Burket, chapter 16, 17

Falace, chapter 23-25

The production of all types of blood cells occurs in the bone marrow as a result of differentiation from pluripotential precursor or primitive stem cells.

This is a self-regulating process, with normal target distribution of cell types and maintenance of a steady state of production balanced with natural senescence and removal from the system.

The hematopoietic system can respond to demands placed upon it by triggers such as infection, immune challenges, hemorrhage, or hypoxia by altering the distribution of cell types, through increasing or decreasing production of certain cell types.

The pluripotent stem cell matures into two common precursor lines, lymphopoietic and hematopoietic.

The lymphopoietic common precursor cell becomes committed to either the B-cell or T-cell lines, which undergo cellular differentiation and maturation into the B memory and B plasma cells and T memory helper suppressor and large granular lymphocyte, respectively.

The hematopoietic common precursor cell becomes committed to megakaryocytic cells that mature to platelets, erythroid cells that mature to erythrocytes, or the myelomonocytic cell line, which undergoes cellular differentiation and maturation to the following cell types: monocytes, eosinophils, neutrophils, and basophils.

Examination of the peripheral blood complete blood count (CBC) and differential of the white blood cells and peripheral blood smear to detect erythrocyte morphology, the presence of abnormal or immature white blood cells, and platelet size, combined with bone marrow examination by biopsy, can reveal much about homeostasis and is important in the diagnosis and management of a variety of clinical disorders.

once formed, different cell types have different normal life spans (eg, 120 days for erythrocytes, 5–10 days for platelets, 6 hours to 3 days for neutrophils) before they become senescent.

Erythrocytosis describes conditions with an increase in circulating red blood cells (RBCs), characterized by a consistently raised hematocrit (HCT).

Conditions of increased circulating RBCs include apparent erythrocytosis, relative erythrocytosis and absolute erythrocytoses (both primary and secondary causes), and idiopathic erythrocytosis (IE).

Apparent erythrocytosis is diagnosed when individuals have an elevated venous HCT but whose RBC mass falls within the reference range.

Relative erythrocytosis generally only exists with the state of significant dehydration, use of diuretics, diarrhea, or burns, where hemoconcentration occurs, such that the RBC mass is in the normal reference range, whereas the plasma volume is below the reference range.

Absolute erythrocytosis is diagnosed when an individual’s measured RBC mass is more than 25% above the mean predicted value.

IE is also characterized by an increase in RBC mass of unknown cause. its diagnosis is based on the exclusion of PV and various congenital primary and secondary acquired erythrocytoses.

PV (Polycythemia Vera) is a chronic myeloproliferative disease characterized by a predominant proliferation of the erythroid cell line and primary bone marrow dysfunction that results in hemorrhage, thrombosis, and increased RBC mass.

PV is usually asymptomatic. When symptoms occur, they may include pruritis, vertigo, gastrointestinal pain, headache, paresthesias, fatigue, weakness, visual disturbances, tinnitus, plethora, and bleeding gums. PV should be suspected in patients with elevated hemoglobin or HCT levels, splenomegaly, or portal venous thrombosis.

PV can manifest intraorally with erythema (red-purple color) of mucosa, glossitis, and erythematous, edematous gingiva. Spontaneous gingival bleeding can occur because the principal sites for hemorrhage, although rare, are reported to be the skin, mucous membranes, and gastrointestinal tract.

Anemia is a disordered process in which the rate of red cell production fails to match the rate of destruction, which results in a reduction in hemoglobin concentration.

Anemia owing to Blood loss: iron Deficiency anemia:

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

Anemia as manifest by reduced hemoglobin and HCT on a CBC is typically the first clue to iron deficiency. in addition, measures of iron-deficient erythropoiesis, such as transferrin iron saturation, mean corpuscular hemoglobin concentration, erythrocyte zinc protoporphyrin, percentage of hypochromic erythrocytes, or reticulocyte hemoglobin concentration, are needed to assist in diagnosis, which is difficult to distinguish from anemia of chronic disease.

