Coagulation abnormalities associated with extensive venous malformations of the limbs: differentiation from Kasabach Merritt syndrome

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1 Clin. Lab. Haem. 2002, 24, E. MAZOYER*, O. ENJOLRAS, C. LAURIANà, E. HOUDART, L. DROUET* Coagulation abnormalities associated with extensive venous malformations of the limbs: differentiation from Kasabach Merritt syndrome *Immuno-Haematology Laboratory, Multidisciplinary Study Group for Vascular Anomalies and Neuroradiology and Interventional Radiology Department, Hospital Lariboisière, àvascular Surgery Department, Hospital Saint Joseph, Paris, France Summary Keywords Confusion in the nomenclature of vascular malformations has been a major obstacle to the understanding of these conditions, so that misdiagnosis and treatment inconsistencies are common. Coagulation abnormalities occurring in combination with venous malformations (VM) have been misdiagnosed as Kasabach Merritt syndrome (KMS), despite marked differences in clinical features, pathology and treatment. A homogenous group of 24 patients with diffuse limb VM was entered into a retrospective chart review study. The VM affected an upper limb in 12 patients, a lower limb in 10 and both in two. Localized intravascular coagulation (LIC) was characterized by a decrease in fibrinogen (0.5 1 g/l), an increase in d-dimers (2 64 lg/ml) and presence of soluble complex of fibrin (+ to +++). Platelet counts were normal or slightly decreased. Higher VM severity scores were associated with more severe LIC. A number of events such as sclerotherapy, surgery, bone fracture, prolonged immobilization and pregnancy or menstruation triggered conversion of the LIC to disseminated intravascular coagulation (DIC), with bleeding related to factor consumption and multiorgan failure related to disseminated microvascular thrombosis. Clinical symptoms associated with worsening of LIC were pain, thrombosis and bleeding at wound sites or during surgery. None of the patients had the large ecchymotic and inflammatory tumours seen in KMS. Graded permanent elastic compression with heparin therapy was the only effective treatment. In conclusion, VM-associated LIC is a distinctive lifelong coagulopathy that must be differentiated from KMS, which is characterized by platelet trapping within a vascular tumour of infancy. The treatment of the two conditions is very different. Coagulation abnormalities, DIC, treatment, venous malformation Introduction In the literature on vascular malformations, similar nomenclature has often been applied to different conditions (Mulliken, 1988). This has been a major obstacle to the understanding and management of vascular malformations, particularly those accompanied with coagulopathies. The resulting treatment inconsistencies have caused harm to patients in some cases. Accepted for publication 8 May 2002 Correspondence: Elisabeth Mazoyer, Hospital Lariboisière, Angio- Haematology, 2 rue Ambroise Paré, Paris France. elisabeth.mazoyer@lrb.ap-hop-paris.fr Ó 2002 Blackwell Science Limited Vascular abnormalities are divided into two main categories, namely, vascular tumours, produced by cellular proliferation (including infantile haemangioma and more recently described infantile tumours such as kaposiform haemangioendothelioma and tufted angioma) and vascular malformations, characterized by abnormal distorted vascular channels (Enjolras & Mulliken, 1998). Vascular malformations are categorized according to flow velocity and the predominant type of channel. Slow-flow malformations can be composed of capillaries, lymphatics and/or veins, whereas fast-flow malformations include aneurysms and arteriovenous malformations. Coagulopathies occur in a minority of vascular malformations. Kasabach Merritt syndrome (KMS) or phenomenon is 243

2 244 Venous malformation and Kasabach Merritt syndrome defined as profound thrombocytopenia related to platelet trapping within a vascular tumour of infancy, either a kaposiform haemangioendothelioma or a tufted angioma (Kasabach & Merritt, 1940; Jones & Orkin, 1989; Zukerberg, Nickoloff & Weiss, 1993; Enjolras et al., 1997b, Enjolras et al., 2000; Sarkar et al., 1997; Vin-Christian, McCalmont & Frieden, 1997). Coagulation abnormalities also occur in children and adults with slow-flow venous or venous-lymphatic malformations (Enjolras et al., 1997a), whose clinical, radiological and pathological features are very different from those of the vascular tumours associated with KMS. The purpose of this retrospective study of 24 patients with diffuse limb venous malformations (VMs) was to illustrate the characteristics of VM-associated coagulation disorders, to establish guidelines for management, and to differentiate this situation from KMS with the goal of avoiding further misdiagnosis and mismanagement (Straub et al., 1972; Mewes et al., 1989; Maceyko & Camisa, 1991; Shoji et al., 1998; Hall, 2001). Patients and methods The study included 24 patients who had been followed for many years at our Multidisciplinary Unit for Vascular Anomalies; nine had been monitored from childhood into adulthood. These 24 patients had