The diagnosis of thrombotic thrombocytopenic purpura (TTP) is primarily a clinical one that is based on the presenting clinical features of MAHA, thrombocytopenia, and organ failure, in the absence of a plausible alternative explanation. A timely diagnosis is essential, because if left unrecognized and untreated, TTP has a mortality rate of 90 % [1, 2]. Clinical presentation of TTP is significantly heterogeneous (Fig. 70.3). The classic pentad of TTP (MAHA, thrombocytopenia, fever, neurologic abnormalities, and acute kidney injury), previously described as occurring commonly, is now quite rare. In one case series of 65 patients with severe ADAMTS13 deficiency, only 5 % were affected by all five of the clinical abnormalities [3]. Prior to advent of early and empiric TPE, patients with TTP would often experience more severe and advanced disease, thus increasing the likelihood of exhibiting the classic pentad prior to death. This likely highlights the greatly improved early recognition of TTP and subsequent initiation of effective therapy which have greatly reduced the risk of developing severe disease with associated multisystem organ failure and mortality. In the same series mentioned earlier, only 37 % had severe neurologic abnormalities and 34 % had no evidence of neurologic dysfunction at all [3]. Acute kidney injury is rare in TTP (seen in only 8 % in that series), as opposed to hemolytic uremic syndrome where it is much more common [3]. Fever was seen in 23 % of the patients with severe ADAMTS13 deficiency and is usually low-grade [3]. A high fever and chills should raise the suspicion for an alternative diagnosis such as sepsis. Since the presence of the classic pentad is now rare and usually present in severe and advanced TTP, clinicians should maintain a high level of suspicion for TTP when only MAHA and thrombocytopenia are found. In these cases, urgent TPE should be undertaken in parallel with an aggressive evaluation for alternative diagnoses. Diseases that may mimic TTP and should be excluded are sepsis, disseminated intravascular coagulation (DIC), autoimmune diseases such as systemic lupus erythematosus (SLE) and scleroderma, vasculitis, malignant hypertension, and malignancy (Table 70.1).

In 1982, patients with hereditary TTP were observed to have unusually large multimers of von Willebrand factor (ULvWF). This led to the discovery and subsequent characterization of a von Willebrand factor-cleaving protease called ADAMTS13 (or A Disintegrin And Metalloproteinase with a ThromboSpondin type 1 motif, member 13) [3, 4]. In the absence of ADAMTS13, ULvWF multimers released from the vascular endothelium are not cleaved properly resulting in spontaneous platelet-rich microvascular thrombosis in conditions of high shear, such as in the brain, heart, and kidneys with resultant ischemic-induced organ dysfunction. ADAMTS13 deficiency is now well-described to be the causal factor for both hereditary TTP (in association with a confirmed ADAMTS13 mutation) and acquired TTP (in association with an ADAMTS13 autoantibody). Hereditary TTP, also known as Upshaw-Schulman syndrome, is caused by homozygous or compound heterozygous ADAMTS13 mutations, and may be apparent at birth or present later into adulthood when precipitated by a stressor such as pregnancy, infection, or surgery [5]. In acquired TTP, severely reduced ADAMTS13 activity levels of less than 5 % and presence of ADAMTS13 autoantibodies confirm the diagnosis [6, 7] and can help distinguish TTP from HUS with a specificity of 90 % [8, 9]. However, reduced ADAMTS13 activity (greater than 5 %, up to 40 %) may be seen in non-TTP disorders such as uremia, inflammatory states, post-operatively, and during pregnancy [10–12]. In addition to aiding in diagnosis, ADAMTS13 activity levels may help identify patients at increased risk for relapse after treatment. Importantly, definitive therapy with TPE should not be delayed while determining these levels.