This review describes the epidemiology, pathophysiology, presentation, clinical causes, treatment, and long-term prognosis of pediatric patients who present with thrombotic microangiopathy. The focus is on hemolytic uremic syndrome and thrombotic thrombocytopenic purpura, the most common phenotypes of thrombotic microangiopathy.
Key points
- •
Thrombotic microangiopathy is a histopathological lesion that is present in all patients with hemolytic uremic syndrome (HUS) or thrombotic thrombocytopenic purpura.
- •
HUS is usually caused by antecedent infection with Shiga toxin producing strains of bacteria. Most patients recover with intensive medical care and less than 25% develop chronic kidney injury.
- •
Familial forms of atypical HUS are linked to genetic mutations in proteins that regulate the activity of the alternative pathway of complement. Eculizumab, a monoclonal antibody to C5a, is the standard of care for these patients.
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Thrombotic thrombocytopenic purpura is rare in children and responds well to treatment with plasmapheresis.
Introduction
Hemolytic uremic syndrome (HUS) and thrombotic thrombocytopenic purpura (TTP) are 2 rare clinical entities. They share a common underlying pathologic process termed thrombotic microangiopathy (TMA), characterized by endothelial cell injury, intravascular platelet-fibrin thrombi, and vascular damage. The 2 illnesses can occur as sporadic cases, in epidemic outbreaks, or in a genetic/familial pattern. Although HUS and TTP are orphan diseases, they remain among the most common causes of acute kidney injury (AKI) in nonhospitalized infants and children. Although most children exhibit recovery of renal function after an episode of TMA, some patients are left with permanent residual sequelae or progress to end-stage kidney disease (ESKD).
The pivotal involvement of endothelial cells in both HUS and TTP was clear from the start based on histopathological examination of biopsy and autopsy material. However, the underlying basis of these disorders remained obscure for several decades after the original description of HUS by Gasser in 1955 and TTP by Moschcowitz in 1925. The landmark article by Karmali and coworkers linking diarrhea-associated HUS to antecedent gastrointestinal infection by strains of Escherichia coli that elaborate a toxin to cultured Vero cells was the first step that advanced the understanding of the cause of TMA. Subsequent studies indicated that the Vero toxin was, in fact, closely related to Shiga toxin (Stx), and were followed by studies that established a role of ADAMTS13 in the processing of von Willebrand factor (VWF) multimers. Moake and colleagues demonstrated that TTP was caused by abnormally high levels of ultralarge VWF multimers due to congenital or acquired reductions in ADAMTS13 activity. In 1998, Warwicker and colleagues confirmed a linkage of atypical HUS (aHUS) to the region on chromosome 1 that contained the genes for several complement regulatory proteins; this was followed by the sequential demonstration that mutations in factor H, factor I, membrane cofactor protein (MCP, CD46), factor B, C3, and thrombomodulin can cause familial cases of aHUS and contribute to all forms of TMA. These advances in molecular genetics began to unravel the cause of hereditary forms of HUS and TTP and led to the development of targeted therapies for both of these causes of TMA.
Thus, there has been substantial progress in the understanding of the pathogenesis and treatment of TMA. This article focuses on both HUS and TTP, with an emphasis on HUS because it is more common than TTP in children. Several excellent reviews of diarrhea-associated HUS, aHUS, and TTP have been published in the last few years. As a consequence, this article details work done during the last decade, from 2000 to the present, and highlights key advances in diagnostic and therapeutic aspects of this fascinating group of disorders.
Introduction
Hemolytic uremic syndrome (HUS) and thrombotic thrombocytopenic purpura (TTP) are 2 rare clinical entities. They share a common underlying pathologic process termed thrombotic microangiopathy (TMA), characterized by endothelial cell injury, intravascular platelet-fibrin thrombi, and vascular damage. The 2 illnesses can occur as sporadic cases, in epidemic outbreaks, or in a genetic/familial pattern. Although HUS and TTP are orphan diseases, they remain among the most common causes of acute kidney injury (AKI) in nonhospitalized infants and children. Although most children exhibit recovery of renal function after an episode of TMA, some patients are left with permanent residual sequelae or progress to end-stage kidney disease (ESKD).
