Professional Documents
Culture Documents
Review
Sixty years ago, Kasabach and Merritt (1940) reported the These cases are similar to those published in the world
association of thrombocytopenic purpura with the presence literature and illustrate the diversity of clinical presentation
of a rapidly enlarging capillary haemangioma in a newborn and unpredictable response to therapy.
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 thrombo-
PATHOGENESIS/PATHOPHYSIOLOGY
cytopenia, nearly always accompanied by a consumptive
coagulopathy, is a complication in only a very small Our understanding of the pathogenesis of KMS has been
proportion of infants with haemangiomata (,0´3% of hampered by the imprecise use of the word `haemangioma'
cases; Shim, 1969). Cutaneous `strawberry' haemangio- to describe a variety of vascular anomalies in children,
mata of infancy are the most common soft tissue tumours in including vascular tumours and malformations. In retro-
infants, occurring in 5±10% of children (Drolet et al, 1999). spect, many reported cases were probably not true KMS. The
They appear at or soon after birth, are `capillary' or classification of vascular tumours in childhood was revised
`cavernous' in nature, proliferate rapidly during the first two decades ago (Mulliken & Glowacki, 1982) and has
18 months of life and undergo slow spontaneous involution allowed the identification of a histological subgroup of
by the age of 5±10 years. They are rarely life threatening haemangioma that is frequently associated with KMS (Niedt
unless massive (`giant'), when high output cardiac failure et al, 1989; Enjolras et al, 1997).
or direct compression of a vital organ can occur, or unless Although massive and deep-seated haemangiomata
the patient develops KMS. Not all haemangiomata are feature frequently in reports of KMS, the majority are still
cutaneous, and those associated with a more severe phenotype cutaneous lesions of varying sizes (Enjolras et al, 2000).
are often visceral, notably retroperitoneal. However, neither What is it about these KMS haemangiomata, if not always
the site nor the size of the haemangioma appears to predict size or site, that determines the development of this
reliably for the subsequent development of KMS, which has catastrophic haematological disturbance? The angiogenic
been associated with a 30±40% mortality (el-Dessouky et al, factor basic fibroblast growth factor (bFGF), known to be
1988) as a result of uncontrollable haemorrhage. elevated in patients with active angiogenesis, was raised in
Patients present to a variety of clinicians: neonatologists, the urine of infants with proliferating endotheliomas
paediatric surgeons, cardiologists and dermatologists. How- regardless of whether they had KMS or not (Dosquet et al,
ever, the haematologist is inevitably involved and is often 1998) and fell drastically in cases with good clinical
asked to manage the patient when surgical or radiological response to therapy (Chang et al, 1997). Hence, prolifera-
intervention is not possible. The therapeutic dilemmas are tion per se is not obviously to blame, although the rate,
similar to those of managing disseminated intravascular perhaps above a certain threshold, may be, as might other
coagulation (DIC), albeit a localized form initially. Manage- as yet unidentified features peculiar to KMS lesions. In
ment involves a two-pronged approach: first, that of addition, little is known about the pathogenesis of involu-
supporting and stabilizing haemostasis while trying to tion. Most haemangiomata that proliferate rapidly subse-
remove or ablate the lesion. Surgical removal is usually quently undergo a period of slow spontaneous involution.
hazardous in the presence of an uncontrolled consumptive Angiogenesis appears to be shut off, either by a decrease in
coagulopathy. Less invasive therapies, which may promote angiogenic factors or by an increase in the endogenous
involution, are usually less precarious but take time to inhibitors of angiogenesis. Clearly, knowing what might
effect a response. Involution therapy, currently, is empirical speed up the process of involution would be helpful in the
and haphazard, as is the response: no one treatment is development of new therapies for KMS.
