AUTHOR AND EDITOR INFORMATION

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INTRODUCTION

Section 2 of 11  

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• Introduction
• Clinical
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• Follow-up
• Miscellaneous
• Multimedia
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Background

Hemolytic-uremic syndrome (HUS) is a clinical syndrome characterized by progressive renal failure associated with microangiopathic (nonimmune, Coombs-negative) hemolytic anemia and thrombocytopenia.

HUS is the most common cause of acute renal failure in children and increasingly recognized in adults. Thrombotic thrombocytopenic purpura (TTP), childhood HUS, and adult HUS differ in their clinical presentations but have many common features. Gasser et al first described HUS in 1955. In 1988, Wardle described HUS and TTP as different entities, but in 1987, Remuzzi suggested that these 2 conditions are various expressions of the same entity. With the recent discovery of von Willebrand factor–cleaving metalloprotease ADAMTS-13, HUS and TTP are clearly different diseases despite their clinical similarities.

Pathophysiology

Damage to endothelial cells is the primary event in the pathogenesis of HUS. The cardinal lesion is composed of arteriolar and capillary microthrombi (thrombotic microangiopathy [TMA]) and RBC fragmentation.

Classification

HUS is classified into 2 main categories depending on whether it is associated with Shiga-like toxin.

The first category is Shiga-like toxin (Stx)–associated HUS (Stx-HUS). This is the classic or typical, primary or epidemic form of HUS. Stx-HUS is largely a disease of children younger than 2-3 years and often results in diarrhea (denoted D+HUS). One fourth of patients present without diarrhea (denoted D-HUS). Acute renal failure occurs in 55-70% of patients, but they have a favorable prognosis, and as many as 70-85% of patients recover renal function.

The second category is non-Stx–associated HUS (non-Stx-HUS), which can be sporadic or familial. As the name implies, infection by Stx-producing bacteria is not the cause, and disease may occur year round without a gastrointestinal prodrome (D-HUS). Overall, patients with non-Stx-HUS have a poor outcome, and as many as 50% may progress to ESRD or irreversible brain damage. Up to 25% of patients die during the acute phase. The familial form is associated with genetic abnormalities of the complement regulatory proteins.

Recent concepts in the pathogenesis of HUS

Stx–associated HUS

In North America and Western Europe, 70% of cases are secondary to Escherichia coli serotype O157:H7. Other E coli serotypes are O111:H8, O103:H2, O121, O145, O26, and O113. In Asia and Africa, it is often associated with Stx-producing Shigella dysenteriae serotype 1. Regarding Stx associated with E coli, Stx-1 is almost identical to Stx associated with S dysenteriae type 1, differing by a single amino acid. Stx-1 is 50% homologous with Stx-2. Stx-2 is associated with severe disease.

After ingestion, Stx-E coli closely adheres to the epithelial cells of the gut mucosa by means of a 97-kD outer-membrane protein (intimin). The route by which Stx is transported from the intestine to the kidney is debated. Recent studies highlight the role of polymorphonuclear neutrophils (PMNs) in the transfer of Stx in the blood because Stx rapidly and completely binds to PMN when incubated with human blood. However, the receptor expressed on glomerular endothelial cells has 100-fold higher affinity than of PMN receptors; in this way thereby transfer the Stx-ligand to glomerular endothelial cells.

The binding of Stx to target cells depends on B subunits and occurs by means of the terminal digalactose moiety of the glycolipid cell-surface receptor globotriaosylceramide Gb3. Both Stx-1 and Stx-2 bind to different epitopes on the receptor with different affinities. Stx-1 binds to and detaches easily from Gb3, whereas Stx-2 binds and dissociates slowly, causing more severe disease than that due to Stx-1.

Data from recent studies suggest that Stx favors leukocyte-dependent inflammation by altering endothelial cell-adhesion properties and metabolism, ultimately resulting in microvascular thrombosis. Findings from earlier studies suggested that fibrinolysis is augmented in Stx-HUS, but results of more recent studies revealed higher-than-normal levels of plasminogen-activator inhibitor type 1 (PAI-1), indicating that fibrinolysis is substantially inhibited.