The pivotal involvement of endothelial cells in both HUS and TTP was clear from the start based on histopathological examination of biopsy and autopsy material. However, the underlying basis of these disorders remained obscure for several decades after the original description of HUS by Gasser in 1955 and TTP by Moschcowitz in 1925. The landmark article by Karmali and coworkers linking diarrhea-associated HUS to antecedent gastrointestinal infection by strains of Escherichia coli that elaborate a toxin to cultured Vero cells was the first step that advanced the understanding of the cause of TMA. Subsequent studies indicated that the Vero toxin was, in fact, closely related to Shiga toxin (Stx), and were followed by studies that established a role of ADAMTS13 in the processing of von Willebrand factor (VWF) multimers. Moake and colleagues demonstrated that TTP was caused by abnormally high levels of ultralarge VWF multimers due to congenital or acquired reductions in ADAMTS13 activity. In 1998, Warwicker and colleagues confirmed a linkage of atypical HUS (aHUS) to the region on chromosome 1 that contained the genes for several complement regulatory proteins; this was followed by the sequential demonstration that mutations in factor H, factor I, membrane cofactor protein (MCP, CD46), factor B, C3, and thrombomodulin can cause familial cases of aHUS and contribute to all forms of TMA. These advances in molecular genetics began to unravel the cause of hereditary forms of HUS and TTP and led to the development of targeted therapies for both of these causes of TMA.
Thus, there has been substantial progress in the understanding of the pathogenesis and treatment of TMA. This article focuses on both HUS and TTP, with an emphasis on HUS because it is more common than TTP in children. Several excellent reviews of diarrhea-associated HUS, aHUS, and TTP have been published in the last few years. As a consequence, this article details work done during the last decade, from 2000 to the present, and highlights key advances in diagnostic and therapeutic aspects of this fascinating group of disorders.
Classification
HUS and TTP are characterized by the triad of microangiopathic anemia with red blood cell fragmentation, thrombocytopenia, and AKI. TTP has the same 3 features plus the presence of fever and neurologic symptoms, creating a pentad. HUS and TTP share a histopathological phenotype called TMA. This pattern of injury is characterized by primary damage to the vascular endothelial cell. The endothelium initially becomes detached from the underlying basement membrane and the subendothelial space is filled with amorphous material and fibrin. Within the vascular lumen, there are platelet-fibrin thrombi that can occlude the vessel completely. Fibrin predominates in HUS and platelets are more prominent in patients with TTP. There are 4 clinical categories of TMA, as follows:
- 1.
Typical, diarrhea-associated HUS
- 2.
Atypical, nonfamilial HUS
- 3.
Atypical, familial HUS
- 4.
TTP
In the past, episodes of HUS that developed after a prodromal gastrointestinal illness were called diarrhea-associated or D+HUS. However, in view of the close linkage between infections with Stx-producing strains of E coli (STEC) in most cases of HUS, the term STEC-HUS has become the preferred nomenclature for this category of TMA. Clinical studies verify that episodes of STEC-HUS can be associated with significant neurologic manifestations and TTP can be triggered by gastrointestinal illnesses, suggesting overlap between these 2 illnesses. However, the distinction between the entities is now on much more solid footing because the contribution of Stx, defective regulation of the alternative complement pathway, and disordered release of VWF in STEC-HUS, aHUS, and TTP, respectively, has been well established by basic science and clinical investigations.
Pathophysiology
STEC-HUS
There are 2 main variants of Stx produced by STEC. Stx2 is more likely to be associated with HUS. The diarrhea and colitis that occur during the prodromal illness probably reflect direct damage to gastrointestinal cells and ischemia from the disseminated microangiopathy. When a person becomes infected with an STEC strain, bacteremia does not result. Instead, Stx is elaborated by the microorganism, crosses the gastrointestinal epithelium via a transcellular pathway, and enters the bloodstream. Stx binds to polymorphonuclear leukocytes, which may enable the toxin to be delivered and unloaded in the peripheral vasculature. Neutrophil-associated Stx is detectable in 60% of patients with STEC-HUS and the amount of cell-bound toxin correlates with the extent of kidney injury. After entering the circulation, Stx rapidly binds to the glycosphingolipid, globotriaosylceramide, which is found on glomerular endothelial cells, mesangial cells, podocytes, and tubular epithelial cells. It also binds to globotriaosylceramide on the endothelium in other organs, especially the brain. Once Stx binds, it is internalized via a retrograde pathway to the Golgi apparatus, where it inhibits protein synthesis and causes damage to endothelial cells. The intracellular trafficking of Stx is blocked by manganese and administration of this cation protects against Stx-induced disease in experimental animals. The vascular damage leads to the release of thrombin and increased fibrin concentrations. In addition to the increased fibrin, increased levels of plasminogen activator inhibitor-1 block fibrinolysis and potentiate the thrombotic cycle. Increased shear stress within occluded vessels leads to perturbations in the processing of VWF multimers with uncoiling of the molecule and fragmentation. Both of these alterations activate platelets and promote thrombus formation. Although HUS only develops in 15% of people infected, microangiopathy and microvascular thrombi occur whether or not a diagnosis of HUS is made.
