Manifestations in the oral cavity in diseases of the blood in children. Tactics children's dentist.

Red and white blood cells are the cornerstones of systemic health, and disorders of these cells may have profound effects on all organ systems. In the periodontium, red blood cells carry oxygen and nutrients to the tissues. Platelets are critical for hemostasis and for production of critical immunoinflammatory mediators. White blood cells protect the periodontium and oral mucosa from bacterial, viral, and fungal pathogens. These cells exist in an exquisite homeostatic balance. Disorders that disturb this balance may manifest within the periodontium or on other mucosal surfaces.

Oral signs and symptoms may be the first clinical evidence of underlying blood disorders, and the dental health practitioner must pay careful attention to possible indicators of occult disease. Diseases of blood frequently affect soft and hard tissues of mouth with different characteristics. Oral manifestation of blood disease affect color of the mucosa hypertrophy of gingiva, mucosal destruction in the form of ulceration, bleeding and hemorrhage, color of the tooth with red discoloration, lymph node and affect the bone with decreased density and enlarged marrow space. Every dentist should be familiarized the wide variety of oral manifestations of the blood diseases to differentiate from other diseases.

An abnormal blood count or blood cell morphology does not necessarily indicate a primary haematology problem because it may reflect an underlying non-haematological condition or may be the result of therapeutic interventions. Anaemia occurs in many conditions, but a primary blood disease should be considered when a patient has splenomegaly; lymphadenopathy; a bleeding tendency or thrombosis; and/or non-specific symptoms (malaise, sweats, or weight loss). As with any clinical problem, the first steps in determining the diagnosis include obtaining a care-ful clinical and drug history and thorough physical examination. The result of these, in combination with the patient’s age, sex, ethnic origin, social and family history, and knowledge of the locally prevalent diseases, will determine subsequent laboratory investigations.

The investigation of specific haematological prob-lems is covered in detail in Chapters 7 (iron deficiency anaemia), 8 (megaloblastic anaemia), 9, 10, and 11 (haemolytic anaemias), 12 (haemoglo-binopathies), and 16 and 17 (coagulation disorders).

Interpretation of Screening Tests

Results of laboratory screening tests should always be interpreted with an understanding of the limi-tations of the tests and the physiological variations that occur with sex, age, and conditions such as pregnancy and exercise. Physiological variations in cell counts are detailed in Chapter 2. Abnormalities of red cells, white cells, or platelets may be quanti-tative (increased or reduced numbers) or qualitative (abnormal appearance and/or function).

Increases Affecting More Than One Cell Line

A simultaneous increase in the cells of more than one cell line suggests that the overproduction of cells originates in an early precursor cell. This occurs in myeloproliferative disorders in which one cell type may predominate, e.g., platelets in essential thrombocythaemia and red cells in polycythaemia vera (primary proliferative polycythaemia), but there are often increases in other cell lines. The diagnosis will depend on which cell line expansion is dominant.

Erythrocytosis

Increases in red cells may be one of the following:

• “Relative” (pseudopolycythaemia) owing to reduced plasma volume

• “Primary” (polycythaemia vera) as part of the spectrum of myeloproliferative disorders

• “Secondary” to chronic hypoxia (e.g., chronic lung disease, congenital heart disease, high-affinity hae-moglobins) or aberrant erythropoietin production

Secondary polycythaemia can generally be excluded by the clinical history and examination, assessment of serum erythropoietin concentration and arterial oxygen saturation, haemoglobin electrophoresis, and abdominal ultrasound. The presence of splenomegaly is suggestive of poly-cythaemia vera, and this diagnosis can be confirmed by demonstrating an absolute increase in total red cell volume and excluding other causes of erythro-cytosis. Measurement of red cell and/or plasma volume will identify pseudopolycythaemia.

Leucocytosis

Neutrophilia

Neutrophils are commonly increased in number during pregnancy and in acute infections, inflam-mation, intoxication, corticosteroid therapy, and acute blood loss or destruction. Neutrophilia with the neutrophils showing heavy cytoplasmic granu-lation (“toxic” granulation) is a common finding in severe bacterial infections. In the absence of any underlying cause, a high neutrophil count with

immature myeloid cells suggests chronic granulocytic leukaemia; cytogenetic and molecular studies the BCR–ABLfusion gene are indicated.

Lymphocytosis

Lymphocytosis is a feature of certain infections, particularly infections in children. It may be especially marked in pertussis, infectious mononucleosis, cytomegalovirus infection, infectious hepatitis, tuberculosis, and brucellosis. Lymphocytosis is also a common transient reaction to severe physical stress. Elderly patients with lymphoproliferative disorders, including chronic lymphocytic leukaemia and lymphomas, often present with lymphadenopathy and a lymphocytosis. Morphology and immuno-phenotyping of the cells combined with histological examination of a bone marrow trephine biopsy are used to classify these disorders and to give an indi-cation of management and prognosis. It is occasion-ally difficult to differentiate between a reactive and a neoplastic lymphocytosis. In this situation, immunophenotyping, immunophenotypic evidence of light chain restriction, and polymerase chain reaction for immunoglobulin or T-cell receptor gene rearrangements may indicate the presence of a monoclonal population of lymphocytes, thereby supporting a diagnosis of neoplastic, rather than reactive, lymphoproliferation. If lymph nodes are enlarged, a fine needle aspirate for cytology and immunocytochemistry or a lymph node biopsy for histology and immunohistochemistry may be help-ful in diagnosis.

Monocytosis

A slight to moderate monocytosis may be associated with some protozoal, rickettsial, and bacterial infec-tions including malaria, typhus, and tuberculosis.

High levels of monocytes in an elderly patient suggest chronic myelomonocytic

leukaemia or, sometimes, atypical chronic myeloid leukaemia. Because these conditions fall into the myeloproliferative/myelodysplastic group of dis-orders, the diagnosis would be supported by finding splenomegaly, quantitative and qualitative abnor-malities in other cell lines, and a clonal cytogenetic abnormality.

Eosinophilia

Eosinophilia is typically associated with allergic dis-orders including drug sensitivity, skin diseases, and parasitic infections. In most cases, the cause is indi-cated from the clinical history, which should include details of all medications and foreign travel, and by examination of the stool and urine for parasites. A diagnosis of chronic eosinophilic leukaemia is made if there is an increase in blast cells in the blood or marrow or if there is cytogenetic or molecular evidence of an abnormal myeloid clone.

Idiopathic hypereosinophilic syndrome is an unusual cause of eosinophilia in which release of the contents of eosinophil granules results in damage to the heart, lungs, and other tissues. This is a diagnosis of exclusion, made only when detailed

investigations exclude all known causes. It is necessary to specifically exclude eosinophilic leukaemia and cytokine-induced eosinophilia result-ing from the presence of a neoplastic clone of T cells before diagnosing a condition as the idiopathic hypereosinophilic syndrome.

Basophilia

Basophilia as an isolated finding is unusual. How-ever, it is a common feature of myeloproliferative disorders and basophils may be particularly pro-minent in chronic granulocytic leukaemia. In this condition, an increasing basophil count may be the first indication of transformation to a more aggressive course.

Thrombocytosis

Thrombocytosis is often associated with infectious and inflammatory conditions such as osteomyelitis and rheumatoid arthritis. Haematological causes of thrombocytosis include chronic blood loss, red cell destruction, splenectomy, and rebound following recovery from marrow suppression. Under these circumstances, a moderately increased platelet count does not usually have any

pathological consequences. Primary (essential) thrombocythaemia belongs to the spectrum of myeloproliferative diseases and is characterized by a persistently high platelet count (often arbitrarily defined as greater than 600 ?10 /l) and thrombotic

or haemorrhagic complications. Further investi-gations to confirm primary thrombocythaemia include bone marrow examination for increased and abnormal megakaryocytes and cytogenetic analysis.

