
Management ofDental Emergencies inChildren andAdolescents, First Edition.
Editedby Klaus W.Neuhaus andAdrianLussi.
© 2019 John Wiley & Sons Ltd. Published 2019 by John Wiley & Sons Ltd.
Companion website: www.wiley.com/go/neuhaus/dental_emergencies
245
Introduction
Uniquely, disruptions in the formation and
function of circulating blood cells trigger
changes in the immune system, blood clotting
and oxygen transportation. Whilst there is a
quite frequent occurrence of anaemia, it plays
a rather minor role in dentistry, since normally
it is only mildly severe and quickly remedied.
Haematological malignancies are rare,
with an incidence of about 30/100 000 (Sant
etal., 2010). The oral cavity is often affected
in patients without functioning defence, and
complications are common during dental
intervention, especially when there is a
lack of neutrophil granulocytes. In general,
seriously ill haematological patients receive
dental treatment at university centres.
Infections within the oral cavity may also
be initial manifestation of a haematological
disorder. This should in particular be con–
sidered when gingival bleeding occurs in
otherwise healthy conditions and in the
presence of petechiae.
Wanted and unwanted medicinal effects on
blood clotting and infection defence occur
very often, due to the wide spread of corre–
sponding diseases. This is related to treat–
ments like the application of corticosteroids or
anticoagulation in connection with atrial
fibrillation. The effects of these medications are
acutely relevant for the choice of dental treat–
ment. However, in children and adolescents,
medicinal anticoagulation is seldom applied.
This is why it is not addressed in this chapter.
High‐dose local irradiation is also rather
seldom administered in the area of the mouth
in children, and so it too is not discussed.
We begin by explaining the basic concepts,
before looking at specific problems associated
with the oral mucosa that are often encoun–
tered in connection with chemotherapy, total
body irradiation and stem cell transplants.
Haemostasis
Stopping the blood flow from injured blood
vessels is a complex process, in which a
number of factors interact. Successful
haemostasis consists in three steps: (i) vaso–
constriction to reduce the blood flow; (ii)
formation of a platelet plug by thrombocyte
adherence, activation and aggregation; and
(iii) plasmatic coagulation by a cascade of
proteins, which forms a stable clot. When
thrombocytes come in contact with collagen
in the exposed connective tissue, they attach
there by mediation of the von Willebrand
factor, a protein that adheres both to collagen
6.3
Oral Problems inPatients Undergoing Haematology
orOncology Treatment
Adrian M. Ramseier
1
, Jakob Passweg
2
and Tuomas Waltimo
1
1
Department of Oral Health & Medicine, University Center for Dental Medicine Basel, University of Basel, Basel, Switzerland
2
Department of Hematology, University Hospital Basel, Basel, Switzerland

6.3 Haematology and Oncology
246
and to thrombocytes. Thus, the thrombo–
cytes are activated. By releasing cytokines,
more thrombocytes are attracted, and the
plasmatic coagulation cascade is initiated.
Through several intermediate stages, pro–
thrombin is transformed, both intrinsically
(activation factors) and extrinsically (tissue
factor in the injured subendothelial tissue),
to thrombin, which in turn polymerises
fibrinogen to fibrin. This results in a net
incorporating aggregated thrombocytes as
well as erythrocytes, and thus forming a
stable blood clot. Other factors are responsible
for preventing exaggerated or spontaneous
thrombus formation.
Cellular Haemostasis Disorders
(Thrombocytes)
Depressed platelet count (thrombocytopaenia)
and dysfunction of the platelet count (throm–
bocytopahthies) can be either congenital or
acquired. Table6.3.1 provides an overview of
possible causes of thrombocytopaenia.
The most commonly isolated thrombo-
cytopaenia in children is the immune
thrombocytopaenia (ITP) (Ishii, 2017).
Thrombo cy to paenia may also occur following
a replacement of normal bone marrow with
leukaemic cells (e.g. in acute leukaemia) or
bone marrow failure, or it may be inherited.
Nonsteroidal anti‐inflammatory drugs
(NSAIDs) inhibit platelet aggregation. With
aspirin, such aggregation is irreversible, except
by the production of new thrombocytes.
Small petechial haemorrhages on skin and
on the mucosa are the typical sign of marred
thrombocytes; often, they occur on the
lower extremities (gravity) or in the oral
cavity. In case of severe thrombocytopaenia,
they can become confluent (ecchymoses).
Spontaneous bleeding starts only with a
platelet count of 20–30 × 10
9
/l (Scully, 2014).
