Unresponsive Thrombotic Thrombocytopenic Purpura (TTP): Challenges and Solutions

Figures & data

Figure 1 Timeline of acute TTP management with favorable (green) and unfavorable (red) outcomes. Non/insufficient response is defined as failure to reach platelet rate >150G/L and/or LDH rate <1.5N and/or occurrence of new/progressive signs of ischemic organ involvement after 5 TPE sessions; Exacerbation is defined as recurrence of any sign of TTP after a phase of clinical response, up to 30 days after the end of therapy; Remission is defined as clinical response maintained over 30 days after cessation of therapy; Relapse is defined as the recurrence of any sign of TTP after remission (ADAMTS13 activity decrease or clinical/biological signs of thrombotic microangiopathy).

Table 1 TMA Differential Diagnosis

	Causes of Cytopenia	Causes of Organ Dysfunction	Evocative Signs
Severe vitamin B9/B12 deficiency	Ineffective erythropoiesis and thrombopoiesis with intra-medullary destruction	Tissular ischemia secondary to profound anemia, bleedings secondary to thrombocytopenia, neurological symptoms secondary to vitamin deficiency	Macrocytosis, unregenerative anemia, megaloblastosis on bone marrow smear
Hematological malignancies/metastatic cancers	Bone marrow involvement by multiple myeloma/cancer metastasis Ineffective erythropoiesis and thrombopoiesis in myelodysplastic syndrome	Tissular ischemia secondary to profound anemia, bleedings secondary to thrombocytopenia, organ involvement of malignancies	Systemic symptoms of cancer, unregenerative anemia, neoplastic cells on bone marrow examination
Evans syndrome	Erythrocytes and platelets destruction secondary to autoantibodies	Tissular ischemia secondary to profound anemia, bleedings secondary to thrombocytopenia	Positive DAT
Hemophagocytic syndrome	Blood cells and precursors phagocytosis by activated macrophages	Cytokine storm, organ involvement of the underlying cause of hemophagocytic syndrome	Fever, HLH2004 criteria

Abbreviations: DAT, direct antiglobulin test; HLH2004, hemophagocytic lymphohistiocytosis.

Table 2 Confounders for TTP Refractoriness

Manifestations	Potential Confounders	Proposed Reaction
Lack of response to first line therapy	Wrong diagnosis: other TMA syndrome (Complement mediated HUS, Shigatoxin-associated HUS, HELLP syndrome, secondary TMA)	- Verify ADAMTS13 study was performed - Verify appropriate TMA diagnostic workup was performed
	Incorrect/sub-optimal first-line therapy	- Verify quality of TPE procedure (substitution fluid = FFP, adequate venous access, no plasma intolerance, no catheter site thrombosis, etc) - Verify type, dosage and timing of immunomodulatory drugs administration are adequate (as soon as possible after last TPE session) - Verify quality of supportive care (blood pressure control, vitamin supplementation, adequate red cell transfusion, etc)
Dissociated clinical/biological response	Alternate diagnosis for clinical/biological anomaly: - Thrombocytopenia: sepsis, HIT, central, etc - Anemia: hemorrhage, iron/vitamin B9 deficiency, etc - Neurological symptoms: citrate overdose, sepsis, ICU delirium, etc - Renal function impairment: acute tubular necrosis, renal involvement of associated disease, etc	- Control ADAMTS13 activity - Perform differential diagnosis workup - Consider patient has refractory TTP until differential diagnosis is established

Abbreviations: TMA, thrombotic microangiopathy; HUS, hemolytic uremic syndrome; HELLP, hemolysis, elevated liver enzymes, low platelets; TPE, therapeutic plasma exchange; FFP, fresh frozen plasma; ICU, intensive care unit; HIT, heparin induced thrombocytopenia.

Figure 2 Pathophysiology, potential therapeutic targets and available therapy for the management of TTP.

Table 3 Therapeutic Options Currently Available for Unresponsive TTP Management

Molecule/Procedure	Dosage	Time to Response	Considerations
First-line treatment adaptation
High dose steroid pulse	1000 mg prednisone equivalent/24h, IV	<7 days	May be included in first-line therapeutic schedule, 1 to 3 pulses
Twice daily TPE	1–1.5 EPV/12h	<7 days	1 to 7 sessions (time-consuming)
Caplacizumab	10 mg, IV before first TPE then 10 mg/day, SC	<7 days	Usually included in first-line therapeutic schedule, duration of treatment 30 days after last TPE (and/or tailored by ADAMTS13 activity)
Rituximab	375 mg/m^2 IV weekly for 4 weeks or D1-D4-D8-D15	>10 days	Fix doses (low or high, 100–1000 mg) may be used, number of injections may be adapted to CD19-B cells count monitoring at day 4 and after, administration of rituximab should take place immediately after a TPE session, SC route may be used for preemptive treatment
Second line therapy
Vincristine	1.4 mg/m^2, maximum dose 2 mg, IV	<7 days	Usually 1 infusion (up to 1/week if necessary)
Cyclophosphamide	500–750 mg/m^2 or 500 mg, IV	>7 days	Usually 1 infusion (up to 1/week if necessary)
Bortezomib	1–1.3 mg/m^2, IV or SC, D1-D4-D8-D11	<7 days	1 infusion may be sufficient
Splenectomy	N/A	< 7 days	Salvage therapy, laparoscopic technique may be preferred
N-acetylcysteine	300 mg/day continuous infusion, IV	<7 days	Limited clinical evidence in TTP, duration of therapy unknown
Ciclosporine A	300 mg/day PO or 2–3 mg/kg/day IV	< 7 days	Continue treatment after remission
Azathioprine	100 mg/day PO	Unknown	Very limited evidence in TTP
Intravenous Immunoglobulin	0.4 g/kg/day IV for 2–6 days	<7 days	Side effects may mimic TTP manifestations (acute kidney injury, headaches, thrombosis, etc)
Eculizumab	900 mg D1-D8-D15-D22 then 1200 mg/2–4 weeks	>7 days	Limited evidence in TTP, complement study should be performed to document potential associated alternate pathway anomalies, if TPE are maintained eculizumab has to be re-administered after each session

Abbreviations: EPV, estimated plasma volume; TPE, therapeutic plasma exchange; D, day.

Figure 3 Unresponsive TTP management algorithm.