Non-Stx–associated HUS

Non-Stx-HUS, or atypical HUS, is less common than Stx-HUS and accounts for 5-10% of all cases. It may occur at all ages, but it is most frequent in adults and occurs without prodromal diarrhea (D-HUS). Patients have an unfavorable prognosis. Stx-HUS can occur in sporadic cases or in families.

Sporadic non-Stx–associated HUS

In sporadic non-Stx-HUS, various triggers have been identified: nonenteric infections, viruses, drugs, malignancies, transplantation, pregnancy, and other underlying medical conditions (rare, eg, antiphospholipid syndrome [APL], systemic lupus erythematosus [SLE]), among others.

Streptococcus pneumoniae infection accounts for 40% of all causes of non-Stx-HUS and 4.7% of all causes of HUS in children in the United States. Bacterial neuroaminidase removes sialic acids and thus lyses cell-surface glycoproteins and exposes Thomsen-Friedenreich antigen to preformed circulating immunoglobulin M (IgM) antibodies. These bind to the neoantigen on platelets and endothelial cells and cause polyagglutination and damage to endothelial cells. On clinical examination, the disease is usually severe and causes respiratory distress, neurologic involvement, and coma, with a mortality rate of up to 50%.

Familial non-Stx–associated HUS

Familial non-Stx-HUS accounts for <3% of all cases of HUS. Both autosomal dominant and autosomal recessive forms of inheritance are observed. Recent data suggest genetic abnormalities in the complement regulatory proteins. Autosomal recessive HUS often occurs early in childhood. The prognosis is poor, recurrences are frequent, and the mortality rate is 60-70%. Autosomal dominant HUS often occurs in adults, who have a poor prognosis. The risk of death or ESRD is 50-90%.

Factor H

Factor H (HF1) consists of 20 homologous units called short consensus repeats (CSRs) and plays an important role in the regulation of the alternative pathway of complement. HF1 also serves as a cofactor for the C3b-cleaving enzyme factor I in the degradation of newly formed C3b molecules. It controls the decay, formation, and stability of C3b convertase (C3bBb), and it protects glomerular endothelial cells and the basement membrane against complement attack by binding to the polyanionic proteoglycans on the surface of endothelial cells and in the subendothelial matrix.

Fifty HF1 mutations have been described in 80 patients who had familial (36 patients) and sporadic (44 patients) forms of non-Stx-HUS. The mutation frequency is 40% in familial form and 13-17% in sporadic form.

Patients with HF1 mutations have partial HF1 deficiency that causes a predisposition to the disease rather than the disease itself. Mutant HF1 has normal cofactor activity in the fluid phase, but its binding to proteoglycans is reduced because the mutation affects the polyanion interaction at the C-terminus of HF1. Suboptimal HF1 activity is often enough to protect the patient from complement activation in physiologic conditions. However, activation of complement pathways results in higher-than-normal concentration of C3b, and its deposition on vascular endothelial cells cannot be prevented because of the inability of mutant HF1 to bind to polyanion proteoglycans.

Two thirds of patients with non-Stx-HUS have no HF1 mutation, though as many as 50% have overactivity of the alternative complement pathway. This observation suggests that uncommon polymorphic variants of the gene for HF1 may be responsible for the disease in patients without an HF1 mutation.

Abnormalities in genes encoding for complement modulatory proteins (MCP gene) have recently been shown to predispose people to non-Stx-HUS.

Frequency

United States

Stx-HUS occurs with a frequency of 0.5-2.1 cases per 100,000 population per year, with a peak incidence in children younger than 5 years, in whom the incidence is 6.1 cases per 100,000 population per year.

Non-Stx-HUS accounts for 5-10% of all cases of HUS, and the incidence in children is about one tenth that of Stx-HUS. This rate corresponds to about 2 cases per 100,000 population per year.

International

In children younger than 15 years, typical HUS occurs at a rate of 0.91 cases per 100,000 population in Great Britain, 1.25 cases per 100,000 population in Scotland, and 1.44 cases per 100,000 population in Canada.