Depending on the severity of the disorder, it
can result from minor traumata, gingival
bleeding or suffusions on the skin.
The normal platelet count is 150–450 × 10
9
/l;
a value of >100 × 10
9
/l is thought to be
ideal for surgical intervention. With values
>50 × 10
9
/l and good functioning of the
existing platelets, dentoalveolar surgery can
normally be performed without bleeding
complications (Henderson et al., 2001).
Measures like compression, wound suture
and local haemostatics are usually sufficient.
With values of <30 × 10
9
/l, spontaneous
bleeding can occur. In this situation, the
indication of surgical treatment should be
carefully considered, and surgery should be
conducted in collaboration with haematology.
Haemostasis can be improved by transfusion
of thrombocyte concentrates. This is recom–
mended during dentoalveolar intervention
with a platelet count of <50 × 10
9
/l, as well as
Table6.3.1 Causes ofthrombocytopaenia
(Hoffbrand andMoss, 2016).
Failure of platelet production
Selective megakaryocyte depression
Rare congenital defects
Drugs, chemicals, viral infections
Part of general bone marrow failure
Cytotoxic drugs
Radiotherapy
Aplastic anaemia
Leukaemia
Myelodysplastic syndromes
Myelofibrosis
Marrow infiltration (e.g. carcinoma, lymphoma,
Gaucher’s disease)
Multiple myeloma
Megaloblastic anaemia
HIV infection
Increased consumption of platelets
Immune
Autoimmune
Idiopathic
Associated with systemic lupus erythematosus,
chronic lymphocytic leukaemia or lymphoma
Infections: Helicobacter pylori, human immuno-
deficiency virus (HIV), other viruses, malaria
Drug‐induced, e.g. heparin
Post‐transfusional purpura
Foeto‐maternal alloimmune thrombocytopaenia
Disseminated intravascular coagulation
Thrombotic thrombocytopaenic purpura
Abnormal distribution of platelets
Splenomegaly, e.g. liver disease
Dilutional loss
Massive transfusion of stored blood to bleeding
patients

Disorders oftheImmune System/Granulocytes
247
during maxillofacial intervention with a
platelet count of <100 × 10
9
/l (Scully, 2014).
The success of thrombocyte transfusions
needs to be checked: it is essential to measure
the platelet count prior to and after trans–
fusion. Patients who do not adequately react
to thrombocyte transfusions constitute a
special problem. In such cases, therapeutic
interventions can be performed whilst trans–
fusion continues.
Plasmatic Coagulation Disorders
Congenital coagulation disorders include
haemophilia A (factor VIII deficiency) and
the much rarer haemophilia B (factor IX
deficiency). Only the male gender is affected
by haemophilia B. Spontaneous haemor–
rhaging and strong life‐threatening postop–
erative bleeding may occur. Missing factors
can be added; however, there is insufficient
evidence from randomised controlled trials
to assess the most effective and safe haemo–
static treatment to prevent bleeding in peo–
ple with haemophilia or other congenital
bleeding disorders undergoing surgical pro–
cedures (Coppola etal., 2015; Spivakovsky
etal., 2015).
In von Willebrand disease, the von
Willebrand factor is missing or malfunc–
tioning. Because of this, platelet function is
impaired. Von Willebrand disease is classified
into a number of subcategories, and is asso–
ciated with slight to considerable bleeding
disorders.
Disorders oftheImmune
System/Granulocytes
Defence comprises cellular elements, all of
which belong to the leucocytes. The various
cells evolved from one multipotent stem cell
of haematopoiesis, which is capable of differ–
entiating into different cell lines with various
functions:
● Neutrophilic granulocytes are implicated
in nonspecific immunity against bacteria
and fungi. Basophilic granulocytes are
involved in hypersensitivity reactions
(asthma, urticaria, allergic rhinitis and
anaphylaxis). Eosinophilic granulocytes
play a role in the defence against parasites.
● Lymphocytes are subdivided into T‐cells,
which have the important function of
differentiating between foreign and self,
B‐cells, which are amongst other things
responsible for the production of antibodies
(plasma cells, memory cells), and NK‐cells,
which play an essential role in protecting
against virus cells and tumour cells.
● Monocytes migrate into tissue, where they
become macrophages. They can recognise
exogenous material, ingest it (phagocyto–
sis), dissolve it and present it at their
cell surface. This causes the activation of
other defence cells (antigen presentation)
(Kasper etal., 2015).
