American Journal of Emergency Medicine 33 (2015) 599.e1–599.e3
Contents lists available at ScienceDirect
American Journal of Emergency Medicine journal homepage: www.elsevier.com/locate/ajem
Case Report
Recombinant thrombomodulin monotherapy for secondary thrombotic thrombocytopenic purpura☆,☆☆ Abstract The use of plasma exchange for the treatment of thrombotic thrombocytopenic purpura (TTP) has reduced the mortality rate, but it remains high, at 20%. Steroids, rituximab, and eculizumab are sometimes used in addition to plasma exchange, but their use is associated with adverse effects, including immunosuppression. Several studies reported that the concomitant use of recombinant thrombomodulin (rTM) in the treatment of TTP was useful; however, no studies have reported the successful treatment of TTP with rTM alone. We present the first case of TTP successfully treated by rTM. Because previous studies showed that rTM alleviates vascular endothelial damage, this agent is also theoretically useful for the treatment of TTP. Recombinant thrombomodulin would be significant in alleviating vascular endothelial damage and decreasing the organ's damage. Thrombotic thrombocytopenic purpura (TTP) is associated with decreased activity of ADAMTS-13, an enzyme that cleaves ultra-large von Willebrand multimers (UL-VWFM). In autoimmune TTP, a decrease in ADAMTS-13 activity due to anti-ADAMTS autoantibodies results in the excessive aggregation of platelets with uncleaved UL-FWFM, leading to vascular endothelial ischemic damage [1]. Thrombotic thrombocytopenic purpura is treated by plasma exchange and fresh-frozen plasma administration; however, TTP often resists treatment, and even after successful treatments, organ dysfunction may persist. Meanwhile, it has been indicated that in ADAMTS-13 inhibitor– negative patients, the excessive release of UL-VWFM due to inflammation or other causes may contribute to the development of secondary TTP [2]. In this case, ADAMTS-13 activity is not significantly decreased [3]. Therapeutic options for TTP other than plasma exchange and fresh-frozen plasma infusion are steroids [4], rituximab [5], and eculizumab [6]. However, they are often associated with adverse effects such as immunosuppression. Recombinant thrombomodulin (rTM), a drug product developed in Japan and composed of the bioactive domains of thrombomodulin, has the effect of reducing vascular endothelial damage. It is theoretically effective for the treatment of TTP. Herein, we report a patient with secondary TTP who was successfully treated by rTM monotherapy. A 76-year-old woman vomited, became incontinent, and was found unconscious at home. She was rushed by ambulance to our hospital. She
☆ Name of organization and date of assembly: Hitachi General Hospital. ☆☆ Source(s) of support in the form of equipment, drugs, or grants (including grant numbers): None.
had no medical history of note and was not taking any medication. Her temperature was 33.9°C; blood pressure, 89/56 mm Hg; heart rate, 83 beats/min; SpO2, 100% (room air); and Glasgow Coma Scale score, E4V3M6. The laboratory data are shown in Table 1. For macrocytic anemia, the transfusion of red blood cells and administration of vitamin B12 and folic acid were started. After admission, the platelet count fell to 14 000/μL, and so 20 U of platelets was transfused. Because blood tests on the fifth hospital day revealed thrombocytopenia (platelet count, 53 000/μL) and coagulation abnormalities (fibrin degradation products [FDP] 23 μg/dL, prothrombin time 72%), the administration of 12 800 units of rTM was started to alleviate vascular endothelial damage. The peripheral blood smear showed fragmented red blood cells, suggesting TTP, so additional tests were ordered, the results of which are also shown in Table 1. These findings led to a diagnosis of TTP, which improved markedly after rTM administration. The patient's prognosis at the start of rTM therapy was not poor, with a Rose index of TTP severity of 3, and so no plasma exchange or fresh-frozen plasma replacement was performed. Figure shows the time course of changes in platelet counts and FDP levels. Because the platelet count was restored, rTM was discontinued on the ninth hospital day. On the 11th hospital day, the platelet count and FDP level had returned to the reference range, and the ADAMTS13 and von Willebrand factor activity levels were 48% and 206%, respectively. Because her general condition and blood examination data improved, she was discharged, walking unaided. Thrombomoduin is known to protect vascular endothelium by activating protein C and degrading inflammatory materials [7–9], and circulating thrombomodulin levels are markedly elevated in patients with TTP. However, these circulating thrombomodulin has very low bioactivity, and the activity of vascular endothelial thrombomodulin is decreased [10]. So we consider that replacement therapy with rTM products compensates for the decreased activity of thrombomodulin. Secondary TTP occurs as a result of increased production and release of UL-VWFM by inflammatory cytokines [11]. Secondary TTP is less responsive to plasma exchange [12], presumably because plasma exchange can remove ADAMTS-13 inhibitors, but cannot suppress the vascular endothelial injury–induced production of UL-VWFM. So in this condition, immediate improvement of vascular endothelial damage seems important. As far as we searched, 9 cases TTP were treated with rTM [13–17]. These cases are summarized in Table 2. Of note, none of them, except for our case, were treated with rTM alone. All patients had secondary TTP, and the treatment with rTM restored their platelet counts and reversed their decreased FDP levels, alleviating vascular endothelial
0735-6757/© 2014 The Authors. Published by Elsevier Inc. This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/3.0/).