Reductions in More Than One Cell Line

A reduction in cell numbers occurs because of in-creased destruction, reduced production, or increased pooling in the spleen or other organ. Reduced production of cells may be the result of aplastic anaemia, a lack of haematinics such as folate or vitamin B12, or interference with normal haemopoiesis by infiltration (e.g., leukaemia, lymphoma, multiple myeloma, metastatic carcinoma — often with

secondary myelofibrosis), infection (e.g., human immunodeficiency virus [HIV] infection, tuberculosis, leishmaniasis), or exposure to toxins (e.g., alcohol) or myelosuppressive drugs (e.g., hydroxycarbamide* or busulphan). Certain myeloid neoplasms (e.g., “idiopathic” myelofibrosis) and the myelodysplastic syndromes (MDS) are characterised by cytopenias, and this is also sometimes a feature of acute myeloid leukaemia (AML). A relatively common cause of a global reduction in circulating cells is pooling of the cells in a grossly enlarged spleen

(hypersplenism), which may be secondary to conditions such as myelofibrosis and portal hyper-tension. Examination of a bone marrow aspirate and trephine biopsy specimen is often helpful in determining the cause of bicytopenia or pancy-topenia for which no obvious cause can be found.

Anaemia

There are many causes of anaemia, and a logical classification would be according to mechanism:

· Decreased production

· Reduced lifespan of red cells

· Blood loss

· Splenic pooling

In practice, if the cause is not readily apparent from the clinical circumstances and an automated blood count is available, classification according to cell size is more practicable. The choice of further investigations is then guided by the mean cell

volume (MCV) and red cell morphology in addition to clinical features.

Anaemia is thus broadly divided into three types:

· Microcytic (low MCV)

· Macrocytic (high MCV)

· Normocytic (normal MCV)

Low MCV may be associated with low mean cell haemoglobin (MCH). A low mean cell haemoglobin concentration (MCHC) is less common and cor-relates with hypochromia. Examination of a blood film will usually suggest the quickest route to the diagnosis; confirmation may require the more specific tests, which are given in the text. The presence of basophilic stippling in a patient with microcytic red cells suggests thalassaemia trait or lead poisoning. A dimorphic blood film is typical of congenital sideroblastic anaemia but is more often the result of iron defi-ciency responding to treatment. Pappenheimer bodies suggest that a microcytic anaemia is the result of sideroblastic erythropoiesis.

Microcytic Anaemia

The most common cause of anaemia worldwide is iron deficiency. It can be suspected from a low MCV and the presence of hypochromic, microcytic red cells. Laboratory confirmation of iron deficiency may include measurements of serum ferritin, serum iron plus either total iron-binding capacity or transferrin assay, red cell proto-porphyrin, and staining of bone marrow aspirates for iron. A diagnosis of iron deficiency requires a search for the cause. This should include

specific questions relating to blood loss and dietary insufficiency and may require stool examination for parasites and occult blood, endoscopic examination of the gastrointestinal tract to exclude occult malig-nancy, and serological or other tests for coeliac disease. The differential diagnosis of iron deficiency anaemia includes anaemia of chronic disease. Clinical and laboratory features of inflammation may suggest this diagnosis, which is confirmed by demonstration of normal or high serum ferritin, low serum iron, and low transferrin and iron binding capacity.

The thalassaemias also cause microcytosis, but both α and β thalassaemia are usually associated with an increased red blood cell count and a normal or near-normal Hb despite a considerable reduction of the MCV and MCH, whereas in iron deficiency the MCV and MCH do not fall until the Hb is significantly reduced. Further investigations, such as haemoglobin electrophoresis, high-performance liquid chromato-graphy (HPLC), or measurement of HbA2 and HbF

usually confirm the diagnosis of β thalassaemia trait. The diagnosis of α thalassaemia trait is more difficult; detection of infrequent HbH inclusions is usually possible in α thalassaemia trait, but definitive diagnosis requires DNA analysis. The diagnosis of α + thalssaemia trait is of less clinical importance; HbH inclusions may not be detected, so DNA analysis is needed.

Macrocytic Anaemia

A high MCV with oval macrocytes and hyper-segmented neutrophils suggests folate or vitamin B12 deficiency and is an indication for assays of these vitamins (see Chapter 8); subsequent investi-gations could include malabsorption studies,

serological test for coeliac disease, and either tests for intrinsic factor antibodies or a Schilling test to detect pernicious anaemia. If intrinsic factor antibodies are detected, a Schilling test is not necessary. A high MCV may also be associated with alcohol excess and liver disease or drugs such as hydroxycarbamide or zidovudine. Macrocytosis resulting from chronic haemolysis is associated with

increased numbers of immature red cells, which appear slightly larger and more blue than normal red cells on a Romanowsky-stained peripheral blood film. Supravital staining of blood films (p. 40) or an automated reticulocyte count can be used to confirm reticulocytosis. Untreated anaemia associated with polychromasia is likely to indicate blood loss or haemolysis. The combination of red cell fragments, thrombocytopenia, and polychromasia indicates microangiopathic haemolytic anaemia and should trigger further tests such as a platelet count, coagulation studies, assessment of renal function, and a search for infection or neoplastic disease. This further assessment is urgent because these may be features of thrombotic thrombocytopenic purpura, which requires speedy treatment by plasma exchange.

Normocytic Anaemia

Normochromic, normocytic anaemia is frequently the result of an underlying chronic, non-haematological disease. Investigations should include screening for renal insufficiency, subclinical infections, autoimmune diseases, and neoplasia. In

the presence of anaemia, a lack of polychromasia, confirmed by reticulocytopenia, points toward a primary failure of erythropoiesis or blood loss or haemolysis without compensatory red cell produc-tion. Examination of the bone marrow may be help-ful in demonstrating haematological causes for the normochromic, normocytic anaemia such as aplastic anaemia or early myelodysplastic syndrome. Stain-ing for iron may also show that there is a block in iron metabolism suggestive of anaemia associated with chronic inflammatory disease.

Leucopenia

Neutropenia

Once physiological variation, ethnicity, and familial or cyclic neutropenia have been excluded, the non-haematological causes of isolated neu-tropenia to be considered include overwhelming infection, autoimmune disorders such as systemic lupus erythematosus, irradiation, drugs (particularly anticancer agents), and large granular lymphocyte leukaemia. Bone marrow examination may assist in determining whether the problem is the result of peripheral destruction (increased marrow myeloid precursors) or stem cell failure (lack of narrow myeloid precursors). Typical marrow appearances occur in drug-induced neutropenia, in which there is a relative paucity of mature neutrophils and in Kostmann’s syndrome (infant genetic agranulocytosis) where there is maturation arrest at the promyelocytic stage.

Reduced Numbers of Lymphocytes, Monocytes, Eosinophils, and Basophils Lymphocytes, eosinophils, and basophils may all be reduced by stress such as surgery, trauma, and infec-tion. Lymphopenia with neutrophilia is a common combination of haematological abnormalities in severe acute respiratory syndrome. Lymphopenia, especially affecting the CD4 cells, may occur in HIV infection and renal failure. Monocytopenia is typically found in hairy cell leukaemia, which is also associated with pancytopenia, typical bone marrow histology, and lymphocytes with a characteristic cytology and immunophenotype.

