Sixty years ago, Kasabach and Merritt (1940) reported the association of thrombocytopenic purpura with the presence of a rapidly enlarging capillary haemangioma in a newborn male baby (Fig 1). Since that time, the term Kasabach–Merritt syndrome (KMS) has been used to describe various cases which broadly fit that first description. The thrombocytopenia, nearly always accompanied by a consumptive coagulopathy, is a complication in only a very small proportion of infants with haemangiomata (∼0·3% of cases; Shim, 1969). Cutaneous ‘strawberry’ haemangiomata of infancy are the most common soft tissue tumours in infants, occurring in 5–10% of children (Drolet et al, 1999). They appear at or soon after birth, are ‘capillary’ or ‘cavernous’ in nature, proliferate rapidly during the first 18 months of life and undergo slow spontaneous involution by the age of 5–10 years. They are rarely life threatening unless massive (‘giant’), when high output cardiac failure or direct compression of a vital organ can occur, or unless the patient develops KMS. Not all haemangiomata are cutaneous, and those associated with a more severe phenotype are often visceral, notably retroperitoneal. However, neither the site nor the size of the haemangioma appears to predict reliably for the subsequent development of KMS, which has been associated with a 30–40% mortality (el-Dessouky et al, 1988) as a result of uncontrollable haemorrhage.
Patients present to a variety of clinicians: neonatologists, paediatric surgeons, cardiologists and dermatologists. However, the haematologist is inevitably involved and is often asked to manage the patient when surgical or radiological intervention is not possible. The therapeutic dilemmas are similar to those of managing disseminated intravascular coagulation (DIC), albeit a localized form initially. Management involves a two-pronged approach: first, that of supporting and stabilizing haemostasis while trying to remove or ablate the lesion. Surgical removal is usually hazardous in the presence of an uncontrolled consumptive coagulopathy. Less invasive therapies, which may promote involution, are usually less precarious but take time to effect a response. Involution therapy, currently, is empirical and haphazard, as is the response: no one treatment is consistently successful and generally several different modalities have to be used.
A retrospective review of cases managed, in the last decade, at two UK institutions, Great Ormond Street Hospital for Children, London, and the Alder Hey Children's Hospital, Liverpool, is included in this review (Table I). These cases are similar to those published in the world literature and illustrate the diversity of clinical presentation and unpredictable response to therapy.
Table I. Clinical data of nine patients with KMS showing mode of presentation, site of lesion, treatment, outcome and histology (if available).
6/52, 6 weeks old; 4/52 prem, 4-week-old 34-week premature infant; Ix, imaging investigations; U/S, ultrasound; CXR, chest radiograph; CT, computerized tomography scan; MRI, magnetic resonance imaging; Angio, angiography; 99mTc, technetium red cell scan; Pred, prednisolone at 3 mg/kg/d; α-IFN, alpha interferon; IV Ig, intravenous immunoglobulin; TA, tranexamic acid; DXT, radiotherapy; VAC, vincristine, actinomycin, cyclophosphomide; N/A, not available.
Napkin area haemangioma, high-output cardiac failure
Cutaneous: perineum and retroperitoneal
Thrombocytopenia resolved with 3 months of prednisolone, lesion continuing to involute off treatment
Enlargement of haemangioma on back, bruising
Cutaneous: Lt scapula
IV Ig, Pred
Platelets returned to normal within month of starting prednisolone lesion resolving off treatment
Enlargement of Rt cervical haemangioma
Cutaneous: Rt side of neck
α-IFN, TA embolization, Pred
Remission/involution after 3 months of prednisolone
Right cheek rapid enlargement
Cutaneous: Rt cheek
Pred, heparin α-IFN embolization × 3
Responded to embolization × 3 α-IFN, involution after 6 months
Rt axilla rapid enlargement mild hepatomegaly
Cutaneous: Rt axilla spreading to mediastinum
Pred, embolization × 5, α-IFN, TA, prostacyclin, 12 Gy DXT
Died from massive pulmonary haemorrhage
Massive enlargement of liver
Liver – single lesion
Died from massive bleed into liver
Liver – multiple lesions
Pred embolization × 1
Initial response to steroids, died from massive bleed into liver
Partial remission post-splenectomy and post-VAC, relapse 5 years later; partial response to α-IFN
Our understanding of the pathogenesis of KMS has been hampered by the imprecise use of the word ‘haemangioma’ to describe a variety of vascular anomalies in children, including vascular tumours and malformations. In retrospect, many reported cases were probably not true KMS. The classification of vascular tumours in childhood was revised two decades ago (Mulliken & Glowacki, 1982) and has allowed the identification of a histological subgroup of haemangioma that is frequently associated with KMS (Niedt et al, 1989; Enjolras et al, 1997).