A serum ferritin level < 30 µg/l in an individual with anemia is diagnostic of iron deficiency anemia, but a higher value does not exclude it.

The most common cause is physiologic and relates to nutritional deficiency.

The prevalence of iron deficiency rises in females during their teenage years when menstrual iron losses become superimposed on growth requirements and among pregnant women with added iron demands of the fetus.

Other less common causes of iron deficiency anemia are increased gastrointestinal blood loss from gastritis due to chronic use of aspirin or other nonsteroidal anti-inflammatory drugs and regular blood donations in premenopausal women.

Pathologic iron deficiency anemia is invariably due to excessive blood loss. in the vast majority of patients, the source of bleeding is the gastrointestinal tract from hemorrhoids, peptic ulcers, esophageal varices, or carcinoma or from excess uterine bleeding in women.

The most important clinical symptom is chronic fatigue. This symptom may be accompanied by certain clinical findings, such as pallor of the conjunctivae, lips, and oral mucosa; brittle nails with spooning, cracking, and splitting of nail beds; and palmar creases that have traditionally been used by physicians in the diagnosis of anemia.

Glossitis and stomatitis are recognized oral manifestations of anemia.

Dietary iron deficiency anemia or anemia of chronic disease should be suspected in every case of glossitis, glossodynia, angular cheilitis, erythematous mucositis, oral candidiasis, recurrent oral ulcers, atrophic changes of the tongue, giving a smooth red tongue appearance and burning mouth when no other obvious causes are identified.

Ferrous sulfate is the preferred form of oral iron because of low cost and high bioavailability, typically administered at 325 mg (60 mg iron) orally three times daily. Side effects of nausea and epigastric pain are reduced with food consumption. A therapeutic response should occur in 4 to 8 weeks.

For dental patients with extremely low hemoglobin levels, physician consultation prior to surgical treatment is recommended. When the hemoglobin is less than 8 g/dl, general anesthesia should be avoided and the potential for clinical bleeding and faulty wound healing should be recognized. Narcotic use should be limited for those with severe anemia, and dentists should be aware that anemia places a patient at increased risk for ischemic heart disease.

Plummer-Vinson syndrome, also called Paterson-Kelly syndrome or sideropenic dysphagia, is a rare syndrome with the classic triad of dysphagia, iron deficiency anemia, and upper esophageal webs or strictures. it usually affects middle-aged white women in the fourth to seventh decade of life but has also been described in children and adolescents.

Symptoms resulting from anemia (weakness, pallor, fatigue, tachycardia) predominate the clinical picture, although splenomegaly and enlargement of the thyroid and upper alimentary tract cancers may also be found. Additional features are glossitis, angular cheilitis, and koilonychia.

Plummer-Vinson syndrome can often be treated effectively with iron supplementation.

anemia owing to Hemolysis:

Hemolytic diseases result in anemia if the bone marrow is not able to replenish adequately the prematurely destroyed RBCs.

The release of free hemoglobin occurring in intravascular hemolysis may present as acute back pain, free hemoglobin in the plasma and urine, and renal failure. in patients with chronic or progressive anemias, symptoms depend on the patients’ age and adequacy of blood supply to critical organs. With moderate anemia, symptoms may include fatigue, loss of stamina, breathlessness, tachycardia, and, less commonly, jaundice and hemoglobinuria. Physical findings include jaundice of skin and mucosae, splenomegaly, and other findings associated with specific hemolytic anemias.

oral signs indicating possible hemolytic anemia may include pallor or jaundice of oral mucosa, paresthesia of mucosa, and, for those with chronic conditions, hyperplastic marrow spaces in the mandible, maxilla, and facial bones.

Paroxysmal nocturnal hemoglobinuria (PNH):

Intravascular hemolysis leads to release of free hemoglobin, which leads to many of the clinical mani- festations of PNH, including fatigue, pain, esophageal spasm, erectile dysfunction, and, possibly, thrombosis.

Glucose-6-phosphate dehydrogenase (G6PD) deficiency:

It is a prototype hemolytic anemia due to enzymopathy, that is, to a primary abnormality of a red cell enzyme. The majority of cases of hemolysis are triggered by exogenous agents.

