Diseases of the Blood and Blood-forming Organs

Clinical Features

Pernicious anemia is rare before the age of 30 years and increases in frequency with advancing age. In the United States, males are affected more commonly than females; in other countries, notably Scandinavia, females are more commonly affected. No apparent racial predilection is noticed.

The disease is often characterized by the presence of a triad of symptoms: generalized weakness, a sore, painful tongue, and numbness or tingling of the extremities. In some cases the lingual manifestations are the first sign of the disease. Other typical complaints are easy fatigability, headache, dizziness, nausea, vomiting, diarrhea, loss of appetite, shortness of breath, loss of weight, pallor and abdominal pain.

Patients with severe anemia exhibit a yellowish tinge of the skin and sometimes of the sclerae. The skin is usually smooth and dry. Nervous system involvement is present in over 75% of the cases of pernicious anemia, and this consists of sensory disturbances including the paresthetic sensations of the extremities described above, weakness, stiffness and difficulty in walking, general irritability, depression or drowsiness as well as incoordination and loss of vibratory sensation. These nervous aberrations are referable to the degeneration of posterior and lateral tracts of the spinal cord with loss of nerve fibers and degeneration of myelin sheaths. Degeneration of the peripheral nerves also occurs.

Oral Manifestations

Glossitis is one of the more common symptoms of pernicious anemia. The patients complain of painful and burning lingual sensations which may be so annoying that the dentist is often consulted first for local relief.

The tongue is generally inflamed, often described as ‘beefy red’ in color, either in entirety or in patches scattered over the dorsum and lateral borders (Fig. 18-1). In some cases, small and shallow ulcers — resembling aphthous ulcers — occur on the tongue. Characteristically, with the glossitis, glossodynia and glossopyrosis, there is gradual atrophy of the papillae of the tongue that eventuate in a smooth or ‘bald’ tongue which is often referred to as Hunter’s glossitis or Moeller’s glossitis and is similar to the ‘bald tongue of Sandwith’ seen in pellagra. Loss or distortion of taste is sometimes reported accompanying these changes. The fiery red appearance of the tongue may undergo periods of remission, but recurrent attacks are common. On occasion, the inflammation and burning sensation extend to involve the entire oral mucosa but, more frequently, the rest of the oral mucosa exhibits only the pale yellowish tinge noted on the skin. Millard and Gobetti have emphasized that a nonspecific persistent or recurring stomatitis of unexplained local origin may be an early clinical manifestation of pernicious anemia. Not uncommonly the oral mucous membranes in patients with this disease become intolerant to dentures.

Farrant and Boen and Boddington have reported that cells from buccal scrapings of patients with pernicious anemia presented nuclear abnormalities consisting of enlargement, irregularity in shape and asymmetry. These were postulated to be due to a reduced rate of nucleic acid synthesis with a reduced rate of cell division. These epithelial cell alterations are rapidly reversible after administration of vitamin B₁₂.

Clinical Features

Sprue occurs both in tropical countries and in temperate zones in persons of all ages, including infants. For example, the frequency of the disease is between 1 in 250 persons and 1 in 300 persons in Italian and Irish populations. In comparison, the disease is rare in Africans or Asians. The symptoms of untreated celiac sprue are divided into gastrointestinal and extraintestinal symptoms.

Gastrointestinal symptoms include diarrhea, which is the most common symptom in untreated celiac sprue due to maldigestion and malabsorption of nutrients. Malabsorption of ingested fat (steatorrhea) resulting in excessive amount of fat passed in the stools. Flatulence results from the release of intestinal gas by the bacterial flora flourishing on undigested and unabsorbed food materials. In infants and young children with untreated celiac sprue, failure to gain weight and growth retardation is common. Other symptoms include weakness and fatigue, severe abdominal pain and excessive malodorous flatus. Occasionally, severe hypokalemia due to the loss of potassium in the stool can cause muscle weakness.

Extraintestinal symptoms include anemia which is usually due to impaired absorption of iron or folate from the proximal small intestine. In severe disease with ileal involvement, absorption of vitamin B₁₂ might be impaired. A bleeding diathesis caused by prothrombin deficiency due to impaired absorption of fat-soluble vitamin K. Excessive amounts of fat are passed in the stools, inducing a concomitant excessive loss of calcium, which in turn causes a calcium deficiency with ensuing low blood calcium levels and occasional tetany. Bone pain occurs due to osteoporosis as a result of calcium and vitamin D deficiency. Nervous irritability as well as numbness and tingling of the extremities occurs, but seldom is there spinal cord involvement as in pernicious anemia. Malaise and generalized weakness are also common. The skin changes are often identical with those of pernicious anemia, but also include irregular brownish pigmentation, particularly on the face, neck, arms and legs, and drying of the skin with a scaly eruption.

Oral Manifestations

The oral changes in sprue are similar to those of pernicious anemia and have been described by Adlersberg from observation of 40 cases. There may be a severe glossitis with atrophy of the filiform papillae, although the fungiform papillae often persist for some time on the atrophic surface. Painful, burning sensations of the tongue and oral mucosa are common, and small, painful erosions may occur. These severe oral manifestations are seldom absent in cases of sprue (Fig. 18-3). Tyldesley has reviewed this problem recently and concluded that there is an association between recurrent oral ulceration, or recurrent aphthous ulcers, and celiac disease and that proper dietary treatment leads to remission of the oral lesions.

Laboratory Findings

The blood and bone marrow changes are often identical with those of pernicious anemia and include a macrocytic anemia and leukopenia. Hypochromic microcytic anemia occasionally occurs. A low serum iron level is common. The prothrombin time (PT) might be prolonged because of malabsorption of vitamin K. The patients do not usually exhibit achlorhydria, nor is the ‘intrinsic’ factor absent.

Small intestinal biopsy, along with appropriate serum antibodies, usually will establish the diagnosis.

Histologic Findings

Celiac sprue primarily involves the mucosa of the small intestine. The submucosa, muscularis, and serosa usually are not involved. The villi are atrophic or absent, and crypts are elongated. The cellularity of the lamina propria is increased with a proliferation of plasma cells and lymphocytes. The number of intraepithelial lymphocytes per unit length of absorptive epithelium is increased.

Treatment

Sprue responds well in most cases to the administration of vitamin B₁₂ and folic acid, although the diet must be carefully supervised and supplemented with vitamins and minerals. Use of food grains containing gluten should be avoided. A small percentage of celiac sprue patients fail to respond to a gluten free diet. In some patients who are refractory, corticosteroids might be helpful. The patients who fail to respond to corticosteroids, other conditions such as lymphomas of the small intestine should be suspected.

Clinical Features

The clinical manifestations of aplastic anemia are referable not only to the anemia, but also to the leukopenia and thrombocytopenia which are variably present. There are few differences in the clinical features of the primary and secondary forms of the disease except in the ultimate prognosis. The onset is insidious, with the initial symptom relating to anemia or bleeding, but fever or infections often are noted at presentation.

The patients usually complain of severe weakness with dyspnea following even slight physical exertion and exhibit pallor of the skin. Numbness and tingling of the extremities and edema are also encountered due to anemia. Petechiae in the skin and mucous membranes occur, owing to the platelet deficiency, while the neutropenia leads to a decreased resistance to infection.

Oral Manifestations

Petechiae purpuric spots or frank hematomas of the oral mucosa may occur at any site, while hemorrhage into the oral cavity, especially spontaneous gingival hemorrhage, is present in some cases. Such findings are related to the blood platelet deficiency (Fig. 18-4). As a result of the neutropenia there is a generalized lack of resistance to infection, and this is manifested by the development of ulcerative lesions of the oral mucosa or pharynx. These may be extremely severe and may result in a condition resembling gangrene because of the lack of inflammatory cell response.

Laboratory Findings

The red blood cell count is remarkably diminished, often to as low as 1,000,000 cells per cubic millimeter, with a corresponding reduction in the hematocrit and hemoglobin levels. A paucity of granulocytes, monocytes, and reticulocytes is found. The thrombocytopenia results in a prolonged bleeding time; the clotting time remains normal. Clot retraction is poor and the tourniquet test is positive. The degree of cytopenia is useful in assessing the severity of aplastic anemia. The presence of teardrop poikilocytes and leucoerythroblastic changes suggest marrow aplasia from infiltrative and dysplastic causes.

Bone marrow smears exhibit variable findings depending on the extent of the anemia and/or pancytopenia. If only an anemia exists, there is erythropoietic depression. Occasionally, however, the marrow appears normal or even hyperplastic. In pancytopenia there is hypoplasia of all marrow elements, and only occasional cells of any type may be found. In cases of less severe damage, moderate numbers of primitive cells persist. In severe cases, hypocellular bone marrow with fatty replacement and relatively increased nonhematopoietic elements such as plasma cells and mast cells may be found. Hemoglobin electrophoresis and blood group testing may show elevated fetal hemoglobin and red cell 1 antigen suggesting stress erythropoiesis, which is observed in both aplastic anemia and myelodysplastic syndromes.

Treatment

Patients with aplastic anemia require transfusion support until the diagnosis is established and specific therapy can be instituted. Infections should be treated appropriately as it is the major cause of mortality. Other treatment options are bone marrow transplantation and immunosuppressive therapy.

