Microangiopathic Hemolytic Anemia



Microangiopathic Hemolytic Anemia


Qian-Yun Zhang, MD, PhD





Key Facts


Terminology



  • TTP is characterized by thrombocytopenia, microangiopathic hemolysis, and platelet microthrombi in multiple organ systems


  • HUS is characterized by progressive renal failure with associated microangiopathic hemolytic anemia and thrombocytopenia


  • DIC is characterized by uncontrolled thrombi formation in microvasculature due to disturbed hemostasis


  • Post-transplantation TMA follows allogeneic hematopoietic stem cell transplantation


Etiology/Pathogenesis



  • ADAMTS13 is severely deficient in TTP


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


  • Tissue factor or bacterial toxin activation of coagulation cascade is primary event in DIC


  • Pathogenesis of post-transplantation TMA is most likely injury to endothelial cells


Clinical Issues



  • RBC fragmentation is common finding in all MAHA


  • Daily plasmapheresis (plasma exchange) is standard treatment for TTP


  • HUS usually shows positive stool culture


  • Supportive care is mainstay in HUS patients


  • DIC panel is positive in patients with DIC


  • Treating primary cause is paramount in DIC


  • Treating post-transplantation TMA is supportive


Diagnostic Checklist



  • MAHA is a diagnosis of clinicopathologic correlation






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.


TERMINOLOGY


Abbreviations



  • Microangiopathic hemolytic anemia (MAHA)


Definitions



  • 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


ETIOLOGY/PATHOGENESIS


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


CLINICAL ISSUES


Presentation



  • TTP



    • TTP triad



      • Thrombocytopenia


      • Microangiopathic hemolytic anemia


      • Microthrombi of small vessels in multiorgan systems


    • Subtypes



      • Congenital TTP is rare, presents at birth/infancy


      • Acquired TTP is the predominant type


    • Clinical signs and symptoms



      • Insidious onset



      • Fluctuation of neurologic signs in most patients (headache, bizarre behavior, transient sensorimotor deficits, seizures, coma)


      • Fever


      • Petechiae on lower extremities


      • Renal impairment in minor subset of patients


    • Secondary DIC may arise from prolonged tissue ischemia


  • HUS



    • HUS triad



      • Thrombocytopenia


      • Microangiopathic hemolytic anemia


      • Progressive renal failure


    • Stx-HUS



      • Classic type; majority of cases


      • Disease of children younger than 2-3 years


      • Prodrome bloody diarrhea often present


      • Most common cause of acute renal failure in children


    • Non-Stx-HUS



      • Rare; accounts for 5-10% of HUS cases


      • Most commonly seen in early childhood, although may occur at any age


      • No prodromal bloody diarrhea and no Stx-producing E. coli infection


      • Streptococcus pneumoniae infection may lead to septicemia, meningitis, and pneumonia in some cases


      • Patient may present with hypertension


      • Some patients show central nervous system involvement at onset with convulsions and alterations of consciousness


      • Renal involvement consists of oliguria or anuria, high renal retention values, or degradation of creatinine clearance


  • DIC

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

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