Thrombotic thrombocytopenic purpura (TTP) is a severe microvascular disorder which may occur in 30% to 70% of patients undergoing bone marrow ...
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accurate diagnosis and is supportive of the need for routine use of immunofluorescent and/or molecular testing for rapid diagnosis of hPIV4. This would enable prompt antiviral treatment with ribavirin, if hPIV is confirmed. F Miall1 A Rye1 M Fraser2 A Hunter1 JA Snowden1
1
Department of Haematology, Leicester Royal Infirmary, Leicester LE1 5WW, UK; and 2 Department of Virology, Leicester Royal Infirmary, Leicester, UK
References 1 Hohenthal U, Nikoskelainen J, Vainionpa¨ a¨ R et al. Parainfluenza virus type 3 infections in a haematology unit. Bone Marrow Transplant 2001; 27: 295–300.
Defibrotide as a promising treatment for thrombotic thrombocytopenic purpura in patients undergoing bone marrow transplantation Bone Marrow Transplantation (2002) 29, 542–543. DOI: 10.1038/sj/bmt/1703414 Thrombotic thrombocytopenic purpura (TTP) is a severe microvascular disorder which may occur in 30% to 70% of patients undergoing bone marrow transplantation (BMT)1 depending on discordant diagnostic criteria.2–9 The current retrospective study emphasizes the possible role of defibrotide (DFT), a polydeoxyribonucleotide salt with an antithrombotic and thrombolytic effect,10,11 which has been beneficial in treating deep vein thrombosis, vasculitis and veno-occlusive disease,3 and could be promising in the treatment of TTP. TTP was diagnosed according to standardized clinical and laboratory criteria, as previously experienced,2 in 12 consecutive patients undergoing BMT in two different centers and treated during the same period (1996–2000). The patients, six males and six females, underwent related (five) or unrelated (seven) BMT at a median age of 33 years (range 1–56) for acute lymphoblastic leukemia (two in second complete remission (CR) and three in more than second CR), for acute myeloid leukemia (two patients in first CR, one with active disease), for chronic myeloid leukemia (two patients, both in first chronic phase for Hodgkin’s lymphoma (one, with active disease) and one for familiar lymphohistiocytosis. Criteria for the diagnosis of TTP included: microangiopathic hemolysis with negative Coombs, unexplained decrease in hemoglobin level and platelet count; increased number of reticulocytes, red cell fragmentation (eventually with erythroblasts), increased value of indirect bilirubin (double the normal level), increased serum lactic acid dehydrogenase (LDH) activity (normal range level 150–350 IU/l), decreased haptoglobin Bone Marrow Transplantation
2 Wendt C, Weisdorf D, Jordan M et al. Parainfluenza virus respiratory infection after bone marrow transplantation. New Engl J Med 1992; 326: 921–926. 3 Nichols WG, Corey L, Gooley T et al. Parainfluenza virus infections after haemopoietic stem cell transplantation: risk factors, response to antiviral therapy, and effect on transplant outcome. Blood 2001; 98: 573–578. 4 Bowden RA. Respiratory virus infections after marrow transplant: the Fred Hutchinson Cancer Research Center experience. Am J Med 1997; 102: 27–30. 5 Lewis VA, Champlin R, Englund J et al. Respiratory disease due to parainfluenza virus in adult bone marrow transplant recipients. Clin Infect Dis 1996; 23: 1033–1037. 6 Frank JA, Warren RW, Tucker JA et al. Disseminated parainfluenza infection in a child with severe combined immunodeficiency. Am J Dis Child 1983; 137: 1172–1174. 7 Rubin EE, Quennec P, McDonald JC. Infections due to parainfluenza virus type 4 in children. Clin Infect Dis 1993; 17: 998–1002.