Thrombocytopenia

Thrombocytopenia is a common isolated finding, and it is important to ensure that the laboratory result reflects a true reduction in platelet count before embarking on further diagnostic tests. Frequent causes of spurious thrombocytopenia include blood clots in the sample, platelet aggregation, and platelet satellitism. Platelet aggregation, which can be seen on the blood film, may occur in vitroas theresult of a temperature-dependent or anticoagulant-dependent autoantibody. Small platelet aggregates are also seen in slides that have been made directly from a fingerprick sample. True thrombocytopenia is most frequently the result of anticancer chemo-therapy, HIV infection, autoantibodies (“idiopathic” autoimmune thrombocytopenic purpura), other drugs (such as thiazide diuretics), alcohol excess, hypersplenism, and MDS (in the elderly). The clinical circumstances, together with bone marrow examination and relevant serological tests, should enable these conditions to be differentiated. Throm-bocytopenia associated with other complications, such as thromboses, disturbed renal or hepatic function, and haemolytic anaemia, should prompt investigations for other diseases such as thrombotic thrombocytopenic purpura or the HELLP (Haemolysis + Elevated Liver enzymes + Low Platelet count) syndrome. A bone marrow examination is often carried out early in the investigation of throm-bocytopenia because it is helpful in excluding con-ditions such as acute leukaemia, which occasionally present with isolated thrombocytopenia.

Pancytopenia

Pancytopenia (reduction in the white cell count, Hb, and platelet count) is most often the result of anticancer chemotherapy, HIV infection, hyper-splenism, and bone marrow infiltration or failure. Careful examination of a blood film is important if the reason for the pancytopenia is not apparent from the clinical history. If this does not reveal the cause, bone marrow aspiration and trephine biopsy may be needed.

Qualitative Abnormalities of Blood Cells

In health, only the most mature forms of cells appear in the peripheral blood. Earlier, less mature cells, such as nucleated red blood cells, polychromatic red cells, myelocytes, and metamyelocytes, may be released from the bone marrow in conditions where the bone marrow is overactive (e.g., acute haemolytic states or recovery after suppression) or functionally abnormal. Their presence in the peripheral blood indicates that active haemopoiesis is taking place.

Abnormalities of All Cell Lines

The combination of anisopoikilocytosis, mild macrocytosis, hypogranular neutrophils with abnor-mal nuclear morphology, and platelet anisocytosis, often with quantitative abnormalities, is virtually pathognomonic of a myelodysplastic syndrome. These features are reflected in the bone marrow with disturbance of the normal developmental pathway and nuclear:cytoplasmic asynchrony. Cytogenetic

studies can confirm the diagnosis when cytological abnormalities are minor and also can assist in determining the prognosis.

Abnormalities of Individual Cell Lines

Red Cells

Congenital abnormalities of the red cell affecting the structure (e.g., spherocytosis, elliptocytosis) and content (e.g., haemoglobinopathies, enzymopathies) often produce typical morphological changes. The type of changes will guide further

investigations toward analysis of structural proteins, haemoglobin electrophoresis, or HPLC and enzyme assays. Acquired red cell abnormalities may also help to indicate underlying pathology. For example, target cells may prompt investigation of liver function, whereas rouleaux may indicate the need for investigations for multiple myeloma or inflammatory conditions such as rheumatoid arthritis.

White Cells

Congenital abnormalities of neutrophils are unusual, but similar morphological abnormalities (e.g., Pelger–Hu?t cells) may be seen in acquired con-ditions such as myelodysplastic syndrome. Reactive changes in lymphocytes including basophilic, faceted cytoplasm, are typically seen in infectious mononucleosis, which can be diagnosed using an appropriate screening test or, if this is negative, by demonstration of immunoglobulin M (IgM) antibodies to the Epstein–Barr virus. These atypical lymphocytes can sometimes be difficult to differentiate from circulating lymphoma cells. Bone marrow histology, combined with immunopheno-typing studies and determination of lymphocyte clonality by demonstration of light chain restriction or by gene rearrangement studies, may be needed to reach a firm conclusion.

Platelets

Platelets that function poorly may not necessarily appear morphologically abnormal, although some-times they are hypogranular or larger than normal. A normal platelet count with a prolonged bleeding time is characteristic of a disorder of platelet func-tion, but some patients with abnormal platelet function are also thrombocytopenic. Hereditary dis-orders of platelet function are uncommon and

usually present as a bleeding diathesis. When a qualitative disorder of platelets is suspected, platelets should be examined to assess size and to detect the cytological features of the grey platelet syndrome. They can broadly be divided into two categories: abnormalities of the platelet membrane (e.g., Bernard–Soulier syndrome, Glanzmann’s thrombasthenia) and of platelet secretory function (e.g., storage pool diseases). In comparison, acquired disorders of platelet function are common.

Haematological conditions associated with platelet dysfunction include myeloproliferative and myelo-dysplastic disorders and dysproteinaemias. Many

widely prescribed drugs can interfere with platelet function, including aspirin and non-steroidal anti-inflammatory agents, whereas systemic conditions, particularly chronic renal failure and cardiopulmonary bypass, are associated with a bleeding tendency as a result of qualitative platelet defects. Most of these acquired functional defects are not associated with any abnormality in platelet appearance but in the myelodysplastic and, to a lesser extent, in the myelo-proliferative disorders there may be hypogranular and giant platelets.

SPECIFIC TESTS FOR COMMON

HAEMATOLOGICAL DISORDERS

Common haematological disorders are outlined in the following sections with suggestions for investi-gations that may be helpful in confirming the diagnosis. The lists are not intended to be exhaustive because the range of tests provided locally will depend on the availability of expertise and tech-nology. The investigations discussed are those that are likely to be available within a general

haematology department.

Red Cell Disorders

Microcytic Hypochromic Anaemias

For more information, see Chapters 7 and 12.

• Measurement of serum ferritin or iron plus either total iron-binding capacity or transferrin assay, red cell protoporphyrin

• Bone marrow aspirate with staining for iron

• Stool examination for occult blood; blood loss studies with 51

Cr-labelled red cells

• Tests for malabsorption

• Serological tests for coeliac disease

• Endoscopic examination with biopsy

• Serum lead (if lead poisoning is suspected)

If thalassaemia is suspected:

• Haemoglobin electrophoresis plus Hb A2 and Hb F measurements or HPLC

• Haemoglobin H preparation

• Family studies

• DNA analysis

Macrocytic Anaemias

Where macrocytic, megaloblastic erythroid maturation is demonstrated, further investigations should be undertaken as described in Chapter 8. If the blood film is typical of megaloblastic anaemia, relevant assays and further investigations are often per-formed without a bone marrow aspirate being done.

Macrocytosis may also be secondary to common conditions such as alcohol excess, liver disease, myelodysplastic syndrome, hydroxycarbamide administration, and hypothyroidism. Reticulocytosis from any cause can also increase the MCV.

Aplastic Anaemia

• Bone marrow aspirate and trephine biopsy

• Acidified serum (Ham’s) test for paroxysmal nocturnal haemoglobinuria (urine examination for haemosiderin and neutrophil alkaline phosphatase if Ham’s test is positive)

• Vitamin B12 and folate assays

• Viral studies, particularly for Epstein–Barr and hepatitis viruses.

If Fanconi’s anaemia is suspected:

• Studies of sensitivity of chromosomes to breakage

by DNA crosslinking agent

• Radiology of hands and forearms

Haemolytic Anaemias

A haemolytic process may be suspected by the presence of a falling haemoglobin, a reticulocytosis, and jaundice with an increase in unconjugated bilirubin level.

The blood may appear entirely normal in some patients with white cell disorders (e.g., lymphoma, myelomatosis, immune deficiency, neutrophil dys-function). Changes in white cell numbers or morphology may occur rapidly in response to local or systemic disorders. The investigation of white cell disorders is more likely to require marrow examination than investigation of red cell disorders, especially when a primary marrow disorder is suspected. In chronic leukaemias, bone marrow examination may add little to the diagnosis, but the pattern of infiltration may have prognostic significance, e.g., in chronic lymphocytic leukaemia.

