Kasabach-Merritt syndrome associated with giant liver hemangioma
Kasabach-Merritt syndrome associated with giant liver hemangioma: the effect of combined therapy with danaparoid sodium and tranexamic acid
E-case haematologica 2005;90:(ECR)29
Yasuo Ontachi,1 Hidesaku Asakura,1 Mika Omote,2 Tomotaka Yoshida,2 Osamu Matsui ,3 Shinji Nakao1
1Department of Internal Medicine (III), Kanazawa University School of Medicine, Kanazawa, Ishikawa, 920-8641, JAPAN; 2The department of Laboratory, Kanazawa University School of Medicine, Takaramachi 13-1, Kanazawa, Ishikawa 920-8641, JAPAN; 3Department of Radiology, Kanazawa University School of Medicine, Kanazawa, Ishikawa, 920-8641, JAPAN
CorrespondenceYasuo Ontachi, Department of Internal Medicine (III), Kanazawa University School of Medicine, 13-1 Takaramachi, Kanazawa, Ishikawa 920-8641, JAPAN. Fax: +81-76-234-4252 E-mail: ontachiy@med3.m.kanazawa-u.ac.jp
Abstract
In patients with Kasabach-Merritt syndrome (KMS), local activation of coagulation commonly results in disseminated intravascular coagulation (DIC). Progress of DIC is associated with 30âÄì40% mortality as a result of uncontrollable hemorrhage. A 39-year-old woman with an enlarging giant liver hemangioma was diagnosed as having KMS with DIC. To control the hemorrhagic diathesis, we commenced combination therapy for DIC with danaparoid (1,250 Ux2/day, intravenously (IV)) and tranexamic acid (0.5 g x 3/day, peros (PO). Rapid improvement of the bleeding tendency and coagulopathy occurred in response to this treatment âÄì that is, DIC was controlled without removing the giant hemangioma. The therapy did not restrict the behavior of the patient by continuous drip and angiography could be performed without bleeding. Such therapy may be beneficial in chronic DIC with activation of fibrinolysis.
Kasabach-Merritt syndrome (KMS) was first reported in 1940 in a neonate as the association of thrombocytopenic purpura and a rapidly enlarging capillary hemangiom.1 Not all hemangiomas in this syndrome are cutaneous, and those associated with a more severe phenotype are often visceral. The incidence of hepatic hemangioma in KMS is reported to be about 2%.2 In patients with this syndrome, local activation of coagulation commonly results in disseminated intravascular coagulation (DIC).3,4 The incidence of clinically overt DIC is 25% among patients with giant hemangiom.1,3 However, neither the site nor the size of the hemangioma appears to reliably predict the subsequent development of KMS, which has been associated with 30âÄì40 % mortality as a result of uncontrollable hemorrhage.5 This report describes a case of chronic DIC associated with KMS and the management with a combination of danaparoid and antifibrinolytics.
Case report
A 39-year old woman was admitted to our hospital in September 2001 due to abdominal swelling. She had previously undergone surgical ligation of the hepatic artery for giant liver hemangioma in 1994. Although this had resulted in temporary remission, abdominal enlargement had gradually recurred. Physical examination on admission revealed several ecchymoses on the upper extremities and hepatomegaly. Coagulation studies demonstrated the following: platelet count, 90x109/L (normal range: 150-300x109/L); prothrombin time (PT), 12.5 sec (normal range: 9.4-11.1 sec); activated partial thromboplastin time (APTT), 32.6 sec (normal range: 27.5-42.1 sec); fibrinogen (Fbg), 100 mg/dl (normal range: 206-369 mg/dL); fibrin/fibrinogen degradation product (FDP), 37.8 µg/mL (normal range: <5>
Discussion
DIC is characterized by the widespread activation of coagulation, which results in the intravascular formation of fibrin. Although it is a severe clinical condition that involves considerable activation of both coagulation and fibrinolysis in the circulating blood, the degree to which the fibrinolytic system is activated in DIC varies according to the underlying disease.3,6,7 In this case of DIC associated with KMS, the data of PIC (above 4 m g/ml) support the existence of activation of fibrinolysis.7 The cornerstone of the management of DIC is treatment of the underlying disorder. The replacement of consumed clotting factors with fresh-frozen plasma or platelet concentrate is only indicated when to prevent bleeding.3 It is known that KMS is a cause of DIC and a strong local activation and local consumption coagulopathy has been reported in hemangioma.4 Elimination of the tumor is needed to control DIC with KMS. However, no treatment modality has been established as consistently effective.5 Radiotherapy is rarely considered as first-line therapy because of its known late effects on tumor growth and secondary malignancies. However, it is non-invasive and can be used in extremis as a last resort and has occasionally been used as first-line therapy for small inaccessible lesions.5,8 It is important to suppress the activated coagulation factor for control of DIC. An oral anticoagulant that can inhibit the activated coagulation factor is not yet commercially available. Warfarin is the only oral anticoagulant at present. There were some previous studies that warfarin treatment in chronic DIC associated with aneurysm was effective.9 Although we discussed possible warfarin treatment for this patient, we rejected warfarin treatment for two reasons. One reason is that its action is only inhibition of production of vitamin K dependent coagulation factor without suppression of activated coagulation factors, and another is that this patient had mild liver dysfunction due to the giant hemangioma.