Although massive and deep-seated haemangiomata feature frequently in reports of KMS, the majority are still cutaneous lesions of varying sizes (Enjolras et al, 2000). What is it about these KMS haemangiomata, if not always size or site, that determines the development of this catastrophic haematological disturbance? The angiogenic factor basic fibroblast growth factor (bFGF), known to be elevated in patients with active angiogenesis, was raised in the urine of infants with proliferating endotheliomas regardless of whether they had KMS or not (Dosquet et al, 1998) and fell drastically in cases with good clinical response to therapy (Chang et al, 1997). Hence, proliferation per se is not obviously to blame, although the rate, perhaps above a certain threshold, may be, as might other as yet unidentified features peculiar to KMS lesions. In addition, little is known about the pathogenesis of involution. Most haemangiomata that proliferate rapidly subsequently undergo a period of slow spontaneous involution. Angiogenesis appears to be shut off, either by a decrease in angiogenic factors or by an increase in the endogenous inhibitors of angiogenesis. Clearly, knowing what might speed up the process of involution would be helpful in the development of new therapies for KMS.
Although the pathogenesis is not established, the pathophysiology of KMS is generally presumed to be that of platelet trapping by abnormally proliferating endothelium within the haemangioma (Gilon et al, 1959). This results in the activation of platelets with a secondary consumption of clotting factors. Various findings support the ‘platelet trapping’ hypothesis, including early isotope studies using 51Cr-labelled platelets (Brizel & Racuglia, 1965), immunohistochemical staining with anti-CD61 antibodies (Seo et al, 1999) and indium-111 platelet scintigraphy used to identify occult lesions and monitor response to therapy (Warrell et al, 1983; Shulkin et al, 1990). The thrombocytopenia is usually profound, with counts often less than 20 × 109/l and the platelet half-life is drastically shortened to between 1 and 24 h (Koerper et al, 1983). How the platelets become trapped is not clear but, if not due to physical entrapment, exposure and adhesion to subendothelial elements or abnormal endothelium within the haemangioma might result in the aggregation and activation of platelets. Excessive flow and sheer rates secondary to arteriovenous shunting would further increase the level of platelet activation. Continued consumption, of both platelets and clotting factors along with the initiation of fibrinolysis, eventually results in intralesional bleeding which manifests as rapid enlargement of the haemangioma, and so the cycle continues. Intralesional thrombosis occurring as part of the DIC-like picture is not often clinically apparent, but would explain the occasional ‘spontaneous’ resolution of some lesions.
The clinical phenotype and response to therapy of KMS haemangiomata appears to vary according to histological type (Mueller & Mulliken, 1999). Because of the critical state of most KMS patients, their lesions are rarely biopsied and histology is not usually obtained before involution of the lesion, unless surgical resection is performed as a curative procedure. When available, the histological type most frequently reported recently has been that of kaposiform haemangioendothelioma (KHE) (Fukunaga et al, 1996; Enjolras et al, 1997; Sarkar et al, 1997) and tufted angiomas (TA) (previously termed angioblastomas; Nakamura et al, 1998). In KHE, in contrast to the distinct nodules of well-formed capillaries of the classic capillary haemangioma, infiltrating sheets or lobules of spindle-shaped or round endothelial cells with red cell microthrombi and haemosiderin deposits are found (Enjolras et al, 2000). KHE is a locally aggressive, low-grade malignant tumour. A tufted angioma (TA) is a benign lesion characterized by a cannonball distribution of small discrete vascular tufts (Sarkar et al, 1997) and aggregates of round dilated capillaries. As with KHE, microthrombi and haemosiderin deposits are often seen in TAs (Enjolras et al, 2000). All patients with available histology from a recent retrospective series of 41 KMS patients were found to have either KHE and/or TA. In the partially resolved lesions of those patients ‘cured’ of their active KMS, TAs predominated (Enjolras et al, 2000). Many lesions, both ‘active’ and ‘cured’, had overlapping features of both KHE and TA (Gianotti et al, 1999) and these two are thought to be in histological continuum (Enjolras et al, 2000).