consistently successful and generally several different Although the pathogenesis is not established, the patho-
modalities have to be used. physiology of KMS is generally presumed to be that of platelet
A retrospective review of cases managed, in the last trapping by abnormally proliferating endothelium within
decade, at two UK institutions, Great Ormond Street the haemangioma (Gilon et al, 1959). This results in the
Hospital for Children, London, and the Alder Hey Children's activation of platelets with a secondary consumption of
Hospital, Liverpool, is included in this review (Table I). clotting factors. Various findings support the `platelet
trapping' hypothesis, including early isotope studies using
51
Correspondence: Dr Georgina W. Hall, Paediatric Haematology/ Cr-labelled platelets (Brizel & Racuglia, 1965), immuno-
Oncology Unit, John Radcliffe Hospital, Headley Way, Headington, histochemical staining with anti-CD61 antibodies (Seo et al,
Oxford OX3 DU9, UK. E-mail: georgina.hall@cellsci.ox.ac.uk 1999) and indium-111 platelet scintigraphy used to identify
occult lesions and monitor response to therapy (Warrell et al, as rapid enlargement of the haemangioma, and so the cycle
1983; Shulkin et al, 1990). The thrombocytopenia is continues. Intralesional thrombosis occurring as part of the
usually profound, with counts often less than 20 109/l DIC-like picture is not often clinically apparent, but would
and the platelet half-life is drastically shortened to between explain the occasional `spontaneous' resolution of some
1 and 24 h (Koerper et al, 1983). How the platelets become lesions.
trapped is not clear but, if not due to physical entrapment,
exposure and adhesion to subendothelial elements or
HISTOLOGY
abnormal endothelium within the haemangioma might
result in the aggregation and activation of platelets. The clinical phenotype and response to therapy of KMS
Excessive flow and sheer rates secondary to arteriovenous haemangiomata appears to vary according to histological
shunting would further increase the level of platelet type (Mueller & Mulliken, 1999). Because of the critical
activation. Continued consumption, of both platelets and state of most KMS patients, their lesions are rarely biopsied
clotting factors along with the initiation of fibrinolysis, and histology is not usually obtained before involution of the
eventually results in intralesional bleeding which manifests lesion, unless surgical resection is performed as a curative
Table I. Clinical data of nine patients with KMS showing mode of presentation, site of lesion, treatment, outcome and histology (if available).
1 At birth F Napkin area haemangioma, U/S Cutaneous: perineum Pred Thrombocytopenia resolved with 3 months NA
high-output cardiac failure MRI and retroperitoneal of prednisolone, lesion continuing to involute off treatment
2 6 month F Enlargement of haemangioma ± Cutaneous: Lt scapula IV Ig, Pred Platelets returned to normal within month NA
on back, bruising of starting prednisolone lesion resolving off treatment
3 10 month M Enlargement of Rt cervical MRI Cutaneous: Rt side of neck a-IFN, TA Remission/involution after 3 months of prednisolone NA
haemangioma embolization, Pred
4 6/52 M Right cheek rapid enlargement U/S Cutaneous: Rt cheek Pred, heparin a-IFN Responded to embolization 3
embolization 3 a-IFN, involution after 6 months NA
5 3/52 F Rt axilla rapid enlargement U/S Cutaneous: Rt axilla Pred, embolization 5, a-IFN, Died from massive pulmonary haemorrhage Haemangioma,
mild hepatomegaly CXR spreading to mediastinum TA, prostacyclin, 12 Gy DXT lymphangioma
6 4/52 M Massive enlargement of liver MRI Liver ± single lesion Pred Died from massive bleed into liver Haemangio-endothelioma
prem Angio
7 2 month F Massive hepatomegaly U/S Liver ± multiple lesions Pred Initial response to steroids, NA
CT embolization 1 died from massive bleed into liver
8 6 month F Autoimmune haemolytic U/S Spleen ± multiple lesions Pred, IV Ig Remission post-splenectomy Haemangiomata ± multiple
anaemia, thrombocytopenia splenectomy
9 13 month M Bruising U/S, CT Spleen ± multiple Pred, splenectomy Partial remission post-splenectomy and Haemangiomata/
Hepatosplenomegaly Angio, Liver ± multiple VAC chemotherapy post-VAC, relapse 5 years later; lymphangiomata
99m
Tc Bony lesions at relapse a-IFN, oral etoposide partial response to a-IFN
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; a-IFN, alpha interferon; IV Ig, intravenous immunoglobulin; TA, tranexamic acid; DXT, radiotherapy; VAC, vincristine, actinomycin,
cyclophosphomide; N/A, not available.