Diagnosis is made by measuring RBC enzyme activity by quantitative assay.

A hemolytic attack often begins with malaise, weakness, and abdominal or lumbar pain. Peripheral vascular collapse is possible.

Today, consumption of fava beans, common in the middle Eastern and southern European diet, is the most common trigger or hemolysis.

The most serious threat of acute anemia is acute renal failure.

The key to management is prevention of acute hemolysis triggering exposures (aspirin).

Neonatal jaundice is usually treated with phototherapy and, when severe, with exchange blood transfusion.

Patients should maintain excellent oral hygiene and comply with routine recall visits so as to prevent oral and periodontal infection. Prompt and aggressive treatment of oral infections once diagnosed is important. Patients should avoid the use of aspirin or other drugs known to trigger hemolysis.

Hemoglobinopathies occur when point mutations or deletions in the globin genes cause changes in the amino acids that make up the globin protein, resulting in abnormal forms of hemoglobin.

Sickle cell disease, or sickle cell anemia (SCA), is the most prevalent genetic hematologic disorder in the United States.

SCA is characterized by a hemoglobin gene mutation, consisting of replacement of the amino acid glutamic acid so that valine is encoded instead in the sixth position on the b-hemoglobin chain.

As a result, the erythrocytes have their normal biconcave discoid shape distorted, generally presenting a sickle-like shape, which reduces both their plasticity and lifetime from the normal 120 days average down to 14 days. This results in the underlying anemia and hypertrophic bone marrow.

Stressors that can lead to vaso-occlusion typically include viral and bacterial infection, hypoxia, dehydration, iron over- load, and cell and fluid phase–related causes. microvascular occlusion arises predominantly in localized areas of marrow, leading to necrosis. inflammatory mediators activate nociceptive afferent nerve fibers, evoking the pain response. Affected areas are the long bones, ribs, sternum, spine, and pelvis, often with multiple-site involvement.

The HbS solubility test (Sickledex) can be performed in 5 minutes for screening of adults for hemoglobinopathies. Prenatal screening by deoxyribonucleic acid (DNA) analysis of amniotic fluid at 14 to 16 weeks can be ordered to investigate alterations and mutations in the genes that produce hemoglobin components.

Known sequelae of SCA include invasive infections, painful episodes, acute chest syndrome, cerebrovascular accidents/ strokes, aplastic crises leading to severe anemia, chronic leg ulcers, hematuria, aseptic osteonecrosis, retinitis leading to blindness, priapism, pregnancy-associated problems, hyposplenism when young and then hyperspenism due to splenic sequestration, renal failure, and chronic pulmonary hypertension.

Acute chest syndrome can be defined as a new infiltrate on chest radiography and one or more new symptoms of fever, cough, sputum production, dyspnea, or hypoxia.

Radiographic findings in patients with SCA include a “stepladder” trabeculae pattern (70%), enamel hypomineralization (24%), calcified canals (5%), increased overbite (30–80%), and increased overjet (56%).

Patients may also have pallor of the oral mucosa and delayed eruption of the teeth.

involvement of the maxillofacial skeleton leading to radio- paque lesions that correspond to bone infarcts in the course of a known vessel or in the apical region of the teeth.

Such lesions combined with facial pain or sensory changes in the distribution of the inferior alveolar nerve during sickle cell crisis and absence of dental pathology should be considered to be of possible vaso- occlusive origin.

Interruption of the blood supply can result in an anesthesia of the inferior alveolar nerve and pulpal necrosis of otherwise sound premolar and molar teeth.

The mainstay of successful treatment remains high-quality supportive care and judicious use of transfusion therapy to prevent mortality.

management of pain continues to be primarily palliative, including supportive, symptomatic, and preventive approaches to therapy. most vasoocclusive episodes resulting in acute pain are managed at home with a combination of anti-inflammatory and analgesic drugs, often with opioids. Episodes of severe pain may require hospitalization for intravenous morphine, hydration, and supplemental oxygen therapy.