Distinct areas of lymphangiomatosis and aberrant lymphatic vessels can be found to a variable degree in both capillary haemangiomata and KHE/TA.
Enjolras et al (2000) now suggest that KMS is not a complication of true classic haemangioma of infancy but of KHE/TA lesions. However, many previously reported cases of KMS including those with visceral and multiple lesions, for example hepatic haemangiomata (Longeville et al, 1997), multiple splenic haemangiomata (Hoeger et al, 1995) and diffuse neonatal haemangiomatosis (Byard et al, 1991), did not have KHE/TA on histology. Equally, review of the histology available on the UK patients (Table I) did not reveal any cases of KHE or TA. The characteristic histological features of KHE and TA are quite distinctive and are not easily missed. With time this matter should be clarified, and it may be that certain common, as yet unidentified, features of KHE/TA and large capillary haemangiomata predispose them to the development of thrombocytopenia and the consumptive coagulopathy of KMS.
Diverse clinical presentation
Review of the literature and the UK patients (Table I) reveals a bagatelle of clinical phenotypes apparently no different from that seen with non-KMS patients with haemangiomata.
Classic capillary (strawberry) haemangiomata of infancy are usually single cutaneous lesions, although approximately 20% can be multiple (Drolet et al, 1999). They are usually bright red, raised, noncompressible plaques, although those that extend deeper into the skin are softer, warmer and have a darker, slightly bluish colour. KHE are often found in non-cutaneous sites such as the retroperitoneum, mediastinum and pelvis as well as the skin and their incidence is equal in both sexes. In contrast, most of the lesions in patients who have capillary haemangiomata, where there is a female predominance of 3:1, are cutaneous. However, in one of the largest series of patients with KMS, the majority (33/41) (Enjolras et al, 2000) had cutaneous lesions, the histology of which, when available, was KHE/TA. Cutaneous KHE lesions are smooth, shiny, dark purple, indurated, tender and poorly delineated and are nearly always single, although there has been a report of a child with multiple KHE (Gianotti et al, 1999).
Visceral haemangiomata can be single, multiple or isolated within one organ as single or diffuse lesions. Retroperitoneal haemangiomata are often large (‘giant’), easily missed clinically and generally associated with a high mortality (Hatley et al, 1993). The diagnosis of visceral lesions can be difficult especially when there are no cutaneous clues so KMS should always be considered in patients presenting with an unexplained thrombocytopenia and coagulopathy (Byard et al, 1991).
However, if large lesions are identified in the liver or spleen, their nature needs to be determined. The differential diagnoses for space-occupying lesions in the liver of a neonate include infantile haemangioendotheliomas (inf HE), hepatoblastoma (HB), mesenchymal hamartoma (mes H) or neuroblastoma (Nbl), and therefore every effort should be made to establish the exact histology of the lesion so as to avoid inappropriate surgery and chemotherapy (von Schweinitz et al, 1995).
Not all congenital haemangiomata resolve; although the majority of classic strawberry haemangioma of infancy resolve completely, approximately 20–40% of children are left with residual skin changes including disfiguring scars. Episodes of acute DIC have been reported in pregnant women with congenital haemangiomata (Lee & Kirk, 1967; Neubert et al, 1995) and in one woman during two successive pregnancies (Singh & Rajendran, 1998). The hormonal alterations and increase in blood volume in pregnancy may affect pre-existing lesions, triggering episodes of acute DIC.
An unusual case of KMS was reported in a 62-year-old woman with a ‘giant’ haemangioma involving the upper and lower limb who developed an acute consumptive coagulopathy 2 d after resection of a solitary bladder tumour (Shoji et al, 1998).
As part of a syndrome
A thrombocytopenic coagulopathy can develop in patients who have haemangiomata as part of a recognized syndrome (Szlachetka, 1998), as follows.
