR and MME, plasma exchange therapy is a rational treatment option. The improvement of MME following plasma exchange may be a specific effect of plasma exchange, since the improvements in these patients were not seen with other thrombotic microangiopathies.

Many cases of thrombotic microangiopathies have unknown causes and may be related to environmental, infectious, or genetic factors. Thrombotic microangiopathies are a common cause of morbidity and mortality in persons of advancing age. Recognition of their association with these 2 very common conditions, Behçet's disease and systemic lupus erythematosus has improved our understanding of this rare entity.

We describe an unexpected, frequent association of thrombotic microangiopathy with systemic vasculitides in the adult, especially in women between 40 and 60 years. We have termed this phenomenon the MRA-SVAS syndrome because it can present as systemic vasculopathies (primarily, acute, acute and chronic venous and/or deep vein thrombosis, cerebral venous thrombotic events, retinal vein occlusion, and/or cerebral arterial thrombotic events) associated with MRA. Clinic diagnosis was essential from diagnostic criteria standpoint; however, pathological confirmation is mandatory. We propose a diagnostic model consistent with the clinical presentation and pathogenetic mechanism of the association.

There is a continuing need for national estimates of the number of patients with thrombotic microangiopathies in the US. These data will be useful for all health care providers and for research and monitoring purposes where there is an increasing need to track and monitor the prevalence of these disorders for which there still seem to be paucity of data.

Thrombotic microangiopathies are notoriously difficult to treat, with low rates of responding to treatment. Most commonly, anti-PF4/heparin antibody are used. Other treatments for antiphospholipid syndrome that are used in acute settings include aspirin, clopidogrel, or heparin reversal agents. Rare options include intravenous recombinant heparin and high-dose prednisone. Low doses of aspirin have been reported to provide satisfactory control and improvement in symptoms in some individuals. Although treatment and prognosis are unpredictable, outcomes have been reported to improve during adolescence, particularly after menopause, with the medication discontinuation of heparin and/or other medications.

Thrombotic microangiopathies have a wide spectrum of signs and symptoms. Most commonly, erythroblastic crises are encountered. However, there is substantial overlap with other hematological conditions, such as myelodysplastic syndrome and myeloproliferative neoplasms. The key distinguishing features of thrombotic microangiopathies are thrombocytes and schistocytes. The signs of thrombotic microangiopathies can be classified in terms of the presence or absence of schistocytes. In cases of schistocyte-positive thrombotic microangiopathy, thrombetocytes are also seen.

This cohort of patients enrolled in rva576 trials generally received the combination of rva576 with other agents. rva576 was well tolerated, but had few side effects. rva576 was associated with lower mean platelet measurements compared with placebo, suggesting an increased bleeding risk.

Since nomacopan did not impair angiogenesis or the development of the vascular network, a pivotal observation from present and previous studies, the potent angioprotective properties of this compound must be explained by different molecular mechanisms, at least in one of three major cell types (MC-1, PBMCs and macrophages) investigated.

Treatment with nomacopan may induce significant anti-coagulative effects and may diminish or stop the clinical and laboratory worsening of the disease associated with other therapeutics, when applied for the first time.

We observed that nomacopan showed a variety of side effects such as gastrointestinal problems, headaches, nausea, fatigue, depression and insomnia. We should understand and report the side effects in prospective studies as well as long-term follow-up studies.

Data from a recent study suggest caution when considering clinical trials in patients with thrombotic microangiopathies and those in whom previous research has uncovered an increased risk.