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K. Ebisawa et al. / American Journal of Emergency Medicine 33 (2015) 599.e1–599.e3
Table 1 Laboratory test White blood cell count Hemoglobin Mean corpuscular volume Platelet count Prothrombin time Activated partial thrombin time Fibrinogen FDPs D-dimer Antithrombin III Total protein Albumin Direct bilirubin Indirect bilirubin Blood urea nitrogen Creatinin Lactate dehydrogenase Haptoglobin Vitamin B12 Folic acid
7200/μL 4.7 g/dL 128 fL 81 000/μL 13.3 s 31.2 s 241 mg/dL 3.3 μg/mL 1 μg/mL 51% 6.6 g/dL 4.1 g/dL 4.8 mg/dL 2.3 mg/dL 48.4 mg/dL 1.4 mg/dL 1965 U/L 2 mg/dL 50 pg/mL 9.4 pg/mL
Antinuclear antibody Blood culture
Negative Negative
Additional test Von-Willebrand factor activity
375%
Reference range, 60%-170%
ADAMTS-13 activity ADAMTS-13 inhibitor Thrombomodulin
45% Negative N32 FU/mL
Reference range, 70%-120%
Ryota Inokuchi, MD Department of Emergency and Critical Care Medicine Hitachi General Hospital, 2-1-1 Jonan Hitachi Ibaraki 317-0077, Japan Department of Emergency and Critical Care Medicine University Hospital, The University of Tokyo 7-1 3-1 Hongo Bunkyo, Tokyo 113-8655, Japan Department of Emergency Medicine JR General Hospital 2-1-3 Yoyogi, Sbuya-ku, Tokyo 151-8528, Japan
damage. As to our patient, we speculate that coagulation abnormalities and vascular endothelial damage in the context of hypothermia resulted in an increased release of UL-VWFM, leading to the development of TTP. In patients with ADAMTS-13 inhibitor–positive primary TTP, plasma exchange should be indicated to replenish ADAMTS-13 and remove the inhibitors. However, rTM would be also significant to alleviate vascular endothelial damage and decrease the organ's damage. The administration of rTM may improve TTP condition, especially in secondary TTP. It would shorten the treatment duration and reduce the organ damage. Kazutoshi Ebisawa, MD Department of Emergency and Critical Care Medicine Hitachi General Hospital, 2-1-1 Jonan Hitachi, Ibaraki 317-0077, Japan Corresponding author. Department of Emergency and Critical Care MedicineHitachi General Hospital. 2-1-1 Jonan Hitachi, Ibaraki 317-0077, Japan Tel.: +81 3 7406 5193; fax: +81 3 23 8351 E-mail address: [email protected] Tatsuma Fukuda, MD Department of Emergency and Critical Care Medicine Hitachi General Hospital, 2-1-1 Jonan Hitachi, Ibaraki 317-0077, Japan Department of Emergency and Critical Care Medicine University Hospital, The University of Tokyo 7-1 3-1 Hongo Bunkyo, Tokyo113-8655, Japan
Reference range, 1.8-3.9 FU/mL
Kensuke Nakamura, PhD Department of Emergency and Critical Care Medicine Hitachi General Hospital, 2-1-1 Jonan Hitachi, Ibaraki 317-0077, Japan Department of Emergency and Critical Care Medicine University Hospital, The University of Tokyo 7-1 3-1 Hongo Bunkyo, Tokyo 113-8655, Japan http://dx.doi.org/10.1016/j.ajem.2014.08.076
References [1] Furlan M, Robles R, Galbusera M, Remuzzi G, Kyrle PA, Brenner B, et al. von Willebrand factor–cleaving protease in thrombotic thrombocytopenic purpura and the hemolytic-uremic syndrome. N Engl J Med 1998;339(22):1578–84. [2] Matsumoto M, Yagi H, Ishizashi H, Wada H, Fujimura Y. The Japanese experience with thrombotic thrombocytopenic purpura-hemolytic uremic syndrome. Semin Hematol 2004;41(1):68–74.