similar limb VMs with impaired motility, intermittent muscle and joint pain, and joint swelling or locking. Magnetic resonance imaging (MRI) with T2-weighted sequences and/or computed tomography (CT) with iodinated contrast injection were performed to evaluate the involvement of skin, muscles, joints and/or organs. A severity scoring system based on the number of limbs and tissue types involved by the VM was used. One point was given for each site, as follows: one limb ¼ 1 point; two limbs or more ¼ 2 points; skin, muscle, bone or joint, organ (gastrointestinal tract, kidney), trunk and genitalia ¼ 1 point each. Thus, the highest possible score was 8. Coagulation tests were done during a period of disease stability. A blood sample was drawn from a peripheral vein not affected by the VM, into a tube containing m of trisodium citrate. The prothrombin time (PT; Neoplastine ISI 1.86, Diagnostica Stago, France; normal, 12.9 s), factor V (FV) level (STA-Deficient V, Diagnostica Stago, France; normal, %), and fibrinogen (Fg) level (Von Clauss technique, Fibromat, Bio Merieux, France; normal, 2 4 g/l) were determined using the same coagulation device (STA, Diagnostica Stago). Plasma d-dimers (Asserachrom D-Di, ELISA, Stago, France; normal < 0.5 lg/ml) and plasma-soluble fibrin complexes (F-S-test, Latex Hemagglutination, Stago, France) were assayed. Platelets in an EDTA blood sample were counted using an automated instrument (STKS, Beckman Coulter, Paris, France). Results The characteristics of the 24 patients are summarized in Table 1. There were 18 women and six men. An upper limb (Figure 1) was affected in 12 patients, a lower limb (Figure 2) in 10, and both in two. Skin temperature was normal. The VMs were blue, non-pulsating, soft masses that were compressible on palpation or easily emptied by elevation of the limb. Their size was substantially diminished by permanent elastic compression but only as long as compression was maintained. Imaging studies showed that all VMs involved the skin and muscles. One or more joints were involved in 15 patients. All patients complained of pain in the involved skin and muscles, particularly when waking up in the morning. Involvement of the knee (n ¼ 7) or elbow (n ¼ 7) resulted in severe disability, with episodes of joint locking followed, after several years, by permanent flexion contracture (n ¼ 6). Three patients experienced bleeding from an organ involved by the VM. Phleboliths within the VM were palpable in all 24 patients and were visible as round calcifications on plain radiographs, CT scans, or MRI scans. The size of the limb VM by MRI (Figure 3) was usually larger than expected based on physical findings. Coagulation abnormalities were present consistently but varied in severity. Platelet counts were normal or slightly decreased (range /l). Plasma fibrinogen was low (range g/l), plasma d-dimers were elevated (range lg/ml), and circulating soluble fibrin complexes were detected in some patients (range, + to +++). The PT was increased only in those patients with extensive VM, the mechanism being consumption of fibrinogen and factor V. When localized intravascular coagulation (LIC) was present, its severity was greatest in patients with the highest VM severity scores (Table 1). Several events modified the course of the chronic LIC: discontinuation of elastic compression was followed by a rapid increase in VM size with trapping of blood in the lesion, and sclerotherapy or partial surgical excision of the lesion caused activation of blood coagulation (Figure 4). Other events that influenced the course of LIC were fracture of a bone involved by the VM, prolonged immobilization (for example during a long trip; Figure 5) and menstruation or pregnancy. Low-molecular-weight heparin (LMWH) was the only effective treatment in patients with very severe pain or

3 E. Mazoyer et al. 245 Table 1. Clinical and laboratory test abnormalities in 24 patients with venous malformation (VM) of the limbs Case Sex Limb Other site Extension Score DDE (lg/ml) SC Fg (g/l) Platelets (/mm 3 ) PT (s) 1 F Lower uni M F Lower uni C F Lower uni C M J F Lower uni Trunk C M F Lower uni Trunk + genitalia C M J F Lower uni Trunk + genitalia C M BJ M Lower uni Trunk + genitalia C M J M Lower uni Trunk + genitalia C M J F Lower bilat Trunk + genitalia C M J M Lower bilat Trunk + genitalia + organs C M F Upper uni C M Upper uni C M Upper uni C M F Upper uni One side of trunk C M F Upper uni One side of trunk C M J F Upper uni One side of trunk C M BJ F Upper uni One side of trunk C M BJ F Upper uni One side of trunk C M J F Upper uni One side of trunk C M J F Upper uni One side of trunk C M BJ M Upper uni One side of trunk C M BJ F Upper uni Trunk C F Upper + lower 24 F Upper + lower uni One side of trunk and face C M BJ bilat Trunk + genitalia C M BJ S: skin; M: muscle; J: joint; and B: bone. Extent and severity of the VM were evaluated using an 8-point scale. The following clotting parameters were determined: d-dimers (DDE) (lg/ ml), soluble fibrin complexes (SFC) ( to + + +), fibrinogen (Fg) (g/l), blood platelet count (Platelet) (/mm 3 ), and prothrombin time (PT) (seconds).

