RED BLOOD CELL DISORDERS

Erythrocytosis

Erythrocytosis occurs when the mass of the red cells reaches 125 percent of the
estimated body mass value of the individual.

Usually, it is characterized by an elevated level of hemoglobin (Hb) (185 mg / dL for

males, > 165 mg / dL for females) or an elevated level of hematocrit (HCT) (> 52 percent
males, > 48 percent females).

Primary erythrocytosis is a disorder in which the erythropoietic compartment extends

independently of, or reacts poorly to, extrinsic influences.

The prevalent type of primary erythrocytosis is polycytemia vera (PV).

Polycythemia Vera

PV is a clonal disorder characterized by a self-determining distribution of a single cell line of

erythroid.

PV has common symptoms with two other forms of myeloproliferative neoplasm: essential
thrombocytosis and main myelofibrosis.

Collectively, these three diseases display fairly mild cellular maturation, phenotypic and
genotypic mimicry, JAK2 gene defects, and a propensity to evolve or acquire myelofibrosis.

Clinical Manifestations

1- PV is usually asymptomatic and often only discovered incidentally.

2- PV should be suspected in patients with elevated Hb or HCT levels, splenomegaly,

or portal venous thrombosis.

3- pruritis, vertigo, gastrointestinal pain, headache, paresthesia, fatigue, weakness,

visual disturbances, tinnitus, plethora, and bleeding gums.

4-
increased bleeding risk results from an altered degradation and function of von
Willebrand factor.

Oral Manifestations

1- Erythema (red–purple color) of mucosa

 2- Glossitis, erythematous, and edematous gingiva.

3- Spontaneous gingival bleeding

Oral Health Considerations

There are no established guidelines addressing the delivery of dental care for the patient
with PV.

The delivery of routine dental care for the well-controlled patient with PV likely incurs
minimal risk.

Low-dose aspirin is rarely associated with hemorrhagic complications from dental

extractions.

Poorly controlled patients are at an increased risk for both thrombotic and hemorrhagic
due to blood hyperviscosity and concurrent qualitative and quantitative platelet
alterations.

Thus, a medical consultation to determine the current patient status should be obtained
and referral is warranted for patients who are poorly controlled or who exhibit signs and
symptoms of poor control.

There are no defined standards for the provision of dental treatment to patients with PV.
The provision of regular dental treatment to a well-controlled PV patient is expected to be
at low risk.
Low-dose aspirin is seldom linked with hemorrhagic risks from dental extraction.
Poorly regulated patients are at elevated risk for both thrombotic and hemorrhagic
responses owing to blood hyperviscosity and concomitant qualitative and quantitative
platelet alterations.
As a consequence, a medical examination to assess the actual condition of the patient will
be sought and a referral is recommended for patients that are improperly managed or
exhibit signs and effects of inadequate regulation.

Anemia

Anemia is a syndrome finding defined as a lower than normal Hb concentration (<13 g/dL
for males and <12 g/dL for females).

The signs and symptoms of anemia occur as a consequence of the hypoxia and
compensatory physiologic responses produced.

Typical symptoms include fatigue and dizziness.

The classic sign of anemia is pallor, which may be observed in the conjunctivae, face, nail
beds, tongue, and palmar creases.
In the elderly, anemia is associated with decreased physical performance of daily
activities, cognitive impairment, depression, diminished quality of life, increased hospital
admissions, and impaired survival.

Anemia is a syndrome described as a lower than usual Hb concentration (< 13 g / dL for

males and < 12 g / dL for females).

Signs and symptoms of anemia are caused by hypoxia and induced physiological reactions.

Typical symptoms include tiredness and dizziness.

The typical symptom of anemia is pallor, which can be found in conjunctivae, nose, nail
beds, lips, and palm wrinkles.

Among the aged, anemia is correlated with diminished physical activity, cognitive decline,
fatigue, lowered quality of life, elevated medical visits, and compromised longevity.

Iron Deficiency Anemia (IDA) and Anemia of Chronic Inflammation (ACI)

Iron deficiency anemia (IDA) is defined as a reduction in total body iron to an extent that
iron stores are fully exhausted and some degree of tissue iron deficiency is present.