Figure. Time course of changes in platelet counts and FDP levels. RCC indicates red cell concentrates; PC, platelet concentrates; Plt, platelet counts.
K. Ebisawa et al. / American Journal of Emergency Medicine 33 (2015) 599.e1–599.e3
598.e3
Table 2 Cases rTM is used for TTP
Age (y) Sex Underlying
Nishijima et al [13]
Okada et al [14]
Tonooka et al [15]
Sakai et al [16]
Inoue et al [17]
Our present case
61 Female condition
1 Female Gemcitabine + bevacizumab for small cell lung cancer
33 Female Umbilical cord blood; transplantation for familial hemophagocytic
24 Female lymphohistiocytosis
n/a n/a TMA associated with SLE
76 Female Peripheral blood stem cell transplantation for DLBCL
n/a
69.8%
N60%
n/a
45%
n/a
Negative
n/a
n/a
Negative
PSL + MMF + rTM
PSL + CPA + rTM Cured
Rituximab + rTM
PSL + CPA + rTM
rTM
Cured
Cured
Cured
Refractory transplantation TMA associated with acute GVHD after intestinal ADAMTS61% 13 activity ADAMTSNegative 13 inhibitor Treatments FFP + rTM
Hypothermia and vitamin B12 deficiency
Outcome
Cured
Cured
n/a indicates not available; FFP, fresh-frozen plasma; PSL, predonisolone; MMF, mycophenolate mofetil; CPA, cyclophosphamide; CyA, cyclosporin. [3] Boyer A, Chadda K, Salah A, Bonmarchand G. Thrombotic microangiopathy: an atypical cause of acute renal failure in patients with acute pancreatitis. Intensive Care Med 2004;30(6):1235–9. [4] Allford SL, Hunt BJ, Rose P, Machin SJ. Haemostasis, Thrombosis Task Force BCfSiH: guidelines on the diagnosis and management of the thrombotic microangiopathic haemolytic anaemias. Br J Haematol 2003;120(4):556–73. [5] Scully M, Cohen H, Cavenagh J, Benjamin S, Starke R, Killick S, et al. Remission in acute refractory and relapsing thrombotic thrombocytopenic purpura following rituximab is associated with a reduction in IgG antibodies to ADAMTS-13. Br J Haematol 2007;136(3):451–61. [6] Tsai E, Chapin J, Laurence JC, Tsai HM. Use of eculizumab in the treatment of a case of refractory, ADAMTS13-deficient thrombotic thrombocytopenic purpura: additional data and clinical follow-up. Br J Haematol 2013;162(4):558–9. [7] Elphick GF, Sarangi PP, Hyun YM, Hollenbaugh JA, Ayala A, Biffl WL, et al. Recombinant human activated protein C inhibits integrin-mediated neutrophil migration. Blood 2009;113(17):4078–85. [8] Xu J, Zhang X, Pelayo R, Monestier M, Ammollo CT, Semeraro F, et al. Extracellular histones are major mediators of death in sepsis. Nat Med 2009;15(11):1318–21. [9] Abeyama K, Stern DM, Ito Y, Kawahara K, Yoshimoto Y, Tanaka M, et al. The Nterminal domain of thrombomodulin sequesters high-mobility group-B1 protein, a novel antiinflammatory mechanism. J Clin Invest 2005;115(5):1267–74. [10] Ohlin AK, Larsson K, Hansson M. Soluble thrombomodulin activity and soluble thrombomodulin antigen in plasma. J Thromb Haemost 2005;3(5):976–82.