Seasonal variation occurs, with the disease peaking in the summer and fall.

Mortality/Morbidity

• Stx-HUS: Acute renal failure occurs in 55-70% of patients and up to 70-85% recover renal function.
• Non-Stx-HUS: Patients have poor outcomes, with up to 50% progressing to ESRD or irreversible brain damage. As many as 25% die during the acute phase.

Race

HUS occurs infrequently in blacks.

Sex

Both sexes are affected equally.

Age

Disease occurs mainly in young children; however, adolescents and adults are not exempt.

• In young children, spontaneous recovery is common.
• In adults, the probability of recovery is low when HUS is associated with severe hypertension.

CLINICAL

Section 3 of 11  

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History

• Prodromal gastroenteritis (83%)
• • Prodrome of fever (56%)
  • Bloody diarrhea (50%) for 2-7 days before the onset of renal failure
• Irritability, lethargy
• Seizures (20%)
• Acute renal failure (97%)
• Anuria (55%)

Physical

• Hypertension (47%)
• Edema, fluid overload (69%)
• Pallor, often severe

Causes

The disease predominantly occurs in infants and children after prodromal diarrhea. In summer epidemics, the disease may be related to infectious causes.

• Bacterial infection
• • S dysenteriae
  • E coli
  • Salmonella typhi
  • Campylobacter jejuni
  • Yersinia pseudotuberculosis
  • Neisseria meningitidis
  • Streptococcus pneumoniae
  • Legionella pneumophila
  • Mycoplasma species
• Rickettsial infection
• • Rocky Mountain spotted fever
  • Microtatobiotes
• Viral infection
• • HIV
  • Coxsackievirus
  • Echovirus
  • Influenza virus
  • Epstein-Barr virus
  • Herpes simplex virus
• Fungal infection - Aspergillus fumigatus
• Vaccination
  • Influenza triple-antigen vaccine
  • Typhoid-paratyphoid A and B (TAB) vaccine
  • Polio vaccine
• Causes of the secondary or sporadic form
  • Pregnancy and puerperium
  • Oral contraception
  • Cancers (chiefly mucin-producing adenocarcinomas)
  • Chemotherapeutic agents (mitomycin-C, cisplatin, bleomycin, gemcitabine)
  • Immunotherapeutic agents (cyclosporine, tacrolimus, OKT3, interferon [IFN])
  • Antiplatelet agents (ticlopidine, clopidogrel)
  • Malignant hypertension
  • Collagen vascular disorder (eg, SLE)
  • Primary glomerulopathies
  • Transplantation (eg, of kidney, bone marrow): This can be de novo or recurrent. It occurs in 5-15% of renal transplant patients who receive cyclosporine and in about 1% of patients who receive tacrolimus.
• Immunodeficiency - Thymic dysplasia
• Familial: This cause accounts for 3% of all cases of HUS, and both autosomal dominant and autosomal recessive forms of inheritance have been reported. Autosomal recessive HUS occurs in childhood, and patients have a poor prognosis with frequent recurrences and a mortality rate of 60-70%. Autosomal dominant HUS occurs mostly in adults, who have a poor prognosis; the cumulative incidence of death or ESRD is 50-90%.
• Idiopathic - No cause identified in about 50% of all cases of sporadic non-Stx HUS.
• Drugs implicated in causing non-Stx-HUS
  • Anticancer agents: These include mitomycin, cisplatin, bleomycin, and gemcitabine. The risk for HUS after mitomycin therapy is 2-10%, and onset may be delayed, occurring almost a year after the patient starts treatment. The prognosis is poor, with a 75% mortality rate at 4 months.
  • Immunotherapeutic agents: Examples are cyclosporine, tacrolimus, OKT3, and IFN.
  • Antiplatelet agents: Examples are ticlopidine and clopidogrel.
  • Posttransplantation HUS is reported with increasing frequency and may be primary (de novo) or recurrent. It is often a consequence of the use of calcineurin inhibitors or of humoral (C4b positive) rejection. It occurs in 5-15% of renal transplant patients treated with cyclosporine and in about 1% of patients treated with tacrolimus.
• Pregnancy-associated HUS occasionally develops as a complication of preeclampsia. Patients may progress to full-blown hemolysis, elevated liver enzymes, and low platelets (HELLP) syndrome. Postpartum HUS usually occurs within 3 months of delivery. The prognosis is poor, with a 50-60% mortality rate, residual renal dysfunction, and hypertension occurring in most patients.
• Idiopathic HUS accounts for 50% of all cases of sporadic non-Stx-HUS.

