Thrombotic Thrombocytopenic Purpura and ADAMTS-13: New Insights into Pathogenesis, Diagnosis, and Therapy

Janis Wyrick-Glatzel, MS, MT(ASCP)

Disclosures

Lab Med. 2004;35(12) 

In This Article

Differential Diagnosis of Patients with TTP and Related Syndromes

Various diseases on initial presentation can manifest similar to TTP. These disorders include: childhood HUS, pregnancy-associated microangiopathy, transplant-associated thrombocytopenic purpura, drug-induced purpura, autoimmune disorders, hemolysis, elevated liver function tests and low platelets (HELLP) syndrome and underlying malignancies ( Table 1 ). The sudden development of clinical symptoms that define TTP in patients with no known underlying disease is referred to as "idiopathic" TTP. In patients with a variety of clinical conditions, the associated symptoms of TTP may be found and therefore is commonly referred to as "secondary" TTP. To date, there is no "absolute" for the diagnosis of TTP. A severe deficiency of less than 5% ADAMTS-13 activity, with clinical symptoms of an acute thrombocytopenia and evidence of a microangiopathic hemolytic anemia, appropriately defines a diagnosis of TTP. Because the sensitivity of ADAMTS-13 deficiency it is not well established, a deficiency of the protein alone does not constitute a diagnosis of TTP. The clinical uncertainty in making a diagnosis of TTP is evident when severely deficient ADAMTS-13 activity does not always produce the clinical entity of TTP; nor does severely deficient ADAMTS-13 activity diagnose those individuals with TTP who should be clinically managed by effective therapy.

Childhood HUS is a diagnostic term used for the development of systemic complications resembling TTP in children usually less than 4-to-5 years of age who present with a prodrome of bloody diarrhea caused by an enterohemorrhagic strain of E. coli 0157:H7. This organism produces a Shiga-toxin-related enterocolitis. Five to ten percent of childhood patients infected with E. coli 0157:H7 present with acute HUS.[22] In contrast to the pentad that typically defines TTP, HUS is characterized by a triad of clinical manifestations, which include thrombocytopenia, microangiopathic hemolytic anemia, and renal failure. Because HUS is often difficult to diagnosis clinically, the term TTP-HUS or thrombotic microangiopathy may be used. Studies show that once the organism attaches to the epithelium of the colon it secretes the toxin. The toxin enters the bloodstream and binds to a glycolipid surface receptor on endothelial cells under the influence of inflammatory cytokines. It is believed that the binding of the Shiga toxin results in platelet clumping. In a study of childhood HUS cases, changes in the fibrinolytic system were noted as seen by an increase in tPA antigen and tPA-PAI-1 complex in response to intravascular fibrin formation.[31] Acute renal failure is the most critical clinical symptom to be managed in HUS. Despite the severity of renal insufficiency, mortality is low and most Shiga-toxin-associated HUS patients respond well to plasma exchange.

The association of pregnancy with TTP may account for some of the hypercoagulable risk in women near term and postpartum. In a large study of TTP cases, 10% of all cases were diagnosed during pregnancy or postpartum, with the majority of episodes occurring near delivery.[32] There appears to be a decreased plasma concentration of ADAMTS-13 activity during the second and third trimesters of pregnancy with a concomitant increase of plasma von Willebrand factor perhaps as a contributing factor.[33] The diagnosis of TTP from other complications such as pre-eclampsia, eclampsia, and HELLP syndrome is often obscured. To make the clinical distinction between TTP, HELLP, or HUS, it should be recognized that neurologic changes are common in TTP, renal failure in HUS, and neither neurologic nor renal changes are present in HELLP. A diagnosis of HELLP is usually made in a clinical setting of preeclampsia with microangiopathic hemolytic anemia and severe thrombocytopenia. This syndrome usually resolves within days following delivery. The risk of TTP in subsequent pregnancies is rather vague and hard to determine.

