Microangiopathic hemolytic anemia is a direct antibody test-negative intravascular hemolysis caused by mechanical damage to red blood cells from excessive shear stress or turbulence in the circulation.
Excessive shear or turbulence in the circulation causes trauma to red blood cells (RBCs) in the peripheral blood, leading to fragmented RBCs (eg, triangles, helmet shapes) called schistocytes. Schistocytes are characteristic, but not specific for microangiopathic hemolytic anemia (1, 2). Schistocytes cause a high RBC distribution width, reflecting the anisocytosis.
Schistocytes (see arrows) are damaged red blood cells, which may occur in microangiopathic hemolytic anemia (including disseminated intravascular coagulation, thrombotic thrombocytopenic purpura/hemolytic-uremic syndrome, and valvular hemolysis).
By permission of the publisher. From Tefferi A, Li C. In Atlas of Clinical Hematology. Edited by JO Armitage. Philadelphia, Current Medicine, 2004.
Microangiopathic hemolytic anemia encompasses RBC fragmentation caused by microvascular injury as well as by mechanical devices. Causes of fragmentation hemolysis include:
Disseminated intravascular coagulation (DIC), a consumptive process secondary to other disorders such as sepsis, cancer (eg, acute promyelocytic leukemia), pregnancy complications, trauma, or surgery. Coagulation studies are abnormal with very elevated D-dimer, distinguishing DIC from other thrombotic microangiopathies
Stenotic or mechanical heart valves, or prosthetic valve dysfunction (ie, perivalvular leak)
Hemolytic-uremic syndrome (typical HUS or Shiga toxin-HUS)
Complement-mediated thrombotic microangiopathies (atypical HUS)
HELLP syndrome (hemolysis, elevated liver enzymes, and low platelet count) and preeclampsia with severe features
Autoimmune thrombotic microangiopathies (catastrophic antiphospholipid syndrome (CAPS) and scleroderma renal crisis)
Rare cases of significant repetitive impact, such as foot strike hemolysis (march hemoglobinuria), karate strikes, swimming, or hand drumming
Symptoms are those of anemia and the underlying cause of the hemolytic anemia.
Treatment addresses the underlying process. Iron deficiency anemia occasionally is superimposed on the hemolysis as a result of chronic hemosiderinuria and, when present, responds to iron-replacement therapy. Keeping the hematocrit > 30% can reduce hemolysis caused by turbulent flow in valvular hemolysis.
General references
1. Schapkaitz E, Mezgebe MH. The Clinical Significance of Schistocytes: A Prospective Evaluation of the International Council for Standardization in Hematology Schistocyte Guidelines. Şistositlerin Klinik Önemi: Hematoloji Standardizasyon Uluslararası Komitesi Şistosit Kılavuzlarının Prospektif Bir Değerlendirmesi. Turk J Haematol. 2017;34(1):59-63. doi:10.4274/tjh.2016.0359
2. Ahmed M, Patel AR. Evaluation of Normal Reference Range of Schistocytes and Burr Cells in Healthy Adults. Blood. 2015;126 (23): 4540. doi: https://doi.org/10.1182/blood.V126.23.4540.4540
Thrombotic Microangiopathy
Thrombotic microangiopathy (TMA) is one cause of microangiopathic hemolytic anemia. Thrombotic microangiopathies result from microvascular thrombus formation, which consume platelets and damage RBCs, leading to ischemic organ damage. Primary thrombotic microangiopathies include the following:
TTP (both immune-mediated and congenital ADAMTS-13 deficiencies)
HUS (typical or Shiga toxin-associated hemolytic uremic syndrome)
Complement-mediated TMA (CM-TMA) also called atypical HUS (AHUS)
TMA can also be secondary to the following:
Medications
Illicit drugs
Systemic rheumatic diseases (eg, systemic lupus erythematosus (SLE), scleroderma renal crisis, catastrophic antiphospholipid syndrome)
Hematopoietic or solid organ transplant-associated TMA
Pregnancy (eg, HELLP syndrome [Hemolysis, Elevated Liver Enzymes, and Low Platelets syndrome])
Evidence suggests that some secondary forms of TMA (eg, HELLP syndrome, CAPS, and transplant-associated TMA) may be complement-mediated (1).
TMA may also be localized to specific organs (eg, the kidney).
TMA can be confirmed by biopsy, but is usually recognized by the following:
Microangiopathic hemolytic anemia
Thrombocytopenia
Compatible clinical findings
The presence of TMA on biopsy does not point to the specific type or treatment, thus is not required for diagnosis. When TMA is suspected, the priority is to use ADAMTS-13 level to exclude TTP, which can be rapidly fatal. If patients have diarrhea or other suggestive findings, testing for Shiga toxin-producing organisms found in HUS is indicated. Usually the platelet count is lower in TTP and renal impairment is less profound than in AHUS/CM-TMA; however, patients, particularly older patients, may have less classical presentations (2).
Treatment is directed at the cause. In AHUS, use of complement inhibitors can be diagnostic as well as therapeutic.
Thrombotic microangiopathy references
1. Palma LMP, Sridharan M, Sethi S. Complement in Secondary Thrombotic Microangiopathy. Kidney Int Rep. 2021;6(1):11-23. doi:10.1016/j.ekir.2020.10.009
2. Liu A, Dhaliwal N, Upreti H, et al. Reduced sensitivity of PLASMIC and French scores for the diagnosis of thrombotic thrombocytopenic purpura in older individuals. Transfusion. 2021;61(1):266-273. doi:10.1111/trf.16188