At present, heparin is commonly used in patients with DIC, being administered in relatively low dosse.3 Low dose heparin has also been used in patients with KMS; however, evidence for its benefit has never been established. As KMS and large aortic aneurysm may both result in local activation of coagulation, coagulopathy in each condition is considered to be similar. Cummins et al. reported that long-term treatment with low molecular weight heparin (LMWH) could provide good symptomatic control of chronic DIC associated with abdominal aortic aneurysm.10 We therefore hypothesized that danaparoid, a kind of heparinoid, might also be able to control DIC occurring in KMS. Danaparoid is a heparinoid which is distinct from unfractionated heparin (UFH) and LMWH.11,12,13 Danaparoid has a longer half life of 20 hours and has a high anti-Xa/anti-IIa ratio (>20 as compared to 1 for heparin and 2 for LMWH). Moreover, as danaparoid also inhibits platelet adherence to a much lesser extent than UFH, its effect on bleeding is less marked.14 In Japan, one double-blind clinical trial in patients with DIC has shown danaparoid to be equivalent to UFH.12 In the present patient, danaparoid was selected for the reason, that is could be injected by bolus and had little risk of hemorrhagic side effects compared with other therapies. Tranexamic acid has been proposed as a hemostatic agent in many clinical conditions characterized by excessive bleeding, but the use of this agent in patients with DIC is generally not recommended.3 Kario et al. described that monitoring of the TAT/PIC ratio may contribute to decisions regarding the institution and performance of combination therapy for DIC using anticoagulant and antifibrinolytic agents.15 With regard to this patient, we decided to use the anticoagulant since the level of TAT was elevated. Rodeghiero et al. reported 268 consecutive patients with acute promyelocytic leukemia.16 Patients were separated into three groups (treated with heparin, with antifibrinolytics, and with supportive therapy alone), and no significant difference was detected between these three groups in terms of overall incidence of early hemorrhagic death.16 Recently, in a tissue factor induced rat DIC model, we demonstrated that tranexamic acid suppressed the elevation in D-dimer levels and it increased organ dysfunction.17 It is considered that inhibition of fibrinolysis using tranexamic acid might cause thrombin formation. On the other hand, a case was reported of a patient with aneurysm in whom hemorrhage stopped abruptly upon the administration of tranexamic acid.18 Moreover, tranexamic acid has also been reported to be efficacious in the treatment of severe KMS in the newborn.19 In the present case, the bleeding tendency improved during the combination therapy described above. When this therapy was transiently discontinued, coagulopathy deteriorated. In this case, from the viewpoint of the characteristics of DIC, danaparoid was useful for inhibiting the activation of coagulation and preventing thrombotic complications. In contrast, tranexamic acid was useful for controlling hemorrhage. In summary, combined therapy with danaparoid (IV) and tranexamic acid (PO) enabled control of the bleeding tendency, and angiography could be performed without limitations in the present patient. Such therapy may be beneficial in chronic DIC with activation of fibrinolysis, in which control of bleeding is required without restricting the behavior of patients by needing continuous drip.