Klippel Trenaunay (KT) syndrome: a rare congenital generalized mesodermal abnormality characterized by macular vascular naevus, skeletal/soft tissue hypertrophy and venous and lymphatic anomalies, including visceral and facial haemangiomata.
Blue rubber bleb naevus syndrome: multiple cavernous haemangiomata, cutaneous and occasionally visceral (Kunishige et al, 1997).
Gorham–Stout disease (‘vanishing bone disease’): massive osteolysis (Gorham's sign) is followed by replacement of the bony matrix by proliferating thin-walled vascular and lymphatic channels; these angiomatous masses can extend out into soft tissues.
The risk of acute episodes of DIC (or KMS) in such patients is life long and not just a problem during infancy. Nearly half of the patients reported in a review of 47 KT patients were said to have KMS (Samuel & Spitz, 1995). However, a dilutional thrombocytopenia and coagulopathy can occur in KT patients which is secondary to chronic ulceration and infection of deep venous varicosities and arteriovenous shunts.
It is essential, for the purposes of follow-up and the development of management guidelines, that cases labelled and reported as KMS are in fact KMS. Haematological and histological evidence that the profound thrombocytopenia and consumptive coagulopathy are due to an enlarging haemangioma and are not, for example, a vascular malformation (Enjolras et al, 2000) is required for a diagnosis of KMS to be made. If there is any doubt about a lesion being a haemangioma, a tissue diagnosis should be sought. It is dangerous to assume, based on clinical appearances alone, that an atypical lesion is a haemangioma as tumours which cause bluish skin lesions (blueberry muffin appearance) such as leukaemia and neuroblastoma can be missed. Current imaging techniques, however, will confirm the vascular nature of most lesions (see below).
The thrombocytopenia in KMS is generally severe (often < 20 × 109/l) and is more dramatic than the dilutional thrombocytopenia that develops with hepatosplenomegaly due to large space-occupying lesions. Regarding the consumptive coagulopathy, hypofibrinogenaemia is prominent and fibrin degradation products (FDPs) are raised. Involvement of the liver, particularly in premature neonates, can result in deranged clotting as a result of the impaired synthesis of clotting factors rather than the consumptive coagulopathy of KMS. Some degree of microangiopathic haemolysis is usually apparent, in keeping with a picture of intravascular coagulopathy, although anaemia is one of the less frequent modes of presentation. Review of the blood film often, although not always, reveals red cell fragmentation which can help in difficult cases.
This should be obtained, if possible, and the subtype of haemangioma should be established, i.e. KHE, TA or capillary/cavernous, but not at the cost of delaying potentially life-saving therapy. The present management of KMS is that of the syndrome and not the histological subtype of haemangioma.
The need for good-quality and thorough screening cannot be overemphasized, especially in delineating the extent of the lesion and whether it is amenable to surgery. Ultrasound is a quick and easy way to identify and monitor most vascular lesions. Haemangiomata are seen as persistently and intensely bright homogeneous masses on contrast-enhanced computerized tomography (CT) scans. Magnetic resonance imaging (MRI) of haemangiomata demonstrates well-circumscribed densely lobulated masses with an intermediate signal intensity on T1-weighted images and a moderately hyperintense signal on T2-weighted images (Drolet et al, 1999).
The MRI findings in KHE are now well established and show diffuse enhancement with ill-defined margins (cutaneous thickening with strands of subcutaneous fat in cutaneous lesions), haemosiderin deposits and small feeding and draining vessels (Sarkar et al, 1997). Haemosiderin deposits on MRI are a useful way of identifying sites of red cell destruction (Mahfouz et al, 1999), although technetium-99m-labelled red cell scans are still used. SPECT (single-photon emission CT) scans have been used with the latter and, like MRI, can obviate the need for potentially life-threatening biopsy (Landor & Petrozzo, 2000).
Angiography is invasive but useful for ascertaining the size, patency and number of feeder and collateral vessels before embolization. This technique combined with MRI, magnetic resonance angiography (MRA), offers invaluable high-quality information in difficult cases.
The premise regarding treatment of KMS is that resolution of the lesion will lead to a correction of the consumptive coagulopathy which is heralded by a recovery in the platelet count. Prompt, vigorous management will certainly help to optimize the outcome, although no one treatment modality has been established as consistently efficacious.
