The thrombotic microangiopathies are a group of disorders that share common clinical and histopathologic features. Two major types are known as thrombotic thrombocytopenic purpura (TTP) and hemolyticuremic syndrome (HUS). TTP is characterized by systemic formation of occlusive microvascular thrombi composed primarily of platelets, which cause organ ischemia that is rapidly fatal if untreated. In HUS the microvascular thrombi are primarily localized to the kidney, with acute kidney injury being the principal clinical feature.
The major laboratory ﬁndings of both TTP and HUS include thrombocytopenia, resulting from plate- let consumption, and microangiopathic hemolytic anemia (MAHA), resulting from the mechanical stress on erythrocytes as they pass through the narrow, thrombosed vessels.
The distinction between TTP and HUS is often made based on the organ system most affected. As stated previously, HUS is said to feature prominent renal dysfunction, whereas TTP is said to feature more systemic abnormalities, including neurologic ﬁndings. In some cases, however, both disease processes can be associated with both renal and neurologic symptoms. Thus a simple classiﬁcation scheme based on symptoms is often unreliable. Recent research, however, has helped elucidate the actual mechanisms that underlie HUS and TTP, which may eventually permit rapid differentiation and focused treatment irrespective of the presenting symptoms.
Hemolytic Uremic Syndrome. HUS may occur in multiple settings, but more than 90% of cases (termed “typical HUS”) are related to infection with bacteria that produce Shiga-like toxins (Stx). In a small number of patients infected with such bacteria, Stx enters the general circulation and binds to receptors on glomerular endothelial cells. The toxin causes extensive endothelial damage and promotes increased expression of cytokines, chemokines, and cell adhesion molecules. The resulting inﬂammation triggers platelet activation and diffuse thrombosis of the renal microvasculature. Bacteremia is neither necessary for this process nor commonly observed.
The incidence is highest in children under 5 years of age, among whom there are 6.1 cases per 100,000 persons per year. The major pathogen is Stx-producing E. coli O157:H7, but other E. coli serotypes may also be responsible. Infection with these pathogens results from ingestion of contaminated food (usually under-cooked ground beef or dairy) or water. Because these pathogens also cause diarrhea in a majority of cases, typical HUS is also known as diarrhea-associated (D+) HUS. The distinct age-related incidence of this condition could be explained by a greater afﬁnity of glomerular endothelial cells for Stx in young children.
Atypical HUS (also called D-HUS because it lacks a diarrhea prodrome), in contrast, may occur for numerous reasons. In some patients, it appears to reﬂect dysregulated activation of the complement system, which leads to endothelial damage and platelet aggregation. Affected individuals have been found to possess mutations in genes encoding inhibitors of the alternative, C3b-mediated complement pathway. These inhibitors include factor H, factor C, factor I, factor B, and membrane cofactor protein (MCP). If severe enough, these mutations cause spontaneous and recurrent activation of the complement system starting in childhood.
The reason for the particular susceptibility of the renal circulation is not clear; however, it has been postulated that the presence of endothelial fenestrations in the glomerulus increases exposure of the circulating factors to subendothelial proteins, which may serve as a focus for complement activation. Patients with such mutations often have a family history of similar events and are the refore said to have a “familial” form of atypical HUS.
The remaining patients with atypical HUS have a “sporadic” form that is either idiopathic or related to triggers, such as pregnancy, infection (e.g., Streptococcus pneumoniae), and certain drugs (e.g., quinine, cyclosporine, tacrolimus). The mechanisms are probably diverse. Quinine, for example, appears to modify an epitope on platelets, leading to binding of antibodies. S. pneumoniae is believed to produce an enzyme that can expose a cryptic antigen on erythrocytes, platelets, and glomeruli endothelial cells, leading to an autoimmune response. Finally, it is possible that some patients have complement mutations that do not cause thrombosis under normal physiologic conditions, but which lead to thrombosis in response to the endothelial damage associated with certain triggers.
Thrombotic Thrombocytopenic Purpura. TTP generally involves more diffuse thrombus formation than HUS. It also occurs in both familial and sporadic forms. The main pathogenetic factor appears to be a deﬁciency of a normal plasma enzyme, ADAMTS13 (A Disintegrin and Metalloprotease with ThromboSpondin type 1 domains, member 13), that is required for processing of von Willebrand factor (vWF) multimers. In normal conditions, endothelial cells constitutively secrete a range of vWF multimers, including unusually large multimers (ULvWF). These unusually large vWF multimers have a much higher platelet binding afﬁnity than the smaller multimers, but under normal conditions they undergo cleavage by ADAMTS13 immediately after release. In TTP, ADAMTS13 may be absent or dysfunctional, and the resulting circulation of ULvWF can cause formation of platelet-rich thrombi.
