Clinical Pearls & Morning Reports
Published March 15, 2023
Microangiopathic hemolytic anemia is a subtype of intravascular hemolysis that is characterized by red-cell fragmentation due to direct trauma; the identification of two or more schistocytes on multiple blood-smear fields at high magnification suggests a diagnosis of microangiopathic hemolytic anemia. Read the NEJM Case Records of the Massachusetts General Hospital here.
Q: What are the cardinal characteristics of thrombotic microangiopathy (TMA)?
A: TMA is characterized by microangiopathic hemolytic anemia and thrombocytopenia, whereby endothelial activation and thrombosis lead to microvascular occlusion, shearing of red cells, and platelet consumption, although a small percentage of patients with TMA may have a normal platelet count on initial presentation. Numerous conditions can give rise to TMA through one of three principal mechanisms: primary or secondary hemostatic derangements or endothelial injury.
Q: What causes shearing of red cells in patients with thrombotic thrombocytopenic purpura (TTP)?
A: TTP is a life-threatening disease arising from primary hemostatic abnormalities. Under physiologic conditions, von Willebrand factor (VWF) mediates platelet binding to subendothelial collagen at sites of vascular injury; during this process, activated endothelial cells release VWF in multimerized forms that are then cleaved by the ADAMTS13 metalloproteinase. In patients with TTP, a deficiency or functional impairment in ADAMTS13 leads to the accumulation of ultra-large VWF multimers, which results in the formation of microvascular platelet–VWF plugs that cause shearing of red cells. ADAMTS13 levels below 10% are diagnostic of TTP, whereas levels exceeding 20% indicate that this diagnosis is unlikely.
A: HUS is a heterogeneous group of TMAs that arise from endothelial injury and predominantly affect the renal glomeruli. Classic HUS is characterized by bloody diarrhea that occurs after consumption of undercooked meats contaminated with Shiga toxin–producing bacteria, which cause direct endothelial injury. Atypical HUS is a complement-mediated disorder, in which germline mutations in — or autoantibodies against — alternative-pathway complement-regulating factors lead to uncontrolled formation of the membrane-attack complex and consequent renal glomerular damage. In patients with atypical HUS, the presentation varies and often resembles TTP. Although a peripheral-blood smear will show abundant schistocytes in both conditions, renal impairment is a predominant clinical feature of atypical HUS, whereas neurologic impairment is more common with TTP.
A: Classically, cancer-associated TMA occurs in patients with adenocarcinomas, particularly of gastric, pulmonary, breast, or prostatic origin; bone marrow infiltration and pulmonary tumor microembolism are common, and most affected patients have laboratory evidence of disseminated intravascular coagulation. In addition to showing schistocytes, the peripheral-blood smear often shows evidence of leukoerythroblastosis with left-shifted myeloid cells, nucleated red cells, and teardrop cells, findings indicative of myelophthisis of the bone marrow by metastatic cancer. The mortality associated with this condition is high, approaching 50% within a month after presentation with TMA. Traditional methods of managing microangiopathic hemolytic anemia such as plasmapheresis or immunosuppression are generally not effective in the context of cancer, and treating the underlying cancer is the mainstay of management.