DIFFERENTIALS

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Other Problems to be Considered

Disseminated intravascular coagulation (DIC)
Decreased platelet count
Decreased plasma levels of clotting factors V and VIII
Increased activated partial thromboplastin time (aPTT) and prothrombin time (PT) increased
Increased D-dimer and fibrinogen-degradation products (FDP)
TMA in patients with cancer

WORKUP

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Lab Studies

• Urinalysis
• • Benign mild proteinuria is frequently present.
  • RBCs and RBC casts may be present.
• Measurement of BUN, serum creatinine, and serum electrolyte levels
• Hemoglobin determination
• • Severe anemia may be present.
  • Perform peripheral smear for schistocytes.
  • The degree of thrombocytopenia is not correlated with the severity or the length of illness. The platelet count usually returns to normal within 2 weeks.
  • Determine aPTT, FDP, and D-dimer values.
• Hemolytic workup
• • Results may show anemia.
  • Bilirubin levels may be elevated.
  • Lactic dehydrogenase (LDH) levels may be elevated.
  • Haptoglobin levels may be decreased.
• Stool culture
• • Obtain a sample for stool culture.
  • Evaluate especially for E coli 0157:H7 and Shigella bacteria.

Imaging Studies

• Perform renal ultrasonography in patients with renal failure to rule out obstruction.

Procedures

• Biopsy findings clinically establish the diagnosis. However, kidney biopsy is not required in children. In adults, kidney biopsy is rarely required.
• Peripheral smears for schistocytes and thrombocytopenia are important.

Histologic Findings

The characteristic pathologic findings are occlusive lesions of the arterioles and small arteries and consequent tissue microinfarctions.

In HUS, the lesions are usually limited to the kidneys, whereas the lesions are more widespread in TTP. Renal lesions are primarily focal and involve both the glomerular capillaries and the afferent arterioles. The venous side of the circulation is usually spared. A fully developed vascular lesion consists of amorphous-appearing, hyalinelike, thrombi-containing platelet aggregates and a small amount of fibrin that partially or fully occludes the involved small vessels (see Images 1-2). Despite extensive arterial changes, no perivascular cellular infiltration or evidence of associated vasculitis is present. Clinicians may observe subendothelial deposits with overlying endothelial proliferation.

As a rule, changes in renal function and the course of renal failure are well correlated with the pathologic findings in the kidney. Obliterative arteriolar lesions are correlated with hypertension and progressive loss of renal function. Glomerular thrombotic microangiopathic lesions and cortical necrosis are the most frequent histologic findings in Stx-HUS, whereas arterial thrombotic microangiopathic lesions are the most frequent features in non-Stx-HUS.

