Rare Thrombotic Diseases Consortium

Thrombotic Thrombocytopenic Purpura (TTP)

Thrombotic thrombocytopenic purpura (TTP) is a rare, life-threatening medical condition involving multiple organ systems. TTP has an estimated annual incidence of 3.7 cases per million individuals and occurs more frequently in women than men (1) . In its fulminant form, it is characterized by microangiopathic hemolytic anemia, thrombocytopenia, neurologic symptoms, fever, and renal dysfunction without signs of disseminated intravascular coagulation (DIC). Hemolytic uremic syndrome (HUS) is also characterized by microangiopathic hemolytic anemia and renal insufficiency, but has less neurologic involvement than TTP. HUS generally manifests with a single occurrence, preceded by an episode of gastroenteritis caused by E. coli O157:H7 or other cytotoxin-producing gram-negative organisms (2) .

Pathophysiology

Investigations of the pathogenesis of TTP have recently focused on von Willebrand factor (vWF) homeostasis and deficiency of a specific proteinase that cleaves vWF in the blood (2) . vWF is secreted by endothelial cells as a large multimeric protein that is cleaved into smaller subunits by this cleaving proteinase, also known as vWF-CP or ADAMTS13 . Unlike the smaller vWF subunits, the large multimeric forms of vWF are hemostatically active and exhibit increased adhesive activity after exposure to high levels of shear stress. In the absence of the vWF-CP, it is proposed that shear-unfolded large vWF multimers accumulate in the circulation, leading to vWF-platelet binding, platelet aggregation, and microvascular thrombosis.

Patients with congenital forms of TTP-HUS appear to have a deficiency of this protein (3) , and mutations have been identified in the ADAMTS13 gene in these families (4) . In contrast, the majority of patients with adult-onset TTP have autoantibodies to vWF-CP (3;5) . vWF-CP activity can be normal in some cases of adult TTP, particularly TTP secondary to drugs, pregnancy, and malignancy, and it is likely that other mechanisms of endothelial injury and/or vWF protein dysfunction contribute to disease pathogenesis in these cases (6) . At present, laboratory assays of vWF-CP are available only through referral laboratories and have not been standardized.

Laboratory Diagnosis

Microangiopathic hemolytic anemia is a sine qua non of this disorder and is a reflection of fragmentation of red blood cells traversing turbulent areas of the microcirculation that are partially occluded by platelet aggregates. This results in the appearance of fragmented erythrocytes, referred to as schistocytes, seen on the peripheral blood smear. Markedly elevated levels of plasma LDH and indirect bilirubin levels with decreased or absent haptoglobin levels reflect the intravascular hemolysis, and the LDH levels are indicators of the severity and evolution of the ongoing hemolysis.

Clinical Management

TTP carries a high mortality rate if untreated. With the introduction of aggressive plasma exchange, long-term survival now approaches 90% and is currently the standard initial therapy in most patients with TTP (7). Although the effectiveness of glucocorticoids in uncertain, they are often started immediately after diagnosis. Serum LDH typically should begin to decrease within three days of initiating plasma exchange and the platelet count should begin to increase within five days, although normal platelet counts may not be observed for several weeks. Generally, impaired renal function is the last abnormality to improve. Plasma exchange is generally continued until neurological symptoms have improved and both a normal platelet count and serum LDH level have been maintained for several days. Even with optimal therapy, there is a 20% risk of relapse in idiopathic TTP cases with the majority of relapses occurring within the first year after the initial course of therapy (8). For patients who do not respond to plasma exchange alone, other treatments include chemotherapeutic agents, splenectomy (9), and the anti-CD20 monoclonal antibody rituximab (10). Without a pathophysiological marker to aid in the detection of subclinical disease in real-time, patients remain at risk for the morbidity and mortality of TTP.

For mildly-affected children with HUS, fluid and electrolyte management may be sufficient treatment. Plasma exchange is less effective in this setting (2) .

References

(1) Torok TJ, Holman RC, Chorba TL. Increasing mortality from thrombotic thrombocytopenic purpura in the United States -- analysis of national mortality data, 1968-1991. Am J Hematol. 1995;50:84-90.

(2) Moake JL. Thrombotic microangiopathies. N Engl J Med. 2002;347:589-600.

(3) Furlan M, Robles R, Galbusera M, Remuzzi G, Kyrle PA, Brenner B et al. von Willebrand factor-cleaving protease in thrombotic thrombocytopenic purpura and the hemolytic-uremic syndrome. N Engl J Med. 1998;339:1578-84.

(4) Levy GG, Nichols WC, Lian EC, Foroud T, McClintick JN, McGee BM et al. Mutations in a member of the ADAMTS gene family cause thrombotic thrombocytopenic purpura. Nature. 2001;413:488-94.

(5) Tsai H-M, Lian ECY. Antibodies to von Willebrand factor-cleaving protease in acute thrombotic thrombocytopenic purpura. N Engl J Med. 1998;339:1585-94.

(6) Vesely SK, George JN, Lämmle B, Studt J-D, Alberio L, El-Harake MA et al. ADAMTS13 activity in thrombotic thrombocytopenic purpura-hemolytic uremic syndrome: relation to presenting features and clinical outcomes in a prospective cohort of 142 patients. Blood. 2003;102:60-68.

(7) George JN. How I treat patients with thrombotic thrombocytopenic purpura-hemolytic uremic syndrome. Blood. 2000;96:1223-29.

(8) Sadler JE, Moake JL, Miyata T, George JN. Recent advances in thrombotic thrombocytopenic purpura. Hematology (Am Soc Hematol Educ Program). 2004;407-23.

(9) Crowther MA, Heddle N, Hayward CPM, Warkentin T, Kelton JG. Splenectomy done during hematologic remission to prevent relapse in patients with thrombotic thrombocytopenic purpura. Ann Intern Med. 1996;125:294-96.

(10) Zheng X, Pallera AM, Goodnough LT, Sadler JE, Blinder MA. Remission of chronic thrombotic thrombocytopenic purpura after treatment with cyclophosphamide and rituximab. Ann Intern Med. 2003;138:105-8.

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