The distribution of white cells is better appreciated in trephine biopsies, whichare particularly important in lymphomas.

Acute Leukaemia

• Bone marrow aspirate

• Bone marrow trephine biopsy if an adequate bone marrow aspirate is not obtained

• Cytochemical stains

• Blood or marrow immunophenotyping, unless obviously myeloid

• Cytogenetic analysis

• Molecular studies (e.g., fluorescence in situ hybridization) for rearrangements of specific oncogenes

Neutropenia

• Serial neutrophil counts for cyclical neutropenia

• Tests for antineutrophil antibodies

• Bone marrow aspirate and trephine biopsy

• Autoantibody screen and investigations for systemic lupus erythematosus

• Vitamin B12 and folate assays

• Acidified serum (Ham’s) test

Chronic Granulocytic Leukaemia

• Bone marrow aspirate

• Cytogenetic analysis

• Molecular studies (e.g., fluorescence in situ hybridization) for BCR–ABLrearrangement

• Neutrophil alkaline phosphatase score, if cyto-genetic and molecular genetic analysis are not available

Chronic Lymphoproliferative Disorders/ Lymphadenopathy

• Serological screening for infectious mononucleosis, cytomegalovirus infection, HIV infection, and toxoplasmosis (if infectious cause suspected)

• Bone marrow aspirate and trephine biopsy (for detection of the presence and distribution of abnormal lymphocytes)

• Immunophenotyping

• Serum protein electrophoresis and immuno-globulin concentrations

• Serum urate, calcium, and lactate dehydrogenase (LDH)

• Lymph node biopsy (aspiration or surgical)

• Cytogenetic or molecular genetic analysis including investigation for immunoglobulin heavy chain or T-cell receptor gene rearrangement if the diagnosis of lymphoma is in doubt

• Radiological studies (X-ray, ultrasonography, computed tomography scan, magnetic resonance imaging)

Myelomatosis

• Bone marrow aspirate

• Bone marrow trephine biopsy if a cellular aspirate is not obtained

• Serum protein electrophoresis and immunoglobulin concentrations

Serum albumin and calcium measurements

• β2-microglobulin

• Urine (random and 24 hours) for Bence–Jones protein detection and quantitation

• Tests of renal function

• Radiological skeletal survey

• Serum free light chain quantification and ratio

Other Disorders

Myeloproliferative Disorders

• Blood volume, red cell mass, and plasma volume (for polycythaemia) measurements

• Bone marrow aspirate and trephine biopsy

• Arterial oxygen saturation and carboxyhaemo-globin level

• Abdominal ultrasound examination

• Neutrophil alkaline phosphatase

• Vitamin B12 (or B 12 -binding capacity)

• Serum urate

• JAK2 analysis

Myelodysplasia

• Bone marrow aspirate and trephine biopsy

• Cytogenetic analysis “Idiopathic” Myelofibrosis

• Bone marrow trephine biopsy

• Red cell folate assay

• Urate

If splenectomy is contemplated:

• Ferrokinetic and red cell survival studies

• Spleen scan and red cell pool measurement.

Pancytopenia with Splenomegaly

• Bone marrow aspirate and trephine biopsy

• Bacterial culture of marrow for tuberculosis

• Marrow examination for amastigotes of Leishmania donovani

• Biopsy of palpable lymph nodes (aspiration or surgical)

• Vitamin B12 and folate assays

• Liver biopsy

• Splenic aspirate

• Acidified serum (Ham’s) test

• Serum rheumatoid factor and autoantibody screen

• Laparotomy and splenectomy.

The rationale behind these tests, and details of investigations outside general haematology practice, can be found in comprehensive haema-tology textbooks, in electronic databases.

Since the late 1970s, acute leukaemia and the MDS have usually been defined and further classified according to the proposals of the French–American–British (FAB) group. These classifications are now being supplanted by the World Health

Organization (WHO) classifications, published in definitive form in 2001. The WHO classifications are much broader in their aims and include myelo-proliferative and chronic lymphoproliferative disorders.

Application of the WHO criteria requires the results of immunophenotyping and cytogenetic analysis. The FAB classifications therefore continue to have a place (a) when these techniques are not available and (b) in making a provisional morpho-logical diagnosis while awaiting the results of further tests. It may be necessary to issue a provisonal report, so that treatment can commence, with a supplementary report following when all diagnostic procedures have been completed. It is important that, whichever classification is used, the criteria are strictly observed so that there is consistency between different centres and countries. To avoid any possibility of confusion, FAB terminology (e.g., M1, M2) should not be applied if the WHO classsification is being used.

Classification of Acute Myeloid Leukaemia

The FAB criteria for a diagnosis of AML are as follows:

1.Blast cells must constitute at least 30% of all bone marrow cells or

2.When erythroid cells are at least 50% of bone marrow cells and blasts cells must be at least 30% of non-erythroid cells (lymphocytes, plasma cells, macrophages, and mast cells also being exluded from the count) or

3. The characteristic cytological features of acute hypergranular promyelocytic leukaemia or

4. Blast cells are shown to be myeloid by either there being at least 3% of blast cells positive for Sudan black B, myeloperoxidase, or nonspecific esterase or by demonstration of myeloid antigens on immunophenotyping.

The WHO classification categorises cases as AML if the following criteria are met:

1.There are at least 20% of blast cells of myeloid lineage in the blood or bone marrow or

2.If the erythroid cells are at least 50% of bone marrow cells, blast cells are at least 20% of nonerythroid cells, or

3.Primitive erythroid cells constitute at least 80% of bone marrow cells or

4.There is a myeloid sarcoma (granulocytic sarcoma) or

5.One of a number of specified chromosomal rearrangements is present.

It should be noted that the WHO classification is hierachical. If appropriate, cases are first assigned to the category of therapy-related leukaemia. Next, cases are assigned, if appropriate, to the category of AML with recurrent genetic abnormalities. Cases continue to be assigned to successive categories in the order with remaining cases finally being categorised as “AML not otherwise categorized.” This final group is further subdivided into categories resembling those of the FAB classification (but defined in quite a different manner). The “not-otherwise-categorized” group includes several entities that are either newly defined (acute panmyelosis with myelofibrosis and pure erythroid leukaemia) or were not specifically men-tioned in the FAB classification (acute basophilic leukaemia and myeloid sarcoma.

The FAB criteria for a diagnosis of MDS are that there is evidence for a myeloid neoplasm with ineffective haemopoiesis but the criteria for AML are not met. Blast cells must be less than 30% in the bone marrow. In the WHO classification, there must be evidence for a myeloid neoplasm with ineffective haemopoiesis and blasts must be less than 20% in both blood and bone marrow. In additon, the specific cytogenetic abnormalities must be absent (or the case is categorized as AML, regardless of the blast count). There is a further major difference between the two classifications, specifically that chronic myelomonocytic leukaemia is classified as MDS in the FAB classification, whereas in the WHO classification it is assigned to a new category of disorder designated myelodysplastic/myeloproliferative diseases. It will be noted that cytogenetic analysis is essential for the application of the WHO classification because cases

of the 5q- syndrome cannot otherwise be recognized.

Like the WHO classification of AML, this is a hierachical classification. Therapy-related MDS is categorized with therapy-related AML. Remaining cases are then assessed as to whether they meet the criteria for the 5q- syndrome. If they do not, they are assigned to the remaining categories, depending on the number of lineages showing dyplasia, the percentage of ring sideroblasts, the presence or

absence of Auer rods, and the percentage of blast cells in the blood and marrow. The details of the WHO classification of the myelodysplastic/ myeloproliferative diseases.