4 246 Venous malformation and Kasabach Merritt syndrome Figure 1. Case 21: child with a congenital venous malformation in the right upper limb and right half of the trunk, with severe local intravascular coagulation. The blue colour of the skin was produced by enlarged and distorted venous channels in the dermis. Phleboliths were felt within the vascular lesions. bleeding. Early in our experience, we used antiplatelet agents (aspirin, ticlopidine alone or with aspirin), and oral vitamin K antagonists, to no effect (Figure 6). LMWH was effective in preventing pain, bleeding (particularly from the gastrointestinal tract), excessive bleeding during surgery in the area of the VM and laboratory test alterations. LMWH was always indicated on clinical grounds to alleviate the pain and to improve motility. Some patients required treatment for only a few days or weeks during an acute episode, while others received LMWH repeatedly, for instance during menstruation, and others needed prolonged or continuous LMWH therapy. One patient (case 16) had been treated with LMWH for 21 years with favourable local effects and no osteoporosis or other adverse effects. The case of a 20-year-old European woman with a VM in both lower limbs and coagulation disorders (case 24) illustrates the adverse consequences of misdiagnosing KMS in this situation. She was referred to us at the age of Figure 2. Case 9: girl with a huge congenital venous malformation in both lower limbs and the pelvis, involving the skin, muscles and knees, with gradually worsening functional impairment and moderately severe local intravascular coagulation. 19 with a diagnosis of KMS. The VM was blue and nonpulsating. Skin temperature was normal. Severe swelling occurred when she removed her elastic stockings. CT and MRI showed a typical VM involving the skin, muscles and joints. There was flexion contracture with cartilage destruction of both knees and ankylosis of one ankle. For several years, she had been on interferon a2a, which is used to treat KMS. This treatment had caused marked side-effects but had failed to prevent extension of the VM, formation of painful phleboliths within the VM, increasing functional impairment, severe joint pain followed by joint ankylosis and ulceration of the skin overlying a large phlebolith in the back with severe bleeding and no tendency toward healing. She had been given numerous blood transfusions and had been confined to a wheelchair for the past year. Laboratory test results were as follows: normal platelet count; slight PT increase (17.2 s), low fibrinogen (0.66 g/l), and presence of soluble fibrin complexes (+++) and d-dimers (> 20 lg/ml). The interferon treatment was discontinued, and LMWH was started

5 E. Mazoyer et al. 247 Figure 3. Case 5: Magnetic resonance imaging, T2-weighted sequence. High-intensity signal from the venous malformation within the skin, thigh muscles and knee. in a curative dosage (100 antixaiu/kg twice a day). The bleeding stopped and the blood coagulation abnormalities resolved within 3 weeks (fibrinogen, 2.4 g/l; d-dimers, 3.38 lg/ml; PT, 14.2 s; and soluble complex of fibrin, negative). This allowed surgical removal of the phlebolith in the back and surgical treatment of the ankylosed ankle. She was then able to walk alone with crutches and to resume her university studies. Discussion VMs are slow-flow, haemodynamically inactive vascular malformations. They are present at birth and worsen slowly with advancing age, showing no tendency toward involution, in contrast to haemangiomas and other vascular tumours present at birth or developing in infancy. Males and females are equally affected (Mulliken, 1988; Enjolras et al., 1997a; Wassef & Enjolras, 1999), and the prevalence of females in our group is not typical. Limb VMs can involve not only the skin but also the muscles and joints, as shown by our study. The severity of functional impairment depends on the location of the lesion and on its extension to deep structures. Abdominal VMs can involve