Clinical Features

In high-risk areas (i.e. Greek and Italian islands), 10% of the population may have homozygous β-thalassemia; 5% in Southeast Asian populations; and 1.5% in African and American black populations. The onset of the severe form of the disease (homozygous β-thalassemia) occurs within the first two years of life, often in the first few months. Siblings are commonly affected. The child has a yellowish pallor of the skin and exhibits fever, chills, malaise and a generalized weakness. Splenomegaly and hepatomegaly may cause protrusion of the abdomen. The face often develops mongoloid features due to prominence of the cheek bones, protrusion or flaring of the maxillary anterior teeth, and the depression of the bridge of the nose which gives rise to the characteristic rodent facies. The child does not appear acutely ill, but the disease follows an ingravescent course which is often aggravated by intercurrent infection. Some patients; however, die within a few months, especially when the disease is manifested at a very early age. Logothetis and his associates have shown that the degree of cephalofacial deformities in this disease (including prominent frontal and parietal bones, sunken nose bridge, protruding zygomas and mongoloid slanting eyes) is closely related to the severity of the disease and the time of institution of treatment.

Thalassemia minor (thalassemia trait) is generally without clinical manifestations.

Oral Manifestations

An unusual prominence of the premaxilla has been described in cases of erythroblastic anemia, such as that reported by Novak, and this results in an obvious malocclusion. The oral mucosa may exhibit the characteristic anemic pallor observed on the skin.

Laboratory Findings

The pronounced anemia is of a hypochromic microcytic type, the red cells exhibiting a poikilocytosis and anisocytosis. These cells are extremely pale, but in some instances appear as ‘target’ cells with a condensation of coloring matter in the center of the cell. The presence of typical safety-pin cells and of normoblasts or nucleated red blood cells in the circulating blood is also a characteristic feature. The white blood cell count is frequently elevated, often as high as 10,000–25,000 or more per cubic millimeter. Supravital staining (methyl violet) of peripheral blood can demonstrate inclusion bodies. Bone marrow smears show cellular hyperplasia with large numbers of immature, primitive and stem forms of red blood cells, all indicating maturation arrest. The serum bilirubin in these patients is also elevated, indicative of the severe hemosiderosis which is almost invariably present. This systemic hemosiderosis has suggested a possible block in iron utilization with accumulation of iron pigment and subsequent inadequate formation of hemoglobin.

Radiographic Features

The skeletal changes in thalassemia are most striking and have been thoroughly described by Caffey. A frequent finding in rib has been referred to as the rib-within-a-rib appearance and is noted particularly in the middle and anterior portions of the ribs. The finding consists of a long linear density within or overlapping the medullary space of the rib and running parallel to its long axis. In the skull, there is extreme thickening of the diploe (medulla), the inner and outer plates (cortices) become poorly defined, and the trabeculae between the plates become elongated, producing a bristle like crew-cut or hair-on-end appearance of the surface of the skull (Fig. 18-5). Because of the lack of hematopoietic marrow, the occipital bone usually is not involved.

Both the skull and long bones exhibit some degree of osteoporosis, but spontaneous fracture of bones is not common. There is typically a widening of the medulla with thinning of the cortices of the long bones. The bony changes may occur early in life and tend to persist, particularly those in the skull.

Proliferation of marrow within the frontal and facial bones impedes pneumatization of the paranasal sinuses. This results in hypertrophy of osseous structures and a consequent prominence of the lateral margins of the malar eminences, together with anterior and medial displacement of developing teeth. Characteristically, ethmoidal sinuses are not involved, a factor attributable to the absence of red marrow in the sinus walls.

Intraoral radiographs in some cases reveal a peculiar trabecular pattern of the maxilla and mandible, characterized by an apparent coarsening of some trabeculae and the blurring and disappearance of others, resulting in a salt and pepper effect. In general, thinning of the lamina dura and circular radiolucencies in the alveolar bone are also found (Dewey et al).

Gall bladder imaging and ultrasound evaluation may reveal pigment stones. Splenic ultrasound may reveal splenomegaly.

Treatment

There is no treatment for this form of anemia. The administration of liver extract, iron or vitamin B₆ is fruitless. Blood transfusions do provide temporary remissions. Bone marrow transplantation may be a definitive treatment option, but long-term results from transplants already performed are not available. The disease is usually fatal, although mild forms which are compatible with life apparently exist. Generally, the earlier in infancy the disease occurs, the more rapidly it proves fatal. Death is generally due to intercurrent infection, cardiac damage as a result of anoxia, or liver failure.

Clinical Features

Sickle cell anemia is more common in females and usually becomes clinically manifest before the age of 30 years. Patients manifest a variety of features related to the anemia per se. Thus the patient is weak, short of breath and easily fatigued. Pain in the joints, limbs and abdomen, as well as nausea and vomiting, is common. Systolic murmur and cardiomegaly also occur. One additional feature characteristically seen is packing of red blood cells in peripheral vessels with erythrostasis and subsequent local tissue anoxia. An infarct of the mandible on this basis has been reported by Walker and Schenck. Sickle cell crises (vaso-occlusive, hematologic, and infectious crises) may occur under a variety of situations, including the administration of a general anesthetic, probably as a result of decreased oxygenation of the blood. Other triggering causes of deoxygenation may include exercise or exertion, infections, pregnancy or even sleep.

Oral Manifestations

According to the studies of Robinson and Sarnat, a majority of patients with sickle cell anemia exhibit significant bone changes in the dental radiographs. These alterations consist of a mild to severe generalized osteoporosis and a loss of trabeculation of the jaw bones with the appearance of large, irregular marrow spaces. The trabecular change is prominent in the alveolar bone. There are no alterations in the lamina dura or periodontal ligament. Similar findings were reported by Morris and Stahl and by Prowler and Smith, not only in patients with sickle cell anemia but also in many with only the sickling trait. However, in a study of 80 patients with sickle cell anemia who were compared with an apparently normal group of patients, Mourshed and Tuckson stated that these two radiographic features of the jaws—increased radiolucency and coarse trabeculation—cannot be considered reliable diagnostic criteria for the disease.

Goldsby and Staats have reported morphologic alterations in the nuclei of epithelial cells in scrapings of the oral mucosa in 90% of all studied cases of patients with homozygous sickle cell disease. These changes were chiefly nuclear enlargement, binucleation and an atypical chromatin distribution. These changes are similar to those that have been reported occurring in pernicious anemia and sprue (Fig. 18-6A, B).

Radiographic Features

Radiographs of the skull exhibit an unusual appearance, with perpendicular trabeculations radiating outward from the inner table producing a ‘hair-onend’ pattern, identical to that seen in thalassemia, congenital hemolytic jaundice and sometimes in chronic iron deficiency anemia and secondary polycythemia of cyanotic congenital heart disease. The outer table of bone may appear absent and the diploe thickened. Generalized osteoporosis may be present. The long bones of children may exhibit enlarged medullary cavities with thin cortices, while the same bones in adults become sclerotic with cortical thickening due to fibrosis of the marrow.

Laboratory Findings

The red blood cell count may reach a level of 1,000,000 cells or less per cubic millimeter with a decreased hemoglobin level. High reticulocyte count indicates anemia and increased marrow response. A major drop in hemoglobin (i.e. more than 2 gm/dl) from previous values indicates a hematological crisis. If the reticulocyte count is low, an aplastic crisis is the probable cause.

On the blood smear, typical sickle-shaped red blood cells are commonly seen, although they are present also in cases of the sickle trait without clinical evidence of the disease (Fig. 18-6C). Elevated levels of lactate dehydrogenase and decreased levels of haptoglobin confirm the presence of hemolysis. Hemoglobin electrophoresis can be done to differentiate homozygous from heterozygous.

Treatment

Treatment strategies include the following five goals:

Because this is a lifelong disease, prognosis is not good. The goal is to achieve a normal lifespan with minimal morbidity.

Pathogenesis

Erythroblastosis fetalis is essentially due to the inheritance by the fetus of a blood factor from the father that acts as a foreign antigen to the mother. The transplacental transfer of this antigen, actually transplacental leaks of red cells, from the fetus to the mother results in immunization of the mother and formation of antibodies which, when transferred back to the fetus by the same route, produce fetal hemolysis. Occasionally, the ABO system may produce a similar type of immunization and hemolysis.

The basic inheritance of the Rh factor is relatively simple. If both parents are homozygously Rh-positive (have the Rh factor), the infant will be Rh-positive, but maternal immunization cannot occur, since both mother and fetus have the same antigen. If the mother is homozygously positive, but the father Rh-negative, the same situation actually exists, since both the mother and the fetus have the same antigen and no immunization can occur. If the father is Rh-positive and the mother Rh-negative; however, the fetus inherits the paternal factor, which may then act as an antigen to the mother and immunize her with resultant antibody formation.

The problem is complicated; however, by the occurrence of numerous immunologically distinct Rh antigens. The strongest of these antigens have been termed C, D and E, and the presence of any one of them constitutes an Rh-positive person. Each of these antigens is normally present in a specific gene, but, if absent, their place is taken by less potent Hr antigens, known as c, d and e. Thus, three Rh or Hr genes are inherited from each parent, constituting three pairs of factors. Any combination of C, D, E and c, d, e is therefore possible, but the only combination producing an Rh-negative person is cde-cde. The D antigen, by far the strongest, is most frequently responsible for the clinical manifestations of erythroblastosis fetalis, and the 85% of the population generally considered Rh-positive actually have the D antigen homozygously (DD) or heterozygously (D-d). The 15% who are Rh-negative have the d antigen homozygously (d-d). Mathematically, according to the laws of random mating, there should be 10 cases of erythroblastosis fetalis in every 100 pregnancies. Clinically, it has been found that only one case in every 200 pregnancies occurs. There are several possible explanations for this discrepancy:

Subsequent pregnancies might cause further immunization with increased antibody formation, so that in ensuing pregnancies clinical hemolysis does occur. This latter explanation is plausible since it explains adequately why the first pregnancy is often uneventful, while erythroblastosis frequently occurs in succeeding pregnancies.