It may occur as a consequence of low dietary intake, impaired absorption, or excessive

iron loss.

ACI, also known as anemia of chronic disease, mimics several clinical and laboratory
features of IDA and is the second most frequent form of anemia observed in practice.

Conditions in which ACI is frequently observed include autoimmune diseases, acute and
chronic infection, malignancies, and chronic kidney disease.

Iron deficiency anemia (IDA) is characterized as a decrease in total body iron to the point that
iron reserves are fully depleted and some degree of tissue iron deficiency is present.

This can arise as a consequence of inadequate food consumption, decreased absorption, or

premature iron loss.

ACI, also known as chronic disease anemia, mimics many clinical and laboratory
characteristics of IDA and is the second most severe type of anemia found in action.

Conditions in which ACI is commonly found include infectious disorders, acute and recurrent
illnesses, malignancies and chronic kidney disease.

Clinical and Oral Manifestations

The most important clinical symptom of anemia is chronic fatigue.

Outward signs include pallor of the conjunctivae, lips, and oral mucosa; brittle nails with
spooning, cracking, and splitting of nail beds; and palmar creases that have traditionally
been used by physicians in the diagnosis of anemia.

Other findings may include palpitations, shortness of breath, numbness and tingling in
fingers and toes, and bone pain.

Chronic fatigue is the most significant health sign of anemia.

Outward symptoms include conjunctiva pallor, cheeks, and oral mucosa; weak nails with
spooning, breaking, and fracturing of nail beds; and palmar creases that have historically
been used by doctors to treat anemia.

Certain symptoms can include palpitations, shortness of breath, numbness and tingling of
fingers and toes, and bone pain.

Glossitis and stomatitis are recognized oral manifestations of anemia.

IDA or ACI should be suspected in every case of glossitis, glossodynia, angular cheilitis,
erythematous mucositis, oral candidiasis, recurrent oral ulcers, and burning mouth when
no other obvious causes are identified.

These findings are believed to be caused by the impaired cellular immunity, deficient
bactericidal activity of polymorphonuclear leukocytes, inadequate anti-body response,
and epithelial abnormalities attributed to iron lack.

Glossitis and stomatitis are oral manifestations of anemia.

IDA or ACI may be presumed in all instances of glossitis, glossodynia, angular cheilitis, erythematous mucositis,
oral candidiasis, chronic oral ulcers and burning of the mouth where no more apparent triggers are known.

Such results are suspected to be related to compromised cell immunity, weakness in the bactericidal function
of polymorphonuclear leukocytes, insufficient antibody reaction, and epithelial defects attributable to iron
deficiency.

Plummer-Vinson Syndrome

Plummer-Vinson syndrome, also called Paterson-Kelly syndrome, is a rare syndrome

characterized by the classic triad of dysphagia, iron deficiency anemia, and upper
esophageal webs or strictures.

It usually affects middle-aged white women in the fourth to seventh decade of life but
has also been described in children and adolescents.

The dysphagia may be intermittent or progressive over years, is usually painless and
limited to solids, and may be associated with weight loss.

Symptoms resulting from anemia (weakness, pallor, fatigue, tachycardia) predominate

the clinical picture.

Other potential findings include glossitis, glossopyrosis, glossodynia, angular cheilitis,

koilonychia, fragility, thinning of nails, and brittle hair.
Plummer-Vinson Syndrome, also known as Paterson-Kelly Syndrome, is a severe condition characterized by a
typical triad of dysphagia, iron deficient anemia, and upper esophageal networks or strictures.

It typically affects middle-aged white women in the fourth to seventh decade of existence, but it has also been
identified in children and teenagers.

Dysphagia can be sporadic or gradual through the years, typically painless and confined to solids, which can be
correlated with weight loss.

Symptoms of anemia (weakness, pallor, exhaustion, tachycardia) predominate in the clinical picture.

Certain possible findings include glossitis, glossopyrosis, angular cheilitis, koilonychia, fragility, thinning of nails,
and brittle hair.