Management considerations for patients with SCA include maintaining good oral hygiene, routine care during noncrisis periods, aggressive treatment of oral infection, avoidance of use of aspirin, caution with respiratory-depressing conscious sedation, and avoidance of long, stressful dental visits. Use of nitrous oxide–oxygen for anxiolysis is safe, with maintenance of adequate flow rates.

Left molar bitewing radiograph in a 32-year-old African American with sickle cell anemia with radiographic stepladder appearance and dense lamina dura, resulting from hyperplastic marrow, evident posterior to the second molar.

Gnathopathy (maxillary excess) of a 28-year-old African American with sickle cell anemia. A, Facial image. B, Intraoral image.

Thalassemia is a group of genetic disorders of hemoglobin synthesis characterized by a disturbance of either alpha (b) or beta (b) hemoglobin chain production.

Cooley’s anemia, or thalassemia major (both b genes are affected), is the name for the severe form of b-thalassemia. a-Thalassemia diseases, often considered benign, are now recognized to be more severe than originally reported, with hemoglobin H disease being among the more severe.

Thalassemia is diagnosed using blood tests, including a CBC and special hemoglobin studies.

In more severe types of thalassemia, such as Cooley’s anemia, signs of severe anemia are seen in early childhood and may include fatigue and weakness, pale skin or jaundice, protruding abdomen with enlarged spleen and liver, dark urine, abnormal facial bones, and poor growth.

Ineffective erythropoiesis and expansion of the bone marrow in every part of the skeleton of individuals with untreated thalassaemia result in skeletal changes, including osteoporosis, growth retardation, platyspondyly, and kyphosis.

Radiographic features of jaws and teeth among people with thalassemia major include the appearance of spiky-shaped and short roots, taurodontism, attenuated lamina dura, enlarged bone marrow spaces, small maxillary sinuses, absence of inferior alveolar canal, and thin cortex of the mandible.

Craniofacial deformities include universal Class II skeletal base relationship with a short mandible, a reduced posterior facial height, increased anterior facial proportions, and 17% with severe facial disfigurements (grade 3 or “chipmunk faces”). dental arch morphologic changes include a narrower maxilla and smaller incisor widths for the maxillary and mandibular arches.

Thalassemia is not associated with increased levels of gingivitis or periodontitis but is associated with higher dental caries experience.

A mainstay of treatment for the most anemic patients is regular RBC transfusions to avoid death from cardiac failure.

Allogeneic HSCT can result in cure in severely affected subjects with both a- and b-thalassemia.

Anemia due to ineffective erythropoiesis may be characterized by macrocytosis associated with a megaloblastic marrow.

The term macrocytosis refers to a blood condition in which RBCs are larger than normal and is reported in terms of mean corpuscular volume (MCV).

There are a large number of causes of macrocytic anemia, with the most frequent being disorders resulting in vitamin B12 or folate deficiency.

Vitamin B12 (cobalamin) deficiency is a common cause of macrocytic anemia.

Causes of the deficiency most frequently include food-cobalamin malabsorption syndrome (>60% of all cases), pernicious anemia (15–20% of all cases), insufficient dietary intake, and malabsorption.

Megaloblastic or pernicious anemia is an autoimmune disease resulting from autoantibodies directed against intrinsic factor (a substance needed to absorb vitamin B12 from the gastrointestinal tract) and gastric parietal cells.

Diagnosis of vitamin B12 deficiency is typically based on measurement of serum vitamin B12 levels; however, about 50% of patients with subclinical disease have normal B12 levels.

Patients with pernicious anemia may have complaints of a burning sensation in the tongue, lips, buccal mucosa, and other mucosal sites. The tongue and mucosa may be smooth or patchy areas of erythema. dysphagia and taste alterations have been reported.

Treatment has traditionally been weekly intra- muscular injections of vitamin B12.

Aplastic anemia (AA) is a rare blood dyscrasia in which peripheral blood pancytopenia results from reduced or absent blood cell production in the bone marrow and normal hematopoietic tissue in the bone marrow has been replaced by fatty marrow.

