Thrombotic microangiopathies (TMA) represent a clinically heterogeneous group of hematological disorders characterized by dysfunctions of the arteriolar and capillary walls leading to microvascular thrombosis and substantial thrombocytopenia clinically [1]. The present case presentation highlights the wide clinical spectrum of presentations of TMA and the importance of maintaining a high index of suspicion for its atypical and unusual presentations and prompt institution of proper treatment, including drug-induced thrombotic microangiopathy and complement-mediated thrombotic microangiopathies.

Complement-mediated TMA and drug-induced TMA are the rare but important causes of microangiopathic hemolytic anemia. Complement-mediated TMA, previously referred to as atypical hemolytic uremic syndrome (aHUS), referred to HUS not caused by Shiga toxin-producing Escherichia coli infection, is associated with congenital or acquired abnormal complement activation and dysregulation, and it can present with renal and neurological dysfunction, and hypertension with a high chance of progressive renal failure if not properly recognized and treated in over one-third of the patients [2,3]. Its presentation should be carefully evaluated after a variety of alternative causes, such as thrombotic thrombocytopenic purpura, are properly excluded. A variety of genetic mutations are found to be associated with complement dysregulation and the subsequent development of complement-mediated TMA, which includes loss of function mutations in genes encoding for factor H, factor H-related proteins, membrane cofactor protein, and factor I. Additional gain of function mutations include complement proteins factor B and complement C3. The genetic mutation detected in our patient, INF2, also called inverted formin-2, is a non-complement related genetic mutation in complement-mediated TMA often found via the use of genetic testing [4]. The use of genetic testing is increasingly critical due to their elucidation of the underlying pathophysiological mechanisms behind the development of complement-mediated TMA and allows personalized and targeted therapy to be applied to patients [5]. Therapeutic plasma exchange and eculizumab, a monoclonal antibody that blocks terminal complement activation in complement-mediated thrombotic microangiopathy are the mainstay treatment options [6,7].

Suspicion for drug-induced thrombotic microangiopathy (DITMA) is based on the observation of the timing of DITMA occurrence, the pattern of disease, and the exclusion of a better explanation through investigation [8]. DITMA suspicion is amplified by DITMA resolution when the drug is withdrawn or there is a recurrent endothelial injury during re-exposure to the drug [8]. All of these criteria fit with our patient. Two major mechanisms have been postulated to cause (DITMA). One is by forming drug-dependent antibodies (immune) and the other is due to direct tissue toxicity forming platelet-rich thrombi in arterioles or capillaries (non-immune) [9]. According to published data about 78 drugs have been suspected of causing DITMA, of which the top three are quinine, cyclosporine, and tacrolimus [9]. Currently, the management of DITMA involves the discontinuation of the offending agent. Plasma exchange and immunosuppression may be reasonable if the diagnosis is uncertain. Eculizumab may be considered in in patients with non-immune DITMA, particularly those deteriorating despite drug discontinuation, and at risk of kidney failure [10]. In the case of primaquine-induced hemolytic anemia, cytoskeleton protein damage underlies the process of removal of erythrocytes when exposed to a phenolic metabolite of primaquine, namely 5-hydroxyprimaquine [11].

This case presentation highlights the importance of maintaining an index of suspicion of DITMA and complement-mediated TMA in patients with TMA and considering drug-induced etiologies and complement-mediated causes in the evaluation of patients.