Oral Health Considerations

For dental patients with extremely low Hb levels, physician consultation prior to surgical
treatment is recommended. Patients with IDA or ACA whose Hb levels are above 11 g/dL
and who are free from symptoms can tolerate routine dental care.

Routine care should be deferred in those patients whose Hb is <11 g/dL or those who
manifest signs and symptoms such as shortness of breath, abnormal heart rate, or
oxygen saturation less than 91% (as determined by pulse oximetry) until their health
status improves.

Narcotic use should be limited for those with severe anemia, and dentists should be
aware that anemia places a patient at increased risk for ischemic heart disease.

Medical examination prior to surgical procedure is indicated for dental patients with
exceptionally low Hb rates. IDA or ACA patients whose Hb levels are above 11 g / dL and
who are free from symptoms can withstand routine dental treatment.

Routine treatment may be postponed for those with Hb < 11 g / dL or those with signs
and indications such as shortness of breath, elevated heart rhythm or oxygen saturation
of less than 91 per cent (as measured by pulse oximetry) before their wellbeing is
enhanced.

Narcotic usage should be reserved for patients with serious anemia, and dentists should
be mindful that anemia puts a individual at an elevated risk of ischaemic cardiac disease.

B12 and Folate Deficiency Anemia

Vitamin B12 or folate deficiency are common causes of macrocytic anemia.

The term macrocytosis refers to a blood condition in which RBCs are larger than normal .
 Both vitamins participate in critical enzyme reactions necessary for proper DNA
synthesis. From hematological perspective, lack of either vitamin results in an essentially
identical megaloblastic anemia.

Vitamin B12 or folate deficiency is a typical cause of macrocytic anemia.

The term macrocytosis applies to a blood disease in which RBCs are higher than average.

both vitamins are involved in the essential enzyme reactions required for proper DNA
synthesis. On a hematological point of view, the absence of any nutrient results in nearly
similar megaloblastic anemia.

Clinical and Oral Manifestations

The typical nonspecific symptoms of IDA or ACI such as fatigue, decreased mental
concentration, and weakness are characteristic of folate or B12 deficiency.

B12 deficiency may present as neurological symptoms such as clumsiness, unsteady gait,
and paresthesia.

Oral signs of folate and B12 deficiency are similar to those observed with IDA or ACI and
include a beefy red tongue with smooth or patchy areas of erythema.

Symptom complaints include soreness or a burning sensation affecting the tongue, lips,
buccal mucosa, and other mucosal sites. Paresthesia and taste alterations have been
reported.

Typical signs of IDA or ACI such as exhaustion, reduced intellectual focus and discomfort
are indicative of folate or B12 deficiency.

B12 deficiency can manifest as neurological symptoms such as clumsiness,

impertinence, and paresthesia.

Oral symptoms of folate and B12 deficiency are close to those associated in IDA or ACI
which involve a beefy red tongue in smooth or patchy erythema regions.

Symptoms involve a soreness or burning feeling involving the mouth, ears, oral mucosa,
and other mucosal locations. Paresthesia and improvements in taste have been
documented.

WHITE BLOOD CELL DISORDERS

Agranulocytosis (Neutropenia, Granulocytopenia)

The terms agranulocytosis, neutropenia, and granulocytopenia are commonly used

interchangeably to note a reduced quantity of leukocytes.
Susceptibility to infectious diseases increases sharply when the ANC falls to <1,000/μL.
When the ANC falls to <500/μL, control of endogenous microbial flora (e.g., mouth, gut)
is impaired.

Clinical symptoms of agranulocytosis include sudden onset of fever, rigors, and sore
throat. When the ANC is <200/μL, the local inflammatory process is absent.

The terms agranulocytosis, neutropenia and granulocytopenia are generally used

interchangeably to suggest a decreased number of leukocytes.

Susceptibility to infectious diseases rises dramatically as the ANC decreases to < 1,000/μL.
As the ANC drop to < 500/μL, the regulation of endogenic microbial flora (e.g., mouth,
intestine) becomes compromised.

clinical signs of agranulocytosis include rapid development of fatigue, weakness, and sore
throat. The local inflammatory cycle is not active when the ANC is < 200/μL.