[11] Asamiya Y, Moriyama T, Takano M, Iwasaki C, Kimura K, Ando Y, et al. Successful treatment with rituximab in a patient with TTP secondary to severe ANCAassociated vasculitis. Intern Med 2010;49(15):1587–91. [12] Kameda T, Dobashi H, Kittaka K, Susaki K, Yamaoka G, Arai K, et al. Two cases of refractory thrombotic thrombocytopenic purpura associated with collagen vascular disease were significantly improved by rituximab treatment. Clin Rheumatol 2007; 26(12):2159–62. [13] Nishijima Y, Hirata H, Himeno A, Kida H, Matsumoto M, Takahashi R, et al. Druginduced thrombotic thrombocytopenic purpura successfully treated with recombinant human soluble thrombomodulin. Intern Med 2013;52(10):1111–4. [14] Okada K, Horino A, Yamasaki K, Tanaka C, Fujisaki H, Osugi Y, et al. Successful treatment for thrombotic microangiopathy with recombinant human soluble thrombomodulin after umbilical cord blood transplantation. Rinsho Ketsueki 2012; 53(2):235–9. [15] Tonooka K, Ito H, Shibata T, Ozaki S. Recombinant human soluble thrombomodulin for treatment of thrombotic microangiopathy associated with lupus nephritis. J Rheumatol 2012;39(8):1766–7. [16] Sakai M, Ikezoe T, Bandobashi K, Togitani K, Yokoyama A. Successful treatment of transplantation-associated thrombotic microangiopathy with recombinant human soluble thrombomodulin. Bone Marrow Transplant 2010;45(4):803–5. [17] Inoue Y, Kosugi S, Miura I, Hatta Y, Takeuchi J. Successful treatment of refractory acute GVHD complicated by severe intestinal transplant-associated thrombotic microangiopathy using recombinant thrombomodulin. Thromb Res 2011;127(6):603–4.
Contents lists available at ScienceDirect
American Journal of Emergency Medicine journal homepage: www.elsevier.com/locate/ajem
Case Report
Recombinant thrombomodulin monotherapy for secondary thrombotic thrombocytopenic purpura☆,☆☆ Abstract The use of plasma exchange for the treatment of thrombotic thrombocytopenic purpura (TTP) has reduced the mortality rate, but it remains high, at 20%. Steroids, rituximab, and eculizumab are sometimes used in addition to plasma exchange, but their use is associated with adverse effects, including immunosuppression. Several studies reported that the concomitant use of recombinant thrombomodulin (rTM) in the treatment of TTP was useful; however, no studies have reported the successful treatment of TTP with rTM alone. We present the first case of TTP successfully treated by rTM. Because previous studies showed that rTM alleviates vascular endothelial damage, this agent is also theoretically useful for the treatment of TTP. Recombinant thrombomodulin would be significant in alleviating vascular endothelial damage and decreasing the organ's damage. Thrombotic thrombocytopenic purpura (TTP) is associated with decreased activity of ADAMTS-13, an enzyme that cleaves ultra-large von Willebrand multimers (UL-VWFM). In autoimmune TTP, a decrease in ADAMTS-13 activity due to anti-ADAMTS autoantibodies results in the excessive aggregation of platelets with uncleaved UL-FWFM, leading to vascular endothelial ischemic damage [1]. Thrombotic thrombocytopenic purpura is treated by plasma exchange and fresh-frozen plasma administration; however, TTP often resists treatment, and even after successful treatments, organ dysfunction may persist. Meanwhile, it has been indicated that in ADAMTS-13 inhibitor– negative patients, the excessive release of UL-VWFM due to inflammation or other causes may contribute to the development of secondary TTP [2]. In this case, ADAMTS-13 activity is not significantly decreased [3]. Therapeutic options for TTP other than plasma exchange and fresh-frozen plasma infusion are steroids [4], rituximab [5], and eculizumab [6]. However, they are often associated with adverse effects such as immunosuppression. Recombinant thrombomodulin (rTM), a drug product developed in Japan and composed of the bioactive domains of thrombomodulin, has the effect of reducing vascular endothelial damage. It is theoretically effective for the treatment of TTP. Herein, we report a patient with secondary TTP who was successfully treated by rTM monotherapy. A 76-year-old woman vomited, became incontinent, and was found unconscious at home. She was rushed by ambulance to our hospital. She
☆ Name of organization and date of assembly: Hitachi General Hospital. ☆☆ Source(s) of support in the form of equipment, drugs, or grants (including grant numbers): None.
