The thrombotic microangiopathies (TMAs) are classified together due to their overlapping clinical and morphologic findings. Their major clinical manifestations include hemolytic anemia, microvascular thrombosis, and thrombocytopenia. Most TMAs have renal involvement with similar morphologic changes in the kidney reflecting the vasculopathy these lesions share. There are a number of underlying etiologic factors inducing TMA including systemic diseases, infection, and medications, which are summarized in Table 34–1.
Table 34–1. Etiologies of Thrombotic Microangiopathies. ||Download (.pdf)
Table 34–1. Etiologies of Thrombotic Microangiopathies.
Thrombotic thrombocytopenic purpura
Hemolytic uremic syndrome
Systemic lupus erythematosus
Escherichia coli 0157:H7
Coxsackie A and B virus
Bone marrow transplantation
TMAs originally were separated into the distinct disease entities of hemolytic uremic syndrome (HUS), thrombotic thrombocytopenic purpura (TTP), and scleroderma renal crisis according to their clinical features. In fact, HUS and TTP were suggested to be varying manifestations of a single disease. However, as the underlying pathogenetic factors are being elucidated, it is clear that the TMAs are distinct entities with specific etiologies and associated laboratory and clinical findings.
- Microangiopathic hemolytic anemia.
- Renal involvement.
Historically, HUS and TTP were considered to be variable expressions of the same disease process. With the identification of etiologic roles for factor H in HUS and for ADAMTS 13 in TTP, these are now thought to be distinct disorders with overlapping clinical features. HUS may present in a diarrheal (D+) or a nondiarrheal (D−) form. Most cases of D+ occur in summer and autumn, and result from Shiga-like toxin producing bacteria, primarily Escherichia coli 0157:H7, although other organisms may be involved. Transmission has occurred via undercooked ground beef, contaminated water, and unpasteurized milk or apple cider, and epidemics may ensue. The Shiga-like toxin binds to colonic epithelium inducing inflammation and tissue injury thereby allowing the toxin to enter the circulation. The toxin then binds to vascular and renal tubular epithelial cell receptors resulting in endothelial injury, inflammation, thrombosis, and renal failure.
The D− form of HUS is less well understood. It is associated with a number of underlying clinical predisposing factors including genetic predisposition, medication use, nongastrointestinal infections, pregnancy, neoplasms, collagen-vascular diseases, systemic vasculitis, and bone marrow transplantation. Deficiency of prostacyclin PGI2
has been implicated in some cases of D− HUS, while other cases likely result from an abnormality of the coagulation cascade or the endothelial cell membrane creating a prothrombotic milieu. A more common atypical subset of HUS is characterized by complement dysregulation due to factor H or membrane cofactor abnormalities. Factor H regulates the alternative complement pathway ...