How would you treat this patient with thrombotic thrombocytopenic purpura (TTP)?

The 2020 ISTH guideline suggests use of rituximab in addition to TPE and steroids in a patients with newly diagnosed TTP.
Thrombopoietin receptor agonist
Correct. Typically given as methylprednisolone (1 g/day IV for 3 days in adults) or high-dose oral prednisolone (1 mg/kg/day).
Platelet transfusion
Relatively contraindicated in TTP unless patient has life-threatening bleed.
Plasma exchange
Plasma exchange is the cornerstone of therapy in TTP.

Overview of treatment of thrombotic thrombocytopenic purpura (TTP):

Pathophysiological basis for treatment:

  • von Willebrand factor (vWF) normally promotes interactions between platelets and the blood vessel wall.
  • vWF circulates as multimers of varying size; the largest of these multimers (called ultra-large multimers) are the most functionally (hemostatically) active.
  • Normally, the protease ADAMTS13, which is synthesized by the liver, cleaves circulating ultra-large vWF multimers, preventing excessive platelet-vessel wall interactions.
  • Immune TTP is caused by antibody-mediated reduction in ADAMTS13 levels.
  • ADAMTS13 deficiency results in excessive ultra-large vWF multimers, leading to uncontrolled platelet activation, adhesion and aggregation, microvascular thrombosis and tissue ischemia.

Treatment approaches:

  • Remove antibodies against ADAMTS13 – therapeutic plasma exchange (TPE) – the mainstay of treatment
  • Replenish ADAMTS13 – TPE
  • Block von Willebrand factor-platelet interactions – caplacizumab
  • Inhibit production of antibodies against ADAMTS 13 – corticosteroids, rituximab

How rapidly should plasma exchange be initiated?

As soon as possible
Thrombotic thrombocytopenic purpura (TTP) is treated as a medical emergency. Treatment should be started as soon as possible (regardless of the time of day)
By the next day
Once the results for ADMATS13 return
Do not delay treatment for confirmatory ADAMTS13 measurement.

What blood test should be sent off before plasma exchange begins?

Genetic analysis for ADAMTS13 mutations
ADAMTS13 activity levels
Yes, since these levels will be affected by early treatment with plasma exchange.
Complement assays

How does plasma exchange work in thrombotic thrombocytopenia purpura (TTP)?

Inhibits ADAMTS13 clearance
Removes autoantibodies against ADMATS13
This is an important mechanism of action in patients with acquired (immune) TTP. Plasma exchange removes patient plasma containing the causative anti-ADAMTS13 antibody and replaces it with donor plasma containing ADAMTS13.
Reduces antibody formation
Replenishes ADAMTS13 levels
This is an important mechanism of action in patients with congenital TTP.

Plasma exchange (together with corticosteroids) is the standard initial therapy for patients with thrombotic thrombocytopenia purpura (TTP):

  • Plasma exchange should not be delayed while waiting for confirmatory ADAMTS13 measurement, especially if the patient has a high clinical suspicion of TTP.
  • Since ADAMTS13 activity level is usually a send-out out test, plasma exchange is typically initiated before ADMATS13 levels are available.
  • Plasma exchange is typically continued until platelet count > 150 × 109/L and lactate dehydrogenase is near normal for 2-3 consecutive days.

For additional information about TPE in TTP, click here.

Other treatment options (which may be added to therapeutic plasma exchange and corticosteroids) include:

  • Rituximab:
    • Antibody that targets CD20 antigen present on B lymphocytes.
    • Inhibits B cell production of anti-ADAMTS13 antibodies, which are present in patients with immune ITP.
    • While often reserved for refractory or relapsing TTP, may be used up front with plasma exchange and corticosteroids in newly diagnosed TTP.
    • Dose: 375 mg/m2 IV weekly for 4 weeks.
    • For additional information about rituximab in TTP, click here.
  • Caplacizumab:
    • Humanized anti-von Willebrand factor (vWF) single-variable-domain immunoglobulin (nanobody) that targets AI domain of vWF, preventing its interaction with platelet glycoprotein 1b-IX-V.
    • FDA approved for treatment of adults with immune TTP in combination with plasma exchange and immunosuppressive therapy. 
    • Does not correct underlying ADAMTS13 deficiency nor does it eliminate anti-ADAMTS13 autoantibodies.
    • Must be given with immunosuppressive treatments such as rituximab and corticosteroids.
    • On day 1, administered IV and SQ on day 1, before and after plasma exchange, respectively; then SQ on subsequent days.
    • For additional information about caplacizumab in TTP, click here.
  • Transfusions – Platelet transfusions should not be routinely administered, but may be given in cases of severe or life-threatening hemorrhage. Platelet transfusions have been shown to be associated with higher odds of arterial thrombosis and mortality among patients with TTP. Learn more here.
  • Thromboprophylaxis with low-molecular-weight heparin (LMWH) once the platelet count has reached > 50 × 109/L in patients with active hemolysis.
  • Folate supplementation

Overview of treatment pre- and post-ADAMTS13 levels:

Treatment algorithm based on ISTH clinical practice guideline. Timeline from top to bottom, beginning with patient presentation. For patients with ADAMTS13 levels between 10-120%, ISTH guideline recommends clinical judgment as to whether to continue or stop plasma exchange and corticosteroids. The ISTH guideline also recommends addition of rituximab and caplacizumab to TPE/corticosteroids, though this is not necessarily standard of care. TTP, thrombotic thrombocytopenic purpura; TPE, therapeutic plasma exchange.

Our 56 year-old patient received received plasma exchange and corticosteroids on the eve of admission. His mental status normalized within 24 hours of treatment and his platelet counts increased over the ensuing days. His ADAMTS13 level returned at <10%, consistent with a diagnosis of thrombotic thrombocytopenic purpura (TTP). Plasma exchange was continued until his platelet count was > 150 x 109/L for 3 consecutive days, 9 days following admission. He was discharged home, and followed by a hematologist without evidence of relapse over the next year.

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