iTTP Diagnosis

  • High clinical suspicion of immune mediated TTP (iTTP) is defined as:

    Thrombocytopenia:
    platelet count < 100,000 and Microangiopathic hemolytic anemia1-2 with two or more of the following criteria:

    Elevated absolute reticulocytes count > 100,000/uL

    Elevated indirect bilirubin  

    Undetectable haptoglobin

    Elevated LDH

    Schistocytes in blood smear:

    Direct Antiglobulin Test ( DAT or Coombs): negative

    ADAMTS-13 activity < 10% and the presence of ADAMTS-13 inhibitor or antibody

     If the diagnosis is uncertain and/or ADAMTS-13 is not available, the USTMA suggests the use of the PLASMIC Score, a clinical prediction tool, as an adjunct to clinical judgment and to guide initial management of patients with TMA (thrombotic microangiopathy). The PLASMIC score does NOT confirm or exclude the diagnosis of iTTP and does not take in consideration patients with comorbidities5.

    TESTING

    Lab tests prior to initiation of plasma exchange:

    For all patients send: ADAMTS-13 activity, ADAMTS-13 antibody or inhibitor titer, and a citrate tube in case of additional testing is needed

    Other supporting tests based on clinical presentation:

    DIC panel

    Troponin as a prognostic indicator

    Hepatitis B panel

    Pregnancy test

    Additional testing in the pediatric population:

    Lupus anticoagulant

    ANA, ds DNA and antiphospholipid antibodies

    C3 and C4

    Shiga Toxin PCR

    If ADAMTS-13 is normal and/or creatinine is > 2.25 then

    Shiga Toxin and stool cultures

    If you still have questions about the diagnosis, then the USTMA suggests referring the patient to the closest academic center to assist with further evaluation. Immediate transfer should be made to a center with plasmapheresis capabilities once the diagnosis of iTTP is suspected even if the diagnosis is not yet confirmed.

    References:

    1. Burns ER, Lou Y, Pathak A. Morphologic Diagnosis of Thrombotic Thrombocytopenic Purpura. American Journal of Hematology 75:18–21 (2004)

    2. Barcellini W, Fattizzo B.Clinical Applications of Hemolytic Markers in the Differential Diagnosis and Management of Hemolytic Anemia. Dis Markers. 2015; 2015: 635670.

    3. ISTH TTP guidelines https://www.isth.org

    4. Bendapudi P.K., Hurwitz S., Fry A., Marques M.B., Waldo S.W., Li A. Derivation and external validation of the PLASMIC score for rapid assessment of adults with thrombotic microangiopathies: a cohort study. Lancet Haematol. 2017;4:157–164.

    5.Chiasakul T, Cuker A. Clinical and laboratory diagnosis of TTP: an integrated approach. Am Soc Hematol Educ Program 2018 (1): 530–538.

iTTP Treatment

  • If a diagnosis of iTTP is suspected, then after sending the confirmatory testing (ADAMTS-13 activity and antibody or inhibitor titer), the USTMA strongly recommends immediate initiation of PLASMA EXCHANGE (PEX). PEX should be initiated while awaiting the result of ADAMTS-13 activity. A pending ADAMTS13 activity should not delay the initiation of PEX if iTTP is suspected.

    INITIAL TREATMENT
    Plasma infusion (Fresh Frozen Plasma) at 25-30 mL/kg can be used as a temporizing measure if there is going to be an unavoidable delay in treatment. However, PEX initiation remains the preferred initial treatment. 

    The first step in management is the immediate initiation of PLASMA EXCHANGE (PEX), which serves to remove the autoantibody and supplement ADAMTS13 activity. The PEX process can be either performed by centrifugation with continuous or intermittent flow or by membrane based depending on the preferred method of each institution. Fresh frozen plasma (FFP) should be the initial replacement fluid during PEX.

    PEX is initiated at 1.0 X plasma volume (PV) (40 mL/kg) daily or 1.5 X plasma volume (PV) (60 mL/kg) daily until 2 days after platelet count normalization (> 150 x 10^9) (1,2,3)

    Exposure to allogenic (donor) plasma may cause serious complications such as hemolytic transfusion reactions, severe anaphylactic reaction or transfusion-related acute lung injury and may increase the risk of transfusion-transmitted disease.

    Solvent/Detergent plasma such as Octaplas has similar properties as standard FFP but might decrease the risk of allergic reactions and inactivate viruses with lipid envelopes.

    CORTICOSTEROIDS
    Use initially to achieve relatively rapid immunosuppression:

    Prednisone 1 mg/kg/day if able to take PO (max dose 100 mg daily) and tapered in 30 days period.

    Methylprednisolone intravenously (1 mg/Kg/day) for 3 days if unable to take PO(4)

    CAPLACIZUMAB
    Caplacizumab is an antibody that targets A1 domain of von Willebrand factor and interacts with platelet glycoprotein 1b which blocks platelet-von Willebrand factor interaction and prevents the formation of microvascular thrombosis.

