emDOCs Podcast – Episode 45: Thrombotic Thrombocytopenic Purpura

Today on the emDOCs cast with Brit Long, MD (@long_brit), we cover a deadly microangiopathic hemolytic anemia: thrombotic thrombocytopenic purpura.

Episode 45: Thrombotic Thrombocytopenic Purpura

• Thrombotic thrombocytopenic purpura (TTP) is a microangiopathic hemolytic anemia.
• It is rare with 2-4 cases per million adults each year.
• Without proper management, mortality is 90%, but drops to 4% when treated correctly early.
• There is also significant morbidity with increased risks of developing chronic hypertension, lupus, and cognitive abnormalities.

Pathophysiology:

• TTP is associated with widespread microvascular thrombosis, and the central cause is a deficiency or dysfunction in ADAMTS13.
• ADAMTS13 is responsible for cleaving large von Willebrand factor pieces into smaller ones.
• TTP typically involves either a dysfunctional ADAMTS-13 or an auto-antibody against ADAMTS13.
• This results in large vWF molecules that are not cleaved, and thus they circulate as large multimers.
• These accumulate platelets and form clots, thereby using up platelets.
• There are two forms: acquired (more common in adults) vs hereditary (pediatric patients).
• There are a variety of triggers.

Presentation:

• Classic pentad: fever, anemia, thrombocytopenia, renal disease, neurologic dysfunction
• However, less than 7% have all five features, and many can be transient. In the ED, ask about current and recent symptoms.
• Neurologic symptoms occur in two-thirds of cases, broken into major symptoms (40%, coma, seizure, or stroke) and minor (25%, headache or transient confusion).
• Petechiae or purpura are present in half of cases, though active bleeding is rare.
• Fever is only present in about 10% of cases.
• Gastrointestinal symptoms are common; up to 70% have abdominal pain, nausea, vomiting, or diarrhea.

Evaluation:

• Laboratory analysis: anemia, thrombocytopenia, and renal injury.
• Hemoglobin is usually less than 10 with evidence of hemolysis (elevated LDH, low haptoglobin, schistocytes).
• Platelets will be less than 150, but exact number can vary.
• Renal failure is not universally present. One study found that nearly half of patients had normal renal function, while most of the remainder had a mild creatinine elevation and only 5% had renal failure.
• If possible, send an ADAMTS13 activity level and anti-ADAMTS-13 antibody test; however, this is not available in most centers.

Differentiating other diseases:

• Patients with DIC have abnormal coagulation panel and low fibrinogen (normal in TTP).
• HUS marked by severe renal disease, thrombocytopenia, high LDH, some sort of preceding illness (especially bloody diarrhea), and more common in pediatric patients.

Diagnosis:

• PLASMIC score 85% sensitive and 89% specific for scores >

Management:

• Resuscitate, stabilize, treat underlying cause.
• FFP was originally used to replace the non-functioning ADAMTS13, but this is only moderately successful because auto-antibodies attack the new ADAMTS13.
• Modern therapy relies on plasma exchange and corticosteroids, which substantially reduce mortality compared with FFP alone.
• Plasma exchange removes the auto-antibodies and replaces non-functioning ADAMTS13 with functional ADAMTS13 using donor plasma.
• FFP can be administered if there will a significant delay in plasma exchange.
• Steroids reduce production of ADAMTS13 autoantibodies. Guidelines recommend methylprednisolone 1 mg/kg per day.
• Despite thrombocytopenia, active bleeding is rare and transfusions generally are not necessary.
  • Platelets should not be routinely administered, but transfusion should be considered if platelets are very low and there is active bleeding or an invasive procedure is planned.

Summary:

• TTP is due to deficiency/inactivity of ADAMTS13.
• TTP is a clinical diagnosis: The classic pentad is rare; suspect TTP in a sick-appearing patient with MAHA and thrombocytopenia. Elevated LDH is also common.
• The PLASMIC score can help you with diagnosis, maybe differentiate from other conditions.
• Treatment is plasma exchange and steroids. FFP can assist if exchange is delayed.

References:

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17. Froissart A, Buffet M, Veyradier A, et al; French Thrombotic Microangiopathies Reference Center. Efficacy and safety of first-line rituximab in severe, acquired thrombotic thrombocytopenic purpura with a suboptimal response to plasma exchange. Experience of the French Thrombotic Microangiopathies Reference Center. Crit Care Med. 2012 Jan;40(1):104-11.