It is of great interest to note that the frequency of erythroblastosis fetalis of Rh incompatibility has shown a dramatic decrease in the past few years and that the eventual elimination of the disease through immunization prevention techniques is a probability. At present, Rh-negative mothers are being given anti-D gamma globulin to prevent immunization, since it binds to antigenic receptor sites on fetal red cells, making them nonimmunogenic.

Clinical Features

The manifestations of the disease depend upon the severity of the hemolysis. Some infants are stillborn. Those that are born alive characteristically suffer from anemia with pallor, jaundice, compensatory erythropoiesis, both medullary and extramedullary, and edema resulting in fetal hydrops. It is of considerable interest that the severe anemia and jaundice do not begin to develop until at least several hours after birth and frequently not for several days. The most important aid in diagnosis of the disease is a positive direct Coombs test on cord blood.

Oral Manifestations

Erythroblastosis fetalis may be manifested in the teeth by the deposition of blood pigment in the enamel and dentin of the developing teeth, giving them a green, brown or blue hue (Fig. 18-7). Ground sections of these teeth give a positive test for bilirubin. The stain is intrinsic and does not involve teeth or portions of teeth developing after cessation of hemolysis shortly after birth.

Enamel hypoplasia is also reported occurring in some cases of erythroblastosis fetalis. This usually involves the incisal edges of the anterior teeth and the middle portion of the deciduous cuspid and first molar crown. Here a characteristic ring-like defect occurs which has been termed the Rh hump by Watson.

Many infants with this disease are stillborn, but an increasing number of those born alive have survived after a total replacement of their blood by transfusion at birth. Thus the dentist may expect to see more children with the peculiar pigmentations of teeth characteristic of the condition, and should be aware of its nature.

Laboratory Findings

The red blood count at birth may vary from less than 1,000,000 cells per cubic millimeter to near a normal level. There are characteristically large numbers of normoblasts, or nucleated red cells, in the circulating blood. Ultimately, severe anemia usually develops within a few days. The icterus index is invariably high and may reach a level of 100 units.

Treatment

No treatment for the tooth pigmentation is necessary, since it affects only the deciduous teeth and presents only a temporary cosmetic problem.

Clinical Features

While an iron-deficiency anemia may occur at any age, the Plummer-Vinson syndrome occurs chiefly in women in the fourth and fifth decades of life. Presenting symptoms of the anemia and the syndrome are cracks or fissures at the corners of the mouth (angular cheilitis), a lemon-tinted pallor of the skin, a smooth, red, painful tongue (glossitis) with atrophy of the filiform and later the fungiform papillae, and dysphagia limited to solid food resulting from an esophageal stricture or web. These oral findings are reminiscent of those seen in pernicious anemia. The mucous membranes of the oral cavity and esophagus are atrophic and show loss of normal keratinization. Koilonychia (spoon-shaped fingernails) or nails that are brittle and break easily have been reported in many patients; splenomegaly has also been reported in 20–30% of the cases.

The depletion of iron stores in the body, manifested as iron-deficiency anemia, may be the direct cause of the mucous membrane atrophy, since the integrity of epithelium is dependent upon adequate serum iron levels. The atrophy of the mucous membranes of the upper alimentary tract predisposes to the development of carcinoma in these tissues. This relationship was first noted by Ahlbom, who reported that half of all women with carcinoma of the hypopharynx and upper part of the esophagus seen at Radiumhemmet in Stockholm suffered from Plummer-Vinson syndrome. Subsequently the predisposition to the development of oral carcinoma was also established.

Laboratory Findings

Blood examination reveals a hypochromic microcytic anemic of varying degree, while sternal marrow examination shows no megaloblasts typical of pernicious anemia. The red blood cell count is generally between 3,000,000 and 4,000,000 cells per cubic millimeter, and the hemoglobin is invariably low. That the anemia is of an irondeficiency type can be confirmed by lack of a reticulocyte response following administration of vitamin B₁₂. A low serum iron and ferritin with an elevated total iron binding capacity (TIBC) are diagnostic of iron deficiency. There is an absence of free hydrochloric acid in the stomach. The achlorhydria is generally the cause of the faulty absorption of iron, since the absence of hydrochloric acid prevents the conversion of unabsorbable dietary ferric iron to the absorbable ferrous state. The absence of stainable iron in a bone marrow aspirate is further diagnostic of iron deficiency. Unusual alterations in exfoliated squamous epithelial cells of the tongue in cases of severe iron-deficiency anemia have been reported by Monto and his associates. These changes consisted of a deficiency of keratinized cells, a reduced cytoplasmic diameter of cells with a paradoxical enlargement of the nucleus, and abnormal cellular maturation characterized by a disturbed nuclear pattern, an increase in nucleoli, presence of double nuclei and karyorrhexis. Testing stool for the presence of hemoglobin is useful in establishing gastrointestinal bleeding as the etiology of iron deficiency anemia; however, they produce a high incidence of false-positive results in people who eat meat.

Treatment and Prognosis

The anemia responds well to iron therapy and a high-protein diet. Because of the predisposition to the development of carcinoma of oral mucous membranes, it is essential that the diagnosis be established early so that treatment may be instituted as soon as possible. Dysphagia may improve with iron replacement alone, particularly in patients whose webs are not substantially obstructive. Dysphagia caused by more advanced webs is unlikely to respond to iron replacement alone, and thus is managed with mechanical dilation.

Clinical Features

Polycythemia vera often manifests itself primarily by headache or dizziness, weakness and lassitude, tinnitus, visual disturbances, mental confusion, slurring of the speech and inability to concentrate. The skin is flushed or diffusely reddened, as a result of capillary engorgement and high red cell mass, as though the patient were continuously blushing. This condition is most obvious on the head, neck and extremities, although the digits may be cyanotic. Increased red blood cell mass increases blood viscosity and decreases tissue perfusion, and also predisposes for thrombosis. If secondary polycythemia is secondary to hypoxia, patients can also appear cyanotic or may have acrocyanosis which is caused by sluggish blood flow through small blood vessels. The skin of the trunk is seldom involved. Splenomegaly is one of the most constant features of polycythemia vera, and the spleen is sometimes painful. Gastric complaints such as gas pains, belching and peptic ulcers are common, and hemorrhage from varices in the gastrointestinal tract may occur. Pruritus results from increased histamine levels released from increased basophils and mast cells and can be exacerbated by a warm bath or shower in up to 40% of patients. The disease is more common in men and usually occurs in middle age or later.

Oral Manifestations

The oral mucous membranes appear deep purplish red, the gingiva and tongue being most prominently affected. The cyanosis is due to the presence of reduced hemoglobin in amounts exceeding 5 gm/dl. The gingivae are often engorged and swollen and bleed upon the slightest provocation. Submucosal petechiae are also common, as well as ecchymoses and hematomas. Intercurrent infection may occur, but this is not related directly to the disease.

Laboratory Findings

Red blood cell mass and plasma volume can be measured directly using radiochromiumlabeled red blood cells which show an increase in mass with a normal or slightly decreased plasma volume. The red blood cell count is elevated and may even exceed 10,000,000 cells per cubic millimeter (Figs. 18-11). The red blood cells in patients with PV are usually normochromic normocytic. The hemoglobin content of the blood is also increased, often as high as 20 gm/dl, although the color index is less than 1.0. Because of the great number of cells present, both the specific gravity and the viscosity of the blood are increased.

Leukocytosis is usual, as is a great increase in the number of platelets (400,000–800,000/dl) (Figs. 18-12, 18-13); in addition, the total blood volume is elevated through distention of even the smallest blood vessels of the body. The leukocyte alkaline phosphatase score is elevated (>100 U/L) in 70% of patients. There is usually hyperplasia of all elements of the bone marrow. Bleeding and clotting times are normal.

Treatment

No specific treatment for polycythemia is known, although several methods are used for relieving its symptoms. The patient may be periodically bled, or substances may be administered either to destroy blood cells (phenylhydrazine) or to interfere with its formation (nitrogen mustard or even X-ray radiation). In recent years, the radioactive isotope of phosphorus, P32, has been used. Any such treatment; however, produces only a remission of the disease; it does not affect a cure. The course of the disease may be protracted over many years.

Etiology

The most common known cause of agranulocytosis is the ingestion of any one of a considerable variety of drugs (Table 18-5) and infections. Those compounds chiefly responsible for the disease are also those to which patients commonly manifest idiosyncrasy in the form of urticaria, cutaneous rashes and edema. For this reason and because often only small amounts of these drugs are necessary to produce the disease, it appears that the reaction may be an allergic phenomenon, although attempts to demonstrate antibodies in affected patients have not been successful. Moreover, in the case of some of the drugs, the disease occurs only after continued administration.

Kracke, in 1931, was one of the first to point out that a rapid increase in the number of cases of agranulocytosis occurred at the time of the introduction of certain coal-tar derivatives for use in therapy. The following drugs and compounds are some of those which have been reported to produce agranulocytosis in some persons:

Most persons can be exposed to these drugs with near impunity; the hematologic reaction to the compounds is actually an uncommon one.

