Microangiopathic Hemolytic Anemia

Microangiopathic Hemolytic Anemia

Qian-Yun Zhang, MD, PhD

Blood smear of a young female with recent diagnosis of TTP reveals marked thrombocytopenia and frequent schistocytes. The patient underwent plasmapheresis and recovered fully.

Blood smear of a 13-month-old girl with hemolytic uremic syndrome (HUS) reveals frequent schistocytes and marked thrombocytopenia. The patient recovered completely.



  • Microangiopathic hemolytic anemia (MAHA)


  • Fragmentation of red blood cells due to narrowing or obstruction of microvasculature

  • Major types and subtypes

    • Thrombotic thrombocytopenic purpura (TTP)

      • Congenital TTP

      • Acquired TTP

    • Hemolytic uremic syndrome (HUS)

      • Shiga-like (vero) toxin-associated HUS (Stx-HUS)

      • Non-Shiga-associated HUS (non-Stx-HUS) (a.k.a. atypical HUS or aHUS): Sporadic or familial

    • Disseminated intravascular coagulation (DIC)

      • Acute DIC

      • Chronic DIC


Thrombotic Thrombocytopenic Purpura (TTP)

  • Etiology

    • Congenital TTP

      • Mutations of ADAMTS13 gene

    • Acquired TTP

      • Autoimmune disorders

      • Malignancy

      • Stem cell transplantation

      • Pregnancy (especially 3rd trimester)

      • Certain drugs (ticlopidine, mitomycin, clopidogrel, cyclosporine)

      • Infection, including HIV

  • Pathogenesis

    • Normal von Willebrand factor (vWF) homeostasis

      • vWF multimers are synthesized by endothelial cells and megakaryocytes

      • vWF are present in platelets, endothelial cells, and subendothelium

      • Protease ADAMTS13 cleaves ultra large vWF multimers into smaller vWF forms

      • VWF mediates platelet aggregation, activation, and thrombus formation at sites of vascular injury

    • Pathogenesis of TTP

      • Congenital TTP: Mutations lead to ADAMTS13 deficiency; episodes are triggered by infection, acute inflammation and pregnancy

      • Acquired TTP: Autoantibodies cause inhibition of ADAMTS13 activity

      • ADAMTS13 deficiency leads to accumulation of ultra large vWF multimers

      • Ultra large multimers have greater ability to react with platelets, causing disseminated platelet microthrombi

      • Pathogenesis unclear in some cases

Hemolytic Uremic Syndrome (HUS)

  • Etiology

    • Stx-HUS

      • Infections with Escherichia coli O157:H7 in 75% cases

      • Enterococcus or Shigella in some cases

    • Sporadic non-Stx-HUS cases

      • Infection with Streptococcus pneumonia in some cases

    • Familial non-Stx-HUS

      • Mutations in complement genes (factor H, membrane cofactor protein, factor I, factor B, C3)

  • Pathogenesis

    • Primary event in HUS is damage to endothelial cells and subsequent microthrombi formation

    • Stx-HUS

      • Exact pathogenesis unknown

      • Shiga toxin is thought to function as a molecular mimic of endothelial cell membrane bound molecule

      • Toxins bind to receptors on glomerular endothelial, mesangial, and tubular epithelial cells

      • Antibody to toxin cross-reacts with endothelial cells, resulting in endothelial cell damage and microvascular thrombosis

    • Non-Stx-HUS (aHUS)

      • Mutations lead to excessive complement activation on renal arterioles and interlobular arteries and interlobular arteries

      • Complement activation leads to endothelial damage, which leads to coagulation activation and thrombotic microangiopathy

    • Other triggers of non-Stx-HUS include nonenteric infections, viruses, drugs, malignancies, organ transplantation, and pregnancy

Disseminated Intravascular Coagulation (DIC)

  • Etiology

    • Infections: Gram positive or negative bacterial infections; rickettsial infection; viral infections

    • Tissue factor activation: Malignancies; tissue injury; extensive burn, brain injury

    • Other: Obstetric disorders; snakebite; vascular disorders; hemolysis

  • Pathogenesis

    • Tissue factor or bacterial toxin activates coagulation cascade resulting in disturbed hemostasis

    • Overproduction of thrombin leads to generation of fibrin monomers, which are crosslinked into insoluble fibrin polymers by FXIIIA

    • Fibrin polymers deposit in microvasculature (microthrombi); leads to tissue ischemia

    • Endothelial cell response to thrombi causes excessive fibrinolysis

    • Fibrin degradation products (FDP) from fibrinolysis interfere with platelet aggregation, potentiate bleeding risk

    • Depletion of platelets, fibrinogen, and other hemostatic proteins increase bleeding risk

    • Cytokines released by macrophages, monocytes, and endothelial cells may lead to shock

Other Types of MAHA

  • Post-transplantation thrombotic microangiopathy (post-transplantation TMA)

    • Poorly defined entity secondary to complications of allogeneic hematopoietic stem cell transplantation

    • Thrombosis limited to kidney

    • Pathogenesis is most likely injury to endothelial cells due to multiple possible factors

    • Diagnosis must exclude other causes of MAHA

  • Mechanical damage

    • Heart valve is classical example

    • Rarely seen in congenital heart malformation secondary to blood turbulence and mechanic damage

  • Miscellaneous causes of MAHA

    • Strenuous physical activity

    • Circulating mucinous material in disseminated carcinoma

    • Following chemotherapy



Jun 13, 2016 | Posted by in PATHOLOGY & LABORATORY MEDICINE | Comments Off on Microangiopathic Hemolytic Anemia
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