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Purpura, thrombotic thrombocytopenic

Thrombotic thrombocytopenic purpura (TTP or Moschcowitz disease) is a rare disorder of the blood coagulation system that in most cases arises from the deficiency or inhibition of the enzyme ADAMTS13, which is responsible for cleaving large multimers of von Willebrand factor. more...

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Medicines

It is a serious condition that leads to hemolysis and end-organ damage, and may require plasmapheresis therapy.

Signs and symptoms

Classically, the following five symptoms are indicative of this elusive disease:

  • Fluctuating neurological symptoms, such as bizarre behavior, altered mental status, stroke or headaches (65%)
  • Kidney failure (46%)
  • Fever (33%)
  • Thrombocytopenia (low platelet count), leading to bruising or frank purpura;
  • Microangiopathic haemolytic anaemia (anemia and a characteristic blood film)

Diagnosis

The combination of the symptoms and a routine blood film often lead to the detection of schistocytes (fragmented red cells) and "helmet cells" on the blood film. This is indicative of breakdown of red blood cells through factors in the small blood vessels.

Other tests to be performed are reticulocyte counts, lactate dehydrogenase, direct antiglobulin test (DAT/Coombs' test), renal function (creatinine), electrolytes and liver enzymes. Very high LDH levels may be present; these mainly originate from the poorly perfused tissues, and not so much from the hemolysis.

The above symptoms and findings are the main criteria for diagnosis, although the fever, renal and neurological symptoms can be absent. Increased lactate dehydrogenase levels and a negative direct antiglobulin test (DAT, Coombs' test) in the context of microangiopathic haemolytic anaemia (MAHA) are indicative of TTP.

The main differential diagnosis is between TTP and hemolytic uremic syndrome (HUS). The syndromes show a remarkable overlap in symptoms, and researchers have argued in the past that the two diseases are part of a continuum. Generally, HUS leads mainly to renal symptoms, while neurological abnormalities tend to be rare in HUS. Also, many HUS cases are preceded by an episode of bloody diarrhea due to infection with a verotoxin-positive E. coli O157:H7 (enterohemorrhagic strain).

Although its utility in clinical settings is still under discussion, measurement of the von Willebrand factor-cleaving metalloproteinase ADAMTS13 (see below) and IgG inhibitors to this enzyme have been shown to aid in the diagnosis of TTP. In the series reported by Zheng et al (2004), low ADAMTS13 activity and detection of an inhibitor predicted response to therapy, and high titres of the inhibitor predicted the necessity of additional therapy.

The inhibitor is measured by inactivating innate ADAMTS13 in the patient's plasma by heating it, and then diluting it (1:1, 1:2, 1:4 etc) in saline by titration. These dilutions are then mixed with normal plasma. If ADAMTS13 activity can be detected in all dilutions, then no inhibitor is detectable. If decreased activity is limited to low dilutions, there are low inhibitor concentrations (low titers), while decreased activity in all or most dilutions shows high inhibitor levels.

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Recognition of TTP Is Key When Prescribing Clopidogrel - Thrombotic thrombocytopenia purpura
From American Family Physician, 12/15/00 by Jeffrey T. Kirchner

Thrombotic thrombocytopenia purpura (TTP) is a serious and often fatal systemic disease manifested as thrombocytopenia, microangiopathic hemolytic anemia, fever, and renal and neurologic symptoms. TTP generally is considered idiopathic but has been associated with use of various medications. The pathophysiology involves the production of an IgG autoantibody against a metalloprotease that degrades von Willebrand factor. The antiplatelet drug ticlopidine has been found to cause TTP in about one of every 1,600 to 5,000 patients treated. Other adverse effects of ticlopidine include neutropenia, adverse skin reactions and gastrointestinal side effects. Because of the problems associated with ticlopidine, a newer agent, clopidogrel, has become more widely used when antiplatelet therapy is indicated for stroke or coronary thrombosis prevention. Both drugs block a binding site on platelets, inhibiting the expression of the glycoprotein IIb/IIIa. Clopidogrel had no reported significant adverse effects, including TTP, when given to almost 20,000 patients in clinical trials. Since its labeling by the U.S. Food and Drug Administration in 1998, clopidogrel has been prescribed to approximately 3 million people. Now that it has achieved widespread clinical use, two cases of TTP have been reported. Bennett and colleagues recently reported the clinical characteristics of 11 patients taking clopidogrel in whom TTP subsequently developed. This adverse event was believed to be serious enough to warrant prepublication release of the information on the Web site of the New England Journal of Medicine.

The 11 patients (six women and five men between 35 and 70 years of age) took clopidogrel between March 1998 and March 2000. The drug was most commonly prescribed to treat coronary artery disease and following coronary stent placement. The duration of therapy ranged from three to 14 days. All patients were actively taking the drug or had recently been taking it at the time TTP was diagnosed. In all patients, the diagnosis was confirmed by clinical and laboratory criteria. Most patients had platelet counts of less than 20,000 per mm3 and hematocrit values of less than 27 percent. Neurologic symptoms such as slurred speech, aphasia, disorientation, confusion and coma developed in seven patients. Four patients had a serum creatinine level of greater than 2.5 mg per dL (221 [micro]mol per L) and two had marked increases in aminotransferase levels, suggesting liver damage.

All patients were treated with plasma exchange, which on average required eight exchanges for resolution of symptoms and laboratory abnormalities. Of these, one patient died. Von Willebrand factor-cleaving protease activity was undetectable in two patients tested, and both of these patients had IgG antibody inhibitors of the protease. Two patients had a relapse within seven months of the initial episode, but both recovered after plasma exchange.

The authors conclude that the early recognition of TTP is of key importance so that treatment with the offending drug is stopped and potentially life-saving plasma exchange can be initiated. Physicians must be aware of the possibility of TTP and its clinical manifestations before prescribing clopidogrel. TTP typically develops within the first two weeks after the initiation of therapy, but recurrence has been reported two months after therapy was discontinued.

EDITOR'S NOTE: Many patients who are given clopidogrel by a cardiologist or neurologist receive follow-up care from their family physician. If TTP is suspected, therapy with the antiplatelet agent must be promptly stopped. Unfortunately, the neurologic symptoms associated with TTP may be mistaken for those of stroke or transient ischemic attack, problems for which the drug was originally prescribed.--j.t.k.

COPYRIGHT 2000 American Academy of Family Physicians
COPYRIGHT 2001 Gale Group

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