Review
853
854 Review
procedure. When available, the histological type most retroperitoneum, mediastinum and pelvis as well as the
frequently reported recently has been that of kaposiform skin and their incidence is equal in both sexes. In contrast,
haemangioendothelioma (KHE) (Fukunaga et al, 1996; most of the lesions in patients who have capillary
Enjolras et al, 1997; Sarkar et al, 1997) and tufted angiomas haemangiomata, where there is a female predominance of
(TA) (previously termed angioblastomas; Nakamura et al, 3:1, are cutaneous. However, in one of the largest series of
1998). In KHE, in contrast to the distinct nodules of well- patients with KMS, the majority (33/41) (Enjolras et al,
formed capillaries of the classic capillary haemangioma, 2000) had cutaneous lesions, the histology of which, when
infiltrating sheets or lobules of spindle-shaped or round available, was KHE/TA. Cutaneous KHE lesions are smooth,
endothelial cells with red cell microthrombi and haemo- shiny, dark purple, indurated, tender and poorly delineated
siderin deposits are found (Enjolras et al, 2000). KHE is a and are nearly always single, although there has been a
locally aggressive, low-grade malignant tumour. A tufted report of a child with multiple KHE (Gianotti et al, 1999).
angioma (TA) is a benign lesion characterized by a
cannonball distribution of small discrete vascular tufts Visceral involvement
(Sarkar et al, 1997) and aggregates of round dilated Visceral haemangiomata can be single, multiple or isolated
capillaries. As with KHE, microthrombi and haemosiderin within one organ as single or diffuse lesions. Retroperitoneal
deposits are often seen in TAs (Enjolras et al, 2000). All haemangiomata are often large (`giant'), easily missed
patients with available histology from a recent retrospective clinically and generally associated with a high mortality
series of 41 KMS patients were found to have either KHE (Hatley et al, 1993). The diagnosis of visceral lesions can be
and/or TA. In the partially resolved lesions of those patients difficult especially when there are no cutaneous clues so
`cured' of their active KMS, TAs predominated (Enjolras et al, KMS should always be considered in patients presenting
2000). Many lesions, both `active' and `cured', had with an unexplained thrombocytopenia and coagulopathy
overlapping features of both KHE and TA (Gianotti et al, (Byard et al, 1991).
1999) and these two are thought to be in histological However, if large lesions are identified in the liver or
continuum (Enjolras et al, 2000). spleen, their nature needs to be determined. The differential
Distinct areas of lymphangiomatosis and aberrant lym- diagnoses for space-occupying lesions in the liver of a
phatic vessels can be found to a variable degree in both neonate include infantile haemangioendotheliomas (inf HE),
capillary haemangiomata and KHE/TA. hepatoblastoma (HB), mesenchymal hamartoma (mes H)
Enjolras et al (2000) now suggest that KMS is not a or neuroblastoma (Nbl), and therefore every effort should
complication of true classic haemangioma of infancy but of be made to establish the exact histology of the lesion so as
KHE/TA lesions. However, many previously reported cases of to avoid inappropriate surgery and chemotherapy (von
KMS including those with visceral and multiple lesions, for Schweinitz et al, 1995).
example hepatic haemangiomata (Longeville et al, 1997),
multiple splenic haemangiomata (Hoeger et al, 1995) and Diffuse/multiple
diffuse neonatal haemangiomatosis (Byard et al, 1991), did Diffuse infantile (or neonatal) haemangiomatosis (DIH/
not have KHE/TA on histology. Equally, review of the DNH), characterized by the presence of multiple cutaneous
histology available on the UK patients (Table I) did not and visceral haemangiomata, has a high morbidity and
reveal any cases of KHE or TA. The characteristic mortality (. 70% in untreated groups) (Teillac-Hamel et al,
histological features of KHE and TA are quite distinctive 1993; Lopriore & Markhorst, 1999; Schulz et al, 1999).