In addition to its direct effects on the endothelium, Stx induces an inflammatory response that is triggered by much lower levels of Stx than the amount needed to inhibit protein synthesis. This process includes a ribotoxic stress response, upregulation of adhesion molecules for leukocytes, and promotion of a prothrombotic state in blood vessels. Stx also directly leads to the release of multiple cytokines such as interleukin-8 and fractalkine and chemokines, which contribute to cell damage. Recent findings indicate that Stx increases endothelial cell expression of the chemokine receptor CXCR4 and its ligand stromal cell-derived factor 1. Specific blockade of this ligand–receptor system ameliorated STEC-HUS in mice. Plasma levels of stromal cell-derived factor 1 are nearly 4-fold higher in children with STEC enteritis who progress to HUS than in children who do not. Finally, there is activation of the alternative pathway of complement in children with STEC-HUS, evidenced by high circulating levels of activated factor B (Bb) and the soluble membrane attack complex (SC5b-9), both of which normalize within 4 to 7 days after the onset of the illness.
aHUS
The injury to endothelial cells in aHUS is direct and is due to medications, infections, or systemic illnesses. In patients with nonfamilial aHUS, the provoking disturbance is generally severe in nature, leading to overt TMA. In contrast, in children with familial aHUS, even slight endothelial damage during a mild viral upper respiratory illness can trigger TMA because of defective regulation of the alternative complement pathway. The alternative complement cascade is constitutively active because binding of C3 to factor B generates a catalytically active complex that leads to continued formation of C3bBb, the pivotal alternative pathway C3 convertase. Several circulating (factors B, H, and I) and membrane-bound (MCP, thrombomodulin) molecules interact to prevent continuous activation of the pathway and endothelial injury. Both inactivating (factors H and I) and activating mutations (factor B) have been linked to increased activity of the complement cascade and the development of aHUS.
TTP
VWF is synthesized by endothelial cells and megakaryocytes and stored as ultralarge VWF multimers in Weibel-Palade bodies in the endothelium and as α granules in platelets. Ultralarge VWF is proteolytically degraded by ADAMTS13 (a disintegrin-like and metalloprotease domain with thrombospondin type-1 motif, number 13) after it is secreted by endothelial cells, preventing accumulation in the bloodstream. In addition, in vitro experiments in the absence of ADAMTS13 have demonstrated that a proportion of these ultralarge VWF multimers remain anchored to the activated endothelium. These multimers unravel, bind platelets, and wave in the direction of the flow. Inadequate ADAMTS13 activity on the cell surface and in the circulation promotes platelet aggregation and the formation of intravascular platelet-fibrin thrombi that are associated with episodes of TTP. In patients with TTP, there can be congenital deficiency (Upshaw-Schulman syndrome) inherited as an autosomal trait with disease onset in the neonatal period. Alternatively, there can be an acquired or idiopathic reduction in the synthesis of ADAMTS13 as a consequence of autoantibodies that disrupt protease activity. Antibody synthesis can be secondary to autoimmune diseases, systemic inflammation, or medications such as clopidogrel. ADAMTS13 proteolytic function declines to undetectable levels during episodes of overt TTP and normalization with resolution of the acute event.
Epidemiology
Because the onset of all forms of TMA is usually abrupt and severe and occurs in previously healthy children, most cases rapidly come to medical attention with prompt diagnosis. There have been case reports of unusual presentations in which one target organ was disproportionately affected, obscuring the systemic nature of the illness and delaying recognition of the underlying TMA. However, STEC infection is included in infectious disease surveillance programs sponsored by the Centers for Disease Control. Moreover, in most states in the United States, STEC-HUS is a reportable disease that yields accurate epidemiologic information about this form of TMA.