level (⬍40 mg/ml). Severe TTP was defined according to the above critera in addition to the central nervous system dysfunction with or without renal impairment and/or the occurrence of gut or bladder bleeding and/or multiorgan failure, with a TTP index (LDH/platelets ratio) ⬎20 (as described in the literature7). TTP was considered resolved when all clinical and laboratory signs disappeared. Some characteristics of the case series are listed in Table 1. Conditioning regimens included total body irradiation in eight out of 12 patients (f-TBI 2 Gy twice a day for 3 days) combined with standard cyclophosphamide or with additional drugs, while four out of 12 patients received high-dose chemotherapy alone. All patients received cyclosporin A (CsA) for GVHD prophylaxis at standard doses (in order to maintain the CsA plasma levels around 200–300 ng/ml), often combined with methotrexate (in 10 out of 12 cases) or other drugs (ATG, steroids, mophetile micophenolate). Despite this prophylaxis, eight out of 12 cases presented with grade II to IV GVHD. TTP was mild in two patients, and severe in 10; seven out of 10 also developed severe multiorgan hemorrhagic symptoms, especially hemorrhagic cystitis or serious nephropathy which resulted in an increased need for blood products and supportive treatment. TTP was diagnosed at a median of 47 days (range 9–100) after BMT and in six of 12 patients resolved after a median of 23 days (range 14–86). We decided to use DFT for treatment due to the difficulty in performing consecutive plasma exchanges for all 12 patients. DFT therapy started at an average of 2 days (range 1–11) after TTP diagnosis at an average dose of 40 mg/kg p.o. daily (range 30–50) and was discontinued after a median of 41 days (range 17–98). Five out of 12 patients (all died) also received two to three nonconsecutive plasmaphereses along with DFT. No patients received plasma. Five out of 12 cases (two mild and three severe) had a complete response in the first 1–3 weeks; one out of 12 cases showed a stabilization of clinical and laboratory signs within 3 months; three out of 12 patients had a partial response; three out of 12 patients did not respond despite prolonged DFT treatment. TTP was not a
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Table 1 Patients Sex
1 2 3 4 5 6 7 8 9 10 11 12
543
Patients, TTP characteristics and outcome
M M M F F F M M M F F F
Age years
3 1 12 7 35 16 33 20 35 37 55 30
Diagnosis at BMT
AML (1st CR) FEL ALL (2nd CR) ALL (3rd CR) CML (1st CP) ALL (3rd CR) HL (PD) ALL (3rd CR) ALL (2nd CR) AML (1st CR) CML (1st CP) AML (PD)
BMT type
Rel Unrel Rel Unrel Unrel Unrel Rel Unrel Unrel Rel Rel Unrel
TTP index
⬍20 ⬎20 ⬎20 ⬎20 ⬎20 ⬎20 ⬎20 ⬎20 ⬎20 ⬍20 ⬎20 ⬎20
LDH maxa
2t 3t 2t 5t 7t 2t 2t 2t 5t 2t 1t 2t
TTP grade
mild severe severe severe severe severe severe severe severe mild severe severe
Symptoms
— SHS SHS SHS CNS — K,SHS CNS, SHS — — SHS SHS
DFT therapy (days)
No. of plasma phereses
Outcome TTP
Patients
17 51 98 61 23 46 30 17 34 38 64 41
— — — — 2 2 — 3 — — 2 3
TR TR TR TRb NR PR TR NR PR TR NR PR
alive alive alive alive dead dead alive dead dead alive dead dead
Cause of death
— — — — PC PD — IP PG — GG IP
a
Expressed as a multiple (times) of the normal level (range 150–300 IU/l). This case showed a total response within 3 months. AML = acute myeloid leukemia; FEL = familiar lymphohistiocytosis; ALL = acute lymphoblastic leukemia; CML = chronic myeloid leukemia; HL = Hodgkin’s lymphoma; CR = complete remission; CP = chronic phase; PD = presence of disease; Rel = related BMT; Unrel = unrelated BMT; SHS = severe hemorrhagic symptoms; K = kidney involvement; CNS = central nervous system involvement; TR = total response; PR = partial response; NR = no response; PC = pulmonary candidiasis; PD = progression of disease; IP = interstitial pneumonia; PG = pulmonary GVHD; GG = gastroenteric GVHD.
