British Journal of Haematology, 2001, 112, 851862

Review
KASABACH MERRITT SYNDROME: PATHOGENESIS AND MANAGEMENT
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 (,03% of
cases; Shim, 1969). Cutaneous `strawberry' haemangiomata of infancy are the most common soft tissue tumours in
infants, occurring in 510% 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 510 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 3040% 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).
Correspondence: Dr Georgina W. Hall, Paediatric Haematology/
Oncology Unit, John Radcliffe Hospital, Headley Way, Headington,
Oxford OX3 DU9, UK. E-mail: georgina.hall@cellsci.ox.ac.uk
q 2001 Blackwell Science Ltd

These cases are similar to those published in the world

literature and illustrate the diversity of clinical presentation
and unpredictable response to therapy.

PATHOGENESIS/PATHOPHYSIOLOGY
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
51
Cr-labelled platelets (Brizel & Racuglia, 1965), immunohistochemical staining with anti-CD61 antibodies (Seo et al,
1999) and indium-111 platelet scintigraphy used to identify

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Fig. 1. Drawing of the affected infant in the

original article by Kasabach & Merritt (1940).

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.
HISTOLOGY
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

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Table I. Clinical data of nine patients with KMS showing mode of presentation, site of lesion, treatment, outcome and histology (if available).
Case Age

Sex Presentation

Ix

Site

Treatment

Outcome

At birth

Napkin area haemangioma,

high-output cardiac failure

U/S
MRI

Cutaneous: perineum
and retroperitoneal

Pred

Thrombocytopenia resolved with 3 months

NA
of prednisolone, lesion continuing to involute off treatment

6 month

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

NA

10 month M

Enlargement of Rt cervical
haemangioma

MRI

Cutaneous: Rt side of neck a-IFN, TA

embolization, Pred

Remission/involution after 3 months of prednisolone

NA

6/52

Right cheek rapid enlargement U/S

Cutaneous: Rt cheek

Responded to embolization  3
a-IFN, involution after 6 months

NA

Pred, heparin a-IFN

embolization  3

Histology

3/52

Rt axilla rapid enlargement

mild hepatomegaly

U/S
CXR

Cutaneous: Rt axilla
spreading to mediastinum

Pred, embolization  5, a-IFN, Died from massive pulmonary haemorrhage

TA, prostacyclin, 12 Gy DXT

Haemangioma,
lymphangioma

4/52
prem

Massive enlargement of liver

MRI
Angio

Liver single lesion

Pred

Died from massive bleed into liver

Haemangio-endothelioma

2 month

Massive hepatomegaly

U/S
CT

Liver multiple lesions

Pred
embolization  1

Initial response to steroids,

died from massive bleed into liver

NA

6 month

Autoimmune haemolytic
anaemia, thrombocytopenia

U/S

Spleen multiple lesions

Pred, IV Ig
splenectomy

Remission post-splenectomy

Haemangiomata multiple

13 month M

Bruising
Hepatosplenomegaly

U/S, CT Spleen multiple

Angio, Liver multiple
99m
Tc
Bony lesions at relapse

Pred, splenectomy
VAC chemotherapy
a-IFN, oral etoposide

Partial remission post-splenectomy and

post-VAC, relapse 5 years later;
partial response to a-IFN

Haemangiomata/
lymphangiomata

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
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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 wellformed 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.
Cutaneous involvement
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, non-compressible 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 involvement
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).
Diffuse/multiple
Diffuse infantile (or neonatal) haemangiomatosis (DIH/
DNH), characterized by the presence of multiple cutaneous
and visceral haemangiomata, has a high morbidity and
mortality (. 70% in untreated groups) (Teillac-Hamel et al,
1993; Lopriore & Markhorst, 1999; Schulz et al, 1999).
KMS has been reported in patients with intraosseal and soft
tissue haemangiomata (Biswal et al, 1993; Carrington et al,
1993; Hoeger et al, 1995) and it can be difficult to
differentiate these cases from those with GorhamStout
(`vanishing bone') disease (see Table I, patient 9).
Adults: life-long haemangioma
Not all congenital haemangiomata resolve; although the
majority of classic strawberry haemangioma of infancy
resolve completely, approximately 2040% 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

