Thrombotic Thrombocytopenic Purpura (TTP)

Background

• TTP is a thrombotic microangiopathy caused by deficiency of the von Willebrand factor (vWF) cleaving protein, ADAMTS13, which results in thrombocytopenia, microangiopathic hemolytic anemia, and widespread multiorgan thrombosis and injury.
• TTP may be congenital (also called Upshaw-Schulman syndrome) or immune-mediated (also called acquired TTP). Types of immune TTP include:
  • primary TTP if there is no underlying cause
  • secondary TTP if there is an underlying cause, including connective tissue disease, HIV, and pregnancy
• TTP is more common in women, Black patients, and young adults.
• The estimated annual incidence of immune TTP is 3.1 per million persons; estimated annual incidence of congenital TTP is < 1 per 1 million persons.
• A deficiency in ADAMTS13 activity can result in increased levels of ultra large vWF multimers, which in turn promote spontaneous intravascular aggregation of platelets and widespread microthrombi, especially in the microvasculature, where shear stress is high. Thrombocytopenia results from platelet consumption and microangiopathic hemolytic anemia from mechanical fragmentation of red blood cells.
• Clinical presentation is variable, ranging from minimal abnormalities to critical illness, but typically includes a combination of microangiopathic hemolytic anemia (MAHA) (median hemoglobin 8-10 g/dL), thrombocytopenia (median platelet count 10-30 × 10⁹/L), and organ dysfunction, with a particular predilection for the neurological system. In contrast to hemolytic uremic syndrome, acute renal failure is rare.

Evaluation

• Suspect diagnosis of immune TTP in adults with:
  • isolated microangiopathic hemolytic anemia without another clinical explanation
  • thrombocytopenia
  • new focal neurological symptoms, seizure, or acute myocardial infarction with unexplained microangiopathic hemolytic anemia
  • prior history of TTP
• Suspect diagnosis of congenital TTP in:
  • neonates with severe jaundice
  • neonates with microangiopathic hemolytic anemia, thrombocytopenia, and jaundice
  • children and adults with a family history of TTP
  • pregnant women with first episode of TTP
• Perform a complete blood count and peripheral blood smear, and obtain blood samples prior to treatment to measure ADAMTS13 activity level and to detect anti-ADAMTS13 antibodies (Strong recommendation). Consider measuring inhibitor titer.
• Make an initial diagnosis based on clinical presentation and routine laboratory parameters, including peripheral blood smear, before the results of ADAMTS13 activity levels are known (Strong recommendation).
• At presentation, also test for a potential condition associated with secondary TTP and/or causes of non-TTP thrombotic microangiopathy as clinically indicated including:
  • serological tests for HIV, hepatitis B virus, and hepatitis C virus (Strong recommendation)
  • neutralizing or non-neutralizing anti-ADAMTS13 autoantibody screen (Strong recommendation)
  • pregnancy test, if appropriate (Strong recommendation)
  • computed tomography (CT) imaging of chest/abdomen/pelvis if malignancy is suspected
  • stool examination for selective culture for STEC or immunoassay for Shigatoxin if clinical suspicion for hemolytic uremic syndrome
• Testing to assess presence and extent of specific organ damage includes urinalysis, serum creatinine, electrocardiogram/echocardiogram, troponin, and brain imaging (CT/magnetic resonance imaging).
• In cases of suspected congenital TTP, measure ADAMTS13 activity, test for anti-ADAMTS13 antibodies, and carry out genetic testing for mutations in the ADAMTS13 gene (Strong recommendation).
• Diagnosis is ultimately confirmed by reduced plasma ADAMTS13 activity (< 5%-10%).
  • Immune TTP is defined by the presence of a functional inhibitor of ADAMTS13 (in mixing studies) or anti-ADAMTS13 immunoglobulin G (IgG) antibodies.
  • Congenital TTP is defined by the absence of anti-ADAMTS13 antibodies, low levels of ADAMTS13 protein, and the presence of homozygous or compound heterozygous ADAMTS13 mutations as determined by genetic screening (Strong recommendation).

Table 1. Testing and Expected Results Consistent With Diagnosis of TTP

Management

• Treat TTP as a medical emergency (Strong recommendation).
• Obtain urgent hematology consult.
• In patients with suspected primary immune TTP:
  • Initiate plasma exchange (Strong recommendation).
    • Start treatment as soon as possible (regardless of the time of day) (Strong recommendation).
    • Do not delay treatment for confirmatory ADAMTS13 measurement.
    • Start plasma exchange with 1-1.5 plasma volume exchanges using plasma, solvent/detergent-treated plasma, or cryoprecipitate-depleted plasma and reassess daily (Strong recommendation).
    • When clinical condition and laboratory values begin to stabilize, consider reducing the exchange volume to 1 plasma volume (Weak recommendation).
    • If the patient's condition is life-threatening, consider intensifying the frequency and/or volume of plasma exchange (Weak recommendation).
    • Consider continuing the daily plasma exchange for at least 2 days after platelet count > 150 × 10⁹/L before stopping (Weak recommendation).
  • Give methylprednisolone (1 g/day IV for 3 days in adults) or high-dose oral prednisolone (1 mg/kg/day) (Strong recommendation).
  • Consider adding rituximab to plasma exchange and corticosteroids (Weak recommendation).
  • Consider adding caplacizumab to plasma exchange and immunosuppressive therapy (Weak recommendation).
• In patients with refractory TTP:
  • Increase frequency of plasma exchange (Strong recommendation).
  • If not already administered, offer rituximab (Strong recommendation).
  • If refractory to plasma exchange, corticosteroids, and rituximab:
    • Cyclosporine is a second-line agent (Strong recommendation).
    • Consider stronger immunosuppressive therapies including vincristine or cyclophosphamide
• In patients with relapsing TTP (occurring more than 30 days after last plasma exchange):
  • Re-start plasma exchange and/or administer rituximab (Strong recommendation).
  • Consider administering caplacizumab (Weak recommendation).
• During remission of immune TTP, if plasma ADAMTS13 activity is still low but there are no clinical signs and symptoms of TTP, consider prophylactic rituximab (Weak recommendation).
• In patients with congenital TTP:
  • Individualize treatment regimens according to the patient's phenotype (Strong recommendation). Some will require ongoing treatment with plasma infusion, while some only intermittently with acute episodes.
  • Give plasma, solvent/detergent-treated plasma, or cryoprecipitate-depleted plasma infusion (Strong recommendation). Plasma infusion dose of 10-15 mL/kg body weight, every 1-3 weeks is suggested.
• In all patients with TTP:
  • Red cell transfusion should be administered according to clinical need especially if there is cardiac involvement (Strong recommendation).
  • Administer folate supplementation during active hemolysis (Strong recommendation).
  • Platelet transfusions should not be routinely administered, but may be given in cases of severe or life-threatening hemorrhage (Strong recommendation).
  • Administer thromboprophylaxis with low-molecular-weight heparin (LMWH) once the platelet count has reached > 50 × 10⁹/L (Strong recommendation).
  • Low-dose aspirin may be considered during platelet recovery (platelet count > 50 × 10⁹/L) (Weak recommendation).
• Patients who are pregnant or have HIV require specific treatment.