    The USTMA suggests considering the use of Caplacizumab in the early phase of the acute event in non-bleeding patients with high clinical suspicion of iTTP (even before the results of ADAMTS-13 activity become available) or in patients with evidence of severe ADAMTS-13 deficiency and presence of inhibitor.(5-6)

    RITUXIMAB
    Consistent with the ISTH guidelines, the USTMA suggests considering upfront (newly diagnosed) Rituximab 375 mg/m2 weekly for 4 weeks. It is removed from the circulation by PEX therefore administration of Rituximab should be given immediately after PEX and try to avoid PEX for at least 12 hours after administration.(7)

    References

    1. Winters JL Plasma exchange: concepts, mechanisms, and an overview of the American Society for Apheresis guidelines Hematology Am Soc Hematol Educ Program (2012) 2012 (1): 7–12.

    2. Sayani FA, Abrams CS. How I treat refractory thrombotic thrombocytopenic purpura. Blood. 2015 Jun 18; 125(25): 3860–3867.

    3. Scully M, Goodship T. How I treat thrombotic thrombocytopenic purpura and atypical haemolytic uraemic syndrome. Br J Haematol. 2014 Mar; 164(6): 759–766.

    4. Balduini CL, Gugliotta L, Luppi M, Laurenti L, Klersy C, Pieresca C, Quintini G, Iuliano F, Re R, Spedini P, Vianelli N, Zaccaria A, Pogliani EM, Musso R, Bobbio Pallavicini E, Quarta G, Galieni P, Fragasso A, Casella G, Noris P, Ascari E, Italian TTP Study Group. High versus standard dose methylprednisolone in the acute phase of idiopathic thrombotic thrombocytopenic purpura: a randomized study. Ann Hematol. 2010 Jun; 89(6):591-6

    5. Peyvandi F, Scully M, Kremer Hovinga JA, et al. Caplacizumab for acquired thrombotic thrombocytopenic purpura. N Engl J Med. 2016; 374:511-522

    6. Scully M, Cataland SR, Peyvandi F, et al. Caplacizumab treatment for acquired thrombotic thrombocytopenic purpura. N Engl J Med. 2019; 380:335-346

    7. McDonald V, Manns K, Mackie IJ, Machin SJ, Scully MA.Rituximab pharmacokinetics during the management of acute idiopathic thrombotic thrombocytopenic purpura. J Thromb Haemost. 2010 Jun; 8(6):1201-8.

iTTP Outpatient Follow Up

  • VISITS AND STANDARD LABS
    After discharge, we recommend weekly clinical evaluations and lab visits for a month or while tapering steroids. Routine labs for monitoring include CBC with differential, comprehensive metabolic panel, reticulocyte count and LDH. Afterwards clinic and lab visits should be conducted monthly for 5 months followed by every 3 months thereafter.

    ADAMTS-13 ACTIVITY TESTING
    If the patient is on Caplacizumab, (1-2) The USTMA recommends checking ADAMTS-13 activity weekly.

    If the ADAMTS-13 has increased > 10% in 2 consecutive weeks or > 30% in one occasion then, Caplacizumab can be discontinued. We suggest checking ADAMTS-13 activity weekly for 1-month followed by monthly for 3 months and then every 3 months subsequently.

    If the ADAMTS-13 remains < 10% after completion of 28 days of Caplacizumab, USTMA suggests considering extending Caplacizumab for an additional 4 weeks and intensifying immunosuppression with Rituximab(3), if not already given, or with cyclosporine, cyclophosphamide, bortezomib, vincristine or mycophenolate. The choice of immunosuppressive therapy is based upon several factors, including the patient’s age, other comorbidities (including renal failure), drug access, and the physician’s comfort level and experience.

    ADAMTS-13 activity should be checked weekly for a month, monthly for 3 months and then every 3-month interval thereafter.

    References

    1. Peyvandi F, Scully M, Kremer Hovinga JA, et al. Caplacizumab for acquired thrombotic thrombocytopenic purpura. N Engl J Med. 2016; 374:511-522

    2. Scully M, Cataland SR, Peyvandi F, et al. Caplacizumab treatment for acquired thrombotic thrombocytopenic purpura. N Engl J Med. 2019; 380:335-346

    3. McDonald V, Manns K, Mackie IJ, Machin SJ, Scully MA.Rituximab pharmacokinetics during the management of acute idiopathic thrombotic thrombocytopenic purpura. J Thromb Haemost. 2010 Jun; 8(6):1201-8.

    4.Jestin M, Benhamou Y, Schelpe AS, et al. Preemptive rituximab prevents long term relapses in immune-mediated thrombotic thrombocytopenic purpura. Blood. 2018;132:2143-2153