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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
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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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
U/S
MRI
Cutaneous: perineum
and retroperitoneal
Pred
6 month
Enlargement of haemangioma
on back, bruising
Cutaneous: Lt scapula
IV Ig, Pred
NA
10 month M
Enlargement of Rt cervical
haemangioma
MRI
NA
6/52
Cutaneous: Rt cheek
Responded to embolization 3
a-IFN, involution after 6 months
NA
Histology
3/52
U/S
CXR
Cutaneous: Rt axilla
spreading to mediastinum
Haemangioma,
lymphangioma
4/52
prem
MRI
Angio
Pred
Haemangio-endothelioma
2 month
Massive hepatomegaly
U/S
CT
Pred
embolization 1
NA
6 month
Autoimmune haemolytic
anaemia, thrombocytopenia
U/S
Pred, IV Ig
splenectomy
Remission post-splenectomy
Haemangiomata multiple
13 month M
Bruising
Hepatosplenomegaly
Pred, splenectomy
VAC chemotherapy
a-IFN, oral etoposide
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.
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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
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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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The evidence base for this care pathway is limited and alterations can be
made when more information is available.
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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
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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
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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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