Oral Health Considerations

There is a direct relationship between the onset and severity of oral complications and
bone marrow status.

Prophylactic antibiotics have been recommended by patients with a hematologic

malignancy–caused ANC <1,000/μL prior to dental extractions.

Evidence from Cochrane reviews confirms that the provision of antibiotic prophylaxis in a
febrile patients with neutropenia (ANC <1,000/μL) reduces mortality, febrile episodes,
and bacterial infections, without apparent development of antibiotic resistance.

Recent studies assessing antibiotics of the quinolone class revealed fewer adverse
events and better outcomes than other classes of antibiotics.

Hence, an oral fluoroquinolone plus amoxicillin/clavulanate (or plus clindamycin if

penicillin allergic) is recommended as empiric therapy, unless fluoroquinolone
prophylaxis was used before fever developed.

Physician consultation is warranted for guidance on the dental management of the

patient with severe neutropenia.

Potential oral findings include gingivitis, thrush, stomatitis, and oral ulcers. These oral
infections should be treated with the appropriate antimicrobial agents.
Cyclic Neutropenia

Cyclic neutropenia is a rare inherited autosomal hematologic disorder, characterized by

repetitive episodes of fever, mouth ulcers, and infections attributable to recurrent severe
neutropenia.

These patients manifest a distinctly cyclical pattern to episodes of neutropenia

(<200/μL).

Neutropenia recurs with a regular 21-day intervals, persists for 3 to 5 days, and is
characterized by infectious events.

Clinical and Oral Manifestations

Periodic oscillations of neutrophil counts associated with fever and mouth ulcers are the
key clinical hallmarks of this disease.

A wide spectrum of symptom severity, ranging from asymptomatic to life-threatening

illness, is seen in autosomal dominant cyclic neutropenia. 129 The phenotype changes with
age, where children display typical neutrophil cycles with symptoms of mucosal
ulceration, lymphadenopathy, and infections.

Adults often have fewer episodes and milder chronic neutropenia without distinct cycles.
The most severe consequences of cyclic neutropenia are gangrene, bacteremia, and
septic shock due to perforating colonic ulcers and infections with Clostridium septicum.

The occurrence of fever, abdominal pain, and a clinical picture of sepsis or a rapidly
spreading area of cellulitis are critical and often life-threatening events in these patients.

The oral manifestations of cyclic neutropenia include recurrent aphthous stomatitis

(RAS), recurrent gingivitis, and periodontitis.

RAS is one of the most common presenting symptoms in cyclic neutropenia;

RAS arises during the nadir and resolves spontaneously as the neutrophil count
improves.

The finding of RAS with or without periodontal disease, particularly in a child, should raise
the suspicion of cyclic neutropenia.

Chronic Neutropenias

Chronic neutropenia can be congenital, acquired, or idiopathic and is defined as a low

ANC for more than 6 months.

The predominant types of chronic neutropenias are chronic benign idiopathic

neutropenia and severe congenital neutropenia (SCN), also known as Kostmann’s
syndrome.

In SCN, children typically have absolute neutrophil counts of <500/μL on a continuing

basis. Chronic benign idiopathic neutropenia is characterized by prolonged non- cyclic
neutropenia as the sole abnormality, with no under- lying disease to which the
neutropenia can be attributed.

Clinical and Oral Manifestations

Patients with SCN experience deep tissue infections with lung abscesses, liver abscesses,
and severe skin infections.

As a consequence, they are chronically ill soon after birth with secondary anemia,
thrombocytosis, and onocytosis.

A BM usually reveals promyelocytic maturation arrest with a paucity of mature cells but
many early forms of the myeloid lineage.

Other manifestations include life-threatening bacterial infections, recurrent gingivitis, and

even severe periodontitis, often starting in early childhood.

Patients with chronic benign idiopathic neutropenia tend to experience a more benign
clinical course compared to SCN.

In light of an otherwise unremarkable medical history, periodontitis of the primary

dentition and early tooth loss may represent the sole manifestations of chronic benign
idiopathic neutropenia affecting a juvenile patient.

SCN patients had significant tissue infections of lung abscesses, kidney abscesses, and
serious skin diseases.