Causes
Haematological Disorders
Abnormalities in the immune response may
have many different causes. There might
be disturbances in the differentiation of
individual or all cell lines. This can result
in functional reduction of the cell line(s)
affected, in a deficiency of these cells (lym–
phopaenia: T‐cells and B‐cells, neutropaenia)
or in an overproduction, which can replace
the production of other cell lines in the bone
marrow. Table6.3.2 provides a list of haema–
tological disorders.
Disorders oftheImmune System
through Medication
Disorders of the immune system can occur
as a wanted or unwanted effect of many
chemotherapeutics and immunosuppres–
sives. Particular emphasis must be given to
glucocorticoids like dexamethasone and
prednisone, but other immunosuppressives
like cyclosporin A (Sandimmun), tacrolimus
(Prograf) and the folic acid antagonist meth–
otrexate (Methotrexat) can also have this
effect.

6.3 Haematology and Oncology
248
Physical Damage
Blood formation can be impaired by irradia–
tion, either therapeutic or accidental. Stem
cells and lymphocytes are especially vulner–
able. Thus, a reduction in lymphocytes can
be observed at a very early stage after irra–
diation, whilst the number of granolocytes,
thrombocytes and erythrocytes decreases
only as damage to the stem cells progresses.
Clinical Oral Appearance
Sometimes, haematological disorders can be
discovered by the dentist. Manifestations of
haematological disorders in the oral cavity
can cause suspicion and suggest additional
investigations:
● Bleeding of the oral mucosa that does not
result from gingivitis may be an indication
of coagulation abnormalities due to a vari–
ety of causes. Petechial haemorrhages, and
haemorrhages at other places in the oral
mucosa, are typical for thrombocytopae–
nia (Hoffbrand and Moss, 2016).
● In case of acute myeloid leukaemia, gingi–
val swelling can be determined (Figure6.3.1)
(Kasper etal., 2015). Occasionally, this can
also be seen after treatment with cyclo–
sporine A and tacrolimus.
Table6.3.2 World Health Organization (WHO) Classification ofHematologic Malignancies (Abridged Version)
(Aster andBunn, 2017).
Subtype Putative cell of origin
Myeloid neoplasms
Acute myeloid leukemia (AML)
AML with recurrent genetic aberrations
AML without recurrent genetic aberrations
AML following cytotoxic therapy
Early myeloid progenitor
Myeloproliferative neoplasms
Chronic myeloid leukemia
Polycythemia vera
Essential thrombocythemia
Chronic eosinophilic leukemia
Primary myelofibrosis
Hematopoietic stem cell or early myeloid
progenitor
Myelodysplastic syndromes Early myeloid progenitor
Lymphoid neoplasms
Immature B‐cell and T‐cell tumors
B‐cell acute lymphoblastic leukemia/lymphoma
T‐cell acute lymphoblastic leukemia/lymphoma
Early B‐cell progenitor
Early T‐cell progenitor
Mature B‐cell tumors
Chronic lymphocytic leukemia/small lymphocytic
lymphoma
Mantle cell lymphoma
Follicular lymphoma
Burkitt lymphoma
Diffuse large B‐cell lymphoma
Post‐germinal center B cell
Naïve B cell
Germinal center B cell
Germinal center B cell
Germinal center or post‐germinal center B cell
Plasma cell tumors and related entities
Multiple myeloma
Lymphoplasmacytic lymphoma
Post‐germinal center B cell
Mature B‐cell
Mature T‐cell and natural killer cell tumors Mature T‐cell or natural killer cell
Hodgkin lymphoma Germinal center or post‐germinal center B cell

Disorders oftheImmune System/Granulocytes
249
● Unusual infections in terms of frequency,
manifestation or the occurrence of rare
microbes are signs of possible immuno–
suppression. Candida infections are
encountered quite often (Figure 6.3.2),
and non‐Candida albicans species (e.g.
tropicalis, krusei and parapsilosis) are
increasingly being seen. What should be
noted is that these are often resistant to
common therapeutics. Typical for leukae–
mias are virus reactivations of, for
instance, herpes zoster and herpes sim–
plex virus (HSV) (Ramseier etal., 2015).
Intraoral ulcers and large aphtae are com–
mon manifestations of HSV. All of these
infections can cause severe pain.
● Swelling of the lymph nodes and anaemia
(recognisable by paleness of the mucosa)
may point towards a haematological dis–
order. So might fever and night sweats
recorded in the medical history.
Clinical Significance
When an immune deficiency exists, a possible
haematogeneous spreading of microorgan–
isms may be expected after intervention.
Together with the haematologist or family
doctor, it needs to be determined whether
prophylactic antibiotics should be imple–
mented or whether treatment should just be
postponed.