had no medical history of note and was not taking any medication. Her temperature was 33.9°C; blood pressure, 89/56 mm Hg; heart rate, 83 beats/min; SpO2, 100% (room air); and Glasgow Coma Scale score, E4V3M6. The laboratory data are shown in Table 1. For macrocytic anemia, the transfusion of red blood cells and administration of vitamin B12 and folic acid were started. After admission, the platelet count fell to 14 000/μL, and so 20 U of platelets was transfused. Because blood tests on the fifth hospital day revealed thrombocytopenia (platelet count, 53 000/μL) and coagulation abnormalities (fibrin degradation products [FDP] 23 μg/dL, prothrombin time 72%), the administration of 12 800 units of rTM was started to alleviate vascular endothelial damage. The peripheral blood smear showed fragmented red blood cells, suggesting TTP, so additional tests were ordered, the results of which are also shown in Table 1. These findings led to a diagnosis of TTP, which improved markedly after rTM administration. The patient's prognosis at the start of rTM therapy was not poor, with a Rose index of TTP severity of 3, and so no plasma exchange or fresh-frozen plasma replacement was performed. Figure shows the time course of changes in platelet counts and FDP levels. Because the platelet count was restored, rTM was discontinued on the ninth hospital day. On the 11th hospital day, the platelet count and FDP level had returned to the reference range, and the ADAMTS13 and von Willebrand factor activity levels were 48% and 206%, respectively. Because her general condition and blood examination data improved, she was discharged, walking unaided. Thrombomoduin is known to protect vascular endothelium by activating protein C and degrading inflammatory materials [7–9], and circulating thrombomodulin levels are markedly elevated in patients with TTP. However, these circulating thrombomodulin has very low bioactivity, and the activity of vascular endothelial thrombomodulin is decreased [10]. So we consider that replacement therapy with rTM products compensates for the decreased activity of thrombomodulin. Secondary TTP occurs as a result of increased production and release of UL-VWFM by inflammatory cytokines [11]. Secondary TTP is less responsive to plasma exchange [12], presumably because plasma exchange can remove ADAMTS-13 inhibitors, but cannot suppress the vascular endothelial injury–induced production of UL-VWFM. So in this condition, immediate improvement of vascular endothelial damage seems important. As far as we searched, 9 cases TTP were treated with rTM [13–17]. These cases are summarized in Table 2. Of note, none of them, except for our case, were treated with rTM alone. All patients had secondary TTP, and the treatment with rTM restored their platelet counts and reversed their decreased FDP levels, alleviating vascular endothelial
0735-6757/© 2014 The Authors. Published by Elsevier Inc. This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/3.0/).