The incidence of STEC-HUS ranges from 6:100,000 in children under the age of 5 years to 1–2:100,000 in the overall population, including adults over 18 years of age. The incidence of STEC-HUS has been steady despite increased public awareness and efforts by governments and the food industry to reduce the risk of food-borne and waterborne transmission of STEC. Girls are affected more often than boys for no apparent reason. It occurs globally and in all racial/ethnic groups, except for African Americans, among whom the disease is distinctly less common than in whites. Again, there is no explanation for this observation. STEC-HUS is primarily seen in children except in epidemics when it may occur in patients with a wider age spectrum. For example, from May 2011 until July 2011, several European countries, particularly Northern Germany, experienced one of the largest STEC-HUS outbreaks ever reported. The E coli strain O104:H4 caused a unique multinational epidemic with 3816 patients who suffered from enterohemorrhagic E coli infection, 845 HUS cases, and 54 deaths. The illness predominately affected adults who experienced severe renal and neurologic complications.
The incidence of both nonfamilial aHUS and familial aHUS is lower than STEC-HUS, and, taken together, they occur at a rate that is at most 10% of that for STEC-related forms of HUS. These 2 subcategories of TMA have been documented in virtually every country without an increased susceptibility by gender or racial group. TTP is as rare as aHUS, with an annual incidence in the range of 1 to 2 cases per million population. Like STEC-HUS, it is more common in girls (3:2) and in whites more than in blacks (3:1). However, in contrast to STEC-HUS, the incidence of TTP peaks during the third and fourth decades of life and is uncommon in pediatric patients.
Clinical causes
STEC-HUS
E coli O157:H7 remains the most common strain that causes STEC-HUS with a minority of cases because of other serotypes such as O111 and O26. The causative strains vary with time and region. Non-O157 strains of E coli are an increasingly common cause of STEC-HUS. In a report about the microbiology of STEC-HUS during the period 2000 to 2006, these strains accounted for half of all STEC infections and the same percentage of isolates produced Stx2 as O157 strains, underscoring the importance of tests to detect Stx directly and that do not rely on stool culture to make the microbiological diagnosis.
Nonfamilial aHUS
The most common infectious trigger is Streptococcus pneumoniae , linked to neuraminidase production by the microorganism. The incidence has been fairly steady, despite widespread use of pneumococcal vaccines with reduced overt disease rates in children. In fact, when serologic studies are performed in a timely manner, it can be demonstrated that pneumococcal-related HUS is caused by bacterial strains that are not included in the 7-valent or 23-valent vaccines, such as serotype 19A. Affected children with pneumococcal HUS tend to be young, with a mean age of 1 to 2 years. In general, the disease is more severe compared with STEC-related disease. Up to 80% of affected patients require dialysis, compared with 40% in STEC-HUS, and there is a higher frequency of serious extrarenal complications; however, despite the initial intensity of the episode, most children recover from the acute illness and have normal kidney function at long-term follow-up. Other infections, medications, and miscellaneous medical conditions can cause aHUS. HIV, Mycoplasma pneumoniae , histoplasmosis, and Coxsackie virus are among the well-recognized infectious causes of sporadic aHUS. The most commonly prescribed drug class associated with TMA is calcineurin inhibitors (eg, cyclosporine and tacrolimus). Chemotherapeutic agents, such as mitomycin C, cytosine arabinoside, cisplatinum, and gemcitabine, have also been implicated in this complication. Antiplatelet drugs, such as ticlopidine and clopidogrel, can cause aHUS. Anti-angiogenesis treatment of malignancies can also provoke TMA. This complication has been reported after treatment with biologic agents that block the activity of vascular endothelial growth factor (VEGF; bevacizumab) or the tyrosine kinase VEGF receptor. The range of malignancies that can cause TMA and aHUS includes solid organ tumors and the various forms of leukemia. Systemic lupus erythematosus and the anti-phospholipid syndrome can lead to aHUS, especially in women. When TMA occurs in the context of pregnancy, it is described by the acronym HELLP (hemolysis, elevated liver enzymes, and low platelet count). In its milder form, it is characterized by hypertension and proteinuria (ie, pre-eclampsia). The full-blown syndrome is associated with increased maternal and infant mortality and high circulating levels of the soluble VEGF receptor (sFlt1) or endoglin that inhibit the activity of VEGF.
The most common causes of nonfamilial HUS in pediatric patients are summarized in Table 1 .
| Category | Examples |
|---|---|
| Medications | Ticlopidine, tacrolimus, bevacizumab |
| Infections | S pneumoniae , HIV |
| Systemic disease | Systemic lupus erythematosus |
| Malignancy | Acute lymphoblastic leukemia Bone marrow transplantation |
| Pregnancy | HELLP (hemolytic anemia, elevated liver enzymes, low platelets) syndrome |
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