the gastrointestinal and genital tracts, causing bleeding. Fifteen of our 24 patients had scores of 5 7 on our 8-point VM-severity scale, and eight of these 15 had severe VM (according to our severity scoring). Blood stagnation with activation of coagulation, consumption of coagulation factors and generation of thrombin and fibrin can occur within the distorted, enlarged, slow-flow venous channels of VMs. This LIC causes pain and thrombosis within the VM. In our patients, LIC severity was positively correlated with VM size. Severe LIC is characterized by low fibrinogen, high d-dimers and the presence of soluble fibrin complexes. LIC should be distinguished from disseminated intravascular coagulation (DIC), which is associated with systemic disorders such as septicaemia. Conversion of LIC to DIC is marked by consumption of platelets and coagulation factors. Increases in PT and decrease in factor V are the earliest signs. In severe forms, bleeding can occur, causing painful haematomas within the VM, haemarthrosis in patients with joint involvement by the VM, or bleeding outside the area of the VM. Severe LIC requires specific treatment to reduce the activation of coagulation and the consumption process, to prevent recurrent intravascular thrombosis and to prevent worsening of the LIC and conversion to DIC. Continuous elastic compression reduces the transmural pressure and parietal distension, thus minimizing blood stasis and local activation of coagulation. Elastic compression not only improves comfort, but also improves the coagulopathy. The management depends on the symptoms. The simplest scenario is the patient requiring cosmetic treatment for a small asymptomatic VM in a single limb segment. In our experience, even the most sensitive tests for activation of coagulation are normal in this situation, and there is no risk of intraoperative bleeding. At the other end of the clinical spectrum is the patient with a large and/or diffuse VM in one or more limbs, sometimes with involvement of the trunk and internal organs. Thromboses within the lesions result in phlebolith formation, pain and impaired function. Laboratory tests often show LIC. Continuous elastic compression reduces the amount of blood trapped in the VM. Long-term LMWH therapy once daily for a few months decreases the risk of thrombosis within the lesions and alleviates the inflammation and pain. When percutaneous sclerotherapy followed by excision of the VM is performed, LMWH therapy before, during and after surgery is indicated, to prevent DIC and bleeding. A third scenario is the patient

6 248 Venous malformation and Kasabach Merritt syndrome Figure 4. Case 20: a 20-year-old woman with an extensive congenital venous malformation involving the skin of the entire upper limb and chest. Severe bleeding with laboratory evidence of disseminated intravascular coagulation (DIC) occurred after excision of the lesions in the tips of the forefinger and ring finger. The activated partial thromboplastin time was normal initially (ratio 1.2). The DIC failed to respond to treatment with fresh frozen plasma (13 units), packed red cells (12 units), platelets (7 units), fibrinogen (1.5 g 19), antithrombin III, aprotinin, and tranexamic acid locally every day. Within 2 days of initiation of low-molecular-weight heparin therapy in a curative dosage, the bleeding stopped and the DIC resolved. Figure 5. Case 10: congenital venous malformation involving the skin and muscles in both lower limbs and pelvis, with moderate chronic local intravascular coagulation. After a long trip, gross haematuria with laboratory test evidence of disseminated intravascular coagulation (DIC) occurred. The initial activated partial thromboplastin time was normal (ratio, 1). Only low-molecular-weight heparin (LMWH) therapy in a curative dosage resulted in gradual resolution of the DIC and, subsequently, of the haematuria. The LMWH therapy was tapered to nothing over several months. Appropriate compression with elastic stockings was prescribed.