References
1) Kasabach HHM, Merritt KK. Capillary hemangioma with extensive purpura. Report of a case. Am J Dis Child 1940; 59: 1063-70.2) Iqbal N, Saleem A. Hepatic hemangioma. Tex Med 1997; 93: 48-50.3) Levi M, ten Cate H. Disseminated intravascular coagulation. N Engl J Med 1999; 19: 586-92.4) Antovic J, Bakic M, Milicevic R, Gojkovic G, Blomback M. Activation of the coagulation system occurs within rather than outside cutaneous haemangiomas. Acta Paediatr 2001; 90: 1137-40.5) Hall GW. Kasabach-Merritt syndrome: pathogenesis and management. Br J Haematol 2001; 112: 851-62.6) Takahashi H, Tatewaki W, Wada K, Hanano M, Shibata A. Thrombin vs. plasmin generation in disseminated intravascular coagulation associated with various underlying disorders. Am J Hematol 1990; 33: 90-5.7) Asakura H, Jokaji H, Saito M, Uotani C, Kumabashiri I, Morishita E,et al. Study of the balance between coagulation and fibrinolysis in disseminated intravascular coagulation using molecular markers. Blood Coagul Fibrinolysis 1994; 5: 829-32.8) Ogino I, Torikai K, Kobayashi S, Aida N, Hata M, Kigasawa H. Radiation therapy for life- or function- threatening infant hemangioma. Radiology 2001; 218: 834-9.9) Micallef-Eynaud PD, Ludlam CA. Aortic aneurysms and consumptive coagulopathy. Blood Coagul Fibrinolysis 1991; 2: 477-81.10) Cummins D, Segal H, Hunt BJ, Awad R, Maddox A. Chronic disseminated intravascular coagulation after surgery for abdominal aortic aneurysm: clinical and haemostatic response to dalteparin. Br J Haematol 2001; 113; 658-60.11) Bradbrook ID, Magnani HN, Moelker HCT, Morrison PJ, Robinson J, Rogers HJ, et al. Org 10172: a low molecular weight heparinoid anticoagulant with a long half-life in man. Br J Clin Pharmac 1987; 23: 667-75.12) Ibbotson T, Perry CM. Danaparoid: a review of its use in thromboembolic and coagulation disorders. Drugs 2002; 62: 2283-314.13) De Boer A, Danhof M, Cohen AF, Magnani HN, Breimer DD. Interaction study between Org 10172, a low molecular weight heparinoid, and acetylsalicylic acid in healthy male volunteers. Thromb Haemost 1991; 66: 202-7.14) Meuleman DG, Hobbelen PMJ, van Dedem G, Moelker HCT. A novel antithrombotic heparinoid (Org 10172) devoid of bleeding enhancing capacity: a survey of its pharmacological properties in experimental animal models. Thromb Res 1982; 27: 353-63.15) Kario K, Matsuo T, Kodama K, Matsuo M, Yamamoto K, Kobayashi H. Imbalance between thrombin and plasmin activity in disseminated intravascular coagulation. Assessment by the thrombin-antithrombin-III complex/plasmin-alpha-2-antiplasmin complex ratio. Haemostasis 1992; 22:179-86.16) Rodeghiero F, Avvisati G, Castaman G, Barbui T, Mandelli F. Early deaths and anti-hemorrhagic treatments in acute promyelocytic leukemia. A GIMEMA retrospective study in 268 consecutive patients. Blood 1990; 75: 2112-7.17) Asakura H, Sano Y, Yamazaki M, Morishita E, Miyamoto K, Nakao S. Role of fibrinolysis in tissue-factor-induced disseminated intravascular coagulation in rats - an effect of tranexamic acid. Haematologica 2004; 89: 757-8.18) Takada A, Takada Y, Mori T, Sakaguchi S. Prevention of severe bleeding by tranexamic acid in a patient with disseminated intravascular coagulation Thromb Res 1990; 58: 101-8.19) Hanna BD, Bernstein M. Tranexamic acid in the treatment of Kasabach-Merritt syndrome in infants. The Am J Pediatric Hematol Oncol 1989; 11: 191-5.