Securing haemostasis while commencing treatment of the underlying cause is essential. The need to monitor and manage the coagulopathy efficiently continues until resolution occurs as most therapies are either inherently hazardous or take time to effect a cure. Deciding which therapies to use depends on the clinical setting initially and the response subsequently.
Table II. Management of Kasabach–Merritt syndrome.
To assess extent of the lesion(s) and identify occult lesions
• Monitoring of haematological parameters
• Blood product support in the presence of sudden decompensation or enlargement of the lesion:
Fresh frozen plasma 15 ml/kg
If fibrinogen still < 1·0 g/l, give cryoprecipitate 5–10 ml/kg
Platelets 15 ml/kg, if thrombocytopenic patient bleeding
If fibrinolysis is profound, consider tranexamic acid 25 mg/kg t.d.s orally or 10 mg/kg i.v.
• Biopsy of lesion for tissue diagnosis (can be obtained at any time during management, once haemostasis secured)
Replacement of consumed clotting factors with fresh-frozen plasma (FFP) (15 ml/kg) is advised in patients with prolonged clotting times who have intralesional haemorrhage, generalized bleeding or before invasive procedures. Cryoprecipitate (5–10 ml/kg) is only required in cases where severe hypofibrinogenaemia is not corrected with FFP alone (Baglin, 1996). Currently, in the UK, solvent–detergent-treated units of FFP derived from pooled plasma is the only available form of virucidally treated FFP; the use of methylene blue-treated single units is still under review. Virucidally treated fibrinogen concentrate might be indicated in fluid-overloaded patients, but it is not licensed for use in children or those with KMS. Platelet transfusions are used in actively bleeding patients at a dose of 10–15 ml/kg. With ongoing consumption, it may be difficult to raise the platelet count much above 20–30 × 109/l and vigorous attempts to do so may prove futile and have been reported as detrimental in one case (Phillips & Marsden, 1993). Patients at risk of fluid overload or with established high-output cardiac failure need careful management of blood product support to avoid further compromise of their cardiac status.
Antifibrinolytic or antiplatelet agents, i.e. tranexamic acid, ε-amino caproic acid, pentoxifylline, ticlopodine, etc.
Experimental therapies (as they become available)
Pulse laser therapy (for cutaneous lesions)
Outlined below are the mainstays of therapy, their advantages and disadvantages.
Surgery Curative surgical excision can be used for single cutaneous lesions, particularly in non-vital sites (Velin et al, 1998), and for multiple lesions in the spleen (splenectomy) (Hoeger et al, 1995; Schulz et al, 1999) or liver (wedge resection/hepatectomy) (von Schweinitz et al, 1995). Wide local excision and even amputation has been performed in some cases (Zukerberg et al, 1993). Although invaluable for histological diagnosis, this approach is not likely to be curative in the less common disseminated forms of the disorder. If the patient's condition can be stabilized and supported before and during surgery then the procedure is less risky, but complete haemostatic control is not generally achievable especially when there is involvement of the liver (Byard et al, 1991).
Compression therapy This modality is particularly useful for limb involvement. Compression bandaging and other intermittent pneumatic compression devices (Drolet et al, 1999) have been used as adjuvant therapy in the medical management of KMS (Sarihan et al, 1998) and particularly in KMS associated with Klippel Trenaunay syndrome (Samuel and Spitz, 1995).
Vascular embolization Arterial embolization, performed by experienced interventional radiologists, can be used for lesions with easily identifiable feeder vessels. Its use in the treatment of KMS is well established (Sato et al, 1987; Hosono et al, 1999; Enjolras et al, 2000), especially when used as an adjuvant. Gelfoam, PVA (polyvinyl alcohol) (Stanley et al, 1986) and metal coils have all been used. Gelfoam is short lived in vivo, starts to degrade after 6 weeks and is best used in emergency situations as the vessel will become recanalized with time. The diameter of PVA ‘beads’ can be chosen so that they occlude the afferent vessels of a lesion and do not pass through the capillary network thus risking embolization to distant sites such as the lungs. This is a particular concern in patients with high-pressure intralesional arteriovenous shunts, and metal ‘microcoils’ are less likely to pass through a lesion (Hosono et al, 1999).