Both the FAB and WHO classifications require that an acute leukaemia be positively shown to be lymphoid before it is categorized as acute lympho-blastic leukaemia (ALL) so as to avoid inadvertently categorising FAB M0 and M7 AML as ALL. The WHO classification groups together ALL and lymphoblastic lymphoma, using the designations precursor B lymphoblastic leukaemia/lymphoblastic lymphoma and precursor T lymphoblastic leukaemia/lymph-oblastic lymphoma. These designations are clearly too cumbersome to use in clinical practice, and undoubtedly haematologists will continue to refer to “acute lymphoblastic leukaemia.” The FAB group classified ALL into three morphological categories, designated L1, L2, and L3 ALL. It is of little significance whether a case falls into the L1 or L2 category, and this distinction can be dropped.

However, L3 morphology—the presence of “blast cells” with basophilic cytoplasm and vacuolation—is of considerable clinical significance. In most, but

not all, of these cases the cells are immunologically mature, expressing surface membrane immunoglobulin, and the condition represents a leukaemic presentation of Burkitt’s lymphoma. The WHO classification categorizes such cases as Burkitt’s lymphoma. This is more appropriate than their being categorized as ALL because the treatment of these cases differs very considerably from the treatment of ALL.

The WHO classification of the myeloproliferative disorders is summarized. Most of these conditions are defined in accordance with established haematological practice. However, the method of distinguishing between essential thrombocythaemia and idiopathic myelofibrosis differs from previous practice with many cases that would previously have been categorized as essential thrombocythaemia now being classified as the cellular phase of myelo-fibrosis; whether this classsification will be widely accepted remains to be seen. The WHO classification of myeloproliferative disorders takes little account of cytogenetic or molecular genetic analysis, only Ph-positive chronic myeloid leukaemia being defined on this basis. It should be noted that the WHO classification defines a case with hypereosinophilia as eosinophilic leukaemia, rather than as the idiopathic

hypereosinophilic syndrome, when there is evidence of clonality. The 4q12 syndrome, resulting from a cryptic deletion at 4q12 with formation of a FIP1L1-PDGFRA fusion gene, is therefore categorized as eosinophilic leukaemia.

Leukocyte Disorders

The importance of an intact host immunoinflammatory response in maintaining periodontal health underscores the changes that may occur when patients have leukocyte disorders (see picture below). The neutrophil or polymorphonuclear leukocyte is the first line of defense against periodontal pathogens. A defect in this cell line has clear negative consequences, often resulting in severe periodontal destruction at an early age.

Although the clinician will not encounter these disorders on a routine basis, the severe periodontal destruction associated with neutrophils disorders can be overwhelming for both the patient and the provider.

Neutrophils circulate within the bloodstream and must pass out of the vessels and into the tissues to defend against periodontal pathogens. Pathogens and host cells produce chemotactic agents that signal neutrophils to enter an area of infection. To be fully functional, neutrophils must be able to do the following:

1. Slow down their flow within the vasculature--a process involving cell surface glycoproteins known as selectins on the surface of neutrophils and endothelial cells lining the blood vessels. Up-regulation of these selectins results in "rolling" of the neutrophils along the endothelial lining of the vessel.

2. Adhere to the endothelial cells—a process involving interaction between receptors called integrins on the surface of neutrophils and receptors on the endothelial cell surface.

3. Pass between the intercellular spaces of the endothelial lining to exit the vessel and to enter the perivascular tissues—a process known as diapedesis.

4. Move toward the pathogens that they will attack—a process involving locomotion (movement) of the neutrophil toward the bacteria or host cells that are producing factors called chemoattractants. This is the process of chemotaxis (directed movement toward a chemoattractant).

5. Bind to the pathogens, engulf them, and move them into the intracellular environment of the neutrophil—a process known as phagocytosis.

6. Kill the offending pathogen—a process called degranulation, involving enzyme release from intracellular granules. Another method of killing involves release of free oxygen radicals. This process not only kills the offending pathogen but may result in host tissue damage, especially if the response is exuberant.

Fig.1(A,B,C).

A, Soft tissue swelling associated with teeth #17 and #18 in a 22-year-old man. Teeth were vital. B, Radiograph revealed periradicular radiolucency associated with the mesial root of #17, with loss of trabeculation in the alveolar crest distal to #17 and between #17 and #18. C, Biopsy revealed numerous giant cells in fibrous stroma, features of a classic giant cell granuloma. Systemic work-up disclosed hyperparathyroid state.

Defects in the response of neutrophils to pathogens can occur at any step along this pathway. This results in an inability to clear a bacterial infection and allows bacteria and their products to continue to destroy host tissues.

Leukocyte Adhesion Deficiency

Leukocyte adhesion deficiency (LAD) is an inherited disorder that follows an autosomal recessive pattern. There have been just more than 600 cases described, each identified shortly after birth. More than 75% of children will die before the age of 5 years if they do not receive a bone marrow transplant. Leukocyte adhesion deficiency is caused by a deficiency in cell surface integrins that prevents the neutrophil from adhering to the vessel wall at the site of an infection. Neutrophils are unable to migrate into the affected tissues and remain within the vasculature. This prevents them from attacking bacterial pathogens. Patients have early loss of teeth, severe alveolar bone loss and attachment loss, and severely inflamed gingival tissues, often with ulceration and necrosis. Both primary and permanent teeth are affected. Treatment is difficult, involving mechanical debridement, topical antimicrobials, and systemic antibiotics. Unfortunately, treatment rarely results in long-term retention of teeth (see picture below).

Fig.2 Patient with generalized aggressive periodontitis.

A, Clinical appearance of a 12-year-old boy with generalized aggressive periodontitis resulting from leukocyte adhesion deficiency (LAD).

B, Gingival tissues are fiery red, painful to touch, and bleed profusely on stimulation.

C, Panoramic radiograph reveals severe bone loss at age 12 years affecting all permanent teeth. Teeth #23 and #26 exfoliated spontaneously.

Neutropenia

The normal adult absolute neutrophil count (ANC) is between 1800 to 8000 cells/^l. Neutropenia (low ANC) is considered clinically significant when the ANC decreases to less than 1000 cells/^l. Chronic neutropenia is defined as a low ANC for greater than 6 months. The risk for infection caused by neutropenia is inversely proportional to the ANC. When the ANC is less than 500 cells/^l, control of endogenous microbiota is often impaired and the risk for serious infection increases. An ANC less than 200 cells/^l results in an inability to mount an inflammatory response.

Chronic benign neutropenia

Chronic benign neutropenia (CBN) is characterized by a prolonged noncyclic neutropenia as the sole abnormality. The neutropenia is not associated with any underlying disease. CBN is the most common form of neutropenia in infants and children younger than 4 years. The clinical presentation is variable, ranging from benign to life-threatening; however, most people with CBN live a normal lifespan. An increased incidence of recurrent oral ulcerations, upper respiratory infections, otitis media, cellulitis, lymphadenopathy, pneumonia, and sepsis occurs as a result of the decreased neutrophil response. The risk for infection appears to decrease with age. Oral manifestations of CBN may include hyperplastic, edematous, and fiery red gingiva with areas of desquamation, although not all patients with CBN are similarly affected. Severe pocketing and bone loss may occur. Ulceration, chronic gingivitis, and chronic periodontitis also have been reported. Within the periodontal tissues, the chronic lack of neutrophils may be counterbalanced by increased antibacterial activity from monocytes. This may explain the milder periodontal findings in some patients with CBN.

