Approach
The main treatment goal for patients with acquired (idiopathic) TTP is to restore normal platelet count and resolve symptoms. A combination of plasma-exchange therapy and corticosteroids is the mainstay of treatment. Caplacizumab may be prescribed as an adjunctive therapy in adults. Additional measures include use of antiplatelet agents (e.g., aspirin), and supportive therapies such as folate supplementation, red cell transfusion, and platelet transfusion.
TTP can be difficult to distinguish from hemolytic uremic syndrome (HUS). The treatment of both conditions is the same in adults, but distinguishing the conditions is more important in children because suspected hemolytic uremic syndrome in children should be treated supportively.[52]
Initial treatment
Plasma exchange should be started within 24 hours of presentation, because delay decreases the chance of response.[53] Single volume plasma exchange daily has been reported; however the British Committee for Standards in Haematology recommends urgent initiation of 1.5 plasma volume exchanges to reduce mortality.[4][54][55][56]
If plasma exchange is not available, patients should be transferred to a location where plasma exchange can be performed. If the initiation of plasma exchange is delayed, plasma infusion can be used (30 mL/kg/day). Bone marrow transplant-associated TTP is less likely to respond to plasma exchange, and it is not appropriate in this patient population.[57] Early testing for pregnancy, HIV, and hepatitis B and C has been suggested before plasma exchange (if possible), as pregnancy and HIV are considered risk factors for TTP, and hepatitis B and C infection have been associated with TTP.[4]
Potential inhibitors to von Willebrand factor cleaving enzyme (ADAMTS-13) are removed and ADAMTS-13 is replaced following plasma exchange. Early (i.e., pre-plasma exchange) testing for ADAMTS-13 may be useful in deciphering this type of TTP.[4] Plasma exchange has improved mortality from >90% to between 10% and 30%. A prospective randomized study by the Canadian Apheresis Group evaluated plasma exchange versus plasma infusion in patients with TTP. Plasma exchange improved mortality (22% versus 37%).[58] A systematic review of randomized controlled trials confirmed the benefit of plasma exchange in the treatment of TTP, with no single replacement fluid being superior.[56]
Plasma exchange should be titrated as needed based on clinical status, platelet count, and LDH. It can be titrated to platelet response up to twice daily or double volume once daily. Withdrawal from plasma exchange is carried out using a slow taper. Premature withdrawal of plasma exchange can result in clinical deterioration, and experience has shown that waiting until the patient's platelet count and LDH are improved and stable for 3 days before initiating the slow taper is optimal. Patients are tapered to a plasma infusion gradually and are then tapered off plasma altogether. Approximately 90% of patients will respond to plasma exchange within 3 weeks, with most responding within 10 days.
Patients receiving plasma exchange should also be given corticosteroids. This combination is the standard of care despite the fact that there have been no studies specifically comparing this combination versus plasma exchange alone. The use of corticosteroids is based on historical evidence that some patients with limited symptoms might respond to corticosteroids alone.[59] There is no agreement about the type of corticosteroid that should be given.
Caplacizumab is the first therapeutic agent approved for acquired TTP. It is a humanized, bivalent variable-domain-only immunoglobulin fragment that blocks the interaction between von Willebrand factor (vWF) and platelets. In a phase III trial of adults with acquired TTP, caplacizumab (in combination with plasma exchange and corticosteroids) reduced TTP-related death, recurrence, or major thromboembolic event (a composite outcome) compared with placebo (12% vs 49%, P <0.001).[60] Caplacizumab also resulted in significantly shorter time to normalization of platelet count.
Aspirin may be combined with plasma exchange and corticosteroids, but this remains controversial. TTP pathophysiology involves platelet aggregation leading to microthrombi; therefore, use of aspirin makes theoretical sense.
Once the acute episode resolves, patients may be kept on aspirin long term to decrease platelet aggregation. In patients with severe thrombocytopenia (i.e., platelet count <10 x 10³/microliter), some practitioners would advocate avoiding antiplatelet agents because of concerns regarding bleeding complications.