As a rule, they became critically sick soon after conception with secondary anemia,
thrombocytosis and onocytosis.

Many symptoms involve life-threatening bacterial infections, chronic gingivitis, and even
serious periodontitis, mostly from early childhood.

In the context of often unremarkable medical history, primary dentition periodontitis and
early tooth loss may be the only symptoms of persistent mild idiopathic neutropenia marking
an adolescent individual.

Agranulocytes

Agranulocytes are mainly lymphocytes (B and T) and monocytes.

Lymphocytes determine and facilitate the body’s humoral and cellular immunity
response to foreign proteins and pathogens.

A decrease in lymphocytes (lymphocytopenia) refers to a count of <1,000/μL of blood in

adults.

Causes of lymphocytopenia may be iatrogenic or due to infections, systemic diseases, or

inherited.

An increase in circulating lymphocytes (lymphocytosis) can be seen following infections

such as infectious mononucleosis and pertussis, or in lymphoproliferative disorders such
as acute and chronic lymphocytic leukemia.

Agranulocytes are mostly lymphocytes (B and T) and monocytes.

Lymphocytes assess and promote the immune reaction of the body against foreign
proteins and pathogens.

Decrease of lymphocytes (lymphocytopenia) leads to a blood count of < 1,000/μL of

adults.

Causes of lymphocytopenia can be iatrogenic or related to illness, autoimmune disorder,

or hereditary.

Increased circulating lymphocytes (lymphocytosis) can be seen after infections such as

acute and chronic lymphocytic leukemia.

Leukemia

Leukemia results from the proliferation of a clone of abnormal hematopoietic cells with
impaired differentiation, regulation, and programmed cell death (apoptosis).

It is defined by a rapid disease course which progresses over weeks to months,

ultimately culminating in bone marrow failure.

Leukemia is classified based on:

- the clinical behavior (acute or chronic)

- the primary hematopoietic cell line affected (myeloid or lymphoid).

Leukemic cells multiply at the expense of normal hematopoietic cell lines, resulting in
marrow failure, altered blood cell counts, and, when untreated, death from infection,
bleeding, or both.

Acute Leukemia
Acute Lymphocytic/Lymphoblastic Leukemia (ALL)

ALL is the most common malignancy in childhood.

ALL is the clonal proliferation of lymphoid cells that have undergone maturational arrest
in early differentiation.

Although the contemporary survival rate approaches 90%, it remains the main cause of
death from disease in children and young adults.

Clinical and Oral Manifestations

Symptoms include fever, weight loss, muscle or joint pain, fatigue/malaise,

anemia/pallor, mucosal bleeding, petechiae, and local infections. Fever and
fatigue/malaise are the most common presenting symptoms in patients with all types of
leukemia.

The most common manifestations or clinical signs of acute leukemia at initial

presentation are lymph- adenopathy , laryngeal pain, gingival bleeding, oral ulceration,
and gingival enlargement.147 In a study of

observed oral manifestations included gingivitis, caries, mucositis, periodontitis, cheilitis,

recurrent herpes, and primary herpetic gingivostomatitis,

Other oral manifestations noted were dry lips, mucosal pallor, mucosal petechiae,
ecchymoses, and ulcers.

The prevalence of oral candidiasis was 6.12%.

It was observed that high risk ALL and poor oral hygiene were important risk factors for
the development of candidiasis and gingivitis.

The type of leukemia, gender and phase of chemo- therapy were apparently associated
with the presence of candidiasis, gingivitis, and periodontitis and could be considered
risk factors for the development of oral manifestations.

Acute Myeloid Leukemia (AML)

AML subtypes are defined on the basis of morphological, cytogenetic, and molecular
criteria.

Acute promyelocytic leukemia (APL) is a specific subset of AML which occurs most often
in adults but has a much more favorable cure rate. Disseminated intravascular
coagulation is a major feature of APL, and until recently, the early death rate exceeded
20% because of hemorrhage.