Cyclic neutropenia

Cyclic neutropenia is characterized by periodic recurring symptoms of fever, malaise, mucosal ulcers, and possibly life-threatening infections related to cyclical fluctuations in the number of neutrophils. This disorder usually presents before age 10 years with episodes of fever, malaise, mood swings, and oral ulcerations that can last 3 to 6 days and recur approximately every 3 weeks. The interval between neutropenic episodes is not always clinically evident and may require frequent laboratory studies to identify. A complete blood count performed twice weekly for 6 weeks generally provides an accurate picture of the cycle. For most patients, the cycle is approximately 21 days, with a 3- to 10-day period of severe neutropenia.

Cyclic neutropenia tends to improve with age. Its clinical presentation may vary widely among individuals. Although usually not fatal, death can occur due to pneumonia, cellulitis, gangrene, or peritonitis. Oral conditions associated with cyclic neutropenia may include recurrent severe gingivitis and oral ulcerations. Periodontitis may progress more rapidly than expected because of periodic diminishment of the neutrophil response. Unfortunately, even with the best of professional and home care, teeth are often lost because of advancing periodontal disease. Treatment to increase neutrophil levels has been successful using recombinant human granulocyte colony-stimulating factor (G-CSF) given three times per week. G-CSF is a hematopoietic growth factor that simulates the proliferation and differentiation of neutrophils. It has been widely successful in correcting chemotherapy-induced neutropenia in patients with cancer, greatly decreasing the risk for life-threatening infections during periods of immunosuppression.

Congenital neutropenia

Congenital neutropenia, also known as Kostmann syndrome, is an inherited disorder manifesting in infancy and characterized by severe bacterial infections. Diminished ANC is the result of arrested neutrophil hematopoiesis. Oral symptoms are virtually universal in congenital neutropenia. Despite their young age, patient with this syndrome not only demonstrate severe gingivitis, but most also have periodontitis with significant alveolar bone loss. In the past, most patients with congenital neutropenia died within the first year of life; however, aggressive antibiotic therapy has more recently prolonged the lifespan of these children.Congenital neutropenia is now treated with G-CSF, which is effective at increasing the ANC to more than 1000/^l in most patients. Although G-CSF treatment improves symptoms, it is not curative and most patients demonstrate cyclic improvements followed by relapses in neutrophil levels. Even with G-CSF treatment, most of these patients have persistent gingivitis, which tends to wax and wane depending on their ANC.

Agranulocytosis

Agranulocytosis is characterized by a reduction or complete elimination of granular leukocytes (neutrophils, basophils, eosinophils). The decreased number of granulocytes can result from either a decreased production or an increased peripheral destruction of cells. Decreased production of granulocytes is often caused by bone marrow hypoplasia; however, it can also be the result of an idiosyncratic drug reaction. Patients with agranulocytosis are often febrile and may exhibit necrotizing nonpurulent lesions of mucous membranes, including oral, gastrointestinal, and vaginal membranes. Oral signs and symptoms include generalized, painful stomatitis, spontaneous bleeding, and necrotic tissue. Severe gingivitis, rapidly progressive bone loss, and tooth loss may appear at an early age. Cases related to drug idiosyncrasy usually occur in adulthood.

Lazy leukocyte syndrome

Lazy leukocyte syndrome is a rare disorder characterized by quantitative and qualitative neutrophil defects. Deficiency in neutrophil chemotaxis combined with systemic neutropenia results in recurrent infections. Impaired neutrophil motility inhibits their migration into tissue sites of inflammation. In the few reported cases of lazy leukocyte syndrome, all have had oral manifestations. In addition to systemic signs and symptoms such as high fever, cough, pneumonia, and purulent skin abscesses, oral manifestations include painful stomatitis, gingivitis, recurrent ulcerations of the buccal mucosa and tongue, rapidly progressive bone loss, and tooth loss at an early age.

Papillon-Lefevre Syndrome

Papillon-Lefevre syndrome (PLS) belongs to a heterogenous group of 19 different skin diseases characterized by hyperkeratosis of the palms of the hands and soles of the feet (palmar-plantar hyperkeratosis). PLS is caused by mutations in the cathepsin C gene located on chromosome 11. Cathepsin C is a protease, normally found in high levels in epithelium and immune cells such as neutrophils, which acts to degrade proteins and activate proenzymes in immune cells. Patients with PLS have little or no cathepsin C activity.

PLS differs from other members of this group of hyperkeratoses in that patients with PLS universally have generalized rapid destruction of the periodontal attachment apparatus resulting in premature loss of primary and permanent teeth. The presence of neutrophil defects in PLS is commonly noted. Diminished chemotaxis, phagocytosis, and intracellular killing of certain bacteria have been reported in some but not all cases. It is possible that neutrophil defects are not entirely responsible for the findings in PLS. Some authors have hypothesized that the hereditary defect in PLS is located in the epithelial barrier, which in the gingival sulcus may lead to a reduced defense against pathogenic bacteria. Alterations in cementum, collagenolytic activity in the periodontal ligament, and osteoclastic activity have also been suggested in some patients with PLS. Taken together, these findings could explain the aggressive periodontal destruction seen in patients with PLS even in the absence of significant neutrophil abnormalities.

The periodontal condition in PLS is difficult to treat, and use of conventional mechanical debridement rarely has been successful. Systemic administration of synthetic retinoids, when combined with meticulous plaque control, debridement, topical antimicrobials such as chlorhexidine, and systemic antibiotic therapy, may give the best chance for preventing progression of periodontitis.

 Treatment Retinoid therapy: Improves the skin condition but not the periodontal therapy. Periodontal condition: No effective treatment

Leukemias

Leukemia is a neoplastic disorder of the blood-forming tissues, primarily affecting leukocytes. This heterogenous group of diseases arises from a neoplastic proliferation in the bone marrow. The replacement of normal bone marrow elements by leukemic cells causes decreased production of erythrocytes, normal white blood cells, and platelets. The clinical result is anemia, with weakness, fatigue, pallor of skin, and mucous membranes; thrombocytopenia with associated bleeding tendencies; and leukopenias resulting in increased susceptibility to infection. Leukemias are classified as either acute or chronic, depending on the presentation of the disease. They are further classified relative to the predominant cell affected as either lymphocytic or myelocytic. Monocytic leukemias form a subgroup of myelocytic leukemia.

Oral involvement is common in leukemia and may represent the first sign of the disease. Dental professionals were responsible for initiating the diagnosis of leukemia in 25% to 33% of cases. Overall, 15% to 80% of patients with leukemia have oral manifestations, with the acute forms presenting oral signs in approximately 65% of cases, compared with only 30% in chronic leukemias. Oral petechiae or bleeding, mucosal ulceration, and gingival enlargement are the most common signs. Acute periodontal infection, pain, pharyngitis, and lymphadenopathy also may be seen.

Gingival enlargement may be localized or generalized and represents an infiltration of leukemic cells into the gingiva, and less frequently into bone (Fig. 3). Gingival enlargement is most common in acute monocytic leukemia (67% of cases), followed by acute myelomonocytic leukemia (18.5%), and acute myelocytic leukemia (4%).— The enlarged gingiva tends to be relatively firm in texture and most prominent in the interdental regions. The marginal tissues may be bluish-red or cyanotic. Gingival enlargement creates pseudopockets where plaque accumulates, stimulating a host response that may further exacerbate the swelling. Gingival bleeding is also common, and may be an early indicator of leukemia. Oral mucosal ulcers are a frequent finding in patients with leukemia. These lesions may result from bacterial invasion caused by severe leukopenia or from mucosal atrophy caused by a direct effect on epithelial cells of the chemotherapeutic drugs used to treat leukemia. Trauma from a dental prosthesis or teeth may result in large secondarily infected ulcers progressing to facial cellulitis and septicemia.

Figure 3.Leukemic gingival enlargement in 33-year-old man.

Biopsy of gingiva revealed large leukemic infiltrate.