The mechanism that causes agranulocytosis is not understood completely. In drug-induced agranulocytosis, the drug may act as a hapten and induce antibody formation. Thus produced antibodies destroy the granulocytes or may form immune complexes which bind to the neutrophils and destroy them. Autoimmune neutropenia due to antineutrophil antibodies is seen in few cases.

Other uncommon causes of agranulocytosis include Kostmann syndrome (severe congenital neutropenia) which is most often inherited in autosomal recessive pattern. Autosomal dominant and sporadic cases have also been reported, most often due to mutations in the granulocyte colony-stimulating factor (G-CSF) receptor.

Chronic severe neutropenia has an underlying unknown cause. Myelodysplasia occurs in early infancy and is associated with recurrent infections. The condition is due to accelerated apoptosis and decreased expression of bcl-x in neutrophil precursors.

Clinical Features

Agranulocytosis can occur at any age, but is somewhat more common in adults, particularly women. The disease frequently affects workers in the health professions and in hospitals (e.g. physicians, dentists, nurses, hospital orderlies, and pharmacists), probably because they have easy access to the offending drugs and often use drug samples injudiciously.

The disease commences with a high fever, accompanied by chills and sore throat. The patient suffers malaise, weakness and prostration. The skin appears pale and anemic, or in some cases, jaundiced. The most characteristic feature of the disease is the presence of infection, particularly in the oral cavity, but also throughout the gastrointestinal tract, genitourinary tract, respiratory tract and skin. Regional lymphadenitis accompanies the infection in any of these locations. If treatment is not promptly instituted, the infection progresses to generalized sepsis, which may be life threatening.

The clinical signs and symptoms develop rapidly in the majority of cases, usually within a few days, and death may occur within a week.

Oral Manifestations

The oral lesions constitute an important phase of the clinical aspects of agranulocytosis. These appear as necrotizing ulcerations of the oral mucosa, tonsils and pharynx. Particularly involved are the gingiva and palate. The lesions appear as ragged necrotic ulcers covered by a gray or even black membrane (Fig. 18-12). Usually no purulent discharge is noticed. Significantly, there is little or no apparent inflammatory cell infiltration around the periphery of the lesions, although hemorrhage does occur, especially from the gingiva. In addition, the patients often manifest excessive salivation.

It is obvious that all oral surgical procedures, particularly tooth extraction, are contraindicated in cases of agranulocytosis.

Histologic Features

The microscopic appearance of sections through the ulcerated oral lesions is a pathognomonic one and accounts for certain clinical features of the disease. Since the essential fault is the lack of development of normal granular leukocytes, the ulcerated areas exhibit no polymorphonuclear reaction to the bacteria in the tissues, and rampant necrosis ensues.

Bauer studied the microscopic appearance of the jaws in agranulocytosis and reported necrosis of the gingiva, beginning adjacent to the sulcus and spreading into the free gingiva, periodontal ligament and even alveolar bone. Rapid destruction of the supporting tissues of the teeth follows.

Laboratory Findings

The white blood cell count in agranulocytosis is often below 2000 cells per cubic millimeter with an almost complete absence of granulocytes or polymorphonuclear cells. The red blood cell count and platelet count are usually normal, although occasionally anemia is present.

The bone marrow is relatively normal except for the absence of granulocytes, metamyelocytes and myelocytes. Promyelocytes and myeloblasts are usually present in near normal numbers; however, and for this reason it appears that the basic defect is an arrest in cell maturation.

Treatment and Prognosis

The treatment of agranulocytosis is not specific, but should consist principally in recognition and withdrawal of the causative drug and in administration of antibiotic drugs to control the infection.

Death is usually related to massive infection, and for this reason the disease carried a high mortality before the advent of the antibiotics. Today, although it is still a serious disease, agranulocytosis has a good prognosis if the responsible agent is discovered. Agranulocytosis secondary to viral infections is usually self-limited, and patients with such conditions have a good prognosis.

Clinical Features

This type of agranulocytosis may occur at any age, although the majority of cases have been reported in infants or young children. The symptoms are similar to those of typical agranulocytosis except that they are usually milder. The patients manifest fever, malaise, sore throat, stomatitis and regional lymphadenopathy, as well as headache, arthritis, cutaneous infection and conjunctivitis. In contrast to other types of primary agranulocytosis, rampant bacterial infection is not a significant feature (Table 18-6), presumably because the neutrophil count is low for such a short time. Entities closely mimic the clinical characteristics of cyclic neutropenia are variable, encompassing a wider spectra (Table 18-7).

Oral Manifestations

Patients with this disease typically exhibit a severe gingivitis, sometimes a stomatitis with ulceration, which corresponds to the period of the neutropenia and is due to bacterial invasion, chiefly from the gingival sulcus, in the absence of a defense mechanism (Fig. 18-13). With return of the neutrophil count to normal, the gingiva assumes a nearly normal clinical appearance. In children, the repeated insult of infection often leads to considerable loss of supporting bone around the teeth (Fig. 18-14). The widespread severe ulceration usually seen in agranulocytosis does not often occur. However, isolated painful ulcers may occur which persist for 10–14 days and heal with scarring. On this basis, it has been suggested by Gorlin and Chaudhry that some cases diagnosed clinically as periadenitis mucosa necrotica recurrens may actually be cyclic neutropenia.

Radiographic Features

The intraoral radiographs typically exhibit mild to severe loss of superficial alveolar bone, even in children, as a result of the repeated cyclic gingivitis, advancing to periodontitis. In children, this loss of bone around multiple teeth has sometimes been termed ‘prepubertal periodontitis’, and it is frequently indicative of a serious systemic disease. Cohen and Morris have discussed the periodontal manifestations of cyclic neutropenia.

Laboratory Findings

Cyclic neutropenia is an unusual disease which manifests the clinical signs and symptoms and blood changes in a periodic fashion. The cycle commonly occurs every three weeks, although in some cases it may be several months or even longer in duration.

The patient may exhibit a normal blood count which, over a period of four to five days, begins to show a precipitous decline in the neutrophil count compensated by an increase in monocytes and lymphocytes. At the height of the disease, the neutrophils may completely disappear for a period of one or two days. Soon; however, the cells begin to reappear, and within four to five days the blood cell count and differential count are essentially normal.

Treatment and Prognosis

There is no specific treatment for the disease, although in some instances splenectomy has proved beneficial. Death occasionally results, usually from intercurrent infection, but the prognosis is generally far better than in typical agranulocytosis. The patients may suffer from their periodic disease for years.

Clinical Features

Chédiak-Higashi syndrome affects all races and usually appears soon after birth or in children younger than five years. This disease is characterized by immune deficiency; partial oculocutaneous albinism; easy bruisability and bleeding as a result of deficient platelet dense bodies; recurrent infections with neutropenia, impaired chemotaxis, and bactericidal activity; and abnormal natural killer (NK) cell function.

The disease is often fatal in childhood as a result of terminal phase characterized by nonmalignant lymphohistiocytic lymphoma like infiltration of multiple organs that occurs in more than 80% of patients. This stage is precipitated by virus infection, particularly by the Epstein-Barr virus. It is associated with anemia, bleeding episodes, and overwhelming infections leading to death. Infections secondary to abnormal functioning of polymorphonuclear leukocytes commonly involve the skin, the lungs, and the respiratory tract. Infections are usually caused by Staphylococcus aureus, Streptococcus pyogenes, and Pneumococcus species. Very few patients live to adulthood and in these patients, a progressive neurologic dysfunction may be the dominant feature. Neurologic involvement is variable but often includes peripheral neuropathy.

Oral Manifestations

Ulcerations of the oral mucosa, severe gingivitis, and glossitis are the commonly described oral lesions, as in the case report of Gillig and Caldwell. Hamilton and Giansanti have pointed out that periodontal breakdown, probably related to defective leukocyte function, may also be a common oral feature.

Laboratory Findings

Hematologic studies show that the patients classically exhibit giant abnormal granules in the peripheral circulating leukocytes, in their marrow precursors, and in many other cells of the body as well. These granules are the hallmark of the syndrome and are invariably present. They are thought to represent abnormal lysosomes and bear resemblance to toxic granulations and Dohle bodies. Pancytopenia is sometimes present. Ultrastructurally viable dividing bacteria, along with abnormal granules, are found in the cytoplasm of periodontal polymorphonuclear leukocytes.

Treatment and Prognosis

There is no specific treatment for the disease. It is often fatal, with death occurring before the child reaches the age of 10 years.

Clinical Features

Frequently seen in epidemic form, infectious mononucleosis is characterized by fever, sore throat, headache, chills, cough, nausea or vomiting and lymphadenopathy (bilateral and symmetrical). Splenomegaly and hepatitis also occur with considerable frequency. Most patients with EBV infectious mononucleosis can be asymptomatic.

The cervical lymph nodes are usually the first to exhibit enlargement, followed by the nodes of the axilla and groin (Fig. 18-15A). Pharyngitis and tonsillitis are common, but not invariably present, and skin rash has occasionally been reported.

The majority of cases in children appear to be asymptomatic. However, the peak incidence of the disease occurs in the 15 to 20-year-old age group. There does not appear to be a sex or seasonal predilection for occurrence.

Oral Manifestations

There are apparently no specific oral manifestations of infectious mononucleosis, although secondary lesions do occur. An excellent review of the literature and study of the oral lesions occurring in 140 patients with infectious mononucleosis was reported by Fraser-Moodie. The oral manifestations consisted chiefly of acute gingivitis and stomatitis, the appearance of a white or gray membrane in various areas, palatal petechiae and occasional oral ulcers. Of his entire series of 140 patients, 32% exhibited oral manifestations, and interestingly, in 50% of the patients with stomatitis the oral lesions were the first sign of the disease. Edema of the soft palate and uvula has also been reported in some cases.