Haematologica
E-case haematologica 2005;90:(ECR)29
Yasuo Ontachi,1 Hidesaku Asakura,1 Mika Omote,2 Tomotaka Yoshida,2 Osamu Matsui ,3 Shinji Nakao1
1Department of Internal Medicine (III), Kanazawa University School of Medicine, Kanazawa, Ishikawa, 920-8641, JAPAN; 2The department of Laboratory, Kanazawa University School of Medicine, Takaramachi 13-1, Kanazawa, Ishikawa 920-8641, JAPAN; 3Department of Radiology, Kanazawa University School of Medicine, Kanazawa, Ishikawa, 920-8641, JAPAN
CorrespondenceYasuo Ontachi, Department of Internal Medicine (III), Kanazawa University School of Medicine, 13-1 Takaramachi, Kanazawa, Ishikawa 920-8641, JAPAN. Fax: +81-76-234-4252 E-mail: ontachiy@med3.m.kanazawa-u.ac.jp
Abstract
In patients with Kasabach-Merritt syndrome (KMS), local activation of coagulation commonly results in disseminated intravascular coagulation (DIC). Progress of DIC is associated with 30âÄì40% mortality as a result of uncontrollable hemorrhage. A 39-year-old woman with an enlarging giant liver hemangioma was diagnosed as having KMS with DIC. To control the hemorrhagic diathesis, we commenced combination therapy for DIC with danaparoid (1,250 Ux2/day, intravenously (IV)) and tranexamic acid (0.5 g x 3/day, peros (PO). Rapid improvement of the bleeding tendency and coagulopathy occurred in response to this treatment âÄì that is, DIC was controlled without removing the giant hemangioma. The therapy did not restrict the behavior of the patient by continuous drip and angiography could be performed without bleeding. Such therapy may be beneficial in chronic DIC with activation of fibrinolysis.
Kasabach-Merritt syndrome (KMS) was first reported in 1940 in a neonate as the association of thrombocytopenic purpura and a rapidly enlarging capillary hemangiom.1 Not all hemangiomas in this syndrome are cutaneous, and those associated with a more severe phenotype are often visceral. The incidence of hepatic hemangioma in KMS is reported to be about 2%.2 In patients with this syndrome, local activation of coagulation commonly results in disseminated intravascular coagulation (DIC).3,4 The incidence of clinically overt DIC is 25% among patients with giant hemangiom.1,3 However, neither the site nor the size of the hemangioma appears to reliably predict the subsequent development of KMS, which has been associated with 30âÄì40 % mortality as a result of uncontrollable hemorrhage.5 This report describes a case of chronic DIC associated with KMS and the management with a combination of danaparoid and antifibrinolytics.
Case report
A 39-year old woman was admitted to our hospital in September 2001 due to abdominal swelling. She had previously undergone surgical ligation of the hepatic artery for giant liver hemangioma in 1994. Although this had resulted in temporary remission, abdominal enlargement had gradually recurred. Physical examination on admission revealed several ecchymoses on the upper extremities and hepatomegaly. Coagulation studies demonstrated the following: platelet count, 90x109/L (normal range: 150-300x109/L); prothrombin time (PT), 12.5 sec (normal range: 9.4-11.1 sec); activated partial thromboplastin time (APTT), 32.6 sec (normal range: 27.5-42.1 sec); fibrinogen (Fbg), 100 mg/dl (normal range: 206-369 mg/dL); fibrin/fibrinogen degradation product (FDP), 37.8 µg/mL (normal range: <5>
Discussion
DIC is characterized by the widespread activation of coagulation, which results in the intravascular formation of fibrin. Although it is a severe clinical condition that involves considerable activation of both coagulation and fibrinolysis in the circulating blood, the degree to which the fibrinolytic system is activated in DIC varies according to the underlying disease.3,6,7 In this case of DIC associated with KMS, the data of PIC (above 4 m g/ml) support the existence of activation of fibrinolysis.7 The cornerstone of the management of DIC is treatment of the underlying disorder. The replacement of consumed clotting factors with fresh-frozen plasma or platelet concentrate is only indicated when to prevent bleeding.3 It is known that KMS is a cause of DIC and a strong local activation and local consumption coagulopathy has been reported in hemangioma.4 Elimination of the tumor is needed to control DIC with KMS. However, no treatment modality has been established as consistently effective.5 Radiotherapy is rarely considered as first-line therapy because of its known late effects on tumor growth and secondary malignancies. However, it is non-invasive and can be used in extremis as a last resort and has occasionally been used as first-line therapy for small inaccessible lesions.5,8 It is important to suppress the activated coagulation factor for control of DIC. An oral anticoagulant that can inhibit the activated coagulation factor is not yet commercially available. Warfarin is the only oral anticoagulant at present. There were some previous studies that warfarin treatment in chronic DIC associated with aneurysm was effective.9 Although we discussed possible warfarin treatment for this patient, we rejected warfarin treatment for two reasons. One reason is that its action is only inhibition of production of vitamin K dependent coagulation factor without suppression of activated coagulation factors, and another is that this patient had mild liver dysfunction due to the giant hemangioma.
