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Thrombotic Thrombocytopenic Purpura (TTP) and Hemolytic-Uremic Syndrome (HUS)

by David J. Kuter, MD, DPhil

Thrombotic thrombocytopenic purpura (TTP) and hemolytic-uremic syndrome (HUS) are acute, fulminant disorders characterized by thrombocytopenia and microangiopathic hemolytic anemia. Other manifestations may include alterations in level of consciousness and kidney 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; eculizumab is rarely indicated.

Pathophysiology

TTP and HUS involve nonimmunologic platelet destruction. Loose strands of platelets and fibrin are deposited in multiple small vessels and damage passing platelets and RBCs, causing significant thrombocytopenia and anemia. Platelets are also consumed within multiple small thrombi. Multiple organs develop bland platelet-von Willebrand factor (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 kidney failure. Typically, disorders in adults are described as TTP and are less likely to involve kidney failure. HUS is used to describe the disorder in children, which typically involves kidney 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—see Infection by Escherichia coli O157:H7 and Other Enterohemorrhagic E. coli (EHEC)).

Adults

Many cases are idiopathic. Known causes and associations include

  • Immunosuppressants (eg, cyclosporine) and cancer chemotherapy drugs (eg, mitomycin C)

  • Pregnancy (often indistinguishable from severe preeclampsia or eclampsia)

  • Hemorrhagic colitis due to Escherichia coli O157:H7 or E. coli O104:H4

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 or 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 symptoms and signs of TTP and HUS are indistinguishable, except that neurologic symptoms are less common with HUS.

Diagnosis

  • CBC with platelets, peripheral blood smear, Coombs test, LDH, PT, PTT, fibrinogen

  • 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 indicative of microangiopathic hemolysis (schistocytes: helmet cells, triangular RBCs, distorted-appearing RBCs)

  • Evidence of hemolysis (falling Hb level, polychromasia, elevated reticulocyte count, elevated serum LDH and bilirubin, reduced haptoglobin)

  • Negative direct antiglobulin (Coombs) test

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

Causes

Although causes (eg, cyclosporine) 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 ( Shiga toxin enzyme-linked immunosorbent assay or specific culture media for E. coliO157:H7) 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

  • In adults with TTP, plasma exchange and corticosteroids

  • In children with HUS, supportive care, often including hemodialysis

  • In refractory atypical HUS, eculizumab

Typical diarrhea-associated HUS in children caused by enterohemorrhagic infection usually spontaneously remits and is treated with supportive care and not antibiotics or plasma exchange; over half of patients require renal dialysis. Untreated TTP 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 require 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 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.

In patients with HUS refractory to plasma exchange and/or corticosteroids and worsening renal insufficiency, complement inhibition with eculizumab can sometimes reverse the renal insufficiency. Children with known or presumed hereditary deficiency in complement regulatory proteins such as factor H are particularly likely to respond to eculizumab.

Key Points

  • Platelets and RBCs are destroyed non-immunologically, leading to thrombocytopenia and anemia; renal failure is common in children.

  • Cause in children is typically hemorrhagic colitis resulting from Shigatoxin–producing bacteria.

  • Cause in adults is commonly associated with antibody against the ADAMTS13 protease but may also be due to certain drugs, pregnancy, and infectious colitis.

  • Typical diarrhea-associated HUS in children usually spontaneously remits with supportive care, although over half of affected children require renal dialysis.

  • Adults require plasma exchange and often corticosteroids.

  • Rarely, worsening renal insufficiency refractory to other treatment may respond to eculizumab.

Resources In This Article

Drugs Mentioned In This Article

  • Drug Name
    Select Trade
  • SOLIRIS
  • MITOSOL
  • NEORAL, SANDIMMUNE
  • RITUXAN

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