Clinical and Oral Manifestations

See section under ALL for clinical and oral manifestations. For precancer treatment–
related oral health considerations, treatment recommendations as well as oral
treatment– related side effects during and after treatment, please refer to Chapter 9.
Chronic Leukemia

Chronic Myelogenous Leukemia (CML)

Chronic leukemia presents with less pronounced marrow failure than acute leukemia.
Most cases of CML occur in adults, but it can occur rarely in children.

Clinical and Oral Manifestations

CML typically follows a chronic and indolent course for 3 to 5 years, followed by an
accelerated phase and blast crisis resembling acute leukemia.

In the acute or blast phase, the most common manifestations are fever, weak- ness,
fatigue, anorexia, weight loss, splenomegaly, anemia, and infection.

In the blast phase, there are excess immature WBCs (more than 30%) in the blood and
bone marrow.

- CML rarely has oral presentations.

Chronic Lymphocytic Leukemia (CLL)

CLL results from the slow accumulation of clonal B lymphocytes in 95% of patients.

There are two kinds of CLL. One grows very slowly, rarely needs to be treated and is
associated with a 15-year or more survival rate.

The other kind of CLL grows faster, is more serious, and the average survival rate is 8
years.

Clinical and Oral Manifestations

Historically, CLL was frequently recognized when patients presented for evaluation of
constitutional symptoms (fever, night sweats, weight loss, fatigue), lymphadenopathy,
anemia, or thrombocytopenia.

Oral manifestations at presentation of CLL are infrequent and generally involve bleeding
or infection.

The oral lesion incidence rate increases once chemotherapy is initiated for treatment.
Please see Chapter 9 for more on oral complications of cancer treatment.

Oral Health Considerations

CLL is a relatively indolent chronic hematologic malignant disease that often has a
prognosis compatible with relatively normal dental treatment planning.
Patients in late-stage disease, with severe thrombocytopenia (<50,000/μL), should be
considered for platelet supplementation prior to dental surgery.

PLATELET DISORDERS

Platelet disorders may be divided into two categories by etiology—congenital and

acquired—and into two additional categories by type—thrombocytopenias and
thrombocyto- pathies.

Thrombocytopenias occur when platelet quantity is reduced and are caused by one of
three mechan- isms: decreased production in the bone marrow, increased sequestration
in the spleen, or accelerated destruction. Thrombocytopathies, or qualitative platelet
disorders, may result from defects in any of the critical platelet reactions. Dysfunctional
platelet mechanisms may occur in isolated disorders or in conjunction with dysfunctional
coagulation mechanisms.

Oral Manifestations

As with systemic hemorrhage associated with thrombocytopenia, oral manifestations are

not pathognomonic for the specific type of clotting disorder. Oral lesions can include
petechiae, ecchymoses, or purpura of the oral mucosa (Fig. 67), as well as spontaneous
oozing of blood from the gingiva and periodontium. Risk for clinical appearance of oral
bleeding due to decreased platelet number typically becomes clinically significant when
baseline circulating platelet counts are <25,000/mm3

Dental Considerations

The dentist’s role in management of the thrombo- cytopenic patient includes two
domains, firstly, reducing the risk for the source of oral bleeding (e.g., reduction of
mucosal trauma, elimination of the gingival/periodontal source of bleeding). This is the
most common role of the dental practitioner for thrombocytopenic patients. Having said
this, it is incumbent upon the oral health practitioner to maintain close interprofessional
communication with the patient’s physician if oral tissue-invasive procedures such as
dental extractions are being considered in order to reduce or eliminate the

source of oral hemorrhage. In these cases it is often clinically important and

advantageous to implement platelet transfusion support approximately 30 minutes prior
to the tissue invasive procedure, if the baseline platelet count is <40,000/ mm3. Further
information on dental management strategies for the patient at risk for bleeding
secondary to dental procedures is covered in the sec- tion on “Anticoagulation” in this
chapter.

Secondarily, but infrequently, the dentist may be among the first healthcare providers to
assess the patient for unexplained bleeding if the condi- tion involves the oral cavity. In
these cases, the dentist should refer the patient for medical evalu- ation of a possible
bleeding diathesis that could be caused by thrombocytopenia and/or another etio- logic
basis for oral hemorrhage.

clinical consultations
dental care

definition
clinical picture or oral manifestation
dental implication or consediration