Kasabach-Merritt phenomenon in Chinese children: Report of 19 cases and brief review of literature

Abstract

Kasabach-Merritt phenomenon (KMP) is life-threatening, charactered by the profound thrombocytopenia and consumptive coagulopathy associated with vascular tumors. The therapy of KMP still remains challenging. In this study, we retrospectively analyzed the clinical data of KMP treated in Nanjing Children’s Hospital and Jinling Hospital, China, and brief reviewed the literature on KMP. From Jan. 2005 to Dec. 2014, a total of 19 cases of KMP were enrolled into this study. Laboratory results showed that seven patients had typical disseminated intravascular coagulation (DIC), and others were atypical DIC. CT scanning showed the low-density tumor with obvious intensification in enhanced scanning, and the large distorted arteries in association with the tumor. After the admission, the patients received the infusion of platelets and the applying of dipyridamole, steroids, and other necessary drugs. Eight patients underwent complete surgical removal of the tumor, or partial removal with subsequent chemotherapy of vincristine. Three patients underwent only the chemotherapy of vincristine. Eight patients underwent the intralesional injection of absolute ethanol. Pathological examination showed eighteen samples were kaposiform hemangioendothelioma, and one tufted agioma. In our cases, six patients died from extensive hemorrhage and subsequent multiple organ failure. The others survived. In conclusion, KMP in Chinese children has typical symptoms. Kaposiform hemangioendothelioma is the most frequent vascular tumor associated with KMP. The individual treatments with surgical management, chemotherapy with vincristine, and intralesional injection of absolute ethanol can achieve good results in most of the patients with KMP.

Introduction

Kasabach-Merritt phenomenon (KMP) is a rare and life-threatening disease in childhood with high mortality rate. It is charactered by the profound thrombocytopenia, microangiopathic hemolytic anemia, and subsequent consumptive coagulopathy in association with vascular tumors, including kaposiform hemangioendothelioma (KHE), tufted angioma, lymphangioendotheliomatosis, and angiosarcoma, etc. [1-4]. Among them, KHE is most frequently reported. Infantile hemangioma doesn’t lead to KMP [5].

Treatments of KMP include surgical management, systemic corticosteroids and interferon, chemotherapy with vincristine, inventional embolization, and radiotherapy [6]. Recently, sirolimus and propranolol were used in the treatment of KMP [6]. In spite of above options, there isn’t a consensus on the optimal medical management due to the variable response of patients. In this study, we retrospectively analyzed the clinical data of 19 cases of KMP treated in our clinic. And we briefly reviewed the diagnosis, therapy and pathogenesis of KMP.

Patients and methods

Clinical data

We retrospectively collected the data of patients with KMP treated in Nanjing Children’s Hospital and Jinling Hospital, Jiangsu, China, from Jan. 2005 to Dec. 2014. The following criteria were used for diagnosis: (1) Vascular tumor. (2) Profound thrombocytopenia and consumptive coagulopathy. (3) Treatment of the tumor can improve clinical symptoms. (4) Other diseases that can cause thrombocytopenia or consumptive coagulopathy were excluded, such as hypersplenism and idiopathic thrombocytopenic purpura. The results of ecsomatics, imageology, and pathology were summarized. The treatments and outcomes of patients were reviewed.

Statistics

Microsoft® Office Excel was used to calculate the average and standard deviation.

Results

Clinical features

Nineteen patients were included in this study, eleven of which were male. The average age of patients at admission was 43.5 days (age range, 1 day~120 days). The surface area of the tumor estimated by physical examination ranged from 6 cm²~210 cm², with an average of 78.3 cm². Tumors were located in the head (n=3), neck (n=2), trunk (n=9), buttocks (n=1), upper extremity (n=2), and lower extremity (n=3). In some cases, the tumors extended into the thoracic cavity and retroperitoneum.

Laboratory results at admission

Platelets and coagulation

The average number of platelets was 22.8×10⁹/L. The lowest number of PLT was 6.22×10⁹/L in a 25-day-old boy with a 30 cm² tumor in the right lower extremity. The averages of PT, TT, KPTT, and FIB were 15.85 s, 23.64 s, 44.26 s, and 1.21 g/L, respectively. The most severe abnormality of PT, TT, KPTT, and FIB were 20.6 s, 31.6 s, 54.2 s, and 0.57 g/L in a just born boy with a 96 cm² tumor in the back. According to the criteria of disseminated intravascular coagulation (DIC) [7], seven patients had typical DIC and the others had atypical DIC.

Erythrocytes

The averages of erythrocytes and hemoglobin were 3.16×10¹²/L and 86.73 g/L. The lowest value of erythrocytes and hemoglobin was 1.71×10¹²/L and 55 g/L in a 52-day-old girl with a 176 cm² tumor in the Left buttock. According to the criteria of anemia, three patients had severe anemia; seven patients had moderate anemia; and nine patients had slight anemia.

