MAHA: TTP HUS DIC

    Intro to Microangiopathic Hemolytic Anemia

     

    • Associated with fragmented RBCs (schistocytes)
    • Pathophysiology:
      • RBC (water balloon) goes through fibrin strands (piano wire), breaking apart. 
      • On smear see fragmented RBCs.
    • Clinical Features:
      • ↓ haptoglobin
      • ↑ LDH
      • Hemoglobinuria (intravascular hemolysis)
    • Causes:
      • Heart valve issues
      • Intravascular Foreign Bodies (i.e. Balloon pumps, mechanical valves)
      • TTP
        • High mortality!
        • Antibodies or lack of enzyme that normally breaks down Von Willebran Factor (sticky protein).
          • VWF accummulates, causes platelet aggregation, fibrin deposition --> MAHA of RBCs.
      • HUS
      • DIC
      • Drug-Induced Microangiopathy
        • Calcineurin inhibitors (Tacrolimus, Cyclosporin)
        • Antiplatelet Drugs (Ticlopidine, Clopidogrel)
        • Chemotherapy (Mitomycin C and Gemcitabine)
      • HELLP
      • Others:
        • Malignant HTN, Severe Vasculitis, Scleroderma Renal Crisis, Catastrophic Antibody Syndrome, Malignancy Drugs, Bone Marrow / Solid organ transplantation
    • Treatment:
      • Depends on underlying diagnosis
      • TTP --> plasma exchange
      • HELLP --> early delivery
      • Malignant HTN --> control BP
      • Vasculitis --> Immunsuppression
      • etc...

    Comparison

    Table TTP and HUS

     

    TTP

    HUS

    Atypical HUS

    Epidemiology

    Predominantly adult

    Predominantly children

    Predominantly Children

    Etiology

    Deficiency of metalloproteinase that breaks down ultra-large vWF multimers

    •  Congenital (genetic absence of ADAMTS-13)

    •  Acquired (drugs, malignancy, transplant,
    HIV-associated, idiopathic)

    Shiga toxin (E. coliserotype O157:H7)

    Distinguished by absence of diarrhea or Shiga toxin-producing E.coli infection.  Responsible for 10% of cases.  Multiple etiologies: 

    -  Complement mutations

    -  Infection (pneumococcal, HIV)

    -  Drugs (transplant, chemo)

     

    Clinical features

    1.  Thrombocytopenia
        (Ecchymosis)

    2.  Microangiopathic hemolytic anemia (MAHA)

    3.  Neurological symptoms: headache, confusion, focal defects, seizures

    4.  Renal failure

    5.  Fever

    Evidence of E.coli O157:H7 infection (i.e. prodromal diarrhea) + triad of:

    1 Severe thrombocytopenia: purpura,
    epistaxis, hematuria, hemoptysis, GI bleed

    2.  Microangiopathic hemolytic anemia (MAHA)

    3.  Renal failure: abnormal urinalysis,
    oliguria, acute renal failure

    Same as HUS, but without prodromal diarrhea.

    Investigations (all three)

    CBC and blood film: decreased platelets and schistocytes

    PT, aPTT, fibrinogen: normal

    Markers of hemolysis: increased unconjugated bilirubin, increased LDH, decreased haptoglobin

    Negative Coombs’ test

    Creatinine, urea, to follow renal function

    Stool C&S (HUS)

     

    TTP

    • High mortality!
    • Pathophysiology:
      • Antibodies or lack of ADAMTS13 protease enzyme that normally breaks down Von Willebran Factor (sticky protein).
        • vWF accumulates --> Platelet Activation --> Fibrin Deposition --> RBC fragmentation (MAHA)
      • ADAMTS13 deficiency can be:
        • Inherited (primary deficiency)
        • Acquired (likely antibody-mediated)
    • Clinical Features:
      • Hyaline microthrombi in microvasculature of brain, kidneys, and other organs causing three things:
    1. Mechanical Hemolytic Anemia
    2. Thrombocytopenia
    3. Renal Failure
    • Treatment:
      • Plasma Exchange is lifesaving.

    HUS

    • Hemolytic uremic syndrome.
    • Similar to TTP, restricted to kidneys (no CNS manifestations)
    • Mainly in children
    • Caused by viral infections or E.coli O157:H7 endotoxin
    • Saw case:
    • patient presents with bloody diarrhea after eating some meat/swimming containing E.coli O157.  He gets admitted, has stool tested...comes back as positive for E.coli O157.  Admitted, supportive (IV fluids) therapy.  Check blood for complications (CBC, creat, urea).  D/C then follow-up bloods every 2-3 days for HUS.  
    • Cannot treat with abx: otherwise E.coli release shinga toxin, causing HUS.
    • Monitor for:
    1. Hemolytic anemia
    2. Thrombocytopenia
    3. Renal Failure
    • Treatment:
      • Plasmapheresis?

    DIC

    • Disseminated Intravascular Coagulation
    • DIC begins with abnormal thrombin generation --> rapid consumption of clotting factors and platelets, accelerated fibrinolysis.
      • Hemorrhage can result, histopathologic examination shows fibrin clots in microvasculature.
    • Thrombotic Microangiopathy can occur:
      • Results in schistocytes in smear (but only seen in 30% of pts).
    • Causes (Many!)
      • Obstetric
      • Infection (any bacteria, Fungal, Rickettsial, Virusis - hemorrhagic fever in dengue and Ebola)
      • Tissue Injury (crush, burns, brain injury)
      • Tumors (solid tumors, leukemias)
      • Envenomations (snake bites, spiders)
    • Labs:  (All 4 are diagnostic)
    1. Low platelets
    2. Prolongued prothrombin time
    3. Low fibrinogen level
    4. Elevated D-Dimer level
    • Treatment:
      • Treat underlying disorders.
      • Supportive transfusions if bleeding
        • Plasma
        • Cryoprecipitate if fibrinogen level is low
        • Platelets
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