Embolization of the hepatic artery in cases of multiple hepatic haemangioendotheliomata requires that patency of the hepatic portal vein is established before the procedure and patients are managed in a specialist liver unit because of the acute and often prolonged hepatic decompensation that occurs following the procedure.
Known risks are ischaemic damage to, and infarction of, vital organs, a worsening of haematological parameters after embolization (Enjolras et al, 1997) and the eventual formation of collateral vessels often with a relapse of symptoms. Several embolizations are often required before a lesion finally resolves (Larsen et al, 1987), as was the case with some of the UK patients.
Radiotherapy Although previously one of the mainstays of treatment (Larsen et al, 1987; el-Dessouky et al, 1988), radiotherapy is rarely considered as first-line therapy nowadays because of its known ‘late effects’ on growth and secondary malignancies. It is, however, non-invasive and can be used in extremis as a last resort but has occasionally been used as first-line therapy for small inaccessible lesions (Bek et al, 1980). Radiotherapy has proved effective when used in conjunction with steroids (Miller & Orton, 1992) and there have been attempts to use low-dose radiotherapy in the multimodal treatment of KMS (Bistolfi et al, 1995). A recent review of seven KMS patients treated over the last 25 years with radiotherapy revealed that although several responded to radiotherapy with a rise in platelet count non-responders who received several courses of limb irradiation not surprisingly suffered shortening of extremities (Mitsuhashi et al, 1997).
Corticosteroids Most patients responding to corticosteroids do so with a dose of prednisolone of 2–3 mg/kg/d within a few days (Esterly, 1983; el-Dessouky et al, 1988; Enjolras et al, 1990). Approximately one-third of patients will be ‘non-responders’. Higher doses of 5 mg/kg/d prednisolone (Enjolras et al, 1990; Ozsoylu, 1991) have been used effectively and ‘megadose’ therapy using 30 mg/kg/d prednisolone for 3 d tailing off over 4–5 weeks had a good effect in 15 reported cases with life-threatening haemangiomata, although only three of the patients had KMS (Ozsoylu, 1993, 1996). Potential side-effects are well known, but are not usually a problem with the 2–3 mg/kg/d dose. If a response is achieved, the dose is reduced slowly; too rapid a reduction in dose, particularly during the proliferative phase, is often associated with a recrudescence of symptoms. If no response is seen within a week or two after starting therapy, then either the dose is increased or an alternative therapy commenced.
Interferon-alpha (α-IFN) α-IFN (2a and 2b) probably works as an antiproliferative/antiangiogenic agent. Clinical regression of haemangiomata during treatment with α-IFN is associated with a reduction in the urinary excretion of the angiogenic factor bFGF, indicating that α-IFN inhibits bFGF-induced angiogenesis (Ezekowitz et al, 1992). α-IFN has been used successfully in a large number of steroid non-responders (Ezekowitz et al, 1992; Hatley et al, 1993; MacArthur et al, 1995; Powell, 1999), but has also been reported as a failure in others (Teillac-Hamel et al, 1992). Its onset of action is generally slower than that of steroids: a response with the standard dose of 3 Mu/m2/d of α-ΙFN can be seen within a week or two, but can take up to a month or more. More than half of the patients treated with α-IFN will have some response (Chang et al, 1997). However, if other modalities are used concurrently, it is difficult to know (1) how much the α-IFN is contributing to the overall response or (2) whether spontaneous involution, possibly secondary to intralesional thrombosis, has occurred simultaneously. The optimum duration of treatment has not been established. Generally, therapy is stopped after a few weeks if no response is seen or continued for several months according to clinical progress (Ezekowitz et al, 1992; Hatley et al, 1993). Fear of relapse, however, may have contributed to the lengthy duration of therapy used in the past, i.e. longer than 12 months. Recent reports of spastic diplegia in children treated with α-IFN (2a and 2b) (Worle et al, 1999), estimated to occur in 2–20% of patients (Barlow et al, 1998; Dubois et al, 1999), confirm that this drug should be reserved for life-threatening cases only and used for shorter periods, for example 6 months, with close monitoring of neurological status.