Leukocytes

The averages of leukocytes, percent of neutrophils, and percent of lymphocytes were 13.18×10⁹/L, 38.56%, and 52.35%, respectively. The value of leukocytes in twelve cases was higher than normal value.

CT scanning

CT scanning showed diffused or clumping low-density tumor with dot or stripe calcification. In enhanced scanning, there was uniform intensification in small tumor or marginal intensification in large tumor. Large distorted arteries flowing into tumor were detected.

Treatment

The patients received the infusion of platelets and the applying of dipyridamole, steroids, and other necessary drugs after admission. Eight patients underwent complete surgical removal of the tumor, or partial removal with subsequent chemotherapy of vincristine. Three patients underwent only the chemotherapy of vincristine. Eight patients underwent the intralesional injection of absolute ethanol. The samples were acquired from all the tumors by the operation or core needl biopy. Eighteen samples were diagnosed as kaposiform hemangioendothelioma and one tufted agioma.

Outcome

Among the nineteen patients, six patients died from extensive hemorrhage and subsequent multiple organ failure. The others survived and were still in follow-up.

Discussion

Diagnosis of KMP

KMP can be diagnosed by symptoms (extensive hemorrhage), signs (purple tumors), laboratory results (profound thrombocytopenia and consumptive coagulopathy), and imaging [8]. CT scanning can show tumor clearly. MRI scanning also can supply useful information [9]. But it needs longer time than CT scanning. The differential diagnosis for vascular tumors complicated by KMP includes KHE, tufted angioma, and lymphangioendotheliomatosis, angiosarcoma, etc. Pathological examination is necessary for the exact diagnosis [3,10].

Therapy of KMP

KMP is life-threatening with high mortality rate. Extensive hemorrhage, respiratory failure due to a pressured airway, and high-output heart failure are the major causes for the death of children. Effective therapy should be started as soon as possible once the diagnosis of KMP is established. The treatments are summarized as following.

Supportive treatment

This includes infusion of blood components (platelets, erythrocytes, and blood plasma), coagulation factors (thrombin and fibrinogen), and anticoagulant or anti-platelet drugs (heparin, warfarin [11] and dipyridamole [12]). Platelets are a particular problem in KHE, as their VEGF content might stimulate tumor growth and thus promote complications. So the infusion of platelets is discouraged in the absence of acute bleeding [13].

Surgical management

Surgical intervention is the first choice if operation will not destroy patient’s appearance or function. Complete removal of the tumor can cure KMP [14]. Partial removal of the tumor with subsequent chemotherapy of vincristine also can effectively release KMP [15].

Embolization

This can be performed on huge tumors which aren’t suitable for surgical management. Interventional or percutaneous puncture was used to embolize the nutritional arteries of tumor [16,17]. Antitumor drugs (such as vincristine and bleomycin A) can be injected simultaneously. Intralesional injection of absolute ethanol also was effective for KMP [18].

Oral corticosteroids

Oral steroids were reported to have effect on KMP a long time ago [12]. The recommended dosage of oral prednisone was 3~5 mg/kg/d [12]. For those patients resistant to steroids, alterative treatments, such as vincristine and interferon, should be adopted in time.

Chemotherapy

Vincristine was reported to successfully treat KMP with mild side effects, and had satisfying long-term outcome so it was recommended as the first choice for KMP [19,20]. Cyclophosphamide and actinomycin-D also was applied in the treatment of KMP [21].

Interferon

Interferon was reported to release KMP which didn’t respond to corticosteroids [12,22]. Notably, spastic diplegia resulted from interferon has been observed in the infants less than 12-month-old [23].

Propranolol

Since the first report in 2008, propranolol has showed many advantages in the treatment of infantile hemangioma [24]. But its effect on KMP still has controversy [25] although there was case report suggesting it may be useful in the mild KMP [26].

Sirolimus (also called rapamycin)

It’s an immunosuppressive preparation, but also shows the effects of inhibiting the vasculogenesis and angiogenesis [27], and has been reported to successfully treat blue rubber bleb nevus syndrome [28]. Recently, several studies reported its use in refractory KMP acquired rapid response [29,30]. Sirolimus may be a new therapeutic option for KMP.

Radiotherapy

It was used on life-threatening KMP which didn’t response to the above treatments [31,32]. But long-term adverse effects after radiotherapy have been reported, including skin atrophy, ulcer, growth retardation, and possible malignant tumor [33].

Pathogenesis of KMP

The mechanism of KMP still remains unclear till now. Radioactive labeling and immunohistochemical markers have demonstrated platelet trapping in KHE [34,35]. Our ultrastructural observation and immunohistochemistry staining revealed the trapping of blood components, not only platelets [36]. The abnormality of PT, TT, KPTT, and fibrinogen reflected the hypofibrinogenemia and fibrinolysis caused by disseminated intravascular coagulation. And sequestration and damage of red cells in the tumor led to severe anemia. Although above results supplied some evidences for explaining the occurring of KMP, but the mechanism of the trapping of platelets and intratumoral coagulopathy still need further study.

Disclosure of conflict of interest

None.