The disorder can be inherited, idiopathic, or acquired. Environmental exposures, such as to drugs, viruses, and toxins, are thought to trigger the aberrant immune response in some patients, but most cases are classified as idiopathic.

Patients with AA usually present with complaints caused by anemia, such as fatigue and malaise, chest pain, or shortness of breath. There may be a more sudden onset of bleeding caused by thrombocytopenia, manifest as increased bruising, evident by purpura and petechiae, and epistaxis or gingival bleeding. leukopenia, particularly neutropenia, can result in fever and infection.

The most common oral manifestation of AA is hemorrhage, which develops most often in patients with platelet counts less than 25x109 cells/l. The second and third most common oral manifestations are candidiasis and viral infection, respectively.

Supportive therapy with blood transfusions to correct anemia and thrombocytopenia can be beneficial for many.

Neutropenia, caused by the disorder itself and its treatment, leads to an increased susceptibility to infection, and thrombocytopenia leads to bruising and mucosal bleeding. Neutropenic fevers must be treated aggressively with parenteral, broad-spectrum antibiotics.

Antifungal therapy should be added when patients are persistently febrile because aspergillosis infections can be difficult to diagnose early.

Attention to details of oral hygiene and hand washing and avoidance of minor injuries or casual exposure to infectious agents can reduce the risk of serious complications.

White blood cell (WBC) disorders primarily involve one or both of the principal components, the lymphocytes or neutrophilic granulocytes.

There are three types of granulocytes, distinguished by their appearance under Wright’s stain: neutrophil granulocytes, eosinophil granulocytes, and basophil granulocytes.

Granulocytosis is an abnormally large number of granulocytes in the blood. Basophilia and eosinophilia are an excess number of basophils and eosinophils, respectively.

Neutrophilia, an excess of neutrophils, is more common. Causes of neutrophilia are varied and include acute infections caused by cocci, bacilli, certain fungi, spirochetes, viruses, rickettsia, and parasites.

Infections may present as furuncles, abscesses, tonsillitis, appendicitis, otitis media, osteomyelitis, cholecystitis, salpingitis, meningitis, diphtheria, plague, and peritonitis.

Noninfectious causes of neutrophilia include burns, postoperative states, acute myocardial infarction, acute attacks of gout, acute glomerulonephritis, rheumatic fever, collagen vascular diseases, and hypersensitivity reactions.

Neutrophilia can also accompany metabolic conditions (diabetic ketoacidosis, preeclampsia, uremia), poisoning (with lead, mercury, digitalis, camphor, antipyrine, phenacetin, quinidine, pyrogallol, turpentine, arsphenamine, and insect venoms), rapidly growing neoplasms, and strenuous exercise.

The terms agranulocytosis, neutropenia, and granulocytopenia are commonly used interchangeably for a reduced quantity of leukocytes.

Clinical symptoms of agranulocytosis include sudden onset of fever, rigors, and sore throat. Neutropenic fevers often reflect an absolute neutrophil count (ANC) of <500 cells/mm³ of blood.

Acquired neutropenias are far more common than congenital forms, often accompany viral infection, or may be drug induced, either due to myelosuppression or antibody-mediated destruction. many drugs, including antineoplastics, antibiotics, anticonvulsants, anti- inflammatories, antithyroid agents, diuretics, and phenothiazines, have neutropenia as a reported potential side effect.

For potential drug-induced neutropenias, discontinuation of the suspected offending drug provides both the diagnosis and the cure.

Neutropenia resulting from myelosuppression in patients on cytotoxic chemotherapy typically reaches a nadir between 7 and 14 days after chemotherapy has been delivered.

Congenital forms of neutropenia need to be considered in children and occasionally in adults presenting with low neutrophil counts.

Prophylactic antibiotics have historically been recommended by some for patients with a hematologic malignancy–caused ANC <1,000 cells/mm³ prior to dental extractions.