At present, heparin is commonly used in patients with DIC, being administered in relatively low dosse.3 Low dose heparin has also been used in patients with KMS; however, evidence for its benefit has never been established. As KMS and large aortic aneurysm may both result in local activation of coagulation, coagulopathy in each condition is considered to be similar. Cummins et al. reported that long-term treatment with low molecular weight heparin (LMWH) could provide good symptomatic control of chronic DIC associated with abdominal aortic aneurysm.10 We therefore hypothesized that danaparoid, a kind of heparinoid, might also be able to control DIC occurring in KMS. Danaparoid is a heparinoid which is distinct from unfractionated heparin (UFH) and LMWH.11,12,13 Danaparoid has a longer half life of 20 hours and has a high anti-Xa/anti-IIa ratio (>20 as compared to 1 for heparin and 2 for LMWH). Moreover, as danaparoid also inhibits platelet adherence to a much lesser extent than UFH, its effect on bleeding is less marked.14 In Japan, one double-blind clinical trial in patients with DIC has shown danaparoid to be equivalent to UFH.12 In the present patient, danaparoid was selected for the reason, that is could be injected by bolus and had little risk of hemorrhagic side effects compared with other therapies. Tranexamic acid has been proposed as a hemostatic agent in many clinical conditions characterized by excessive bleeding, but the use of this agent in patients with DIC is generally not recommended.3 Kario et al. described that monitoring of the TAT/PIC ratio may contribute to decisions regarding the institution and performance of combination therapy for DIC using anticoagulant and antifibrinolytic agents.15 With regard to this patient, we decided to use the anticoagulant since the level of TAT was elevated. Rodeghiero et al. reported 268 consecutive patients with acute promyelocytic leukemia.16 Patients were separated into three groups (treated with heparin, with antifibrinolytics, and with supportive therapy alone), and no significant difference was detected between these three groups in terms of overall incidence of early hemorrhagic death.16 Recently, in a tissue factor induced rat DIC model, we demonstrated that tranexamic acid suppressed the elevation in D-dimer levels and it increased organ dysfunction.17 It is considered that inhibition of fibrinolysis using tranexamic acid might cause thrombin formation. On the other hand, a case was reported of a patient with aneurysm in whom hemorrhage stopped abruptly upon the administration of tranexamic acid.18 Moreover, tranexamic acid has also been reported to be efficacious in the treatment of severe KMS in the newborn.19 In the present case, the bleeding tendency improved during the combination therapy described above. When this therapy was transiently discontinued, coagulopathy deteriorated. In this case, from the viewpoint of the characteristics of DIC, danaparoid was useful for inhibiting the activation of coagulation and preventing thrombotic complications. In contrast, tranexamic acid was useful for controlling hemorrhage. In summary, combined therapy with danaparoid (IV) and tranexamic acid (PO) enabled control of the bleeding tendency, and angiography could be performed without limitations in the present patient. Such therapy may be beneficial in chronic DIC with activation of fibrinolysis, in which control of bleeding is required without restricting the behavior of patients by needing continuous drip.