TREATMENT

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Medical Care

• Treatment of Stx-HUS: No treatment of proven value has been identified, and comprehensive supportive therapy is still the mainstay during the acute phase.
  • Antibiotics: There is no clear consensus on the use of antibiotics and the evidence supports that antibiotics should be avoided unless patient is septic.
• • Stx-binding agent: Oral administration of SYNSORB, which is composed of silicon particles linked to globotriaosylceramide, failed to provide a benefit over placebo.
  • Renal transplantation: This procedure is safe and effective for children who progress to ESRD, with a recurrence rate of 0-10%.
  • Other therapies: Other treatments, including plasma therapy and use of intravenously infused immunoglobulin (IgG), fibrinolytic agents, antiplatelet agents, corticosteroids, and antioxidants were ineffective in controlled clinical trials during the acute phase of the disease.
• Treatment of non-Stx-HUS
  • Plasma manipulation, exchange versus infusion: The mortality rate decreased from 50% to 25% with the introduction of plasma manipulation, but its efficacy during acute phase is debated. Exchange might be more effective than infusion, as it removes potentially toxic substances from the circulation. Plasma exchange instead of infusion should be considered first-line therapy in situations, such as renal or heart failure, that limit the amount of plasma that can be infused. Plasma treatment should be started within 24 hours of the patient's presentation to decrease treatment failures and continued once or twice a day for at least 2 days after complete remission. Plasma therapy is contraindicated in S pneumoniae–induced non-Stx-HUS; it may exacerbate the disease because adult plasma contains antibodies against the Thomsen-Freidenreich antigen.
  • Renal transplantation: This procedure is not an option for non-Stx-HUS because of the 50% recurrence rate and >90% rate of graft failure in patients with recurrence. Recurrence rates (30-100%) are significantly higher in patients with HF1 mutations than in those without this mutation. In patients with MCP mutation, outcomes are favorable, and renal transplantation may correct the local MCP dysfunction, as MCP is a membrane-bound protein that is highly expressed in the kidney.
  • Liver transplantation: In patients with HF1 genetic defect, liver transplantation was thought to correct the defect because HF1 is a plasma protein of liver origin. However, simultaneous liver and kidney transplant in 2 children were complicated by premature liver failure. At present, this procedure should not be performed unless patient is at imminent risk for life-threatening complications.
• Supportive therapy
  • Maintain fluid and electrolyte balance.
  • Adequate blood-pressure control and adequate renin-angiotensin blockade is helpful for patients who have chronic kidney disease after an episode of Stx-HUS.
  • For seizure control, consider prophylactic phenytoin in patients with neurologic symptoms, as 20-40% of patients have seizures.
  • Control azotemia.
  • Optimize nutrition.

Surgical Care

• Some children with gastrointestinal involvement may require surgery and prolonged parenteral feeding.
• Splenectomy is used as a last resort in refractory TTP; however, the basis for this treatment is unknown.

Consultations

Patients may require consultation with the following subspecialists:

• Nephrologist
• Hematologist
• Neurologist in cases of neurologic involvement
• Intensivists for ICU care

Diet

Provide nutritional support during acute illness. If patients have severe diarrhea, they may require parenteral nutrition. Early restriction of proteins, in addition to renin-angiotensin blockade, may have a beneficial effect on the long-term renal outcome in patients who develop chronic kidney disease after Stx-HUS.

MEDICATION

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Clinicians have attempted various treatments based on different theories.

Drug Category: Antiplatelet agents

These agents inhibit the cyclo-oxygenase system, decreasing the level of thromboxane A₂, a potent platelet activator.

FOLLOW-UP

Section 8 of 11  

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Further Inpatient Care

• Provide nutritional support during acute illness.
• Closely monitor electrolyte levels, renal function, and platelet counts.

Further Outpatient Care

• Monitor renal function and blood pressure because as many as 80% of adults with HUS require long-term dialysis or renal transplantation.
• Ensure adequate blood pressure control and consider renin-angiotensin blockade with angiotensin-converting enzyme inhibitors or angiotensin-receptor blockers.
• Early protein restriction may be needed in patients who develop residual chronic kidney disease after the acute phase.

Transfer

• The patient may need to be transferred to a tertiary care facility for specialized treatment (eg, plasma exchange, dialysis, ICU monitoring).

Deterrence/Prevention

• Because typical HUS commonly occurs in epidemics, consider this possibility and inform health authorities to monitor for the possibility of index cases and to prevent the spread of disease in the community.
• At present, prevention is the main approach to decreasing the morbidity and mortality associated with Stx-E coli infection.
• Antibiotic treatment of children with E coli O157:H7 infection increases the risk of HUS and should be avoided unless they have septicemia.