A focus search should be conducted prior
to haematological treatment by chemother–
apy or haematopoietic stem cell transplan–
tation (HSCT). Ideally, located infection
foci are treated first; however, this is not
always possible because of the already limited
immune response and wound healing, or
because of the urgency of treating the malig–
nant tumours.
In patients who have received allogeneic
stem cell transplantation, the current situa–
tion concerning immune response should
always be clarified with the attending haema–
tologist: when appropriate, prophylactic
antibiotics should be given prior to tooth
cleaning, deep scaling, caries treatment and
extractions, or else the treatment must simply
be postponed.
In chemotherapeutic treatment, which
is sometimes accompanied by total body
irradiation, hyposalivation occurs on a
regular basis. The result may be increased
susceptibility to caries, gingivitis, periodon–
titis, mucocutaneous diseases and fungal
infections (Bagattoni etal., 2014; Buglione
etal., 2016).
After allogeneic stem cell transplantation,
acute and chronic rejection reactions may
occur (graft‐versus‐host disease, GvHD).
The oral mucosa shows typical lichenoid
changes with or without erythematous lesions,
ulcers or mucoceles. Often, hyposalivation
takes place at the same time, combined with
a correspondingly increased risk of caries,
periodontitis and infections of the mucosa.
Long‐term effects include secondary malig–
nant tumours of the oral mucosa. Because of
this, the oral mucosa needs to be inspected
regularly and thoroughly. The indication for
Figure6.3.1 Gingival swelling and acute myeloid
leukaemia.
Figure6.3.2 Thrush (Candida).

6.3 Haematology and Oncology
250
biopsy sampling should be wide and generous
for the exclusion and detection of malig–
nancy, respectively (Elad etal., 2015).
Anaemia
Anaemia is defined by a reduction of the
haemoglobin concentration in the blood.
Common causes are vitamin B
12
, folic acid
and iron deficiencies caused by chronic
bleeding, for instance due to excessive men–
strual flow or chronic diseases like tumours.
Other causes include innate haemoglobin
synthesis disorders such as sickle‐cell anaemia
and thalassaemia.
Clinical Significance
Anaemias hardly have an effect on dental
treatment. The following manifestations could
indicate anaemia and necessitate further
clarification with the family doctor: com–
plaints about reduced performance, weak–
ness, heart palpitations and dyspnoea under
stress, as well as the occurrence of pale skin or
mucosa. Angular cheilitis, burning tongue or
dysphagia (Plummer–Vinson syndrome) may
appear in case of iron deficiency. Vitamin B
12
and folic acid deficiencies cause burning
tongue with impaired sense of taste and
trophic glossitis with disappearing papillae.
Mucositis
Mucositis is an inflammation of the mucous
membranes of the gastrointestinal tract as a
consequence of chemotherapy and radiation
therapy. Patients who are receiving HSCT or
irradiation in the area of the mouth are
affected particularly often.
Oral mucositis is associated with ery–
thema, and at times with ulcerations and
violent pain. It is one of the most frequent
side effects of cancer treatment, and is often
the reason for reducing the treatment dose
or for having to postpone treatment. It also
may necessitate tube feeding or parenteral
nutrition.
Pathogenesis has not yet been fully clarified,
although considerable progress has been
made in recent years. The procedure can be
broken down into five stages: initiation, pri–
mary damage response, signal amplification,
ulceration and healing (Sonis, 2004). It is a
complex interaction of cells from the mucosa
and submucosa that is regulated by cytokines
such as tumour necrosis factor alpha
(TNF‐α), interleukins 6 (IL‐6) and 1b (IL‐1b)
and cyclooxygenase 2 (COX‐2). The oral
microbiome also plays a role (Sonis, 2011;
Al‐Dasooqi etal., 2013; Villa and Sonis, 2015;
Cinausero etal., 2017).
There are a variety of approaches to the
treatment and prophylaxis of oral mucositis.
Cryotherapy and low‐level light therapy
(LLLT) are recommended for children
receiving chemotherapy or HSCT condition–
ing with regimens associated with a high rate
of mucositis, whilst keratinocyte growth fac–
tor (KGF) is recommended for cooperative
children receiving HSCT conditioning with
regimens associated with a high rate of severe
mucositis (Lalla etal., 2014; Villa and Sonis,
2016; Sung etal., 2017):
● Cryotherapy involves cooling the oral
mucosa with ice whilst the patient receives
chemotherapy by short infusion. Because
of the vasoconstriction in the cooled
mucosa, fewer cytotoxic substances are
supposed to arrive there. Thus, the method
is only suitable for chemotherapeutic
agents which are administered in short
infusion and have a short half‐life. However,
it is inexpensive and readily accessible
(Sung etal., 2017).