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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).
GorhamStout 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.
KT has been diagnosed antenatally with ultrasound, and
newborn infants have developed KMS during the immediate
post-natal period (Raman et al, 1996; Christenson et al,
1997). Episodes of acute DIC can also occur in some adults
with KT (Aronoff & Roshon, 1998), whereas others have
chronic DIC (Mori et al, 1995).
DIAGNOSIS
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).
Haematology
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

855

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.
Histology
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.
Imaging
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 contrastenhanced 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 lifethreatening 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.
MANAGEMENT
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

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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.
Supportive therapy (Table II)
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 (510 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 1015 ml/kg.
With ongoing consumption, it may be difficult to raise the
platelet count much above 2030  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.
Treatment options (Table III)
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
Table II. Management of KasabachMerritt syndrome.
Baseline investigations/support:
X Imaging
To assess extent of the lesion(s) and identify occult lesions
X Monitoring of haematological parameters
X Blood product support in the presence of sudden decompensation or
enlargement of the lesion:
Fresh frozen plasma 15 ml/kg
If fibrinogen still , 10 g/l, give cryoprecipitate 510 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.
X Biopsy of lesion for tissue diagnosis (can be obtained at any time during
management, once haemostasis secured)

Table III. Treatment options for KasabachMerritt syndrome.

First-line therapies
In simple/single lesions
Vascular ligation, embolization, or surgical excision
In diffuse or extensive disease (not amenable to the above)
Prednisolone 3 mg/kg/d (increasing to 5 mg/kg/d) and/or
Alpha interferon 3 Mu/m2/d s.c.
Second-line or adjuvant therapies
If no response and patient in extremis
Vincristine 15 mg/m2 (max. 2 mg) i.v. weekly for 4 weeks
Localized radiotherapy (if accessible)
Combination chemotherapy (vincristine, cyclophosphamide, etc.)
Antifibrinolytic or antiplatelet agents, i.e. tranexamic acid, 1-amino
caproic acid, pentoxifylline, ticlopodine, etc.
Experimental therapies (as they become available)
Pulse laser therapy (for cutaneous lesions)
Antiangiogenic agents
Peg-rHuMGDF

The evidence base for this care pathway is limited and alterations can be
made when more information is available.

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.

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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 23 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 45 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 23 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 (a -IFN). a-IFN (2a and 2b) probably
works as an antiproliferative/antiangiogenic agent. Clinical
regression of haemangiomata during treatment with a-IFN
is associated with a reduction in the urinary excretion of the
angiogenic factor bFGF, indicating that a-IFN inhibits bFGFinduced angiogenesis (Ezekowitz et al, 1992). a-IFN has
been used successfully in a large number of steroid nonresponders (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 a-FN 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 a-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 a-IFN is contributing to the overall response

857

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 a-IFN (2a and 2b) (Worle et al,
1999), estimated to occur in 220% 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 12 mg/m2 weekly have had
dramatic responses (Enjolras et al, 2000) within 13 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, 15 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

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858

Review

Fig. 2. Management options for Kasabach

Merritt syndrome.

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 a-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 1aminocaproic acid (Shulkin et al, 1990; Dresse et al, 1991)

q 2001 Blackwell Science Ltd, British Journal of Haematology 112: 851862

Review
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
Laser therapy
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.
Antiangiogenic agents
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).
Peg-rHuMGDF
Pegylated recombinant human megakaryocyte growth and
development factor (Peg-rHuMGDF) has been used in a

859

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.
CONCLUSIONS
KMS is clinically heterogeneous. The development of a lifethreatening 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.
Paediatric Haematology/Oncology
Unit, John Radcliffe Hospital, Oxford
OX3 DU9, UK

Georgina W. Hall

ACKNOWLEDGMENTS
The author thanks Drs Ian Hann, Paula Bolton-Maggs,
Bridget Wilkins and Alan Ramsay and Professor Judith
Chessells for their helpful comments and advice.
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Keywords: KasabachMerritt, haemangioma, consumptive

coagulopathy.

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