Treatment for leukemia may include chemotherapy, radiation therapy, and BMT, each of which has the potential to produce a wide range of oral complications. Mucositis, xerostomia, and secondary infection with a variety of bacterial, viral, and fungal agents may occur. Candidiasis is almost universally seen in hospitalized patients with leukemia undergoing chemotherapy. Infections with unusual organisms (e.g., Pseudomonas and Klebsiella species) are common in this group of patients. Many drugs used for chemotherapy are neurotoxic and may cause intense oral pain, which is usually transient. These symptoms must be distinguished from pain of odontogenic origin. Patients undergoing BMT require special consideration because they receive very high-dose chemotherapy, often in combination with total body irradiation. The extreme immunosuppression experienced by patients with BMT predisposes to systemic spread of even mild infections. A large percentage of patients with BMT develop graft-versus-host disease, a condition where transplanted immunocompetent marrow cells recognize the host tissues as foreign and react against them, resulting in fever, mucosal ulcerations, skin erythema, and systemic involvement (Fig.3).

It is critical that dental needs be assessed as soon as a definitive diagnosis of leukemia has been rendered and a decision is made to initiate a radiation, chemotherapy, or BMT protocol. Unfortunately, oral care has been overlooked in the past, but aggressive promotion of dental intervention as a part of leukemia treatment protocols in recent years has dramatically decreased the incidence of oral complications.

During the acute phase of the disease only those procedures that are necessary to alleviate the discomfort and hemorrhaging should be performed. Conversely, during a period of remission every attempt should be made to achieve a state of periodontal health. The treatment should be conservative, consisting of the removal of all local irritants and instruction in good plaque control techniques. The distinct benefits of strict plaque control in severely granulocytopenic leukemia patients have been demonstrated: obtaining excellent gingival health and minimizing oral ulceration throughout chemotherapy.

Fig.4.Ulcerations on lips of a female patient with graft-versus-host disease (GVHD) after bone marrow transplantation. Severe intraoral ulcerations also were present on the buccal mucosa, the floor of mouth, and the ventral surface of the tongue. The patient died within 1 month of this photograph.

Severe gingival bleeding resulting from thrombocytopenia often can be managed successfully with localized treatment. The use of an absorbable gelatin sponge with topical thrombin or placement of microfibrillar collagen is often sufficient. Some authors report successful management of gingival bleeding with oral rinses of antifibrinolytic agents. If these measures are not successful in stopping blood flow from an oral site, platelet transfusions may be necessary.

Management of oral ulcers in patients with leukemia should be directed toward preventing the spread of localized infection and bacteremia, promoting healing of the lesion, and decreasing pain. Oral ulcers or extensive tissue sloughing may serve as the source of life-threatening septicemia in patients with leukemia (Fig.4). Topical antibacterial and antifungal medication should be used. Chlorhexidine mouth rinses are effective in reducing the severity of oral ulcerations, primarily by minimizing secondary infection of these lesions. Severe ulcers showing clinical signs of infection should be treated with a combination of topical medication and systemic antibiotics.

Patients with myelosuppressed leukemia are at risk for a variety of viral infections, most commonly herpes simplex, varicella zoster, and cytomegalovirus (CMV; Fig.5,6). These infections may become severe and must be recognized early. Herpes simplex virus and varicella zoster virus respond well to systemic acyclovir or other antiviral agents, and many patients with leukemia undergoing chemotherapy are treated prophylactically to prevent infection.

Fig.5 Herpes zoster. A, Unilateral right palatal ulcerations noted in 68-year-old man. Lesions were acutely painful. Patient had no history of trauma in this region. B, Ulcerations also noted on labial mucosa of lower lip. Again, lesions were confined to the patient's right side. A diagnosis of herpes zoster was made. C, Within 1 week, this patient had major skin ulcerations on the right side extending across the entire distribution of the trigeminal nerve. The patient was treated with systemic acyclovir. The lesions resolved but resulted in significant and prolonged postherpetic neuralgia.

Figure. 6.A 43-year-old male patient with severe myelosuppression secondary to immunosuppressive drug therapy. Sloughing of gingiva is apparent around all teeth and affects both marginal and papillary gingival.

Coagulation Disorders

The predominant inherited coagulation disorders are hemophilia A, hemophilia B, and von Willebrand disease. Coagulopathies may also be acquired. Liver disease affects coagulation because most of the clotting factors are synthesized in the liver; thus the clinician should be wary of coagulation disorders in alcohol abusers and patients with hepatitis. Vitamin K deficiency, usually associated with long-term antibiotic usage or with malabsorption syndromes, can result in coagulation problems. Several of the clotting factors are dependent on vitamin K for their synthesis.

Anemias

Anemias are qualitative or quantitative deficiencies of the blood, usually resulting from a decrease in the number of circulating red blood cells (erythrocytes) or in the amount of hemoglobin, or from a qualitative change in erythrocytes. The major categories of anemias include the following:

Normocytic-normochromic anemia

Macrocytic hyperchromic anemia

Microcytic hypochromic anemia

Sickle cell anemia

Aplastic anemia

Aplastic anemia is a form of normocytic-normochromic anemia that results from a lack of bone marrow production of erythrocytes and other blood cells. The disorder may be genetic or acquired. The acquired form usually follows exposure to certain drugs, toxic chemicals, or ionizing radiation. The severity of the clinical manifestations is directly dependent on the degree of pancytopenia. Because all bone marrow-derived cells are affected, including leukocytes and platelets, hemorrhage and infection are the major threats to patients with aplastic anemia. Oral manifestations include petechiae, gingival swelling and bleeding (often spontaneous), gingival overgrowth, and herpetic infections. Rapid bone loss has been reported, and periodontal infections have led to severe, life-threatening systemic infection. Fanconi's anemia is a rare form of aplastic anemia in which chromosomes break and rearrange easily. Most patients with Fanconi's anemia have birth defects involving multiple organ systems, and early-onset periodontitis may be seen.¹⁰⁶ BMT may provide the best long-term outcome for individuals with aplastic anemia.

Pernicious anemia (B-12 deficiency anemia)

Pernicious anemia (B-12 deficiency anemia) (Fig. 7), a form of macrocytic hyperchromic anemia, is caused by a lack of intrinsic factor, normally produced by the gastric mucosa. Intrinsic factor is essential to the absorption of vitamin B₁₂ and to the formation of erythrocytes. The condition can vary in its clinical severity. Like many anemias, the complexion may appear pale.Gingival pallor is also common. The tongue is affected in more than 75% of cases; atrophy of the papillae leaves the dorsal surface red, shiny, and smooth. It is often painful to eat. Pernicious anemia is treated with vitamin B₁₂ supplementation either orally or by injection.

Fig.7 Pernicious anemia: red and smooth dorsum of the tongue

Fig.8 Plummer–Vinson syndrome: redness and atrophy of the lingual papillae, associated with angular cheilitis

Iron deficiency anemia

Iron deficiency anemia, a microcytic hypochromic anemia, is the most common form of anemia. In addition to the presence of hypochromic, microcytic red blood cells, it is characterized by low iron stores, low serum iron concentration, and low hemoglobin concentration or hematocrit. Iron deficiency anemia may result from blood loss, such as an occult gastrointestinal bleed or excessive menstruation. Oral signs and symptoms are similar to pernicious anemia and primarily affect the tongue and gingiva. Iron deficiency anemia is present in a disorder known as Plummer-Vinson syndrome (see above Fig.8) and warrants particular attention. This syndrome is characterized by the glossitis seen in other forms of iron deficiency anemia, combined with enlargement of the tongue, ulceration of the oral and esophageal mucosa, and dysphagia (difficulty swallowing). Patients with Plummer-Vinson syndrome are at significantly increased risk for esophageal squamous cell carcinoma and should undergo frequent esophageal endoscopy. Iron supplementation is the key to management of iron deficiency anemia and may relieve the dysphagia associated with Plummer-Vinson syndrome.