Hence, prophylaxis with fluoroquinolones is now being recommended as a routine practice for patients with acute leukemia, lymphoma, and solid organ tumors who are anticipated to receive regimens that cause severe neutropenia.

Cyclic neutropenia is a rare hematologic disorder, characterized by repetitive episodes of fever, mouth ulcers, and infections attributable to recurrent severe neutropenia.

Neutropenia recurs with a regular periodicity of 21 days, persists for 3 to 5 days, and is characterized by infectious events that are usually less severe than in severe chronic neutropenia.

Periodic oscillations of neutrophil counts associated with fever and mouth ulcers are the key clinical hallmark of this disease. Serial blood counts may be needed to establish the diagnosis.

Hematopoietic growth factors, such as G-CSF, have reduced the number and severity of infectious episodes, prolonging the survival and the extent of time during which neutropenic patients remained free of life-threatening infections.

Chronic neutropenia is defined as a low ANC for more than 6 months. Chronic neutropenia can be congenital, acquired, or idiopathic.

Neutropenia is an absolute decrease in the number of circulating neutrophils in the blood that results in susceptibility to severe pyogenic infections.

Manifestations include life- threatening bacterial infections, recurrent gingivitis, and even severe periodontitis, often starting in early childhood.

Various oral findings, such as recurrent gingivitis, severe periodontitis, alveolar bone loss, and ulceration, may be seen in neutropenic patients.

G-CSF together with a dental care regimen resulted in resolution of neutropenic ulceration and periodontal breakdown within 2 weeks of treatment initiation in a patient with severe chronic neutropenia, whereas normalized ANC levels were not sufficient to resolve chronic periodontal disease in other severe chronic neutropenia patients.

Chediak-Higashi syndrome (CHS) is a rare autosomal recessive immunodeficiency disorder characterized by partial oculoalbinism, easy bruisability and bleeding as a result of deficient platelet-dense bodies, neutropenia and defective neutrophil function with abnormal lysosomal inclusions, impaired chemotaxis and bactericidal activity, and abnormal natural killer cell function contributing to recurrent infections, most commonly involving the skin and respiratory systems.

The only laboratory diagnostic test is examination of bone marrow aspirate.

The complete syndrome includes oculocutaneous albinism with photophobia, neurologic features, recurrent infections, and enterocolitis. Neurologic involvement is variable but often includes peripheral neuropathy. Abnormalities can be found in the hematopoietic tissues, hair, ocular pigment, skin, adrenal and pituitary glands, gastrointestinal organs, peripheral nerves, and elsewhere.

Patients with CHS may present with serious periodontal destruction with acute inflamed gingiva and ulcers. Patients are particularly susceptible to sinus and oral infections caused by b-hemolytic Streptococcus, S. aureus, gram-negative organisms, Candida, and Aspergillus.

Oral radiographic status showed extensive loss of alveolar bone leading, in most cases, to tooth exfoliation.

When oral surgical procedures are planned, excessive operative blood loss should be anticipated secondary to qualitive defects in platelet function. intramuscular injections should be avoided. Patients often have photophobia and may be sensitive to the bright operatory lights. Patients can be encouraged to bring sunglasses to dental appointments.

Asymptomatic lymphocytosis is not always due to chronic lymphocytic leukemia (CLL) or malignant disease.

Flow cytometry and a peripheral blood smear can help distinguish between clonal disorders and a nonclonal process (reactive lymphocytosis). infectious disease causes include viral (human immunodeficiency virus [HIV], human T-lymphotrophic virus 1 [HTLV-1], cytomegalovirus, hepatitis, Epstein-Barr virus [EBV], and influenza) or other infections (tuberculosis, rickettsia, brucellosis, toxoplasmosis, syphilis) or other causes (drug induced, hyperthyroidism, autoimmune disease, and thymoma).

Clonal disorders can be T-cell disorders, such as large granular lymphocyte leukemia, T-cell non-Hodgkin’s lymphoma (NHL), T-cell prolymphocytic leukemia, HTLV-1 and T-cell leukemia or lymphoma, or Sézary syndrome, and may require bone marrow or lymph node biopsy to clarify diagnosis.