References
1) Kasabach HHM, Merritt KK. Capillary hemangioma with extensive purpura. Report of a case. Am J Dis Child 1940; 59: 1063-70.2) Iqbal N, Saleem A. Hepatic hemangioma. Tex Med 1997; 93: 48-50.3) Levi M, ten Cate H. Disseminated intravascular coagulation. N Engl J Med 1999; 19: 586-92.4) Antovic J, Bakic M, Milicevic R, Gojkovic G, Blomback M. Activation of the coagulation system occurs within rather than outside cutaneous haemangiomas. Acta Paediatr 2001; 90: 1137-40.5) Hall GW. Kasabach-Merritt syndrome: pathogenesis and management. Br J Haematol 2001; 112: 851-62.6) Takahashi H, Tatewaki W, Wada K, Hanano M, Shibata A. Thrombin vs. plasmin generation in disseminated intravascular coagulation associated with various underlying disorders. Am J Hematol 1990; 33: 90-5.7) Asakura H, Jokaji H, Saito M, Uotani C, Kumabashiri I, Morishita E,et al. Study of the balance between coagulation and fibrinolysis in disseminated intravascular coagulation using molecular markers. Blood Coagul Fibrinolysis 1994; 5: 829-32.8) Ogino I, Torikai K, Kobayashi S, Aida N, Hata M, Kigasawa H. Radiation therapy for life- or function- threatening infant hemangioma. Radiology 2001; 218: 834-9.9) Micallef-Eynaud PD, Ludlam CA. Aortic aneurysms and consumptive coagulopathy. Blood Coagul Fibrinolysis 1991; 2: 477-81.10) Cummins D, Segal H, Hunt BJ, Awad R, Maddox A. Chronic disseminated intravascular coagulation after surgery for abdominal aortic aneurysm: clinical and haemostatic response to dalteparin. Br J Haematol 2001; 113; 658-60.11) Bradbrook ID, Magnani HN, Moelker HCT, Morrison PJ, Robinson J, Rogers HJ, et al. Org 10172: a low molecular weight heparinoid anticoagulant with a long half-life in man. Br J Clin Pharmac 1987; 23: 667-75.12) Ibbotson T, Perry CM. Danaparoid: a review of its use in thromboembolic and coagulation disorders. Drugs 2002; 62: 2283-314.13) De Boer A, Danhof M, Cohen AF, Magnani HN, Breimer DD. Interaction study between Org 10172, a low molecular weight heparinoid, and acetylsalicylic acid in healthy male volunteers. Thromb Haemost 1991; 66: 202-7.14) Meuleman DG, Hobbelen PMJ, van Dedem G, Moelker HCT. A novel antithrombotic heparinoid (Org 10172) devoid of bleeding enhancing capacity: a survey of its pharmacological properties in experimental animal models. Thromb Res 1982; 27: 353-63.15) Kario K, Matsuo T, Kodama K, Matsuo M, Yamamoto K, Kobayashi H. Imbalance between thrombin and plasmin activity in disseminated intravascular coagulation. Assessment by the thrombin-antithrombin-III complex/plasmin-alpha-2-antiplasmin complex ratio. Haemostasis 1992; 22:179-86.16) Rodeghiero F, Avvisati G, Castaman G, Barbui T, Mandelli F. Early deaths and anti-hemorrhagic treatments in acute promyelocytic leukemia. A GIMEMA retrospective study in 268 consecutive patients. Blood 1990; 75: 2112-7.17) Asakura H, Sano Y, Yamazaki M, Morishita E, Miyamoto K, Nakao S. Role of fibrinolysis in tissue-factor-induced disseminated intravascular coagulation in rats - an effect of tranexamic acid. Haematologica 2004; 89: 757-8.18) Takada A, Takada Y, Mori T, Sakaguchi S. Prevention of severe bleeding by tranexamic acid in a patient with disseminated intravascular coagulation Thromb Res 1990; 58: 101-8.19) Hanna BD, Bernstein M. Tranexamic acid in the treatment of Kasabach-Merritt syndrome in infants. The Am J Pediatric Hematol Oncol 1989; 11: 191-5.
Haematologica
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