Cox’s Conference: Thrombotic Thrombocytopenic Purpura

In this week’s Ambulatory Cox’s Conference, Dr. Esther de Boer presented a case of a young female who presented with altered mental status in the setting of severe thrombocytopenia. Our expert discussant, Dr. Nagalla guided us through the differential diagnosis of microangiopathic hemolytic anemia (MAHA).

The differential diagnosis for our patient with altered mental status and severe thrombocytopenia included intracranial hemorrhage in the setting of immune thrombocytopenia (ITP), cerebral vascular accident in the setting of heparin-immune thrombocytopenia (HIT), thrombotic thrombocytopenic purpura (TTP), disseminated intravascular coagulation (DIC) in the setting of sepsis, paroxysmal nocturnal hemoglobinuria (PNH), HELLP syndrome in the setting of pregnancy, acute liver failure, and tick-born illnesses such as ehrlichiosis. In addition to severe thrombocytopenia, the patient was also found to have severe anemia and evidence of hemolysis on laboratory evaluation. A peripheral smear revealed numerous schistocytes consistent with MAHA. The patient was started on plasma exchange and an ADAMTS13 activity level was sent off which later returned as < 5% and a high ADAMTS13 inhibitor titer consistent with acquired TTP.

Thrombotic Thrombocytopenic Purpura Pearls:

  • TTP is defined as a severe deficiency in ADAMTS13 (less than 10%). It can be hereditary due to inherited mutations (Upshaw-Shulman Syndrome) or acquired by formation of an autoantibody against ADAMTS13.
  • ADAMTS13 is a protein that cleaves von Willebrand factor (vWF). Deficiency in this protein leads to formation of platelet microthrombi in the microvasculature.1

Clinical Presentation:

  • Patients can present with non-specific symptoms such as fatigue, generalized weakness, GI symptoms (nausea, vomiting, abdominal pain), dyspnea, petechiae (or other bleeding), headaches and altered mental status.
  • The classic “pentad” of TTP which includes thrombocytopenia, fever, acute renal failure, and severe neurologic findings is rare and occurs in <5% of patients.2
  • Laboratory evaluation will show severe thrombocytopenia, anemia, and evidence of hemolysis with elevated LDH, low haptoglobin, and increased unconjugated bilirubin. Hemolysis can also elevate the AST, but not the ALT.

Diagnosis:

  • When TTP is suspected, urgent review of the peripheral blood smear is needed.
  • Schistocytes and thrombocytopenia on a peripheral smear is concerning for TTP.
  • ADAMTS13 activity and inhibitor testing should be sent before starting treatment.
  • The diagnosis is confirmed with ADAMTS13 activity < 10%. Acquired TTP will show the presence of ADAMTS13 inhibitor.

Treatment:

  • The mainstay of treatment for TTP is therapeutic plasma exchange. If TTP is suspected, plasma exchange should be initiated while ADAMTS13 testing is pending.
  • The addition of glucocorticoids to plasma exchange and use of rituximab have been shown to improve outcomes and decrease the need for plasma exchange sessions.3
  • Plasma exchange should be continued daily until platelet count recovery.

References:

  1. George JN, Nester CM. Syndromes of thrombotic microangiopathy. N Engl J Med 2014; 371:654.
  2. Griffin D, Al-Nouri ZL, Muthurajah D, et al. First symptoms in patients with thrombotic thrombocytopenic purpura: what are they and when do they occur? Transfusion 2013; 53:235.
  3. Som S, Deford CC, Kaiser ML, et al. Decreasing frequency of plasma exchange complications in patients treated for thrombotic thrombocytopenic purpura-hemolytic uremic syndrome, 1996 to 2011. Transfusion 2012; 52:2525.