and are not easily missed. With time this matter should KMS has been reported in patients with intraosseal and soft
be clarified, and it may be that certain common, as yet tissue haemangiomata (Biswal et al, 1993; Carrington et al,
unidentified, features of KHE/TA and large capillary 1993; Hoeger et al, 1995) and it can be difficult to
haemangiomata predispose them to the development of differentiate these cases from those with Gorham±Stout
thrombocytopenia and the consumptive coagulopathy of (`vanishing bone') disease (see Table I, patient 9).
KMS.
Adults: life-long haemangioma
Not all congenital haemangiomata resolve; although the
DIVERSE CLINICAL PRESENTATION
majority of classic strawberry haemangioma of infancy
Review of the literature and the UK patients (Table I) reveals resolve completely, approximately 20±40% of children are
a bagatelle of clinical phenotypes apparently no different left with residual skin changes including disfiguring scars.
from that seen with non-KMS patients with haemangiomata. Episodes of acute DIC have been reported in pregnant
women with congenital haemangiomata (Lee & Kirk, 1967;
Cutaneous involvement Neubert et al, 1995) and in one woman during two
Classic capillary (strawberry) haemangiomata of infancy successive pregnancies (Singh & Rajendran, 1998). The
are usually single cutaneous lesions, although approxi- hormonal alterations and increase in blood volume in
mately 20% can be multiple (Drolet et al, 1999). They are pregnancy may affect pre-existing lesions, triggering episodes
usually bright red, raised, non-compressible plaques, of acute DIC.
although those that extend deeper into the skin are softer, An unusual case of KMS was reported in a 62-year-old
warmer and have a darker, slightly bluish colour. KHE woman with a `giant' haemangioma involving the upper
are often found in non-cutaneous sites such as the and lower limb who developed an acute consumptive
concentrate should be reserved for situations where a haemorrheologic agent in peripheral vascular disease and
significant deficiency of antithrombin is first demonstrated. in children with type I insulin-dependent diabetes mellitus
A 20-year-old woman who presented at birth with a giant (IDDM) (Macdonald et al, 1994), also has antiplatelet
haemangioma and KMS and who required a below knee activity. It stimulates prostacyclin release from vascular
amputation at the age of 2 years had received long-term endothelium, increases platelet cyclic adenosine monophos-
warfarin therapy (Mori et al, 1995) with no recrudescence phate (cAMP) and increases fibrinolytic activity. Clinically, it
of symptoms. The exact histology of the `tumour' in this appears not to cause appreciable bleeding. One infant with
case was not recorded, but it might have been an extensive KMS, unresponsive to multiple therapies (steroids, ticlo-
venous vascular malformation associated with a life-long pidine and aspirin, embolization, radiotherapy and a-IFN),
chronic DIC rather than a capillary haemangioma; such appeared eventually to have responded to pentoxifylline (de
cases are known to derive benefit from anticoagulant Prost et al, 1991), although another four infants treated
therapy (Maceyko & Camisa, 1991; Enjolras et al, 2000). with this drug failed to respond (Enjolras et al, 1997). It
Antiplatelet agents. The combination of ticlopidine, an must be remembered that spontaneous involution second-
antiplatelet agent, with aspirin has been used in the ary to intralesional thrombosis, especially in patients
treatment of KMS patients with some apparent success receiving prolonged and multiple therapies, might be the
(Drouet & Caen, 1989; Enjolras et al, 1997). Ticlopidine, cause of any clinical improvement.
used routinely by cardiologists after coronary artery stent Antifibrinolytic agents. Some authors have attributed the
insertion, inhibits the binding of fibrinogen to platelets, arrest of bleeding and even the involution of the haeman-
although the exact mechanism of action is not known. gioma in KMS to the use of the antifibrinolytic agents 1-
Pentoxifylline, a synthetic xanthine derivative used as a aminocaproic acid (Shulkin et al, 1990; Dresse et al, 1991)