Transplantation-associated thrombotic microangiopathy (TA-TMA) is a severe complication which affects 5–74% of patients undergoing allogeneic HSCT.1 Risk factors for TA-TMA include the use of high doses of radio- and chemotherapy, infections, GVHD, and the use of cyclosporine (CsA) or tacrolimus.1, 2
There is no consensus on the most appropriate treatment for patients with TA-TMA. The role of plasma exchange (PE) is controversial3 since response rates are considerably lower than in patients with thrombotic thrombocytopenic purpura (TTP). Thus, many patients require additional therapeutic strategies such as protein A immunoadsorption, splenectomy, nitric oxide, defibrotide, and immunosuppressive agents such as vincristine or steroids.4, 5, 6
We have treated seven allograft recipients developing TA-TMA from 2002 to 2004. Patient characteristics are shown in Table 1. TA-TMA occurred at a median of 61 days (25–276). Diagnosis was based on the presence of anemia and thrombocytopenia (median 30 × 109/l; range 6–50), increased LDH (median 1424 U/l; range 955–2127), and schistocytosis. Renal impairment occurred in one patient and neurological disturbances in three patients. Treatment plan consisted of switch from CsA to tacrolimus maintaining blood levels at the lower end of the therapeutic range (5 ng/ml), with PE and/or vincristine being added for the lack of response.
Four of seven patients were classified as grades 3–4 according to the grading system reported by Zeigler et al.,7 and three patients as grade 2. All patients classified as grades 3–4 received daily PE, except for one who was hemodynamically unstable and received vincristine alone. In the absence of response to PE, vincristine was added to the treatment. Patients classified as grade 2 TA-TMA received only vincristine, which was administered at a dose of 1 mg once daily i.v. (patients younger than 6 and 9 years received 0.6 and 0.7 mg, respectively) on days 1, 4, 8, and also on day 11 when they had not responded after three doses (only one patient received two doses due to a drop in WBC counts).
Overall, six out of the seven patients responded and only one of them died due to TA-TMA-related complications. The remaining six patients reached complete response at a median of 11 days (range: 7–90 days) with platelet counts >100 000/mm3 and hemoglobin levels >10 g/dl. Among responding patients, clinical response was observed within 11 days of treatment although, in two patients, biological parameters improved after 70 days. During treatment with vincristine, WBC counts decreased in four patients but all recovered normal values within 2 weeks and only one patient did not receive the planned dose due to toxicity. After 565 days (170–1060 days), all the responding patients were alive and in complete response. No TA-TMA recurrence was observed.
Only two studies have reported on the combined use of PE and vincristine in the treatment of post transplant TA-TMA.1, 5 Silva et al.5 described one response out of eight patients diagnosed with TA-TMA, while Daly et al.1 described four patients treated with vincristine among 25 TA-TMA patients. Mortality rate reached 96% in this latter study for the whole series of patients.
Pathogenesis of TA-TMA within the allogeneic transplant setting has been attributed to the endothelial cells damage induced by radiotherapy, chemotherapy, infections, or GvHD.3 This endothelial damage favours the release of tissue factor into the circulation and the formation of platelet thrombi.8 PE is useful in TTP because it removes autoantibodies against ADAMTS-13, UlvWF multimers, which are related with the development of TTP. The addition of vincristine early in the course of the disease contributes to reduce autoantibodies and improves the response rates to PE.9 In TA-TMA, in contrast, plasmapheresis induces a lower response rate, which may be partially attributed to the persistence of factors perpetuating endothelial injury.3 In this subset of patients, vincristine alters the platelet membrane glycoprotein receptors, thus preventing their upregulation and binding to von Willebrand factor multimers.9 In addition, its immunoregulatory effect also contributes to the control of underlying mechanisms that perpetuate the TA-TMA.10
The results described in the current study, although in a low number of patients, show that vincristine is a secure and useful adjuvant to PE in severe TA-TMA, while in less severe cases it can be used as a single agent. Our study supports the development of further studies in a larger numbers of patients using vincristine earlier in the course of the disease.
Daly AS, Hasegawa WS, Lipton H, Messner HA, Kiss TL . Transplantation-associated thrombotic microangiopathy is associated with transplantation from unrelated donors, acute graft-versus-host disease and venooclusive disease of the liver. Transfus Apher Sci 2002; 27: 3–12.
Fuge R, Bird J, Fraser A, Hart D, Hunt L, Cornish J et al. The clinical features, risk factors and outcome of thrombotic thrombocytopenic purpura ocurring after bone marrow transplantation. Br J Haematol 2001; 113: 58–64.
Llamas P, Romero R, Cabrera R, Sanjuan I, Forés R, Fernandez MN . Management of thrombotic microangiopathy following allogenic transplantation: what is the role of plasma exchange? Bone Marrow Transplant 1997; 20: 305–306.
Daly AS, Xenocostas A, Lipton JH . Transplantation-associated thrombotic microangiopathy: twenty-two years later. Bone Marrow Transplant 2002; 30: 709–715.
Silva VA, Frei-Lahr D, Brown RA, Herzig GP . Plasma exchange and vincristine in the treatment of hemolytic uremic syndrome/thrombotic thrombocytopenic purpura associated with bone marrow transplantation. J Clin Apher 1991; 6: 16–20.
Böhm M, Betz C, Miesbach W, Krause M, Von Auer C, Geiger H et al. The course of ADAMTS-13 activity and inhibitor titre in the treatment of thrombotic thrombocytopenic purpura with plasma exchange and vincristine. Br J Haematol 2005; 129: 644–652.
Zeigler ZR, Shadduck RK, Nemunaitis J, Andrews DF, Rosenfeld CS . Bone marrow transplant-associated thrombotic microangiopathy: a case series. Bone Marrow Transplant 1995; 15: 247–253.
Mayer S, Aledort L . Thrombotic microangiopathy: differential diagnosis, pathophysiology and therapeutic strategies. Mount sinayi J Med 2005; 72: 166–175.
Ziman A, Mitri M, Klapper E, Pepkowitz SH, Goldfinger D . Combination vincristine and plasma exchange as initial therapy in patients with thrombotic thrombocytopenic purpura: one institution’s experience and review of the literature. Transfus pract 2005; 45: 41–49.
Ferrara F, Annunziata M, Pollio F, Palmieri S, Copia C, Mele G et al. Vincristine as treatment for recurrent episodes of thrombotic thrombocytopenic purpura. Am J Hematol 2002; 81: 7–10.
About this article
Allogeneic reactivity–mediated endothelial cell complications after HSCT: a plea for consensual definitions
Blood Advances (2019)
Emerging Concepts in Hematopoietic Stem Cell Transplantation–Associated Renal Thrombotic Microangiopathy and Prospects for New Treatments
American Journal of Kidney Diseases (2018)
Critical Reviews in Oncology/Hematology (2016)
Clinical and Applied Thrombosis/Hemostasis (2016)
Hematopoietic stem cell transplant-associated thrombotic microangiopathy: review of pharmacologic treatment options