598.e2
K. Ebisawa et al. / American Journal of Emergency Medicine 33 (2015) 599.e1–599.e3
Table 1 Laboratory test White blood cell count Hemoglobin Mean corpuscular volume Platelet count Prothrombin time Activated partial thrombin time Fibrinogen FDPs D-dimer Antithrombin III Total protein Albumin Direct bilirubin Indirect bilirubin Blood urea nitrogen Creatinin Lactate dehydrogenase Haptoglobin Vitamin B12 Folic acid
7200/μL 4.7 g/dL 128 fL 81 000/μL 13.3 s 31.2 s 241 mg/dL 3.3 μg/mL 1 μg/mL 51% 6.6 g/dL 4.1 g/dL 4.8 mg/dL 2.3 mg/dL 48.4 mg/dL 1.4 mg/dL 1965 U/L 2 mg/dL 50 pg/mL 9.4 pg/mL
Antinuclear antibody Blood culture
Negative Negative
Additional test Von-Willebrand factor activity
375%
Reference range, 60%-170%
ADAMTS-13 activity ADAMTS-13 inhibitor Thrombomodulin
45% Negative N32 FU/mL
Reference range, 70%-120%
Ryota Inokuchi, MD Department of Emergency and Critical Care Medicine Hitachi General Hospital, 2-1-1 Jonan Hitachi Ibaraki 317-0077, Japan Department of Emergency and Critical Care Medicine University Hospital, The University of Tokyo 7-1 3-1 Hongo Bunkyo, Tokyo 113-8655, Japan Department of Emergency Medicine JR General Hospital 2-1-3 Yoyogi, Sbuya-ku, Tokyo 151-8528, Japan
damage. As to our patient, we speculate that coagulation abnormalities and vascular endothelial damage in the context of hypothermia resulted in an increased release of UL-VWFM, leading to the development of TTP. In patients with ADAMTS-13 inhibitor–positive primary TTP, plasma exchange should be indicated to replenish ADAMTS-13 and remove the inhibitors. However, rTM would be also significant to alleviate vascular endothelial damage and decrease the organ's damage. The administration of rTM may improve TTP condition, especially in secondary TTP. It would shorten the treatment duration and reduce the organ damage. Kazutoshi Ebisawa, MD Department of Emergency and Critical Care Medicine Hitachi General Hospital, 2-1-1 Jonan Hitachi, Ibaraki 317-0077, Japan Corresponding author. Department of Emergency and Critical Care MedicineHitachi General Hospital. 2-1-1 Jonan Hitachi, Ibaraki 317-0077, Japan Tel.: +81 3 7406 5193; fax: +81 3 23 8351 E-mail address: [email protected] Tatsuma Fukuda, MD Department of Emergency and Critical Care Medicine Hitachi General Hospital, 2-1-1 Jonan Hitachi, Ibaraki 317-0077, Japan Department of Emergency and Critical Care Medicine University Hospital, The University of Tokyo 7-1 3-1 Hongo Bunkyo, Tokyo113-8655, Japan
Reference range, 1.8-3.9 FU/mL
Kensuke Nakamura, PhD Department of Emergency and Critical Care Medicine Hitachi General Hospital, 2-1-1 Jonan Hitachi, Ibaraki 317-0077, Japan Department of Emergency and Critical Care Medicine University Hospital, The University of Tokyo 7-1 3-1 Hongo Bunkyo, Tokyo 113-8655, Japan http://dx.doi.org/10.1016/j.ajem.2014.08.076
References [1] Furlan M, Robles R, Galbusera M, Remuzzi G, Kyrle PA, Brenner B, et al. von Willebrand factor–cleaving protease in thrombotic thrombocytopenic purpura and the hemolytic-uremic syndrome. N Engl J Med 1998;339(22):1578–84. [2] Matsumoto M, Yagi H, Ishizashi H, Wada H, Fujimura Y. The Japanese experience with thrombotic thrombocytopenic purpura-hemolytic uremic syndrome. Semin Hematol 2004;41(1):68–74.
Figure. Time course of changes in platelet counts and FDP levels. RCC indicates red cell concentrates; PC, platelet concentrates; Plt, platelet counts.