Reports by Shiver and his coworkers and by Courant and Sobkov emphasized the finding of petechial hemorrhages of the soft palate near the junction with the hard palate as an early manifestation of infectious mononucleosis (Fig. 18-16). These have been described as pinpoint petechiae, numbering from a dozen to several hundred, which appeared a few days after other symptoms in 50–65% of the patients in these series. The lesions persisted for 3–11 days and then gradually faded. They must be differentiated from areas of increased vascularity and pigmented areas. This occurrence of palatine petechiae as an early clinical diagnostic sign of infectious mononucleosis has also been confirmed by Schumacher and Barcay. They reported that approximately 7% of a series of 452 patients with this disease had hemorrhagic manifestations, nearly half of these presenting with palatine petechiae. About one-third of the patients with the hemorrhagic tendency exhibited oronasopharyngeal bleeding, including bleeding from the gingiva.

Laboratory Findings

The patient exhibits atypical lymphocytes in the circulating blood, as well as antibodies to the EB virus and an increased heterophil antibody titer (Fig. 18-15B). However, the increased heterophil is present only in a small minority of children with the disease. The normal titer of agglutinins and hemolysins in human blood against sheep red blood cells does not exceed 1 : 8. In infectious mononucleosis; however, the titer may rise to 1 : 4096. This is referred to as a positive Paul-Bunnell test and is both characteristic and pathognomonic of the disease. Agglutination of horse RBCs on exposure to EB virus heterophile antibodies (Monospot test) is a highly specific test. In acute infection, the viral core antigen antibody of IgM class titer against EBV is increased. Later in the course of infection, the increase in IgM viral core-antigen (VCA) antibodies may be accompanied by an increase in IgG VCA antibodies and an increase in IgG EBNA (EBV nuclear antigen antibodies). EBNA appears after one to two months and persists throughout life. Thus the presence of this antibody suggests previous exposure to the antigen. The erythrocyte sedimentation rate is elevated in most patients with EBV infectious mononucleosis. An increase in the white blood cell count is also common, and this is almost invariably a lymphocytosis. In fact, infectious mononucleosis is defined partly on the basis that the patient has more than a 50% lymphocytosis, of which 10% or more are the ‘atypical’ forms. These ‘atypical’ forms consist of either oval, horseshoe-shaped or indented nuclei with dense, irregular nuclear chromatin and a basophilic, foamy or vacuolated cytoplasm. A thrombocytopenia is also present in some patients. It is an interesting finding that during the acute phase of infectious mononucleosis, patients frequently have a normal sedimentation rate.

Treatment

There is no specific treatment for this disease. The various antibiotics have been used without great success. Bed rest and adequate diet are probably of as great a benefit as any other form of therapy. Short-term steroid therapy has occasionally been used, but the results have been somewhat inconsistent. The disease generally runs its course in two to four weeks, and there seldom are complications.

Etiology

The etiology of leukemia is unknown. Certain aspects of the disease have suggested an infectious origin to some investigators, but a specific causative organism has never been isolated. Of these, viruses have been suspected for many years of being most closely related to this disease. It has been recognized for many years that a variety of animal leukemias were almost certainly of viral origin. It has been shown by Stewart and Eddy that the ‘polyoma’ virus is capable of producing numerous different types of neoplasms in a variety of animals, one of these neoplasms being leukemia.

It is rather well accepted by most workers in the field of viral oncology today that avian, feline and murine leukemia are caused by leukemogenic viruses. However, the animals must be rendered immunologically vulnerable and it is possible that, in the human as well as in the experimental animal, radiation and a variety of chemicals, both of which have been closely associated with leukemia for many years, may be at least one key to this immunologic susceptibility. Not only is the incidence of leukemia among radiologists approximately 10 times higher than among general practitioners of medicine, but also the data indicate a general rise in the incidence of this disease among the Japanese exposed to the atomic bomb blasts at Hiroshima and Nagasaki. In addition, chronic exposure to benzol, aniline dyes and related chemicals has been recognized for many years as being associated with the development of leukemia.

The Epstein-Barr (EB) virus, a herpes like virus, has been implicated as being the most likely leukemogenic virus in humans because of the high antibody titer against this virus in leukemic patients, as well as the finding in leukemic cells of viruses with a morphologic similarity to the EB virus. Human T-cell leukemia virus-1 (HTLV-1) is known to be associated with a form of T-cell leukemia/lymphoma that is endemic in certain parts of Japan and the Caribbean basin.

It is also recognized that chromosomal abnormalities commonly occur in leukemic patients. One such abnormality is the finding of the Philadelphia chromosome in between 85 and 95% of patients with chronic myeloid leukemia. This Philadelphia chromosome, at one time thought to be a partial deletion of the long arm of chromosome 22, is now recognized as a translocation of chromosomal material from chromosome 22 to chromosome 9. In about 5% of cases, the translocation occurs to other chromosomes. It is interesting to note that this chromosome disappears from the circulation during remission of the disease in many cases but will reappear when there is a relapse. In addition, a variety of other chromosomal abnormalities also have been recognized as occurring in over 50% of patients with different forms of poorly differentiated leukemia.

It should be remembered that mongolism or Down syndrome is due to a defect or trisomy of chromosome 21. Interestingly, it has been found that the incidence of leukemia in mongoloids is between three and 15–20 times that of the general population. However, this type of leukemia in mongoloids is generally an acute form of leukemia in contrast to the chronic leukemia associated with the Philadelphia chromosome.

The importance of various cofactors or predisposing characteristics, such as genetics, age, hormones, immune competence and stress, must all be considered in determining the susceptibility to tumor development of an individual infected with an oncogenic virus. Only when this has been accomplished can there be any attempt at specific cure or even prevention of the disease.

Clinical Features

The age of the patients affected by leukemia varies remarkably, but generally may be correlated with the course of the disease. Thus acute leukemia occurs more commonly in children and young adults, while chronic leukemias are most frequently seen in adults of middle age or older. There are; however, many exceptions to this general rule. There is some difference in the gender predilection, males being affected more often than females. No notable differences exist in the clinical manifestations of the morphologic forms of leukemia except that most cases of acute leukemia in adults are of the monocytic variety; thus all types of acute leukemia present a similar clinical picture and cannot be differentiated without recourse to laboratory studies. The same is true for chronic leukemia. For this reason the clinical features of leukemia can be discussed under the general categories of acute and chronic forms of the disease.

Laboratory Findings

Hematologic examination constitutes the basis for the final diagnosis of any type of leukemia. It is recognized; however, that ‘subleukemic’ or ‘aleukemic’ forms of the disease exist in which the white blood cell count of the peripheral blood is normal or even subnormal and in which these are or are not abnormal or immature leukocytes present.

Oral Manifestations

Oral lesions occur in both acute and chronic forms of all types of leukemia: myeloid, lymphoid and monocytic. These manifestations are far more common; however, in the acute stage of the disease, and according to Burket, are most common in monocytic leukemia. In a series of cases he reported oral lesions in 87% of patients with monocytic leukemia, in 40% of patients with myeloid leukemia, and in 23% of those with lymphoid leukemia. Osgood found a similar high incidence of oral manifestations in monocytic leukemia, reporting that 80% of affected patients exhibited gingival hyperplasia. An 80% incidence of positive oral findings was reported in a series of 38 leukemic patients by Duffy and Driscoll. Interestingly, those patients not manifesting oral lesions were either very young children or edentulous persons. In a study of 292 children with leukemia of different types, Curtis found that only slightly less than 30% had oral findings suggestive of leukemia. He pointed out that this infrequency of oral manifestations in childhood leukemia is due primarily to the high incidence of acute lymphocytic leukemia in this age group, since this type is least likely to produce oral lesions.

Often a patient with leukemia presents himself to his/her dentist for treatment of oral lesions, not suspecting that they are more than local in nature. These primary clinical manifestations of the disease may consist of gingivitis, gingival hyperplasia, hemorrhage, petechiae and ulceration of the mucosa.

The gingival hyperplasia, which may be one of the most constant features of the disease except in edentulous patients, is usually generalized and varies in severity. In severe cases the teeth may be almost completely hidden (Fig. 18-18). The gingivae are boggy, edematous and deep red. They bleed easily. The gingival swelling is due to the leukemic infiltration in areas of mild chronic irritation (Fig. 18-19). Purpuric lesions of the oral mucosa analogous to the cutaneous ecchymoses may also be seen.

The gingival hemorrhage which commonly occurs is due to ulceration of the sulcus epithelium and necrosis of underlying tissue. Since the normal white blood cells distribution is greatly disturbed, a normal inflammatory response to even a mild infection is impossible. For this reason severe ulceration of the oral mucosa and even the development of a nomalike condition is not unusual. Thrombosis of gingival vessels appears to contribute to this phenomenon.

Rapid loosening of the teeth due to necrosis of the periodontal ligament has been reported, and destruction of alveolar bone also occurs in some cases. The use of panoramic radiographs in a study of 214 children with acute leukemia has been reported by Curtis to be useful in demonstrating previously overlooked changes in the jaws. Of this group, approximately 63% exhibited osseous changes in the jaws, including alterations in developing tooth crypts, destruction of lamina dura, displacement of teeth and poor radiographic definition of bone, sometimes extending to the crest of alveolar bones, with destruction of the bone in this area.

