Shulman-Upshaw syndrome

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

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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