K. Ebisawa et al. / American Journal of Emergency Medicine 33 (2015) 599.e1–599.e3
598.e3
Table 2 Cases rTM is used for TTP
Age (y) Sex Underlying
Nishijima et al [13]
Okada et al [14]
Tonooka et al [15]
Sakai et al [16]
Inoue et al [17]
Our present case
61 Female condition
1 Female Gemcitabine + bevacizumab for small cell lung cancer
33 Female Umbilical cord blood; transplantation for familial hemophagocytic
24 Female lymphohistiocytosis
n/a n/a TMA associated with SLE
76 Female Peripheral blood stem cell transplantation for DLBCL
n/a
69.8%
N60%
n/a
45%
n/a
Negative
n/a
n/a
Negative
PSL + MMF + rTM
PSL + CPA + rTM Cured
Rituximab + rTM
PSL + CPA + rTM
rTM
Cured
Cured
Cured
Refractory transplantation TMA associated with acute GVHD after intestinal ADAMTS61% 13 activity ADAMTSNegative 13 inhibitor Treatments FFP + rTM
Hypothermia and vitamin B12 deficiency
Outcome
Cured
Cured
n/a indicates not available; FFP, fresh-frozen plasma; PSL, predonisolone; MMF, mycophenolate mofetil; CPA, cyclophosphamide; CyA, cyclosporin. [3] Boyer A, Chadda K, Salah A, Bonmarchand G. Thrombotic microangiopathy: an atypical cause of acute renal failure in patients with acute pancreatitis. Intensive Care Med 2004;30(6):1235–9. [4] Allford SL, Hunt BJ, Rose P, Machin SJ. Haemostasis, Thrombosis Task Force BCfSiH: guidelines on the diagnosis and management of the thrombotic microangiopathic haemolytic anaemias. Br J Haematol 2003;120(4):556–73. [5] Scully M, Cohen H, Cavenagh J, Benjamin S, Starke R, Killick S, et al. Remission in acute refractory and relapsing thrombotic thrombocytopenic purpura following rituximab is associated with a reduction in IgG antibodies to ADAMTS-13. Br J Haematol 2007;136(3):451–61. [6] Tsai E, Chapin J, Laurence JC, Tsai HM. Use of eculizumab in the treatment of a case of refractory, ADAMTS13-deficient thrombotic thrombocytopenic purpura: additional data and clinical follow-up. Br J Haematol 2013;162(4):558–9. [7] Elphick GF, Sarangi PP, Hyun YM, Hollenbaugh JA, Ayala A, Biffl WL, et al. Recombinant human activated protein C inhibits integrin-mediated neutrophil migration. Blood 2009;113(17):4078–85. [8] Xu J, Zhang X, Pelayo R, Monestier M, Ammollo CT, Semeraro F, et al. Extracellular histones are major mediators of death in sepsis. Nat Med 2009;15(11):1318–21. [9] Abeyama K, Stern DM, Ito Y, Kawahara K, Yoshimoto Y, Tanaka M, et al. The Nterminal domain of thrombomodulin sequesters high-mobility group-B1 protein, a novel antiinflammatory mechanism. J Clin Invest 2005;115(5):1267–74. [10] Ohlin AK, Larsson K, Hansson M. Soluble thrombomodulin activity and soluble thrombomodulin antigen in plasma. J Thromb Haemost 2005;3(5):976–82.
[11] Asamiya Y, Moriyama T, Takano M, Iwasaki C, Kimura K, Ando Y, et al. Successful treatment with rituximab in a patient with TTP secondary to severe ANCAassociated vasculitis. Intern Med 2010;49(15):1587–91. [12] Kameda T, Dobashi H, Kittaka K, Susaki K, Yamaoka G, Arai K, et al. Two cases of refractory thrombotic thrombocytopenic purpura associated with collagen vascular disease were significantly improved by rituximab treatment. Clin Rheumatol 2007; 26(12):2159–62. [13] Nishijima Y, Hirata H, Himeno A, Kida H, Matsumoto M, Takahashi R, et al. Druginduced thrombotic thrombocytopenic purpura successfully treated with recombinant human soluble thrombomodulin. Intern Med 2013;52(10):1111–4. [14] Okada K, Horino A, Yamasaki K, Tanaka C, Fujisaki H, Osugi Y, et al. Successful treatment for thrombotic microangiopathy with recombinant human soluble thrombomodulin after umbilical cord blood transplantation. Rinsho Ketsueki 2012; 53(2):235–9. [15] Tonooka K, Ito H, Shibata T, Ozaki S. Recombinant human soluble thrombomodulin for treatment of thrombotic microangiopathy associated with lupus nephritis. J Rheumatol 2012;39(8):1766–7. [16] Sakai M, Ikezoe T, Bandobashi K, Togitani K, Yokoyama A. Successful treatment of transplantation-associated thrombotic microangiopathy with recombinant human soluble thrombomodulin. Bone Marrow Transplant 2010;45(4):803–5. [17] Inoue Y, Kosugi S, Miura I, Hatta Y, Takeuchi J. Successful treatment of refractory acute GVHD complicated by severe intestinal transplant-associated thrombotic microangiopathy using recombinant thrombomodulin. Thromb Res 2011;127(6):603–4.
