Oral Problems in Patients Undergoing Haematology or Oncology Treatment

Created January 31, 2020
Author DentistryKey
Category General Dentistry
Comments 43

Management ofDental Emergencies inChildren andAdolescents, First Edition.

Editedby Klaus W.Neuhaus andAdrianLussi.

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

etal., 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 inPatients Undergoing Haematology

orOncology Treatment

Adrian M. Ramseier

, Jakob Passweg

and Tuomas Waltimo

Department of Oral Health & Medicine, University Center for Dental Medicine Basel, University of Basel, Basel, Switzerland

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. Table6.3.1 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

/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

/l;

a value of >100 × 10

/l is thought to be

ideal for surgical intervention. With values

>50 × 10

/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

/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

/l, as well as

Table6.3.1 Causes ofthrombocytopaenia

(Hoffbrand andMoss, 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 oftheImmune System/Granulocytes

247

during maxillofacial intervention with a

platelet count of <100 × 10

/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 etal., 2015; Spivakovsky

etal., 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 oftheImmune

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 etal., 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. Table6.3.2 provides a list of haema–

tological disorders.

Disorders oftheImmune 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 (Figure6.3.1)

(Kasper etal., 2015). Occasionally, this can

also be seen after treatment with cyclo–

sporine A and tacrolimus.

Table6.3.2 World Health Organization (WHO) Classification ofHematologic Malignancies (Abridged Version)

(Aster andBunn, 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 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 oftheImmune 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 etal., 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 etal., 2014; Buglione

etal., 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

Figure6.3.1 Gingival swelling and acute myeloid

leukaemia.

Figure6.3.2 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 etal., 2015).

Anaemia

Anaemia is defined by a reduction of the

haemoglobin concentration in the blood.

Common causes are vitamin B

, 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

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 etal., 2013; Villa and Sonis, 2015;

Cinausero etal., 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 etal., 2014; Villa and Sonis,

2016; Sung etal., 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 etal., 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

GraftversusHost 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 etal.,

2017).

As with all children, good oral hygiene should

be ensured. Professional tooth cleaning can

reduce pain in case of mucositis (Kubota

etal., 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 etal., 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 (Figure6.3.3). Addi-

tionally, ulcerations and superficial mucoce–

les may occur. The ulcerations can be very

painful. In certain circumstances, severe

(a) (b)

(c)

Figure6.3.3 (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 etal., 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 etal., 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 etal., 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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Non‐infective Swellings: Cysts, Tumours and Ranulas