Chemotherapy It seems logical that rapidly expanding tumours with active angiogenesis should respond to chemotherapy, especially those considered to be low-grade malignant tumours, e.g. KHE. The risk of known side-effects must be weighed against the very real risk of death in the setting of KMS. Several steroid non-responders receiving vincristine at a dose of 1–2 mg/m2 weekly have had dramatic responses (Enjolras et al, 2000) within 1–3 weeks (Perez-Payarols, 1995). Cyclophosphamide at a dose of 10 mg/kg/d for 3 d each month, in combination with other therapies, has been used successfully in a particularly resistant case (Blei et al, 1998). Combination chemotherapy with VAC (vincristine, 1·5 mg/m2; actinomycin, 1 mg/m2; cyclophosphamide, 500 mg/m2) was used with good effect in one of the UK patients who had developed bony lesions years after a splenectomy for multiple splenic haemangiomata (Table I, patient 9) and also in a young girl with an unresectable steroid-resistant KHE who received six cycles of VAC (Hu et al, 1998). As actinomycin has been associated with the development of veno-occlusive disease (VOD) of the liver, most particularly in children with Wilm's tumours (Tornesello et al, 1998) as well as other soft tissue sarcomas, it is probably advisable to reserve its use for cases who have failed to respond to other forms of therapy.
Anticoagulants, antiplatelet and antifibrinolytic agents
The following agents have been used in an attempt to control the consumptive process and, as in the management of DIC, their use remains controversial. The use of antiplatelet and antifibrinolytic agents should be considered carefully as there is little evidence of benefit and more harm may be caused by altering the already delicate balance between thrombosis, fibrinolysis and haemorrhage.
Anticoagulants Low-dose heparin has been used in patients with KMS. As with DIC, the role, dose and frequency of treatment with heparin is not established, and with regard to the management of KMS there is no evidence, even anecdotal, that it helps. There have been two reports of the allegedly successful use of antithrombin (ATIII) concentrate in KMS, one of a child with occult splenic haemangiomatosis resistant to steroid therapy (Schulz et al, 1999) and the other of a woman with Klippel Trenaunay syndrome who developed DIC after gynaecological surgery (Aronoff and Roshon, 1998). The use of ATIII concentrate should be reserved for situations where a significant deficiency of antithrombin is first demonstrated. A 20-year-old woman who presented at birth with a giant haemangioma and KMS and who required a below knee amputation at the age of 2 years had received long-term warfarin therapy (Mori et al, 1995) with no recrudescence of symptoms. The exact histology of the ‘tumour’ in this case was not recorded, but it might have been an extensive venous vascular malformation associated with a life-long chronic DIC rather than a capillary haemangioma; such cases are known to derive benefit from anticoagulant therapy (Maceyko & Camisa, 1991; Enjolras et al, 2000).
Antiplatelet agents The combination of ticlopidine, an antiplatelet agent, with aspirin has been used in the treatment of KMS patients with some apparent success (Drouet & Caen, 1989; Enjolras et al, 1997). Ticlopidine, used routinely by cardiologists after coronary artery stent insertion, inhibits the binding of fibrinogen to platelets, although the exact mechanism of action is not known.
Pentoxifylline, a synthetic xanthine derivative used as a haemorrheologic agent in peripheral vascular disease and in children with type I insulin-dependent diabetes mellitus (IDDM) (Macdonald et al, 1994), also has antiplatelet activity. It stimulates prostacyclin release from vascular endothelium, increases platelet cyclic adenosine monophosphate (cAMP) and increases fibrinolytic activity. Clinically, it appears not to cause appreciable bleeding. One infant with KMS, unresponsive to multiple therapies (steroids, ticlopidine and aspirin, embolization, radiotherapy and α-IFN), appeared eventually to have responded to pentoxifylline (de Prost et al, 1991), although another four infants treated with this drug failed to respond (Enjolras et al, 1997). It must be remembered that spontaneous involution secondary to intralesional thrombosis, especially in patients receiving prolonged and multiple therapies, might be the cause of any clinical improvement.