● LLLT (also called photobiomodulation,
PBM) is the therapeutic use of light (e.g.
visible, near‐infrared or infrared light),
which is absorbed by endogenous
chromophores and triggers nonthermal,
noncytotoxic biochemical reactions by
photochemical and photophysical effects,
leading to physiological alterations
(Bensadoun and Nair, 2012, 2015; Zecha

GraftversusHost Disease
251
et al., 2016a,b). However, the method is
laborious and is not available everywhere.
● KGF (e.g. Palifermin) is an epithelium
growth factor. Since there are no studies
on its use, and since there is the possibility
of thickening the oral mucosa and causing
long‐term damage, it should only be
applied in selected cases where there is a
high risk of severe mucositis (Sung etal.,
2017).
As with all children, good oral hygiene should
be ensured. Professional tooth cleaning can
reduce pain in case of mucositis (Kubota
etal., 2015).
Graft‐versus‐Host Disease
Despite immunosuppressive treatment, GvHD
occurs in almost 25% of cases following
allogeneic HSCT, with the mouth being
one of the most frequently affected organs
(Flowers etal., 2002; Meier, 2011). It can
significantly impair quality of life. Oral
GvHD impresses by hyposalivation, lichenoid
hyperkeratotic striae or plaque with or without
erythematous changes (Figure6.3.3). Addi-
tionally, ulcerations and superficial mucoce–
les may occur. The ulcerations can be very
painful. In certain circumstances, severe
(a) (b)
(c)
Figure6.3.3 (a–c) Graft‐versus‐host disease.

6.3 Haematology and Oncology
252
sclerosis develops as a late effect, restricting
mouth or jaw opening and reducing mobility
of the tongue. Persistant chronic GvHD is
associated with increased risk of squamous
cell carcinomas. Viral factors like human
papillomavirus (HPV) seem to be of signifi–
cance in the aetiology and pathogenesis of
this type of carcinoma.
Management
In case of existing abnormalities of the oral
mucosa like aphthae and GvHD, products
containing sodium lauryl sulphate or men–
thol frequently cannot be tolerated because
they cause pain. Affected patients mostly
avoid them, along with spicy food. They may
have to use toothpaste that is free of sodium
lauryl sulphate. Products with antimicrobial
and protective effects on the oral mucosa are
recommended for oral rinsing. Alleviating
dry mouth with moisturising agents and cov–
ering open aphthae can help relieve the pain.
After allogeneic HSCT, regular examina–
tions of the mucous membranes are essen–
tial, in order to discover secondary carcinoma
early (Majhail etal., 2012). Secondary infec–
tions occur frequently in cases of poor oral
hygiene, which may also increase the inten–
sity of GvHD. Thus, maintaining good oral
hygiene is very important. However, such
lesions may hamper attempts in this direc–
tion, because of the pain. Depending on the
condition, several dental hygiene treatments
a year–including oral hygiene instructions–
are recommended.
For oral GvHD, topical steroids (e.g. bude–
sonide or dexamethasone) are recommended
as first‐line therapy. Extracorporeal photo–
pheresis is considered a second‐line systemic
therapy for steroid‐refractory GvHD. Local
anaesthetics may be helpful in pain control
(Dignan etal., 2012).
All carious lesions should be restored.
It is advisable to encourage patients to
practise good oral hygiene and additional
fluoridation (either by direct application or
via fluoridation splints at home or in a
dental practice).
Existing odontogenic infections should
receive therapy, preferably prior to immuno–
suppression. In this way, systemic infections
connected with blood stem cell transplants
can be reduced by one‐third, and the deaths
of an additional 18/10 000 treated patients
can be avoided (Elad etal., 2008). However,
the extraction of teeth necessitates a long
healing period (2 weeks), and there is often
an urgent need for therapy, especially in leu–
kaemia patients, so dental treatment must
frequently be postponed until after blood
stem cell transplantation. Due to the danger
of haematogenic spread, dental treatments
should be conducted by giving antibiotic
prophylaxis.
Generally, in immunosuppressed patients,
contact should be made with the attending
physician as soon as is possible. At times,
referral to university dental clinics is recom–
mended, as they deal with immunosup–
pressed patients every day–including during
inpatient treatment–and can meet all diag–
nostic needs. The objectives in giving dental
treatment to immunosuppressed patients are
prevention of infection, pain relief, mainte–
nance of function, treatment of complica–
tions and improvement of quality of life.
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