Education & Research

Thrombotic thrombocytopenia purpura (TTP) is a rare form of thrombotic microangiopathy (TMA) characterized by microangiopathic hemolytic anemia (MAHA), severe thrombocytopenia, and ischemic end-organ damage resulting from formation of platelet-rich thrombi in the microvasculature.¹ TTP is distinguished from other TMAs by severe deficiency of ADAMTS13 (a disintegrin and metalloproteinase with a thrombospondin type 1 motif, member 13), a plasma protein that cleaves von Willebrand factor (VWF) multimers. Without the proteolytic activity of ADAMTS13, the uncleaved ultralarge VWF multimers accumulate and induce excessive platelet adhesion and aggregation, leading to formation of disseminated microthrombosis and the clinical features of TTP. In patients with congenital TTP (cTTP), severe ADAMTS13 deficiency results from biallelic mutations in the ADAMTS13 gene, whereas immune-mediated TTP (iTTP) is associated with anti-ADAMTS13 autoantibodies, which neutralize or induce clearance of the ADAMTS13 protein.

Despite its rarity, timely recognition of TTP is critical, as emergent initiation of therapeutic plasma exchange (PEX) may be life-saving. Diagnosis of TTP is nonetheless challenging. The spectrum of clinical presentation can be remarkably variable, from subtle nonspecific symptoms to major neurological abnormalities. Distinction of TTP from other TMA syndromes is not always readily discernible because of the overlapping clinical manifestations of TTP with other TMAs. Measurement of ADAMTS13 activity is an important means of confirming the diagnosis, but results may not be available rapidly enough to guide initial management decisions. It is therefore incumbent on the clinician to identify patients most likely to benefit from plasma exchange based on immediately available data. In this article, we review recent evidence on the epidemiology, natural history, and clinical manifestations of TTP as well as the utility of ADAMTS13 laboratory testing, and we suggest an evidence-based approach to the diagnosis of TTP that integrates clinical and laboratory information.

Epidemiology and Natural History of TTP

The estimated incidence of TTP is 2 per million per year.² National and regional registries have provided important insights on the demographic and clinical features of this rare disease.

iTTP occurs far more commonly in adulthood, with a median age at onset around the fourth decade of life. Women were more likely to be affected across all studies, with a female to male ratio of 2 to 3:1. Blacks have a sevenfold higher incidence than nonblacks.⁵ TTP presenting in infancy strongly favors diagnosis of the congenital form. In the French registry, however, genetic mutations in ADAMTS13 were identified in approximately 3% of patients with adult-onset TTP (first episode of TTP at age ≥18 years). Interestingly, all such cases occurred in association with a first pregnancy.³ Thus, all women who present with a first episode of TTP during pregnancy should be evaluated for the hereditary form of the disease.

iTTP may occur in isolation (ie, primary TTP) or in association with a predisposing condition (ie, secondary TTP). Predisposing conditions include other autoimmune diseases (eg, systemic lupus erythematosus), malignancy, infection (eg, HIV), pregnancy, and certain drugs. Predisposing conditions have been identified in 27% to 69% of patients with TMA and severe ADAMTS13 deficiency.^3,9–11 A breakdown of various predisposing conditions as a proportion of all cases of TTP is illustrated in Figure 1. A focused history, physical examination, and laboratory evaluation to exclude these conditions should be undertaken in all patients presenting with TTP. In the French registry, platelet count lower than 20 × 10⁹/L, a positive anti-ADAMTS13 antibody titer, and the presence of gastrointestinal symptoms were predictive of primary TTP, whereas severe anemia (hemoglobin < 7 g/dL) and presence of fever were associated with secondary TTP.³ In the United Kingdom TTP Registry, neurological involvement was more common and more severe in primary TTP, with a greater percentage of cases presenting with stroke and coma. 

The introduction of plasma exchange dramatically reduced mortality associated with TTP, but the disease remains fatal in 5% to 16% of cases (Table 1). Compared with other TMAs, patients with TTP have a more favorable prognosis, including shorter hospitalization, more rapid platelet count recovery, and higher overall survival.⁶

Among patients with TTP, approximately 95% achieve normalization of the platelet count with acute treatment and 87% ultimately achieve remission. However, exacerbation (a fall in platelet count requiring resumption of plasma exchange within 30 days) and relapse (recurrent TTP after 30 days) remain frequent clinical problems, occurring in 53% and 30% to 50% of patients, respectively.²

Compared with initial episodes, relapses tend to be less severe (eg, less severe anemia and thrombocytopenia, less frequent cardiac and neurological involvement, lower lactate dehydrogenase),^2,13,14 likely because of earlier recognition on the part of the patient and clinician. Relapsed patients also require fewer plasma exchange treatments.¹⁴ However, there were no differences with respect to response, exacerbation, and mortality rates between relapse and initial episodes.

Thrombotic Thrombocytopenic Purpura is a rare blood disorder that is considered a true medical emergency. TTP is diagnosed at a rate of 3-4 in 1 million people per year. Potentially fatal complications can result from internal blood
clotting, with damage to critical organs such as the brain and heart.
Due to a deficiency in the ADAMTS13 enzyme, blood becomes “sticky” and forms clots in blood vessels throughout the body. These clots are made up of platelets, one of the elements in blood. Vital blood flow to the body’s organs is restricted, placing the organs at risk for damage due to a lack of oxygen and nutrients from the blood. Moreover, since platelets are being used to form numerous unnecessary blood clots, their availability to perform their normal function, which is to seal injury sites to prevent excess bleeding, is compromised.

• National Heart, Lung, and Blood Institute: https://www.nhlbi.nih.gov/health/thrombotic-thrombocytopenic-purpura