Antifibrinolytic agents Some authors have attributed the arrest of bleeding and even the involution of the haemangioma in KMS to the use of the antifibrinolytic agents ε-aminocaproic acid (Shulkin et al, 1990; Dresse et al, 1991) and tranexamic acid (Bell et al, 1986; Hanna & Bernstein, 1989), although success is usually seen when these agents are used in combination with other therapies. If these agents are to be used then it should be when fibrinolysis is the main component of the coagulopathy (Colvin, 1998).
Potential future therapies
The 585-nm pulsed dye laser has been used successfully in the treatment of rapidly proliferating superficial cutaneous haemangiomata, especially those showing signs of ulceration (Barlow et al, 1996). It is most commonly used for the treatment of port-wine stains, but with a depth of penetration of approximately 1 mm it is of limited use for deeper visceral lesions. The carbon dioxide laser has been useful for the ablation of small, solitary mucosal lesions especially in the subglottic space (Sie et al, 1994), but few of these are associated with KMS. Compared with radiotherapy, this technique has very few obvious side-effects, but its efficacy has yet to be assessed in patients with KMS.
Naturally occurring angiogenesis inhibitors such as angiostatin (the proteolytic degradation product of plasminogen) and endostatin (a cleavage product of XVIII type collagen) are both candidates for use in vascular proliferative diseases (Harris, 1998). Human angiostatin used in a murine model of KMS with cutaneous haemangioendotheliomas resulted in a marked volume reduction in tumour size and improvement of thrombocytopenia and anaemia. Although increased tumour cell apoptosis was noted, cellular proliferation was not reduced (Lannutti et al, 1997). Little is known about where, in man, these two inhibitors are produced or what role they play in normal, or aberrant, endothelial growth.
Although several antiangiogenic factors [CM101, CA1, TNP470, squalamine, interleukin 12 (IL-12), Vitaxin] have entered phase II clinical trials, and Marmistat and antivascular endothelial growth factor (VEGF) monoclonal antibody have entered phase III studies (Talks & Harris, 2000), none is freely available for clinical use. Thalidomide, known to inhibit bFGF-induced angiogenesis in animal models (D'amato et al, 1994), is available and is currently undergoing phase II trials in the treatment of AIDS-related Kaposi's sarcoma, which has a similar histology to KHE. There is only limited experience of the use of thalidomide in children, for example for graft-versus-host disease (GVHD) in bone marrow transplantation, and thus the side-effect profile in children is not fully established, although so far it appears similar to that seen in adults, namely axonal neuropathy, constipation and sedation (Metha et al, 1999).
Further details on antiangiogenic factors can be obtained from a recent review on the subject in this journal (Talks & Harris, 2000).
Pegylated recombinant human megakaryocyte growth and development factor (Peg-rHuMGDF) has been used in a murine model of KMS, resulting in a significant reduction in the size of the tumours, recovery of the platelet count and the finding of fresh fibrin clots on histological examination (Verheul et al, 1999). It was concluded that intralesional thrombosis secondary to an increase in platelet production had promoted this resolution and, hence, Peg-rHuMGDF may yet be another potential candidate for the management of KMS.
KMS is clinically heterogeneous. The development of a life-threatening thrombocytopenic consumptive coagulopathy in association with a haemangioma especially in an infant or young child warrants aggressive management as outlined in this review. Caveats and dilemmas in managing a case of KMS include: (1) the delays involved in diagnosing cases because of occult lesions, (2) ensuring the lesion is a haemangioma and not something else and (3) being unable to control the coagulopathy promptly or adequately. In older patients, or patients with haemangiomata as part of a recognized syndrome, DIC rather than KMS may develop acutely, e.g. post-operatively or in association with acute sepsis. Management of KMS is currently empirical, and with a better understanding of the pathogenesis more appropriate and efficient therapies could be developed. Conversely, any benefits derived from the use of new experimental therapies might hasten that understanding.
Guidance for clinicians encountering patients with KMS is limited and because of the life-threatening and heterogeneous presentation of KMS randomized controlled trials of these therapies, to yield evidence-based management protocols, are difficult to perform. Until more definite guidelines can be established, suggestions for the management of life-threatening KMS are outlined in Fig 2 and Tables II and III.
The author thanks Drs Ian Hann, Paula Bolton-Maggs, Bridget Wilkins and Alan Ramsay and Professor Judith Chessells for their helpful comments and advice.