7 E. Mazoyer et al. 249 Figure 6. Case 9, same girl as in Figure 2: between 12 and 21 years of age, this patient experienced repeated episodes of thrombosis in the knee, with painful haemarthrosis. Surgical excision of the venous malformation was attempted. When she was 21 years of age, she received low-molecular-weight heparin (LMWH) to treat a large haemarthrosis with worsening local intravascular coagulation (LIC). The initial activated partial thromboplastin time was normal (ratio 1.19). The LIC improved promptly and the pain abated. However, when a vitamin K antagonist was substituted for the heparin the LIC converted to DIC. LMWH therapy was successful. Subsequently, LMWH failed to prevent LIC worsening in association with sclerotherapy. with bleeding from an accidental or surgical wound in the area of the VM. In our experience, LMWH therapy is the only effective means of rapidly stopping the bleeding in this situation. Antiplatelet agents such as aspirin or ticlopidine have provided little or no clinical benefit in patients with VMassociated LIC or DIC. This was to be expected, as the flow conditions within VMs give a predominant role to coagulation factors, with little or no involvement of platelets. In our experience, heparin was far more effective than oral vitamin K antagonists. Heparin was effective in a patient with bleeding 5 days after partial excision of a VM (misdiagnosed as a haemangioma; Elly, 1969). In a pregnant woman with a gluteal VM (according to the photograph shown in the article) misdiagnosed as Klippel Trenaunay syndrome, bleeding occurred a few days after a caesarean section and stopped on initiation of heparin therapy (Neubert, Golden & Rose, 1995). Heparin was effective in a 62-year-old woman with extensive VM of the extremities (misdiagnosed as giant haemangioma) and severe bleeding after excision of a bladder tumour. Corticosteroid treatment was used also but was probably unnecessary (Shoji et al., 1998). In our experience, heparins with lower molecular weights are more effective: we obtained the greatest benefits using CY222, an ultra- LMWH that is not commercially available (Drouet et al., 1993). Coagulation abnormalities associated with limb VMs should not be called KMS, as is often the case in the literature (Table 2). This is extremely important because the treatment of the two conditions differs. Failure to recognize this can lead to complications related to inappropriate treatment, as shown by the case described above. KMS, as described initially in 1940 (Kasabach & Merritt, 1940), is characterized by profound thrombocytopenia (as low as /l) complicating an aggressive infantile vascular tumour, now called kaposiform haemangioendothelioma or tufted angioma (Jones &

8 250 Venous malformation and Kasabach Merritt syndrome Table 2. Main differences between Kasabach Merritt syndrome and venous malformation with local intravascular coagulation Differences Kasabach Merritt syndrome VM-associated LIC Ages Birth and infancy: abnormalities in growth Lifelong LIC with flares and haematological parameters Childhood: resolution of haematological Risk of DIC abnormalities, residual tumour Clinical features Congenital plaque or tumour, or no lesion at birth Sudden development of a distinctive ecchymotic and inflammatory mass Patches or masses, blue colour of skin, soft consistency, normal skin temperature, Swelling when dependent and with exercise Purpura and bruises Haematology Severe thrombocytopenia (often < 5000/mm 3 ), Mild thrombocytopenia or normal platelet count Low fibrinogen Very low fibrinogen Moderate D-Dimer elevation Elevated D-Dimers Course Sudden growth Persists lifelong Involution of the tumour is slow and continues Worsens slowly but continuously after resolution of haematological abnormalities Pathology Kaposiform haemangioendothelioma or tufted angioma Venous malformation Dysplastic venous channels with irregular walls, dissecting the skin and other soft tissues Radio-imaging Doppler: high flow Doppler: no arterial flow, venous slow flow MRI: parenchymal signal, flow voids MRI: high signal on T2 Radiograph: phleboliths Treatments Heparin ineffective Heparin is the only effective drug A number of drugs are effective: corticosteroids, interferon alpha, vincristine, ticlopidine + aspirin. Elastic stocking VM, venous malformation; LIC, local intravascular coagulation; DIC, disseminated intravascular coagulation. Orkin, 1989; Zukerberg, Nickoloff & Weiss, 1993; Enjolras et al., 1997b, Enjolras et al., 2000; Sarkar et al., 1997; Vin-Christian, McCalmont & Frieden, 1997). Although fibrinogen consumption and d-dimer elevation