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Thrombotic thrombocytopenic purpura and hemolytic-uremic syndrome are acute, fulminant disorders characterized by thrombocytopenia and microangiopathic hemolytic anemia. Other manifestations may include alterations in level of consciousness and renal failure. Diagnosis requires demonstrating characteristic laboratory test abnormalities, including Coombs'-negative hemolytic anemia. Treatment is plasma exchange and corticosteroids in adults and supportive care (sometimes including hemodialysis) in children.

Pathophysiology

Thrombotic thrombocytopenic purpura (TTP) and hemolytic-uremic syndrome (HUS) involve nonimmunologic platelet destruction. Loose strands of von Willebrand's factor (VWF) or fibrin are deposited in multiple small vessels, which damage passing platelets and RBCs causing significant thrombocytopenia and anemia. Platelets are also destroyed within multiple small thrombi. Multiple organs develop bland platelet-VWF thrombi (without the vessel wall granulocytic infiltration characteristic of vasculitis) localized primarily to arteriocapillary junctions, described as thrombotic microangiopathy. The brain, heart, and kidneys are particularly likely to be affected.

TTP and HUS differ mainly in the relative degree of renal failure. Typically, disorders in adults are described as TTP and are less likely to involve renal failure. HUS is used to describe the disorder in children, which typically involves renal failure.

Etiology

Children: Most cases follow acute hemorrhagic colitis resulting from Shiga toxin–producing bacteria (eg, Escherichia coli O157:H7, some strains of Shigella dysenteriae).

Adults: Many cases are idiopathic. Known causes and associations include

• Drugs: Quinine Some Trade Names
  QUALAQUIN
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  (most common), immunosuppressants, and cancer chemotherapy drugs (eg, cyclosporine Some Trade Names
  NEORAL
  SANDIMMUNE
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  , mitomycin Some Trade Names
  MUTAMYCIN
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  C)
• Pregnancy (often indistinguishable from severe preeclampsia or eclampsia)
• Rarely, hemorrhagic colitis from Escherichia coli O157:H7

A predisposing factor in many patients is congenital or acquired deficiency of the plasma enzyme ADAMTS13, which cleaves VWF and thus eliminates abnormally large VWF multimers that can cause platelet thrombi;

Symptoms and Signs

Manifestations of ischemia develop with varying severity in multiple organs. These manifestations include weakness, confusion and coma, abdominal pain, nausea, vomiting, diarrhea, and arrhythmias caused by myocardial damage. Children usually have a prodrome of vomiting, abdominal pain, and diarrhea (frequently bloody). Fever may occur, but high fever with chills does not occur in TTP or HUS and suggests sepsis. The clinical syndromes of TTP and HUS are indistinguishable, except that neurologic symptoms are less common with HUS.

Diagnosis

• CBC with platelets, peripheral blood smear, Coombs' test
• Exclusion of other thrombocytopenic disorders

TTP-HUS is suspected in patients with suggestive symptoms, thrombocytopenia, and anemia. If the disorder is suspected, urinalysis, peripheral blood smear, reticulocyte count, serum LDH, renal function tests, serum bilirubin (direct and indirect), and Coombs' test are done. The diagnosis is suggested by:

• Thrombocytopenia and anemia
• Fragmented RBCs on the blood smear (helmet cells, triangular-shaped RBCs, distorted-appearing RBCs—these changes describe microangiopathic hemolysis)
• Evidence of hemolysis (falling Hb level, polychromasia, elevated reticulocyte count, elevated serum LDH)
• Negative direct antiglobulin (Coombs') test

Otherwise unexplained thrombocytopenia and microangiopathic hemolytic anemia are sufficient evidence for a presumptive diagnosis.

Causes: Although causes (eg, quinine Some Trade Names
QUALAQUIN
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sensitivity) or associations (eg, pregnancy) are clear in some patients, in most patients TTP-HUS appears suddenly and spontaneously without apparent cause. TTP-HUS is often indistinguishable, even with renal biopsy, from syndromes that cause identical thrombotic microangiopathies (eg, preeclampsia, systemic sclerosis, accelerated hypertension, acute renal allograft rejection).

Testing for ADAMTS13 activity is appropriate in patients with suspected TTP-HUS, except in children who have typical diarrhea-associated HUS. Although the results of ADAMTS13 testing do not affect initial treatment, results are important prognostically.

Stool testing (specific culture for E. coli O157:H7 or Shiga toxin assay) is done in children with diarrhea and also adults who had a prodrome of bloody diarrhea; however, the organism and toxin may have cleared by the time of presentation.

Treatment

• Plasma exchange and corticosteroids in adults

Typical diarrhea-associated HUS in children caused by enterohemorrhagic infection usually spontaneously remits and is treated with supportive care and not plasma exchange; over half require renal dialysis. In other cases, untreated TTP-HUS is almost always fatal. With plasma exchange, however, > 85% of patients recover completely.

Plasma exchange is continued daily until evidence of disease activity has subsided, as indicated by a normal platelet count, which may be several days to many weeks. Adults with TTP are also given corticosteroids. In patients with recurrence when plasma exchange is stopped or in patients with relapses, more intensive immunosuppression with rituximab Some Trade Names
RITUXAN
Click for Drug Monograph
may be effective. Most patients experience only a single episode of TTP-HUS. However, relapses occur in about 40% of patients who have a severe deficiency of ADAMTS13 activity caused by an autoantibody inhibitor. Patients must be evaluated quickly if symptoms suggestive of a relapse develop.

Last full review/revision May 2009 by James N. George, MD

Content last modified May 2009