It is imperative that the dentist maintain a high index of suspicion in cases of periodontal lesions with a somewhat unusual appearance. The complaint of a patient that he/she has experienced sudden gingival bleeding or gingival hyperplasia should suggest the possibility of leukemia. As Michaud and her coworkers have indicated in a study of 77 children with the disease, the oral manifestations of acute leukemia may be varied; they are not pathognomonic. Any disease that causes immunosuppression, bone marrow suppression, and disease of the blood-forming organs may have one or more of the oral findings of acute leukemia at the time of its initial diagnosis.

Treatment

Spectacular advances have been made in the treatment of the leukemias over the past few years. At one time, the prognosis for this disease was almost hopeless. Today, a wide array of chemotherapeutic drugs, radiation therapy and corticosteroids under certain circumstances offer prolonged remissions and apparent cures in at least some forms of the disease. For example, the most common form of leukemia in children, acute lymphocytic leukemia, once almost always fatal within a few months, now has a prolonged remission and a probable cure rate approaching 50%. Because this area of treatment is changing so rapidly with the introduction of new drugs and new techniques, to cite data on therapeutic responses would not be meaningful. It is sufficient to note that while leukemia is still a serious disease, the outlook for the leukemic patient today is far more promising than it was only a few decades ago and will probably continue to improve.

(a) Primary or 'essential' purpura

(b) Secondary or symptomatic purpura.

Clinical Features

Thrombocytopenic purpura is characterized by the spontaneous appearance of purpuric or hemorrhagic lesions of the skin which vary in size from tiny, red pinpoint petechiae to large purplish ecchymoses and even massive hematomas. The patient also exhibits a bruising tendency.

Epistaxis, or bleeding from the nose, is a common manifestation of the disease, as are bleeding in the urinary tract, resulting in hematuria, and bleeding in the gastrointestinal tract, producing melena or hematemesis. A possible complication is intracranial hemorrhage, which may result in hemiplegia. The spleen is usually not palpable. If it is palpable, leukemia should be suspected instead of thrombocytopenic purpura.

According to Wintrobe and his associates, over 80% of cases of primary thrombocytopenic purpura occur before the age of 30 years, with the greatest incidence before 10 years. Many patients present a familial history of purpura. Secondary thrombocytopenia has no particular age predilection.

Oral Manifestations

One of the prominent manifestations of thrombocytopenic purpura is the severe and often profuse gingival hemorrhage which occurs in the majority of cases (Fig. 18-21). This hemorrhage may be spontaneous and often arises in the absence of skin lesions.

Petechiae also occur on the oral mucosa, commonly on the palate, and appear as numerous tiny, grouped clusters of reddish spots only a millimeter or less in diameter. Actual ecchymoses do occur occasionally.

The tendency for excessive bleeding contraindicates any oral surgical procedure, particularly tooth extraction, until the deficiency has been compensated.

Laboratory Findings

The thrombocytopenia may be exceptionally severe, and the platelet count is usually below 60,000 platelets per cubic millimeter. As a consequence, the bleeding time is prolonged, often to one hour or more. The coagulation time is normal, although the clot does show failure of retraction. As might be expected from the clinical findings, the capillary fragility is increased and the tourniquet test is strongly positive. The red and white blood cell counts are normal unless secondarily disturbed by frequent episodes of hemorrhage or drug or X-ray-induced pancytopenia. Giant platelets on peripheral smear suggest congenital thrombocytopenia.

It is important to understand the basic mechanisms underlying the determination of bleeding and clotting times. Cessation of bleeding as measured by the bleeding time, depends upon the physical blockade of severed capillaries by platelets; as long as the number of platelets present in the blood stream is normal and the platelets aggregate properly, there is no alteration in bleeding time. But if the number of circulating platelets is decreased, the normal platelet plugging of the capillaries occurs more slowly and the bleeding time is consequently prolonged. On the other hand, the role of the platelets in the blood clotting mechanism is through release of a thromboplastic factor from agglutinated platelets. This is present in sufficiently large quantities so that, even when there is a reduction in the number of circulating platelets, sufficient thromboplastic substance is released to maintain normal coagulation. Therefore, in thrombocytopenia, the coagulation time remains normal.

The blood platelets are probably also related to capillary fragility, although the exact mechanism is unknown. It has been suggested that all capillaries undergo 'daily wear and tear' with minor injuries to their walls which are normally plugged by the platelets. If the platelets are diminished; however, there is failure of this maintenance of capillary integrity, resulting in an apparent increase in the capillary fragility.

Treatment and Prognosis

There is no specific treatment for this disease, although splenectomy probably has proved more beneficial than any other form of therapy aside from symptomatic relief such as transfusions and bed rest. Corticosteroids have been used in many cases with excellent results, although remissions may be temporary. The prognosis for patients with this disease is fairly good, since remissions are common. Unfortunately, exacerbations are also common. When death ensues, it is usually from sudden severe hemorrhage.

In secondary thrombocytopenia, correction or removal of the etiologic factor is essential.

Clinical Features

The disease generally occurs in young adults and is more common in females than in males. It is characterized by thrombocytopenia, hemolytic anemia, fever, transitory neurologic dysfunction and renal failure.

Histologic Features

The major findings in this disease are the widespread microthrombi in the arterioles, venules, and capillaries in all tissues and organs throughout the body. These intravascular thrombi are composed of loose aggregates of platelets that become organized into amorphous plugs, which are then replaced by fibrin. All of the clinical features can be traced to the thrombosed microcirculation.

It has been reported by Goldenfarb and Finch that biopsy of gingival tissue in patients suspected of having this disease will frequently confirm the diagnosis. Although tissue from many other sites may be used, they believe that gingival tissue is preferable because of its accessibility to rapid hemostasis. The characteristic microscopic gingival changes are described as occlusive subintimal deposits of PAS (periodic acid-Schiff)-positive material at arteriolocapillary junctions.

Laboratory Findings

On blood examination thrombocytopenia and anemia can be noted. Fragmented RBCs (schistocytes) consistent with hemolysis are noticed in peripheral smear. Reticulocyte count is also elevated in few cases. Prothrombin time (PT) and activated partial thromboplastin time (aPTT) are within normal limits. LDH levels are increased. Indirect bilirubin is elevated due to extensive hemolysis. Urinalysis shows proteinuria and microscopic hematuria.

Treatment and Prognosis

At one time, this disease was almost uniformly fatal. However, many patients now survive with the help of modern therapeutic drugs and techniques, including corticosteroids, platelet aggregation inhibitors, splenectomy and exchange transfusions.

Clinical Features

The disease is characterized by thrombocytopenic purpura, eczema, usually beginning on the face, and a markedly increased susceptibility to infection due to cellular and humoral immunodeficiency and an increased risk of autoimmune disease and hematologic malignancy. Petechiae and a purpuric rash or ecchymoses of the skin may be early signs of the disease. The eczema has been thought to be allergic in nature. These patients commonly manifest boils, otitis media, bloody diarrhea, and respiratory infection. The increased susceptibility to infection appears related to an antibody deficiency—in particular, a poor antibody response to protein antigens. Serum IgM levels are low, IgG levels are relatively normal, but IgA and IgE levels may be normal or elevated. Thus, patients are unable to form antibody against polysaccharide-containing organisms such as pneumococci, Hemophilus influenzae and coliform bacilli. It is generally agreed that these patients have T- and B-cell abnormalities, although these cells may be relatively normal during early infancy.

One of the important features of the disease is the occurrence of a lymphoreticular malignant neoplasm, commonly a malignant lymphoma, which is often discovered incidentally at autopsy, although it is the specific cause of death in about 10% of cases.

Oral Manifestations

Spontaneous bleeding of the gingiva is frequently seen as well as bleeding from the gastrointestinal tract and nose. Palatal petechiae may also be present.

Laboratory Findings

One of the basic defects appears to be both a qualitative and quantitative abnormality of the platelets. Because of the thrombocytopenia, generally between 18,000 and 80,000 per cubic millimeter, these patients have a prolonged bleeding time. In addition, there is considerable anisocytosis—alterations in the size and shape of platelets, with most platelets being smaller than normal. At the electron microscope level there are alterations in the cell membrane, while biochemically there is a deficiency of the adenosine diphosphate nucleotide storage pool, although platelets can aggregate. Quantitatively, there appears to be decreased production and defective maturation of platelets since normal megakaryocytes may be seen in the marrow, but little platelet formation. There also seems to be accelerated platelet clearance from peripheral blood.

Treatment and Prognosis

There is no specific treatment for the disease, and death usually occurs within the first five years of life as a result of secondary infection or hemorrhage. Some patients have been treated with antibiotics and platelet transfusions, bone marrow transplantation, and even transfer factor. The eventual prognosis, however, is poor.

Clinical Features

Patients with this disease exhibit the usual characteristics of excessive bleeding, either spontaneous or following minor traumatic injury. Both genders may be affected, and in females, the onset of menarche may be a critical event. Purpuric hemorrhages of skin are common, as are epistaxis and gastrointestinal bleeding. Hemarthrosis has also been reported.

Oral Manifestations

Spontaneous bleeding from the oral cavity, particularly gingival bleeding, is often seen in these patients as are palatal petechiae.

Laboratory Findings

The bleeding time is prolonged in familial thrombasthenia, while clot retraction characteristically is impaired. However, the platelet count is normal, as is the clotting time. The aggregation of platelets by epinephrine, ADP and thrombin is defective. In addition, it is now recognized that there are reduced amounts of certain membrane glycoproteins on the surface of platelets in this disease. This membrane abnormality may be at least partly responsible for the hemostatic defect.