Complications

• Renal failure
• Stroke
• Coma
• Seizures
• Bleeding complications

Prognosis

• Stx-HUS
  • Acute renal failure occurs in 55-70% of patients, but 85% recover renal function with supportive therapy.
  • Approximately 15-20% of children may develop hypertension 3-5 years after the onset of disease.
  • Recurrence with renal allografting is 10% or lower.
• Non-Stx-HUS
  • Patients collectively have a poor prognosis, and as many as 50-60% progress to ESRD (50% in those with sporadic forms and 60% in those with familial forms) or develop irreversible brain damage. About 25% die during the acute phase.
  • The recurrence rate in patients receiving renal transplants is as high as 50%, with graft loss occurring in more than 90% who have recurrence. Recurrence rates are higher in patients with HF1 mutation
• Factors predictive of poor prognosis
• • Non-Stx-HUS
  • Prolonged oliguria or anuria
  • Severe hypertension (especially delayed onset of hypertension)
  • Involvement of medium-sized arteries
  • Severity of CNS symptoms
  • Persistent consumption of clotting factors
  • Extensive glomerular involvement (>80%)
  • Age older than 5 years

Patient Education

• Advise patients to avoid eating raw or partially cooked meat.
• Educate patients on the proper treatment of drinking water.
• Educate patients about proper hygienic measures, especially in cattle fields and farms.

MISCELLANEOUS

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Medical/Legal Pitfalls

• Improperly cooked or contaminated meat is a potential source of E coli O157:H7.
• Communities must make adequate efforts to ensure proper treatment and monitoring of drinking water.

Special Concerns

• Antibiotic treatment for children with E coli O157:H7 infection increases the risk of HUS.
• Plasma therapy is contraindicated in non-Stx-HUS caused by S pneumoniae.

MULTIMEDIA

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Media file 1:  Photomicrograph (hematoxylin and eosin, original magnification X25) shows diffuse thickening of the glomerular capillary wall with double contouring (arrow) and swelling of endothelial cells. Fibrin thrombi and packed RBCs are visible in the lumina (arrowhead) Courtesy of Madeleine Moussa, MD, FRCPC, Department of Pathology, London Health Sciences Centre, London, Ontario, Canada.
	View Full Size Image
Media type:  Photo

Media file 2:  Photomicrograph (periodic acid-Schiff, original magnification X40) shows diffuse thickening of the glomerular capillary wall with double contouring (arrow) and swelling of endothelial cells. Courtesy of Madeleine Moussa, MD, FRCPC, Department of Pathology, London Health Sciences Centre, London, Ontario, Canada.
	View Full Size Image
Media type:  Photo

REFERENCES

Section 11 of 11

• Authors and Editors
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• Morel-Maroger L, Kanfer A, Solez K, et al. Prognostic importance of vascular lesions in acute renal failure with microangiopathic hemolytic anemia (hemolytic-uremic syndrome): clinicopathologic study in 20 adults. Kidney Int. May 1979;15(5):548-58. [Medline].
• Ponticelli C, Rivolta E, Imbasciati E, et al. Hemolytic uremic syndrome in adults. Arch Intern Med. Mar 1980;140(3):353-7. [Medline].
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• Siegler R, Oakes R. Hemolytic uremic syndrome; pathogenesis, treatment, and outcome. Curr Opin Pediatr. Apr 2005;17(2):200-4. [Medline].
• Siegler RL. Management of hemolytic-uremic syndrome. J Pediatr. Jun 1988;112(6):1014-20. [Medline].
• Tarr PI, Gordon CA, Chandler WL. Shiga-toxin-producing Escherichia coli and haemolytic uraemic syndrome. Lancet. Mar 19-25 2005;365(9464):1073-86. [Medline].
• Tsai HM, Lian EC. Antibodies to von Willebrand factor-cleaving protease in acute thrombotic thrombocytopenic purpura. New England Journal of Medicine. 1998;339:1585-94. [Medline].
• Wong CS, Jelacic S, Habeeb RL, et al. The risk of the hemolytic-uremic syndrome after antibiotic treatment of Escherichia coli O157:H7 infections. N Engl J Med. Jun 29 2000;342(26):1930-6. [Medline]. [Full Text].

Article Last Updated: Jul 5, 2006