can occur in this life-threatening condition, the predominance of platelet consumption is in contrast to the predominance of coagulation factor consumption that characterizes VM-associated LIC (Enjolras et al., 1997a). The four most effective treatments in KMS are corticosteroids, interferon a, vincristine and ticlopidine plus aspirin. With these agents, the platelet count returns to normal and the tumour decreases in size (Neubert, Golden & Rose, 1995). None of these agents are effective in VM-associated coagulopathies, and heparin therapy is ineffective in KMS. In conclusion, coagulation abnormalities occurring in association with severe VMs of the limbs are a specific entity that must be distinguished from KMS. The coagulopathy persists throughout life, and the course is marked by exacerbations and remissions. When local complications occur or when there is a need for surgery on the affected limb, particularly the joints or muscles, heparin should be given in curative or prophylactic doses, according to the clinical and laboratory test findings. Our experience suggests that LIC may be far more common in patients with limb VMs than in those with craniofacial VMs. Studies are needed to look for other prothrombotic or genetic factors associated with a risk of severe coagulopathy-related symptoms in patients with VM-associated coagulopathy. References Drouet L., Bal dit Sollier J.P., Enjolras O. & Merland J.J. (1993) Is CY222 angiogenic in patients with lymphatic malformation? Thrombosis and Haemostasis 422, 659. Elly G.L. (1969) Heparin therapy for bleeding associated with hemangioma. Surgery 65, Enjolras O., Ciabrini D., Mazoyer E., Laurian C. & Herbreteau D. (1997a) Extensive pure venous malformations in the upper or lower limb: a review of 27 cases. Journal of American Academy of Dermatology 36, Enjolras O. & Mulliken J.B. (1998) Vascular tumors and vascular malformations, new issues. Advances in Dermatology 13, Enjolras O., Mulliken M.W., Wassef M. et al. (2000) Residual lesions of Kasabach Merritt phenomenon in 41 patients. Journal of American Academy of Dermatology 42, Enjolras O., Wassef M., Mazoyer E. et al. (1997b) Infants with Kasabach Merritt syndrome do not have ÔtrueÕ hemangiomas. Journal of Pediatrics 130, Hall G.W. (2001) Kasabach Merritt syndrome: pathogenesis and management. British Journal of Haematology 112,

9 E. Mazoyer et al. 251 Jones E.W. & Orkin M. (1989) Tufted angioma (angioblastoma): a benign progressive angioma not to be confused with Kaposi s sarcoma or low-grade angiosarcoma. Journal of American Academy of Dermatology 20, Kasabach H.H. & Merritt K.K. (1940) Capillary hemangioma with extensive purpura: report of a case. American Journal of Disease in Childhood 59, Maceyko R.F. & Camisa C. (1991) Kasabach Merritt syndrome. Pediatric Dermatology 8, Mewes T., Moldenhauer H., Pfeifer J. & Papenberg J. (1989) The Kasabach Merritt syndrome: severe bleeding disorder caused by celiac arteriography: reversal by heparin treatment. American Journal of Gastroenterology 84, Mulliken J.B. (1988) Classification of vascular birthmarks. In: Vascular Birthmark (Mulliken J.B, Young A, eds), pp W.B. Saunders Company, Philadelphia. Neubert A.G., Golden M.A. & Rose N.C. (1995) Kasabach Merritt coagulopathy complicating Klippel Trenaunay Weber syndrome in pregnancy. Obstetrics and Gynecology 85, Sarkar M., Mulliken J.B., Kozakewich H.P., Robertson R.I. & Borrows P.E. (1997) Thrombocytopenic coagulopathy (Kasabach-Merritt phenomenon) is associated with kaposiform hemangioendothelioma and not with common infantile hemangioma. Plastic Reconstruction Surgery 100, Shoji N., Nakada T., Sugano O., Suzuki H. & Sasagawa I. (1998) Acute onset of coagulopathy in a patient with Kasabach Merritt syndrome following transurethral resection of bladder tumor. Urology International 61, Straub P.W., Kessler S., Schreiber A. & Frick P.G. (1972) Chronic intravascular coagulation in Kasabach Merritt syndrome. Preferential accumulation of fibrinogen 131 I in a giant hemangioma. Archives of Internal Medicine 129, Vin-Christian K., McCalmont T.H. & Frieden I.J. (1997) Kaposiform hemangioendothelioma. An aggressive, locally invasive vascular tumor that can mimic hemangioma of infancy. Archives of Dermatology 133, Wassef M. & Enjolras O. (1999) Les malformations vasculaires superficielles: classifications et histopathologie. Annals of Pathology 19, Zukerberg L.R., Nickoloff B.J. & Weiss S.W. (1993) Kaposiform hemangioendothelioma of infancy and childhood. An aggressive neoplasm associated with Kasabach Merritt syndrome and lymphangiomatosis. American Journal of Surgery and Pathology 17,