09. Thrombotic Microangiopathies

Definition

Thrombosis in the small blood vessels with thrombocytopenia, microangiopathic hemolytic anemia (MAHA), and organ injury, but usually normal PT, PTT (differentiates from DIC).

Etiology

May be hereditary or acquired; characterized by causal abnormalities and distribution of thrombi.

  • Thrombotic thrombocytopenic purpura (TTP): systemic platelet thrombi are caused by failure to degrade large multimers of von Willebrand factor (vWF). Results from low levels of ADAMTS 13 (a metalloproteinase that cleaves vWF), leading to large vWF clusters that cause platelet aggregation. ADAMTS 13 deficiency may be either inherited (genetic) or acquired due to inhibitory antibodies.
  • Complement-mediated TMA, including Shiga-toxin hemolytic-uremic syndrome (ST-HUS): predominantly intrarenal platelet-fibrin microthrombi. May be caused by Shiga toxin (commonly produced by E. coli O157:H7), a familial defect in plasma factor H (or several other mutations), or antibodies to complement, leading to unregulated activation of alternative pathway of complement.
  • Drug-mediated TMA: caused by either non-dose-related, idiosyncratic immune reaction or toxic effects dependent on dose and timing. Common culprits include quinine, quetiapine, immunosuppresants, chemotherapeutic agents, calcineurin inhibitors (cyclosporine and tacrolimus) and VEGF inhibitors. 

Diagnosis

In all suspected cases, obtain a CBC, smear, BMP, PT/PTT, and LDH.

  • TTP: classic pentad of fever, thrombocytopenia, MAHA, elevated creatinine, and neurologic symptoms is seen in only 1/3 of patients. Most patients have neurologic symptoms (seizures, altered mental status, strokes, etc.). Look for triad of elevated LDH (due mainly to tissue hypoxia/injury and not hemolysis), schistocytes on smear, and thrombocytopenia. Check serum ADAMTS 13 levels—a level indicating less than 10% normal activity is characteristic. It is important to note that a clinical diagnosis must be made at the time of presentation with institution of therapy; the ADAMTS 13 test typically takes 1-2 weeks to return.
  • Complement-mediated/Shiga toxin-mediated HUS (ST-HUS): characteristically with renal dysfunction and hypertension as the predominant findings. ST-HUS may also be suspected over TTP in the context of bloody diarrhea and/or suspected E. coli O157:H7. Check stool cultures. ST-HUS is much more common in children. Consider complement-mediated disease in the presence of elevated Cr, MAHA, thrombocytopenia, ADAMTS13 activity of 5% or more, and negative stool tests for Shiga toxin-producing infection. Complement genetic studies may provide a specific diagnosis, but serum complement levels can be normal.
  • Drug-mediated TMA: suspect immune reaction in the sudden onset of severe, systemic symptoms (often with anuria) within hours after initiation of a new drug. Dose-related TMA is marked by gradual loss of kidney function and hypertension.

Treatment

  • TTP
    • Urgent plasma exchange (this replaces ADAMTS13 in congenital causes and removes antibodies in acquired causes). 
    • If your institution doesn’t have plasma exchange, initiate infusion of plasma (FFP).
    • Glucocorticoids, are standard treatment in acquired causes. Rituximab, vincristine, and splenectomy are also used as well in refractory cases.
    • Avoid platelet transfusion, even when placing catheter for plasma exchange. Only use platelet transfusion with life-threatening bleeds. Platelet transfusion associated with worse outcome from increased thrombotic complications. 
  • Complement-mediated/ST-HUS
    • ST-HUS has equivocal response to plasma exchange; treatment is largely supportive, with early aggressive hydration. Patients frequently require dialysis. Avoid anti-motility agents (e.g. loperamide).
    • Complement-mediated TMA: generally treated like TTP, as above. Consider adding anticomplement therapy with eculizumab (a monoclonal antibody that blocks the generation of C5a and C5b).
  • Drug-mediated TMA
    • Supportive care and drug avoidance may be the only beneficial management. In practice, plasma exchange is often pursued in the setting of suspected TTP, and a drug-mediated cause may not always be apparent. In some cases of dose-related TMA (e.g., with calcineurin inhibitors), dose reduction may be sufficient.

Key Points

  • Treatment of TMA is determined based on the cause.
  • Given the devastating nature of TTP, it must be considered in patients with unexplained thrombocytopenia.
  • Altered mental status and fever may be present but are not required for the diagnosis.
  • An elevated LDH, normal PT and schistocytes on a smear may confirm the diagnosis. 
  • Confounders may exists: a patient with hepatic dysfunction may have an elevated PT while still having TTP, and many patients with hematologic malignancies can have MAHA and an elevated LDH without TTP.

George JN and Nester CM. Syndromes of Thrombotic Microangiopathies. N Engl J Med 2014; 371:654-666

Levy GG, Motto DG, Ginsburg D. ADAMTS13 turns 3. Blood 2005 106: 11-17.

Moake JL.  Thrombotic Microangiopathies.  N Engl J Med 2002;347:589-600.