Thrombotic Thrombocytopenic Purpura

Pathophysiology

The first description of TTP was by Moschowitz in 1924. These descriptions were of a disease presenting as a pentad of signs and symptoms (thrombocytopenia, fever, anemia, hemiparesis and hematuria). Postmortem examination revealed widespread thrombi in the terminal circulation of organs. In 1982, the presence of ultralarge von Willebrand factor (VWF) multimers was described by Moake et al. in a patient with relapsing TTP. These ultralarge VWF multimers are thought to adhere to platelets and contribute to the thrombotic occlusion of small vessels. The presence of ultralarge VWF provided significant insight into the pathophysiology of small vessel thrombi, but the reason for their accumulation was unclear until the late 1990s, when a deficiency of VWF cleaving protease was identified in a patient with chronic relapsing TTP. The cleaving protease was defined as a disintegrin and metalloprotease with thrombospondin type 1 motif, 13 (ADAMTS13). Currently, the predominant mechanism believed to be responsible for TTP is ADAMTS13 deficiency, resulting in the accumulation of platelet-hyperadhesive ultralarge VWF multimers, which bind platelets, and leads to both thrombi in the microvasculature and thrombocytopenia. The mechanism for severe ADMATS13 deficiency in acquired TTP is via autoantibodies directed against ADAMTS13, as demonstrated by anti-ADAMTS13 IgG (rare IgA and IgM) in ∼75% of patients with TTP during the acute phase. Anti-ADAMTS13 antibodies can alter ADAMTS13 activity by several mechanisms: (1) inhibit the VWF proteolytic activity of ADAMTS13, (2) form ADAMTS13-specific immune complex, and (3) increase clearance of ADAMTS13. The mechanism by which ADAMTS13 becomes deficient or dysfunctional in those patients without detectable anti-ADAMTS13 IgG (20%–25% of acute patients TTP) remains unclear, though several potential mechanisms have been hypothesized and include (1) lack of sensitivity of anti-ADAMTS13 IgG assays in detecting IgG trapped within immune complexes, (2) involvement of other Ig isotypes, or (3) other nonimmune mechanisms. Congenital TTP (Upshaw-Schulman syndrome) is caused be recessive inherited biallelic mutations of the ADMATS13 gene (homozygous or compound heterozygous), causing congenital TTP. Worldwide, there are 150 distinct mutations of ADAMTS13 gene located in the N -terminal region consisting in ∼70% of missense mutations and ∼30% of truncating mutations with variable clinical penetrance.

Secondary forms of TTP can also be associated with drugs (clopidogrel, mitomycin C, cyclosporine, quinine, ticlopidine), bacterial infection and HIV, pregnancy and postpartum, cancer and organ transplantation, and autoimmune disease (connective tissue disease). The pathophysiology of these secondary types of TTP is varied and depends on the underlying cause; some disorders are associated with ADAMTS13 autoantibody formation, whereas other disorders are driven by endothelial cell activation and damage. Despite the link between ADAMTS13 and TTP, ADAMTS13 deficiency is not pathognomonic for TTP. Low ADAMTS13 activity can be seen in healthy individuals and in individuals with disseminated intravascular coagulopathy, immune thrombocytopenia, sepsis, hepatic dysfunction, malignancy, and pregnancy. Furthermore, patients with TTP have been reported to have normal or minimally reduced ADAMTS13 activity. Therefore, the diagnosis of TTP remains a clinical one.

TTP can at times be difficult to distinguish from hemolytic uremic syndrome (HUS). Typical HUS is secondary to bacterial enterocolitis, most commonly Escherichia coli 0157:H7. Atypical HUS (aHUS), also called diarrhea-negative HUS, is the result of uncontrolled complement activity (see Chapter 106 ).

Epidemiology

The annual prevalence is ∼10 cases/million people and an annual incidence of 1 new case/million. Approximately 90% of all TTP cases occur during adulthood and 10% occur during childhood and adolescents. There is a predilection for women of African ancestry to be affected. Specifically, the incidence of acquired TTP is 2.5 times greater in women than in men and 4.9 times greater in African Americans compared with other races. TTP can affect all ages, though the median age at presentation of acquired TTP is 49 years (interquartile range [IQR] 35–63 years) and in those with ADAMTS13 activity of <10%, the median age is 40 years (IQR 33–50 years). TTP remains life-threatening disease with a mortality rate of 10%–20% in spite of appropriate therapeutic management.

Clinical Manifestations

Although part of the early descriptions of TTP, the classic pentad of anemia, thrombocytopenia, fever, neurological signs, and renal failure is present in only 10% of patients. Severe thrombocytopenia (<30 × 10 ⁹ /L) and microangiopathic hemolytic anemia characterized by schistocytes on the blood smear are the constant signs of TTP associated with skin and mucosal hemorrhage, weakness, and dyspnea. The most common organ ischemia/infarction manifestations are in the brain, heart, and mesenteric ischemia. Approximately 60% have neurological symptoms at presentation: headache, confusion, stroke, seizures, and coma. Twenty five percent have heart ischemia manifest as isolated EKG abnormalities to myocardial infarction, and 35% present with abdominal pain and diarrhea due to mesenteric ischemia. Overall, fever is present in 24% of patients and renal abnormalities in 59% and may manifest as proteinuria or increasing serum creatinine level. Importantly, the absence of fever, renal dysfunction, neurologic findings or other end-organ damage does not exclude the diagnosis of TTP. Patients with congenital TTP related to a mutation of the ADAMTS13 gene, and resulting ADAMTS13 deficiency, may present any time from the neonatal period through young adulthood. In two-thirds of patients, the interval between relapses is every 2–3 weeks, and in one-third of patients the interval between relapses may be as long as years.