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Thrombotic thrombocytopenic purpura (TTP) is defined clinically by the abnormalities caused by systemic thrombotic microangiopathy: thrombocytopenia and microangiopathic hemolytic anemia. Additional clinical features may include neurologic abnormalities, renal failure, and gastrointestinal symptoms
Hemolytic-uremic syndrome (HUS) is another clinical presentation of thrombotic microangiopathy. Like TTP, HUS is manifested by thrombocytopenia and microangiopathic hemolytic anemia with the additional abnormality of renal failure. Although it is commonly stated that HUS is manifested primarily by renal failure whereas TTP is manifested primarily by neurologic abnormalities, these 2 syndromes cannot be distinguished clinically, because many patients have both renal failure and severe neurologic abnormalities, or neither. The term HUS is often restricted to children. In adults, all syndromes are referred to as TTP, whether or not neurologic abnormalities or renal failure are present
Amorosi EL, Ultmann JE. Medicine (Baltimore) 1966;45:139–159
George JN. N Engl J Med 2006;354:1927–1935
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Classification
Congenital:
Patients with congenital TTP, presumably caused by inherited abnormalities of the ADAMTS13 gene, may present in early childhood, as adults, or may remain asymptomatic. Also, congenital abnormalities of complement regulation can cause syndromes of HUS
Acquired:
Idiopathic: Most patients with TTP present without an associated condition or apparent etiology
Allogeneic hematopoietic stem cell transplantation: Although there are reports describing TTP as a specific complication of allogeneic hematopoietic stem cell transplantation, this may not exist as a specific entity. In most patients diagnosed with TTP following allogeneic hematopoietic stem cell transplantation, the clinical features suggesting thrombotic microangiopathy are caused by systemic infection (eg, aspergillus, cytomegalovirus), regimen-related toxicity, or acute graft-versus-host disease. These syndromes are now described as transplantation-associated thrombotic microangiopathy, not as TTP
Pregnancy/postpartum: Pregnancy is a risk factor for developing TTP, particularly in patients with congenital TTP. Congenital and acquired TTP typically occur near term or postpartum. Other pregnancy-related complications, such as severe preeclampsia and the HELLP (Hemolysis, Elevated Liver function tests, and Low Platelets) syndrome may have clinical features identical to TTP
Drug-associated, immune-mediated: Hypersensitivity reactions to drugs can cause the complete syndrome of TTP. Most frequent is quinine hypersensitivity; also reported are ticlopidine, clopidogrel
Drug-associated, dose-dependent toxicity: The clinical and pathologic features of TTP can be caused by dose-dependent toxicity of chemotherapeutic agents, most commonly mitomycin, and immunosuppressive agents. Among the latter, most commonly cyclosporine
Shiga toxin: Enterohemorrhagic infections producing Shiga toxin, characteristically Escherichia coli 0157:H7, can cause all clinical features of TTP. Shiga toxin causes the characteristic HUS of young children, and may also cause TTP in adults, with or without renal abnormalities
Association with established autoimmune disorders: In some instances, the clinical syndrome of TTP occurs in a patient with an established diagnosis of an autoimmune disorder, such as systemic lupus erythematosus or the antiphospholipid antibody syndrome. Whether TTP is merely an additional manifestation of an established autoimmune disorder or should be considered a distinct entity, is never clinically clear
George JN et al. Semin Hematol 2004;41:60–67
Kojouri K et al. Ann Intern Med 2001;135:1047–1051
Kojouri K, George JN. Curr Opin Oncol 2007;19:148–154
Vesely SK et al. Blood 2003;102:60–68
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Pathology
The clinical syndrome of TTP is caused by disseminated platelet thrombi obstructing arterioles and small vessels. The characteristic histologic pattern is described as thrombotic microangiopathy. TTP, like other thrombotic and vascular disorders, is the result of multiple etiologies and risk factors
ADAMTS13 deficiency. Best-described etiology is a congenital or acquired deficiency of the plasma von Willebrand factor-cleaving protease, ADAMTS13. Severe deficiency of ADAMTS13 results in an accumulation of unusually large von Willebrand factor multimers that can cause platelet agglutination in regions of high shear stress, resulting in platelet–von Willebrand factor thrombi
Shiga toxin damage of endothelial cells
Drug-dependent antibodies directed against platelets, granulocytes, and endothelial cells
Dose-dependent drug toxicity
Additional risk factors include factor V Leiden, female gender, African American ethnicity, and obesity
Moake JL. N Engl J Med 2002;347:589–600
Raife TJ et al. Blood 2002;99:437–442
Vesely SK et al. Blood 2003;102:60–68
Differential Diagnosis
The diagnosis of TTP is based on the observation of thrombocytopenia and microangiopathic hemolytic anemia without another clinically apparent cause. In rare instances, even these 2 cardinal features may not be present, as for example, patients with previously diagnosed episodes of TTP who subsequently have acute neurologic symptoms without thrombocytopenia or anemia, and are documented to have severe ADAMTS13 deficiency. Many years ago, TTP was diagnosed by a pentad of clinical features: thrombocytopenia, microangiopathic hemolytic anemia, neurologic abnormalities, renal insufficiency, and fever. In the current era, urgency of diagnosis is required to initiate effective treatment. Therefore only thrombocytopenia and microangiopathic hemolytic anemia are required to establish the diagnosis of TTP. Neurologic abnormalities, renal insufficiency, and fever are uncommon and not necessary for the diagnosis. Therefore the differential diagnosis includes all conditions associated with the clinical features of TTP
Systemic infections
Systemic fungal infections. Aspergillosis and other angioinvasive fungi can cause all clinical features of thrombotic microangiopathy
