Our patient presented several symptoms and signs of TTP, such as thrombocytopenia, anemia with elevated LDH, and neurological deficit; however, there were no pathognomonic schistocytes on her blood smear. Her extremely low ADAMTS13 activity (<1%) confirms the diagnosis of TTP. Although her ADAMTS13 inhibitor test result was reported as equivocal, it does not exclude the diagnosis of acquired TTP. In some patients of acquired TTP, the inhibitor level is too low to be detected in the conventional mixing test for inhibitors [10
]. In fact, her episode of exacerbation during the course of TPE suggests that she had acquired TTP rather than congenital TTP. Patients of congenital TTP do not have inhibitors. Hence, they respond readily to fresh frozen plasma, with the platelet count increasing to the normal range for at least two weeks after a two-unit infusion of fresh frozen plasma [11
Previously, a pentad of thrombocytopenia, MAHA, neurological deficits, fever, and renal dysfunction was proposed to constitute the diagnosis of TTP. Subsequently a diagnosis of TTP was presumed when a patient presented with the dyad of MAHA and thrombocytopenia, based on the need to promptly treat such patients [11
]. With the discovery that thrombosis of TTP is due to profound ADAMTS13 deficiency [11
], it is increasingly recognized that a lack of MAHA and/or thrombocytopenia does not exclude the diagnosis of TTP, as has been described in various reports in the literature [3
]. In 2002, O’Brien et al. [3
] reported two patients who presented with neurological deficits with roughly normal hematological findings. They were initially treated for transient ischemic attack (TIA) or conversion disorder before they developed thrombocytopenia and MAHA two and six weeks later, respectively. Of note, ADAMTS13 activity and inhibitor levels were not tested in those two patients; hence the diagnosis of TTP should only be considered presumptive. In 2003, Tsai et al. [4
] reported a patient with relapsed TTP who presented with CVA but only developed schistocytes and thrombocytopenia three weeks after the stroke. After achieving hematologic remission with plasma exchange therapy, the patient continued to experience recurrent episodes of dizziness and blurred vision. Her ADAMTS13 activity was repeatedly 10% or less and an ADAMTS13 inhibitor test was positive despite multiple normal hemoglobin levels and platelet counts. Her ADAMTS13 level increased and her symptoms subsided after rituximab therapy [4
]. Similarly, two cases of relapsed TTP presenting with CVA without overt signs of MAHA and thrombocytopenia were reported by Downes et al. [5
] in 2004. Four more cases of TTP presenting with symptoms suggestive of macrovascular arterial involvement and minimal schistocytes were reported in 2012 [6
]. In more recent years, several cases were reported [7
] in which TTP either first presented or relapsed as CVA without clear signs of MAHA and/or thrombocytopenia. Notably, it has been almost seventeen years since publication of the earliest reports of such atypical presentations of TTP [3
]. Atypical presentation of TTP has also been incorporated into a hematology textbook [11
]. However, there may still be an under-recognition of TTP presenting without typical features of MAHA or thrombocytopenia. TTP occurs at an estimated rate of 14.5 cases per 106
] and it is even rarer to have an atypical manifestation of TTP as CVA without features of MAHA, which poses a diagnostic challenge, particularly in community healthcare settings.
In regard to the etiology of a lack of overt hematological abnormalities in the uncommon cases of TTP, one might hypothesize that the extent of thrombus formation is not widespread enough to lead to fragmented red blood cells and/or thrombocytopenia. However, symptoms of TIA or stroke may occur if the early microvascular thrombosis of TTP happens to affect a vital region of the brain. Macrovascular stroke ensues if the microvascular thrombosis affects the vasa vasorum of a large artery, resulting in endothelial injury and thrombosis of the affected vessel [11
]. If TPE is not started, it is plausible that patients without initial hematological abnormalities of TTP will eventually develop overt MAHA and thrombocytopenia.
Therefore, diagnosis of TTP does not require the presence of thrombocytopenia and MAHA. TTP should be included in the differential diagnosis for a patient presenting with stroke at a young age, without conventional cardiovascular risk factors, or with unexplained thrombocytopenia and/or anemia. For such patients, ADAMTS13 activity and inhibitor tests should be performed to exclude or confirm the diagnosis of TTP.