Diagnosis of TTP
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 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. 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. The 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.
Treatment of TTP
TREATMENT PROTOCOL FOR NEW ONSET IMMUNE THROMBOTIC THROMBOCYTOPENIC PURPURA (ITTP)
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 test shouldn’t 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 allogeneic (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 has similar properties as standard FFP but may decrease the risk of allergic reactions & 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
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)
Outpatient Management of TTP
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. Afterward 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.
INITIAL TREATMENT
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.
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