As discussed in Chapter 10, the term thrombotic microangiopathy (TMA) refers to lesions seen in various clinical syndromes characterized by microvascular thrombosis accompanied by microangiopathic hemolytic anemia, thrombocytopenia, and, in certain instances, renal failure. The primary forms of TMA include those with a known etiology, while the secondary forms develop in the background of other diseases or conditions without well-defined etiology. Common primary forms of TMA include Shiga toxin– mediated hemolytic uremic syndrome (HUS); atypical HUS, also called complement-mediated TMA because excessive complement activation is an important pathogenic mechanism; thrombotic thrombocytopenic purpura (TTP); and some of the drug-mediated TMAs. Malignant hypertension and scleroderma-associated TMA represent examples of the secondary forms.
The major pathogenetic factors in the thrombotic microangiopathies are endothelial cell injury and platelet activation and aggregation. They can be caused by diverse insults, including external toxins, drugs, autoantibodies, and inherited mutations, which can lead to excessive small vessel thrombosis in the capillaries and arterioles in various organs. Vascular compromise results in ischemic injury and organ dysfunction. The classic laboratory manifestations of thrombotic microangiopathy are thrombocytopenia caused by excessive platelet consumption, and microangiopathic hemolytic anemia due to mechanical injury (shearing) of red cells as they pass through vascular channels narrowed by thrombi. In the primary forms of thrombotic microangiopathies, the etiology is well-defined (
Table 14.4 ), while the secondary forms are associated with various underlying conditions and diseases, such as malignant hypertension, scleroderma, pregnancy, chemotherapy, anti-phospholipid antibodies, and transplant rejection, with less well-defined etiology and pathogenesis. Only the three major forms of primary thrombotic microangiopathies are sufficiently common to merit discusson.
Shiga toxin–mediated HUS. As many as 75% of cases follow intestinal infection with Shiga toxin–producing
E.
coli, such as occurs following ingestion of contaminated ground meat (e.g., in hamburgers) and infections with Shigella dysenteriae type I. The pathogenesis is related to the effects of Shiga toxin. The basis for thrombus formation in small vessels, particularly in the kidney, is complex, but most studies suggest endothelial damage has a central role. Renal glomerular endothelial cells are vulnerable because they express the membrane receptor for Shiga toxin. At low doses, the toxin activates endothelial cells, leading to leukocyte adhesion,
Table 14.4 Etiologic Classification of the Major Forms of Primary Thrombotic Microangiopathy
ADAMTS13, vonWillebrandfactorcleavingprotease;HUS, hemolyticuremicsyndrome;TMA, thromboticmicroangiopathy;TTP, thromboticthrombocytopenicpurpura.
http://ebooksmedicine.net increased endothelin production and decreased nitric oxide production (both favoring vasoconstriction), as well as other changes that may promote platelet adhesion and activation. At high doses, the toxin causes endothelial cell death. All of these alterations may contribute to the formation of thrombi, which tend to be most prominent in glomerular capillaries, afferent arterioles, and interlobular arteries.