Treatment

There is no specific treatment. However, Perking and his coworkers have discussed this disease and reported two cases of patients requiring oral surgery who were treated with a microfibrillar collagen preparation and with a fibrinolytic inhibitor, c-aminocaproic acid, to control postoperative hemorrhage.

Clinical Features

Patients with thrombocytopathic purpura have a severe bleeding tendency and bruise easily after only minor trauma. Spontaneous ecchymoses are common, although petechial hemorrhages are rare. Epistaxis and bleeding into the gastrointestinal tract are frequent clinical findings. In some cases, menstrual bleeding has been so severe as to require blood transfusions.

Oral Manifestations

The oral manifestations are those that might be expected in such a hemorrhagic disorder. Spontaneous gingival bleeding is common, while mucosal ecchymoses occasionally occur. Excessive and prolonged bleeding from dental extractions may be a serious management problem.

Laboratory Findings

The platelet count is nearly always normal, but the bleeding time is either normal or prolonged. This is generally due to defective platelet aggregation, even though there is normal release of ADP and ATP, so that normal capillary plugging is impaired. This failure of normal aggregation can often be seen in routine blood smears. Since there are a number of forms of this disease, a variety of different platelet defects seem to exist. For example, in one type called 'storage pool disease', there is a deficiency in the nonmetabolic storage pool of platelet adenine nucleotides. Another form is the 'Portsmouth syndrome', discussed by Roser and his associates, in which there is normal ADPinduced platelet aggregation but abnormal or absent collageninduced aggregation. In the Bernard-Soulier syndrome, there is normal platelet aggregation to collagen and ADP but an abnormal response to fibrinogen.

Treatment

There is no satisfactory treatment for this disease, although conventional hemostatic agents and blood transfusions aid in controlling the severe hemorrhage. Apparently, death due to prolonged bleeding is rare, but obviously could occur.

Clinical Features

No gender or age predilection is seen. Patients with thrombocythemia almost invariably show a bleeding tendency in spite of the fact that their platelet count is elevated. Epistaxis and bleeding into the gastrointestinal tract as well as bleeding into the genitourinary tract and central nervous system are common. Hemorrhage into the skin is also found. Few patients can be asymptomatic and are identified on routine blood counts.

Oral Manifestations

Spontaneous gingival bleeding is one of the more commonly reported findings in cases of thrombocythemia, but petechiae are rare. Excessive and prolonged bleeding also frequently occurs after dental extractions. Pogrel has discussed this disease as a cause of oral hemorrhage.

Laboratory Findings

The platelet count in thrombocythemia is greatly increased, and it has been suggested that this high concentration interferes with the formation of thromboplastin. One case reported in the literature showed 14,000,000 platelets per cubic millimeter by a method whereby the normal value was approximately 250,000. In addition, there is abnormal platelet aggregation in response to several aggregating agents. The clotting time, prothrombin time, clot retraction and tourniquet test are all normal, although the bleeding time is frequently prolonged. In primary thrombocythemia, both the red and white blood cell counts are normal. But in secondary thrombocythemia, there may be alterations in the red and white cell counts, depending upon the associated condition.

Treatment

The most common treatment has been the administration of radioactive phosphorus (P32) and blood transfusions in cases of severe hemorrhage. Certain cytotoxic drugs, heparin during thrombotic episodes, corticosteroids and aspirin have also been used with some degree of success.

Etiology

There are a number of different types of hemophilia, and there has been extensive investigation and clarification of this disease in recent years. In light of our present knowledge, three chief forms of hemophilia may be described: hemophilia A (classic hemophilia), B, and C. Each of these differs from the others only in the particular deficiency of the blood clotting factor involved:

The genes for factor VIII and factor IX are located on the long arm of the X chromosome in bands q28 and q27, respectively. Genetic abnormalities include deletions of variable size, abnormalities with stop codons, and frame-shift defects. Recent data suggest that 45% cases of severe hemophilia A result from an inversion mutation. In hemophilia B several mutations such as partial and total deletions, missense mutations that result in the decrease or absence of factor IX or the production of an abnormal molecule. The factor XI gene is located on chromosome 4. Mutations of factor XI gene cause failure, reduced production of the active protein, and rarely production of an abnormal molecule result in factor XI deficiency.

A deficiency of AHG (factor VIII) results in the occurrence of hemophilia A, which is the most common type of hemophilia. However, recent studies now show that factor VIII is a glycoprotein which contains three distinct components:

Therefore, in hemophilia A (classic hemophilia), there is only an absence of the clot-promoting factor. Hemophilia B, due to a PTC deficiency, is also known as Christmas disease (named after the first patient in whom it was described). Apparently two forms of hemophilia B exist: one in which there are apparently normal levels of the inactive protein, another in which there are deficient levels of the coagulant factor. A PTA deficiency is the cause of hemophilia C. Despite the fact that different blood components are involved in each of these diseases, their clinical and oral manifestations are identical. They will therefore be described together as a single disease. In addition, some of the characteristics of the various hemophilioid disorders are shown in Table 18-13.

Clinical Features

Patients with hemophilia exhibit persistent bleeding, either spontaneous or following even slight trauma that produces the mildest of abrasions or cuts. Hemorrhage into the subcutaneous tissues, internal organs, and joints is also a common feature and may result in massive hematomas. It is of interest, though still unexplained, that there is a wide range in the degree of severity of factor VIII deficiencies, with some patients showing only rare and mild bleeding, and others frequent and severe bleeding.

The disease is usually present from birth, but may not become clinically apparent for several years. Approximately, 30–50% of patients with severe hemophilia present with manifestations of neonatal bleeding such as prolonged bleeding from the umbilical cord. Spontaneous cyclic remissions and exacerbations of hemophilia are common.

Petechiae usually do not occur in patients with hemophilia because they are manifestations of capillary blood leaking, which typically is the result of vasculitis or abnormalities in the number or function of platelets.

Hemophilia is classified according to the clinical severity as mild, moderate, or severe (Table 18-14).

Hemophilia C can be distinguished from hemophilias A and B by the absence of bleeding into joints and muscles and by its occurrence in individuals of either genders.

Oral Manifestations

Hemorrhage from many sites in the oral cavity is a common finding in hemophilia, and gingival hemorrhage may be massive and prolonged. Even the physiologic processes of tooth eruption and exfoliation may be attended with severe prolonged hemorrhage. The oral manifestations of the various forms of hemophilia have been discussed by Spiegel and by Steg and his coworkers. In addition, mandibular 'pseudotumor' of hemophilia has been reported by Stoneman and Beierl, a condition in which there is subperiosteal bleeding, with reactive new bone formation causing tumor like expansion of the bone.

The problem of dental extractions is a difficult one in hemophiliacs. Without proper premedication, even a minor surgical procedure may result in death from exsanguination. Tooth extraction by means of rubber bands has often been used successfully, the rubber band being placed around the cervix of the tooth and allowed to migrate apically, causing exfoliation of the tooth through pressure necrosis of the periodontal ligament.

Laboratory Findings

The characteristic defect of hemophilia is a prolonged coagulation time. The bleeding time is normal, as is the prothrombin time and platelet aggregation. Usually, the activated partial thromboplastin time (aPTT) is prolonged; however, normal aPTT does not exclude mild or even moderate disease. Functional assay of factors is useful in diagnosing hemophilia caused due to dysfunction of coagulation factors. The combination of low factor VIII and low von Willebrand's factor indicate von Willebrand's disease. In vitro, the deficiency of the clot-promoting factor in the plasma of hemophiliacs impairs clotting because it appears to retard development of the substance responsible for conversion of prothrombin to thrombin. Separation of the various forms of hemophilia and proper diagnosis depends upon demonstration that the plasma of a patient with a known form of hemophilia does not correct the plasma clotting defect in the patient under observation.

Treatment and Prognosis

There is no known cure for hemophilia. The affected persons should be protected from traumatic injuries.

If a surgical procedure such as tooth extraction must be carried out, the operation should be considered a major one, to be performed only in a hospital.

The greatest number of fatalities in hemophiliacs have resulted from surgical procedures, including tooth extraction. Preoperative transfusion of whole blood and the administration of antihemophilic factor concentrate are recommended. Nevertheless, oral surgery is a dangerous procedure and should be avoided whenever possible. Unfortunately, a small percentage of hemophiliacs have circulating anticoagulant, probably an antibody, which specifically inactivates antihemophilic factor, negating the effects of transfusion.

The prognosis is variable, and many affected persons die during childhood.

Clinical Features

Prevalence worldwide is estimated at 0.9–1.3%. Many children with vWD are asymptomatic and are diagnosed as a result of a positive family history or during routine preoperative screening. Excessive bleeding, either spontaneously or following even minor trauma, is the chief feature of the disease. The most common sites of bleeding are nose, skin, and gingiva. Spontaneous nosebleeds and spontaneous cutaneous ecchymoses can be seen in these cases. Bleeding into the gastrointestinal tract and severe menorrhagia are also common, although hemarthrosis is rare. However, a wide variation in the clinical manifestations exists, even for the members of the same family. This bleeding tendency is often cyclic or sporadic.

Oral Manifestations

Gingival bleeding occurred in this same series in 39% of the patients. In some instances this was spontaneous bleeding; in other cases bleeding occurred only after brushing of the teeth.