Sickle cell anemia

Sickle cell anemia is a hereditary hemolytic anemia that is found almost exclusively in black individuals. An abnormal hemoglobin gene is present. During conditions of decreased oxygen tension, the red blood cells change shape and resemble a sickle. This can result in sickle cell crisis, in which the oxygen-carrying capacity of the erythrocytes is diminished and blood viscosity is increased. Sickle cell crisis is a life-threatening phenomenon. Sickle cell anemia may present with pallor of the gingiva and oral mucosa. Studies have not demonstrated an increased risk for gingivitis or periodontitis in individuals with sickle cell anemia. However, it is important for the clinician to thoroughly examine the periodontium of these patients, because acute periodontal infection may precipitate sickle cell crisis.

Thalassemia

This is a type of anemia where the haemoglobin of RBC is affected and this is more of racial disease affecting Italin, Greek, Syrian and American in nature. This is hereditary disease – a congenital defect of globin synthesis resulting unstable haemoglobin is formed.

Clinical features:

If it develops in early stage, it will lead to fatal stage. The child is yellowish with pallor of skin fever, chills and malaise. Spleenomegaly and hepatomegaly may develop.

Oral manifestations :

An unusual prominence of the premaxilla and oral mucosa have pale color, maxillary teeth are irregularly arranged. Intraoral radiography shows peculiar trabecular pattern of maxilla. Coarsening of trabecula and blurring, disappearance of other resulting “salt and pepper effect.” Thickening of diploe of skull. Inner and outer plates become elongated producing bristals like crew cut or hair on end appearance.

Treatment:

B12, B6 injection with liver extract.

Polycythemia

Abnormal increase of erythrocytes is called polycythemia. The count reaches to 70,000,000 to 10,000,000 per cu mm .This is accompanied by increased haemoglobin and hematocrit value.

Clinical features:

Patient will have headache, tinnitus and visual disturbance. The skin will be reddened. Gastric complains like gas, pain, belching and peptic ulcer, haemorrhage.

Oral manifestation:

1) Gingiva mucosa, tongue will be deepened;

2) Gingiva is congested enlarged and spongy bleeding;

3) Petechia and ecchymosis are common in mucosa;4) Cyanosis will occur

Fig.9 Polycythemia vera

The disease is known by many other names, like:

· Cryptogenic polycythemia

· Erythremia

· Erythrocytosis megalosplenica

· Myeloproliferative disorder

· Osler’s disease

· Primary polycythemia

· Polycythemia rubra vera

· Polycythemia with chronic cyanosis – Myelopathic polycythemia

· Splenomegalic polycythemia

· Vaquez’s disease

Treatment:

Over activity of marrow to produce RBC should be suppressed. Phenyle hydrizane and Myleron are used to destroy RBC and inhibit production of red blood cell.

Thrombocytopenia

Thrombocytopenic purpura is a blood dyscrasia associated with a decrease in circulating platelets. Thrombocytopenia of clinical significance exists when the whole blood platelet count is less than 150,000/mm³, although the precise limits for normal vary slightly among laboratories. Excessive hemorrhage during or after invasive dental treatment is often seen with platelet counts less than 50,000/mm³. The most common manifestation of thrombocytopenic purpura is spontaneous hemorrhage into the skin and mucous membranes. The disease is also characterized by prolonged bleeding. Two major forms of thrombocytopenic purpura—primary and secondary—have been described. Primary (idiopathic) thrombocytopenic purpura (ITP) (Fig.10) is of unknown etiology. This is a relatively common form of the disease and may be seen at any age. Secondary thrombocytopenia is caused by a known etiologic factor such as chemicals or drugs.

Two forms of ITP are recognized: acute and chronic. Acute ITP is a self-limited disease that generally remits permanently without sequel. The onset is usually sudden, with thrombocytopenia manifested by bruising, bleeding, and petechiae a few days to several weeks after an otherwise uneventful viral illness. Conversely, chronic ITP is usually a disease of adults and can be sudden or insidious in onset. It is more frequent in women than in men, and the course is characterized by remissions and exacerbations. In both acute and chronic ITP, thrombocytopenia and its manifestation are the only physical or laboratory abnormalities.

 The oral manifestations of thrombocytopenia may be the first clinical signs of the disease. Purpura, the most common oral sign, is defined as any escape of blood into subcutaneous tissues. Purpura includes petechiae, ecchymoses, hemorrhagic vesicles, and hematomas. These may appear on any mucosal surface and are often seen on the tongue, lips, and occlusal line of the buccal mucosa secondary to minor trauma. Purpura may be differentiated from vascular lesions by applying pressure directly to the area. Because purpura results from blood extravagated into the tissues, these lesions will not blanch. Other oral signs include spontaneous gingival hemorrhage and prolonged bleeding after trauma, toothbrushing, extractions, or periodontal therapy. Similar purpuric findings are seen on the skin. The patient may have a positive history of epistaxis (bleeding from the nose), hematuria (blood in urine), melena (darkening of feces caused by blood pigments), and increased menstrual bleeding.Good oral hygiene and complete removal of plaque and calculus help to minimize gingival inflammation and reduce gingival bleeding associated with thrombocytopenia. Gentle plaque control reduces the risk for bleeding. Periodontal therapy should be limited unless platelet counts exceed a minimum of 50,000/mm³, and surgery should be avoided until platelet counts are greater than 80,000/mm³. Any drug previously associated with the onset of thrombocytopenic episodes should be avoided. Aspirin and nonsteroidal antiinflammatory agents should also be avoided, because they may potentiate prolonged bleeding.bleeding, is generally associated with surgical therapy. On occasion, a patient with a coagulation disorder will have spontaneous gingival bleeding. This is usually caused by accumulation of plaque, and its presence emphasizes the importance of excellent oral hygiene in these patients

Erythremia (Vaquez disease)

  Erythremia or chronic erythromyelosis is characterized with abnormal increasing of red blood cells-a type of chronic hyperplasia of bone marrow which we called true red. Those middle and old aged males are often more prone to this disease. The clinical signs are peculiar plethoric redness of skin and mucosa, especially neck, cheek, lip, ear, nose and the most at distal part of limbs, hyperemic of eye conjunctiva, resembles the face of a drunken person. The other symptoms are such as headache, heaviness in the head, noise in ears, weakness and numbness of limbs; severe patients may even have impaired vision, narrowing of vision field, double vision, skin itching, about 1/3 even develop thromboses causing thrombosis of peripheral, brain and coronary arteries, often caused duodenal ulcers, rheumatoid arthritis and etc.

The etiology of this disease is still unknown clearly, considering the increasing of red blood cells is due to erythrocytosis (increased production of red blood cells or erythrocytes) and is not due to prolongation of life span of red blood cells. The researches shown that the increasing of red blood cells is related to the abnormality of hemopoeitic stem cells.

The diagnose is mainly based on clinical symptoms and blood analysis. The blood volume may increases to 120-240ml/kg (in norm 65-90ml/kg), hematocrit >50%, slow erythrocyte sedimentation rate, hemoglobin maybe more than 18-24g/dm, often accompanied by increasing of white blood cells, erythrocyte network normal or increased, neutrophils and alkaline phosphotase increased. The regenerative activity of bone marrow is obviously marked hyperactive and the ratio between neutrophils and young erythrocytes is decreased. Besides, there are positive result of iron dye and decreased iron storage in bone marrow.

The modern medical treatment mainly uses phlebotomy, new cytostatics (marcofan and myelosan) and radioactive phosphorus (32P).