b
cause of death in any patient per se: six out of 12 patients died (3/6 non-responders, 3/6 partial responders) because of causes unrelated to TTP (two of interstitial pneumonia, one of interstitial candidiasis, one of pulmonary GVHD, one of gastroenteric GVHD, one of disease progression) at a median of 4 months after BMT (range 2–12). In our experience, DFT was beneficial in about 50% of the patients. It is worth noting that most of our patients suffered from severe TTP and showed a good response to DFT, probably due to the early start of treatment which helped to avoid TTP-related complications. Notwithstanding that the current experience suggests a promising efficacy of DFT in the treatment of post-BMT severe microangiopathy, a multicenter study should be performed in order to draw reliable conclusions.
Acknowledgements We would like to thank Miss Joanna Upton for her language review, Miss Sara Vaghi for secretarial services and the ‘Comitato Maria Letizia Verga per lo Studio e la Cura delle Leucemie del Bambino for its continuous support of our research projects. P Corti1 C Uderzo1 A Tagliabue1 A Della Volpe2 C Annaloro2 E Tagliaferri2 A Balduzzi1
1 Bone Marrow Transplantation Center, Paediatric Dept of Universita` di Milano-Bicocca, San Gerardo Hospital, Monza, Italy; and 2Bone Marrow Transplantation Center, Universita` di Milano, Ospedale Maggiore IRCCS, Milano, Italy
References 1 Busca A, Uderzo C. Bone marrow transplant associated thrombotic microangiopathy. Hematology 2000; 5: 53–67. 2 Uderzo C, Fumagalli M, De Lorenzo P et al. Impact of thrombotic thrombocytopenic purpura on leukemic children undergoing bone marrow transplantation. Bone Marrow Transplant 2000; 26: 1005–1009. 3 Richardson PG, Elias AD, Krishnan A. Treatment of severe venoocclusive disease with defibrotide: compassionate use results in response without significant toxicity in a high risk population. Blood 1998; 92: 737–744. 4 Pettitt AR, Clark RE. Thrombotic microangiopathy following bone marrow transplantation. Bone marrow Transplant 1994; 14: 495–504. 5 Valilis PH, Zeigler ZR, Shadduck RK et al. A prospective study of bone marrow transplant associated thrombotic microangiopathy (BMT-TM) in autologous and allogeneic BMT. Blood 1995; 86: 970a (Abstr. 3870). 6 Schriber JR, Herzig GP. Transplantation-associated thrombotic thrombocytopenic purpura and hemolytic uremic syndrome. Semin Hematol 1997; 34: 126–133. 7 Zeigler ZR, Shadduck RK, Nemunaitis J et al. Bone marrow transplant-associated thrombotic microangiopathy: a case series. Bone Marrow Transplant 1995; 15: 247–253. 8 Iacopino P, Pucci G, Arcese W et al. Severe thrombotic microangiopathy: an infrequent complication of bone marrow transplantation. Bone Marrow Transplant 1999; 24: 47–51. 9 George JN, Berkowitz SD, Raskob GE. Platelets: acute thrombocytopenia – thrombotic thrombocytopenic purpura and hemolytic uremic syndrome. The ASH Meeting. Blood Educational Program Book 1998; pp 379–383. 10 Mitra D, Jaffe EA, Weksler B et al. Thrombotic thrombocytopenic purpura and sporadic hemolytic-uremic syndrome plasmas induce apoptosis in restricted lineages of human microvascular endothelial cells. Blood 1997; 89: 1224–1234. 11 Moake JL. Studies of the pathophysiology of thrombotic thrombocytopenic purpura. Semin Hematol 1997; 34: 83–89.
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