The disease may be discovered after dental extractions because of the prolonged and excessive bleeding. The profuse bleeding may commence at the time of the extraction and continue indefinitely, or it may begin several hours subsequent to surgery and result in an almost unmanageable flow.

Laboratory Findings

The bleeding time of patients with this disease is increased to an extremely variable degree. Bleeding times of over 300 minutes have been recorded, but more often they range between several minutes and one hour. The bleeding time also shows wide variation in the same patient at different times. Prothrombin time (PT) is normal and aPTT increased in approximately 25% of type 1 vWD. The clotting time of the blood is usually normal, but may be slightly prolonged, while capillary fragility is reportedly increased with a positive tourniquet test in about 50% of cases. The clot retraction is normal. Characteristically, poor platelet adherence is also demonstrable.

Treatment

Bleeding episodes are best treated by transfusions of plasma and/or antihemophilic factor and by local control of hemostasis. Unfortunately, some patients become refractory to this treatment after repeated transfusions, and occasionally patients develop antibodies against antihemophilic factor.

Death from bleeding in pseudohemophilia is reportedly rare despite what appears to be excessive loss of blood. Nevertheless inherent dangers of tooth extraction should be recognized by the dentist so that if such a procedure is absolutely necessary, he/she may be on guard to institute prompt measures to control bleeding, should it occur. In general, all surgical procedures of an unessential nature should be avoided.

Clinical Features

Parahemophilia is generally thought to be inherited as an autosomal recessive trait. Both genders are affected. Patients with parahemophilia exhibit a severe bleeding tendency. Spontaneous epistaxis, bleeding into the gastrointestinal tract and menorrhagia are common. Cutaneous ecchymoses and hematomas are frequently seen, although petechiae are rare. Intraocular hemorrhage and hemorrhage into the central nervous system have been reported in some patients, but hemarthrosis is seldom seen.

Oral Manifestations

Spontaneous gingival bleeding occurs in some cases of parahemophilia. Petechiae of the oral mucosa are rare. Prolonged bleeding following dental extractions is common, and this may terminate fatally.

Laboratory Findings

The blood platelet level is normal in cases of parahemophilia. Both the clotting time and prothrombin time are prolonged, but the bleeding time is normal. The basic defect in the disease is the reduction of plasma proaccelerin.

Treatment

There is no effective treatment for parahemophilia. Transfusions, as well as freshly frozen plasma, are given to replace blood lost through hemorrhage or prior to a necessary surgical procedure. The prognosis is good, although a few deaths have been reported as a result of the hemorrhage.

Clinical Features

Patients with hypofibrinogenemia or afibrinogenemia exhibit severe bleeding episodes, throughout their lives in the congenital type, and the disease is clinically indistinguishable from hemophilia. However, characteristically in the congenital type, the patients may have long periods of freedom from bleeding. Epistaxis, bleeding into the gastrointestinal tract and central nervous system, and cutaneous ecchymoses and hematomas are all common. Hemarthrosis is not as prominent as in hemophilia. In affected females, menstrual bleeding is usually normal.

Oral Manifestations

The oral manifestations of congenital afibrinogenemia have been reviewed by Kranz and Ruff, and those of the acquired type by Rose. These consist of spontaneous gingival bleeding and prolonged and excessive bleeding following dental extractions. Petechiae of the oral mucosa are rare.

Laboratory Findings

Patients with congenital afibrinogenemia have normal red blood cell, white blood cell and platelet counts, although thrombocytopenia has been occasionally reported. The bleeding time may be normal or slightly prolonged. The most dramatic feature is that the clotting time and prothrombin time are infinite, although this is not necessarily the case in hypofibrinogenemia. The peripheral blood fails to clot even after the addition of thrombin. The tourniquet test in these patients is normal. Finally, the erythrocyte sedimentation rate is zero, the cells remain suspended even after 24 hours.

Treatment

There is no specific treatment for the disease except for transfusions, particularly of concentrated fibrinogen, during bleeding episodes. Occasional patients develop antibodies against the administered fibrinogen, thus disrupting therapy. Unfortunately, the prognosis is poor, and many patients die of hemorrhage during infancy or early childhood. Some patients do reach adult life. The acquired form of the disease is less serious if recognized in time.

Laboratory Findings

Prothrombin time (PT) is prolonged (the most sensitive screening test). Activated partial thromboplastin time (aPTT) may be prolonged.

Treatment

Medical treatment is not required in majority of patients. Fresh frozen plasma or cryoprecipitate may be transfused in case of bleeding.

Clinical Features

Patients with this deficiency have severe postsurgical bleeding episodes which are typically delayed for 24–36 hours, hemarthrosis and defective wound healing. Bleeding and clotting times are both normal. Bleeding from the stump of the umbilical cord within the first days to weeks of life is a characteristic sign that occurs in 80% of affected individuals. Soft tissue bleeding and bruising are very common, as is bleeding into the mouth and gums during teething.

Laboratory Findings

Measurement of clot stability is the most commonly used screening test for factor XIII deficiency. In the absence of factor XIII, the clot dissolves in minutes to hours. Factor XIII a and factor XIII ß antigen levels can be quantified by means of enzyme-linked immunosorbent assay (ELISA) techniques.

Treatment

Plasma, cryoprecipitate, and factor XIII concentrates have been used for replacement of factor XIII and the treatment of bleeding.

Etiology

The etiology of macroglobulinemia is unknown. It has been suggested to be related to:

It is now generally classified as a plasma cell dyscrasia (monoclonal gammopathies) so that the excessive proliferation of B-lymphocytes, the precursor of the plasma cell, results in the production of large amounts of electrophoretically homogeneous M-type IgM globulins which characterize the disease.

The clinical presentation of WM is similar to that of multiple myeloma (MM) except that organomegaly is common in WM and is uncommon in MM, and lytic bony disease and renal disease are uncommon in WM but are common in MM.

Clinical Features

The protean clinical manifestations of this rare disorder result from two important components of the disorder. First, secretion of the IgM paraprotein leads to hyperviscosity and consequent vascular complications because of certain physical, chemical, and immunological properties of this paraprotein. The monoclonal IgM causes hyperviscosity syndrome; cryoglobulinemia types 1 and 2; coagulation abnormalities; polyneuropathies; cold agglutinin disease and anemia; primary amyloidosis; and tissue deposition of amorphous IgM in skin, the GI tract, kidneys, and other organs.

Second, neoplastic lymphoplasmacytic cells infiltrate tissue. The abnormal clone of lymphoplasmacytic cells infiltrate the bone marrow, spleen, lymph nodes, liver, lungs, GI tract, kidneys, skin, eyes, and CNS. The infiltration of these organs causes numerous organ specific clinical symptoms and signs. Occasionally, IgM paraprotein has rheumatoid factor activity, antimyelin activity that can contribute to peripheral neuropathy, and immunologically related lupus anticoagulant activity.

Macroglobulinemia occurs most frequently in persons over the age of 50 years, seldom under 40 years. Males and females are about equally affected.

The chief clinical signs are pallor, weakness and weight loss, lymphadenopathy and hepatomegaly occurring commonly. Hemorrhages from the nasal and oral cavity are characteristic of the disease, and subarachnoid and ocular hemorrhages are also frequently seen, according to Voight and Frick. Bone lesions such as those that occur in myeloma are exceedingly rare.

Oral Manifestations

Oral lesions are common in macroglobulinemia, and these have been reviewed by Gamble and Driscoll. They consist of spontaneous gingival hemorrhage, often with continued oozing of blood; bleeding oral ulcers on the tongue, palate, buccal mucosa or gingiva; and focal areas of hyperemia which appear edematous and are painful. Severe and prolonged bleeding following dental extractions is common. Salivary gland involvement with xerostomia has also been reported.

These bleeding diatheses appear to be related to proteinprotein interactions, with formation of complexes between IgM globulins and coagulation factors such as fibrinogen, thrombin and factors V and VII, as well as interference with platelet agglutination and capillary damage.

Laboratory Findings

Waldenstrom was the first to demonstrate by ultracentrifugation technique that the serum of patients with this disease contained a fraction in the serum proteins, presumably globulins, with molecular weights near 1,000,000 as contrasted to the highest normal globulin molecular weight of 150,000. In addition to the macroglobulinemia and hyperglobulinemia, these patients generally manifested severe anemia with hemoglobin levels near 4–6 gm/dl, an extremely elevated sedimentation rate, demonstrable euglobulins and frequent gelling of the serum upon cooling to room temperature or lower. The viscosity of the blood serum was usually extremely high.

The white blood cell and platelet counts, as well as the bleeding, clotting, and prothrombin times, are usually within normal limits, although lymphocytosis, neutropenia, and thrombocytopenia are occasionally observed.

Bone marrow smears are generally confusing, since they show an increase in mononuclear cells that have been interpreted variously as plasma cells, lymphoid cells, or lymphoid reticulosis.

Bence Jones proteinuria is present in a limited number of patients with macroglobulinemia. Serum protein electrophoresis results indicate evidence of a monoclonal spike.

Treatment

There is no specific treatment for the disease other than supportive therapy with whole blood replacement. Chlorambucil in relatively high doses has produced prolonged remissions in many patients. Repeated plasmapheresis has often been used for temporary treatment.

Treatment

The goal of therapy is the limitation of precipitant cryoglobulin and the resultant inflammatory effects; however, asymptomatic cryoglobulinemia does not require treatment. In case of secondary cryoglobulinemia underlying malignancy or associated disease should be treated. Otherwise, cryoglobulinemia is treated simply by suppression of the immune response.