Viral infections. Disseminated CMV infection can cause all clinical features of thrombotic microangiopathy. HIV infection can also mimic TTP, typically related to additional opportunistic infections
Rickettsial infections. For example Rocky Mountain spotted fever
Bacterial sepsis, especially bacterial meningitis
Systemic malignancy
Disseminated micrometastatic malignancies may mimic all clinical features of TTP, without apparent evidence by imaging studies. Although disseminated intravascular coagulation (DIC) can occur in patients with disseminated malignancy, systemic small-vessel metastases causing obstruction and thrombosis can occur without evidence of DIC. A syndrome mimicking TTP may occur with breast cancer, pancreatic cancer, gastric cancer, and non–small cell lung cancer
Complications of pregnancy
Severe preeclampsia and the HELLP (Hemolysis, Elevated Liver function tests, and Low Platelets) syndrome may mimic all clinical features of TTP
Malignant hypertension
Severe hypertension may cause all clinical features of TTP, including thrombocytopenia, severe microangiopathic hemolysis, renal failure, and acute central nervous system abnormalities
Autoimmune disorders
Patients with acute systemic symptoms related to systemic lupus erythematosus, antiphospholipid antibody syndrome, acute systemic sclerosis, polyarteritis nodosa, and other autoimmune disorders can have all clinical features of TTP
Downes KA et al. J Clin Apher 2004;19:86–89
Francis KK et al. Oncologist 2007;12:11–19
George JN et al. Semin Hematol 2004;41:60–67
McMinn JR, George JN. J Clin Apher 2001;16:202–209
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Work-up
CBC: Thrombocytopenia and anemia should be present; the white blood cell count is typically normal
Peripheral blood smear should demonstrate polychromasia consistent with a high reticulocyte count and fragmented red blood cells (schistocytes)
Serum chemistry profile: Most remarkable should be the increased LDH level, a manifestation of severe systemic tissue ischemia as well as hemolysis. An elevated indirect bilirubin level indicates hemolysis. Elevated creatinine is commonly present
Urinalysis: Proteinuria and microscopic hematuria are nearly always present
Imaging studies: X-rays and scans are typically normal. Pulmonary manifestations are uncommon. The head CT scan is typically normal even in the presence of severe central nervous system abnormalities, because abnormalities are caused by diffuse small-vessel disease
Microbiology: Cultures and serologic tests for infectious etiologies should be negative in patients with TTP, though these studies are an essential part of the evaluation to exclude infections as an alternative etiology for the presenting signs and symptoms. Patients presenting with bloody diarrhea need a stool culture on special media to detect E. coli 0157:H7
Plasma sample for assay of ADAMTS13 activity and ADAMTS13 inhibitor activity: Normal values for ADAMTS13 activity do not exclude the diagnosis of TTP and do not suggest that plasma exchange treatment is not indicated. A severe deficiency of ADAMTS13 activity may be specific for TTP, but may also occur in asymptomatic individuals following recovery from an acute episode of TTP. ADAMTS13 activity may also be absent in patients with severe systemic infections or liver disease. The demonstration of severely decreased ADAMTS13 activity in association with a high-titer inhibitor is consistent with an autoimmune etiology and may predict a prolonged and severe course of illness and a 30–40% risk for relapse. ADAMTS13 circulates for several days in the plasma, therefore levels can be falsely elevated as a result of previous transfusions; patients with TTP are commonly transfused with red cells and platelets upon initial emergency room evaluation, and, therefore, plasma samples for ADAMTS13 activity are commonly inaccurate
Furlan M, Lämmle B. Best Pract Res Clin Haematol 2001;14:437–454
George JN. N Engl J Med 2006;354:1927–1935
Zheng XL et al. Blood 2004;103:4043–4049
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Treatment Options
Congenital TTP
Plasma infusion:
Congenital TTP because of an abnormality of the ADAMTS13 gene is caused by a deficiency of ADAMTS13 activity. These rare patients can be treated simply with plasma infusion to restore ADAMTS13 activity. Once the diagnosis of congenital TTP is established, regular infusions of 10 mL/kg of fresh-frozen plasma given at intervals of approximately 2–3 weeks are appropriate lifetime prophylactic treatment. Whole fresh-frozen plasma and cryoprecipitate-poor plasma are equivalent
Acquired TTP
Plasma exchange treatment is the key element for management of TTP. It is the one treatment with effectiveness documented by a randomized controlled clinical trial in which plasma exchange was compared with plasma infusion. Plasma exchange is urgently indicated in all patients with a clinical diagnosis of TTP. Although there are no data that clearly support the efficacy of glucocorticoids, they are commonly given in addition to plasma exchange as acquired TTP is commonly thought to have an autoimmune etiology. Many other immunosuppressive agents have been used in the treatment of TTP, such as rituximab and cyclosporine. These are used in patients with disease refractory to plasma exchange and glucocorticoids
Transfusion therapy:
Most patients with TTP will require red cell transfusions during their acute illness. Several well-publicized anecdotes of individual patients have suggested that platelet transfusions may be harmful in patients with TTP. However, many patients with TTP have received platelet transfusions appropriately given for overt bleeding or for invasive procedures without complications
Aspirin 81–325 mg/day may be used in patients with TIA or stroke symptoms, as in patients without TTP. However, it is prudent to avoid aspirin in patients with platelet counts <20,000/mm3
Barbot J et al. Br J Haematol 2001;113:649–651
George JN. N Engl J Med 2006;354:1927–1935
Swisher KK et al. Transfusion 2009;49:873–887
Zheng X et al. Ann Intern Med 2003;138:105–108