Few studies have defined the etiology of post bone marrow transplantation and TTP. Schriber and colleagues reviewed all cases of TTP associated with post-bone marrow transplantation (BMT) through 1996. The study recognized that fatal outcomes in patients were observed when (1) TTP developed within 120 days posttransplant, (2) patients were treated with cyclosporine for graft-vs-host disease, (3) received an allogeneic BMT, and (4) had renal and neurologic abnormalities.[34] Cyclosporine has a cytotoxic effect on endothelial cells and produces an increase in vWf release. Following BMT, however, many patients do not develop TTP yet are on clinical regimes that include immunosuppressive drugs. Other factors most likely contribute to the development of TTP.

Many therapeutic agents have been associated with TTP-HUS like syndromes. Some of the more common drugs implicated are quinine, mitomycin, penicillin, oral contraceptives, and anti-platelet agents such as ticlopidine and clopidogrel. The mechanism by which TTP develops may follow either an acute immune-mediated response with the development of drug dependent antibody formation or an insidious dose-related toxic effect. Quinine is commonly associated with thrombocytopenia. Initially, the development of quinine-dependent platelet antibodies occurs with subsequent development of antibodies to multiple target tissues, which result in the systemic involvement seen in TTP. Mitomycin initiation of the TTP syndrome appears to be a dose-related effect and is associated with microangiopathic hemolytic anemia and thrombocytopenia. The onset may be sudden due to the initial toxicity or may appear gradually due to the cumulative toxicity of the drug. Most patients in this category responded well to plasma exchange. In some patients receiving the antiplatelet agents, ticlopidine and clopidogrel, a reported deficiency of ADAMTS-13 and an inhibitor of ADAMTS-13 activity has been noted.[11] Despite the development of TTP within 14 days following the administration of clopidogrel, most patients responded to plasma exchange.[11]

Thrombotic thrombocytopenic purpura may clinically complicate the course of patients with such autoimmune diseases as antiphospholipid syndrome, systemic lupus, polyarteritis nodosa, and scleroderma. In some patients with these multi-organ involvement diseases, the associated pathologic features are indistinguishable from those of TTP. The commonality between the disorders may complicate the clinical diagnosis and thus may prevent initiation of effective treatment.

The association of various malignancies with altered coagulation is well documented. Adenocarcinomas are commonly associated with TTP-HUS; and of these cancers, gastric adenocarcinoma has a high association with TTP. Defining the predisposing mechanism of TTP in the cancer population is difficult at best since many chemotherapeutic agents are also associated with the initiation of TTP. Also, similarity exists between the clinical features of cancer and TTP. However, evaluating the degree of anemia and thrombocytopenia relative to the malignancy may help identify and diagnose TTP in patients in this clinical setting. In a study by Murgo and colleagues[11] characteristics to differentiate cancer-related TTP from chemotherapy-related TTP were examined. The study defined those patients who developed TTP while in remission as chemotherapy-induced cases. In patients with cancer, TTP may be treated by means of plasmapheresis, immunosuppressive agents, and immunoadsorption with varying degrees of efficacy.

Acute idiopathic TTP is difficult to recognize and diagnose clinically. A large percentage of cases of acquired idiopathic TTP are due to autoantibody formation. The autoantibody mediates a severe ADAMTS-13 protease deficiency. These cases often show remission associated with the absence of the autoantibody and normal ADAMTS-13 activity. Reappearance of the autoantibody generally precedes the clinical relapse and results in a subsequent episode of severe ADAMTS-13 deficiency. Relapses are considered common and frequent in patients with acute idiopathic TTP. ULVWF multimers are detected during acute episodes in some patients with acute idiopathic TTP. Focus is now pointed to the antigenic epitope of the autoantibody related to the efficacy of standard plasma exchange with replacement FFP in these patients. It is thought that this therapy removes the inhibitory autoantibody by plasma exchange and supplies the ADAMTS-13 protease during FFP replacement.

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