Management ofDental Emergencies inChildren andAdolescents, First Edition. Editedby Klaus W.Neuhaus andAdrianLussi. © 2019 John Wiley & Sons Ltd. Published 2019 by John Wiley & Sons Ltd. Companion website: www.wiley.com/go/neuhaus/dental_emergencies245 IntroductionUniquely, 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 etal., 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. HaemostasisStopping 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 6.3Oral Problems inPatients Undergoing Haematology orOncology TreatmentAdrian M. Ramseier1, Jakob Passweg2 and Tuomas Waltimo11 Department of Oral Health & Medicine, University Center for Dental Medicine Basel, University of Basel, Basel, Switzerland2 Department of Hematology, University Hospital Basel, Basel, Switzerland 6.3 Haematology and Oncology246and 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. Table6.3.1 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 × 109/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 × 109/l; a value of >100 × 109/l is thought to be ideal for surgical intervention. With values >50 × 109/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 × 109/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 × 109/l, as well as Table6.3.1 Causes ofthrombocytopaenia (Hoffbrand andMoss, 2016).Failure of platelet productionSelective megakaryocyte depressionRare congenital defectsDrugs, chemicals, viral infectionsPart of general bone marrow failureCytotoxic drugsRadiotherapyAplastic anaemiaLeukaemiaMyelodysplastic syndromesMyelofibrosisMarrow infiltration (e.g. carcinoma, lymphoma, Gaucher’s disease)Multiple myelomaMegaloblastic anaemiaHIV infectionIncreased consumption of plateletsImmuneAutoimmuneIdiopathicAssociated with systemic lupus erythematosus, chronic lymphocytic leukaemia or lymphomaInfections: Helicobacter pylori, human immuno-deficiency virus (HIV), other viruses, malariaDrug‐induced, e.g. heparinPost‐transfusional purpuraFoeto‐maternal alloimmune thrombocytopaeniaDisseminated intravascular coagulationThrombotic thrombocytopaenic purpuraAbnormal distribution of plateletsSplenomegaly, e.g. liver diseaseDilutional lossMassive transfusion of stored blood to bleeding patients Disorders oftheImmune System/Granulocytes247during maxillofacial intervention with a platelet count of <100 × 109/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 DisordersCongenital 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 etal., 2015; Spivakovsky etal., 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 oftheImmune System/GranulocytesDefence 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 etal., 2015).CausesHaematological DisordersAbnormalities 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. Table6.3.2 provides a list of haema-tological disorders.Disorders oftheImmune System through MedicationDisorders 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 Oncology248Physical DamageBlood 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 AppearanceSometimes, 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 (Figure6.3.1) (Kasper etal., 2015). Occasionally, this can also be seen after treatment with cyclo-sporine A and tacrolimus.Table6.3.2 World Health Organization (WHO) Classification ofHematologic Malignancies (Abridged Version) (Aster andBunn, 2017).Subtype Putative cell of originMyeloid neoplasmsAcute myeloid leukemia (AML)AML with recurrent genetic aberrationsAML without recurrent genetic aberrationsAML following cytotoxic therapyEarly myeloid progenitorMyeloproliferative neoplasmsChronic myeloid leukemiaPolycythemia veraEssential thrombocythemiaChronic eosinophilic leukemiaPrimary myelofibrosisHematopoietic stem cell or early myeloid progenitorMyelodysplastic syndromes Early myeloid progenitorLymphoid neoplasmsImmature B‐cell and T‐cell tumorsB‐cell acute lymphoblastic leukemia/lymphomaT‐cell acute lymphoblastic leukemia/lymphomaEarly B‐cell progenitorEarly T‐cell progenitorMature B‐cell tumorsChronic lymphocytic leukemia/small lymphocytic lymphomaMantle cell lymphomaFollicular lymphomaBurkitt lymphomaDiffuse large B‐cell lymphomaPost‐germinal center B cellNaïve B cellGerminal center B cellGerminal center B cellGerminal center or post‐germinal center B cellPlasma cell tumors and related entitiesMultiple myelomaLymphoplasmacytic lymphomaPost‐germinal center B cellMature B‐cellMature T‐cell and natural killer cell tumors Mature T‐cell or natural killer cellHodgkin lymphoma Germinal center or post‐germinal center B cell Disorders oftheImmune System/Granulocytes249 ● 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 etal., 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 SignificanceWhen 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 etal., 2014; Buglione etal., 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 Figure6.3.1 Gingival swelling and acute myeloid leukaemia.Figure6.3.2 Thrush (Candida). 6.3 Haematology and Oncology250biopsy sampling should be wide and generous for the exclusion and detection of malig-nancy, respectively (Elad etal., 2015). AnaemiaAnaemia is defined by a reduction of the haemoglobin concentration in the blood. Common causes are vitamin B12, 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 SignificanceAnaemias 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 B12 and folic acid deficiencies cause burning tongue with impaired sense of taste and trophic glossitis with disappearing papillae. MucositisMucositis 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 etal., 2013; Villa and Sonis, 2015; Cinausero etal., 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 etal., 2014; Villa and Sonis, 2016; Sung etal., 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 etal., 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 GraftversusHost Disease251et 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 etal., 2017).As with all children, good oral hygiene should be ensured. Professional tooth cleaning can reduce pain in case of mucositis (Kubota etal., 2015). Graft‐versus‐Host DiseaseDespite immunosuppressive treatment, GvHD occurs in almost 25% of cases following allogeneic HSCT, with the mouth being one of the most frequently affected organs (Flowers etal., 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 (Figure6.3.3). Addi-tionally, ulcerations and superficial mucoce-les may occur. The ulcerations can be very painful. In certain circumstances, severe (a) (b)(c)Figure6.3.3 (a–c) Graft‐versus‐host disease. 6.3 Haematology and Oncology252sclerosis 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. ManagementIn 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 etal., 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 etal., 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 etal., 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. ReferencesAl‐Dasooqi, N., Sonis, S. T., Bowen, J. M., Bateman, E., Blijlevens, N., Gibson, R. J., etal. 2013. Emerging evidence on the pathobiology of mucositis. Supportive Care in Cancer, 21(11), 3233–41.Aster, J. C., Bunn, H. F. 2017. Pathophysiology of Blood Disorders, 2nd edn. New York: McGraw‐Hill.Bagattoni, S., D’Alessandro, G., Prete, A., Piana, G., Pession, A. 2014. Oral health and References253dental late adverse effects in children in remission from malignant disease. A pilot case‐control study in Italian children. 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