The familial form of TTP, known as Upshaw-Schul-man syndrome, accounts for a very small fraction of cases. In this case, there is near total absence of the ADAMTS13 protein. The disease often appears shortly after birth, with subsequent relapses occurring in the setting of infection, pregnancy, or other physiologic stressors, presumably because of increased ULvWF multimer production. In some cases, however, the ﬁrst episode may not occur until these stressors are experienced in adulthood. Inheritance follows an autosomal recessive pattern.
A sporadic, acquired form of TTP accounts for a majority of cases and typically affects adults. Most cases appear to reﬂect abnormal production of anti-ADAMTS13 IgG autoantibodies, which either promote clearance of ADAMTS13 or neutralize its binding site. It is not known why certain individuals develop these antibodies, which often disappear after symptoms resolve.
Secondary TTP may occur in susceptible individuals, such as in the setting of pregnancy. It is not clear why certain triggers cause systemic platelet thrombosis; however, it is possible that ongoing endothelial stress leads to an overwhelming increase in ULvWF secretion.
PRESENTATION AND DIAGNOSIS
Patients with either TTP or HUS can have acute kidney injury, manifesting as oliguria, fatigue, nausea, and vomiting; ﬂuctuating neurologic symptoms, such as seizures, focal deﬁcits, or even coma; or both. In addition, patients may have fever and purpura, although overt bleeding is unusual. These symptoms are often sudden, but in up to one fourth of patients they can be present for weeks before presentation.
On further investigation, patients are found to have thrombocytopenia, with platelet counts often below 20,000/µL; MAHA, evidenced as numerous schistocytes on a peripheral blood smear; and elevated lactate dehydrogenase (LDH). Serum creatinine concentration is elevated if there is renal involvement, and urinalysis may be normal or reveal RBCs and mild proteinuria. Prothrombin and partial thromboplastin times, as well as levels of individual clotting factors, should be normal in both TTP and HUS and can help facilitate the distinction from disseminated intravascular coagultion (DIC).
The laboratory ﬁndings of thrombocytopenia, elevated LDH, and schistocytosis in the absence of another apparent cause (such as DIC, malignant hypertension, or recent stem cell transplantation) are sufﬁcient to make the diagnosis of TTP or HUS.
The deﬁnitive distinction between TTP and HUS is neither possible nor necessary in the acute setting. In all patients, the drug regimen should be examined and potential precipitants stopped. Supportive care should focus on managing ﬂuid and electrolyte status, treating hypertension, and offering dialysis, packed RBC transfusions, or antiepileptic drugs as needed. The indications for dialysis in TTP and HUS are the same as in other settings. Platelet transfusion should not be performed unless there is overt bleeding or an invasive procedure is required because it may precipitate the formation of additional thrombi.
Further management depends on patient characteristics and clinical ﬁndings. Infants and young children with a recent history of bloody diarrhea, for example, likely have typical HUS and usually recover completely with supportive therapy alone. Plasma exchange/infusion and Shiga-toxin binding agents do not appear to improve outcomes. Antimotility agents and antibiotics may actually worsen the toxinmediated damage. In most patients, hematologic markers will return to normal within 1 to 2 weeks. Infants and young children without a recent history of bloody diarrhea could have typical HUS, atypical HUS, or Upshaw-Schulman syndrome. In this case, patients typically receive plasma infusions, which replace the missing factors in the hereditary conditions. Genetic testing should be performed to guide further management.
Older children and adults could have any form of TTP or HUS, and the distinction is often unclear at initial presentation. For example, adults with a recent history of bloody diarrhea could have typical HUS caused by E. coli 0157:H7 infection or TTP with mesenteric ischemia. Likewise, the presence of a potential trigger for either secondary TTP or atypical HUS does not exclude the possibility of idiopathic TTP.
Thus plasma exchange should be offered to all older children and adults to remove possible ADAMTS13 autoantibodies. After the initiation of plasma exchange, symptoms and laboratory markers should improve within 1 to 3 days. If there is a lack of response, patients may be candidates for pharmacologic immunosuppression, which reduces the production of autoantibodies.
In children, the prognosis of typical HUS is excellent if appropriate supportive care is given, with most recovering normal renal function. All patients should undergo annual monitoring for late complications such as hypertension and mild proteinuria. Relapses are very rare. In familial D-HUS, the prognosis depends on the responsible mutation. For example, patients with complement factor H mutations may become dependent on plasma exchange. The possible role of complement cascade inhibitors such as eculizumab, an anti-C5 monoclonal antibody, is currently under investigation.
In adults, the prognosis of untreated TTP or HUS is extremely poor, with survival rates of only 10%. With plasma exchange, however, survival rates have improved to 80%, although relapses occur in one third of patients with TTP associated with ADAMTS13 autoantibodies. Chronic kidney disease generally does not occur in patients with ADAMTS13 autoantibodies; however, patients may report persistence of minor cognitive symptoms, such as poor concentration or memory.