Revised outcome definition in TTP
The International Working Group on TTP has proposed a new consensus definition of clinical response and remission.[61] The definition incorporates ADAMTS-13 activity and the effects of anti-VWF therapy, by using an estimate-talk-estimate approach. The updated definitions distinguish clinical remission and clinical relapse (defined primarily by platelet count) from ADAMTS-13 remission and ADAMTS-13 relapse (defined by ADAMTS-13 activity). Partial ADAMTS-13 remission is defined as ADAMTS-13 activity ≥20% to < lower limit of normal (LLN) and complete ADAMTS-13 remission defined as ADAMTS-13 activity ≥ LLN. ADAMTS-13 remission (partial or complete) is always accompanied by clinical remission, however, clinical remission may occur with or without an ADAMTS-13 remission.[61]
Supportive care
Patients can be given folate supplementation for a presumed relative folate deficiency from hemolysis and high demand for folate. However, high doses of folic acid might obscure a vitamin B12 deficiency, and supplementation can also result in nausea, loss of appetite, irritability, and loss of sleep.
Patients can receive red-cell transfusions according to clinical need as there is no single reliable cut-off. Platelet transfusion should be considered for a bleeding patient or when invasive procedures and central lines are required for plasmapheresis. Although this was previously thought to trigger worsening of disease, a retrospective review does not support this.[62]
Refractory disease
If the patient deteriorates clinically or does not respond to initial treatment, subsequent treatments include vincristine, rituximab, cyclophosphamide, cyclosporine, or splenectomy. The efficacy and comparative benefits of these therapies have not been established in randomized controlled trials, and all patients with refractory disease should be referred to a specialist center and/or for clinical trial participation.
Rituximab is a monoclonal antibody specific for the CD20 B-cell marker. It is used frequently for the treatment of B-cell non-Hodgkin lymphoma. Studies have evaluated its use in autoimmune processes, including acquired (idiopathic) TTP, because it is a relatively safe and easy method for targeting antibody production. A systematic review of rituximab in the management of refractory and/or relapsing acquired (idiopathic) TTP found that most patients treated with rituximab (approximately 95%) achieved complete remission within weeks of the initial administration.[63] The reported relapse rate was low in this patient subgroup, which carried an anticipated relapse rate of up to 60%. However, caution in interpreting these data is needed given the relatively short median duration of follow-up. Rituximab is becoming more commonly used than the other immunosuppressive agents in the US. In the past it has been used in the salvage setting with suboptimal response, whereas now it is being used in the frontline setting, resulting in a reduced risk of relapse.[64] One meta-analysis suggests treating with rituximab in the acute phase may also reduce mortality.[65]
There are case reports and small retrospective studies to suggest that vincristine may be temporally associated with platelet recovery in refractory TTP.[66][67][68] Support for the use of cyclophosphamide in the treatment of refractory TTP comes from small case reports and the theoretical benefit of immunosuppression.[69][70][71] Cyclosporine is associated with an increased risk of post-bone marrow transplantation microangiopathy but has also shown some activity in the treatment of refractory, severe intermittent, and postautologous bone marrow transplantation TTP.[72][73] The optimal duration of cyclosporine treatment is unclear and there appear to be relapses after stopping therapy.
In the pre-plasma exchange era, splenectomy had been tried in combination with corticosteroids for the treatment of acquired (idiopathic) TTP, with some long-term responses. With the advent of plasma exchange, its benefit has been questioned. A review looked at the 20-year experience with TTP at a single center[74] and found that 9 out of the 10 patients who underwent splenectomy for refractory TTP developed a complete response, so splenectomy may be considered for refractory disease. After splenectomy, patients are at higher risk of fatal bacterial infections and should be instructed to seek urgent medical treatment in the case of febrile illness. At least 2 weeks before splenectomy, patients should receive polyvalent pneumococcal vaccine, Haemophilus influenzae b vaccine, and quadrivalent meningococcal polysaccharide vaccine. Another review suggested that splenectomy may be of some benefit in relapsing/remitting disease. Out of 5 new cases and 87 patients from the literature who had splenectomy for refractory or relapsing thrombotic thrombocytopenic purpura, only 8% had refractory disease after splenectomy and another 17% relapsed.[75]
Use of this content is subject to our disclaimer