Clonal B-cell disorders can by diagnosed with immunophenotyping and possibly bone marrow or lymph node biopsy as CLL or other B-cell malignancies, such as mantle cell lymphoma, follicular NHL, hair cell leukemia, nodal or splenic marginal zone lymphoma, lymphoplasmacytoid lymphoma, and B-cell prolymphocytic leukemia.

Leukemia results from the proliferation of a clone of abnormal hematopoietic cells with impaired differentiation, regulation, and programmed cell death (apoptosis). leukemia is classified based on clinical behavior (acute or chronic) and the primary hematopoietic cell line affected (myeloid or lymphoid).

The four principal diagnostic categories are the following: (1) acute myelogenous leukemia (AML), (2) acute lymphocytic leukemia (ALL), (3) chronic myelogenous leukemia (CML), and (4) CLL.

Acute Lymphocytic/Lymphoblastic Leukemia: Acute leukemia presents with flu-like symptoms and bone

pain, joint pain, or both, caused by malignant marrow expansion. marrow failure results in thrombocytopenia, manifested by petechial skin and posterior palate hemorrhages and gingival bleeding, gingival infiltration by leukemic cells, and gingival ulcerations as a result of infection by normal oral flora in the setting of neutropenia.

The goal of remission-induction therapy is to eradicate more than 99% of the initial burden of leukemia cells and to restore normal hematopoiesis and a normal performance status.

once remission is achieved, intensification therapy is given. After intensification therapy, consolidation chemotherapy

or HSCT is necessary. HSCT is recommended for high-risk patients in the first

complete remission and low-risk patients in the second complete remission.

Acute Myelogenous (Nonlymphocytic) Leukemia:

In the absence of treatment, bone marrow failure and fatal infection, bleeding, or organ infiltration (brain and lung) may occur within 1 year of diagnosis.

Symptoms include fever, weight loss, muscle or joint pain, fatigue/malaise, anemia/ pallor, mucosal bleeding, petechiae, and local infections. Fever and fatigue/malaise are the most common presenting symptoms in patients with all types of leukemia. The most common manifestations or clinical signs of acute leukemia at initial presentation are lymphadenopathy, laryngeal pain, gingival bleeding, oral ulceration, and gingival enlargement.

Gingival hyperplasia secondary to leukemia cell infiltra- tion may be a first sign, heralding the presence of acute leukemia.

In addition, extensive leukemic tumor infiltration in the gingiva or oral mucosa can be seen in some patients with acute leukemias.

Herpes simplex virus– related ulcerations of oral mucosa in patients undergoing oncologic therapy, particularly for AML, may show atypical clinical patterns, leading to misdiagnosis.

Chemotherapy-induced mucositis and infection, including herpes simplex ulcers and oral candidiasis, are commonly observed complications of leukemia in the oral cavity.

Primary oral manifestations of leukemia patients under treatment include mucosal pallor secondary to anemia, odontalgia, ulceration of the palate, gingival bleeding, gin- givitis, petechiae, and ecchymoses of the hard and soft palate, tongue, and tonsils.

oral mucositis, beginning with erythema and progressing to ulceration, often begins within 7 to 10 days of the onset of chemotherapy and usually resolves within 2 weeks of cessation of cytotoxic drugs.

oral mucosal lesions may also be a manifestation of graft-versus-host disease in patients who have undergone allogeneic HSCT.

meticulous oral hygiene is critically important in the patient with neutropenia. oral care is facilitated by frequent mechanical cleaning and alternating rinses of sodium bicarbonate with saline solution and 0.12% chlorhexidine gluconate and nystatin. These topical antimicrobials may reduce the risk of systemic infection of oral origin. Topical anesthetics (diphenhydramine, 2% lidocaine, or 0.5–1.0% dyclonine hydrochloride) and systemic analgesics may be required.

Prechemotherapy dental assessment, maintenance of oral hygiene, and management of periodontal infection that may exacerbate in neutropenic patients have been shown to be effective in preventing oral and systemic complications during treatment.

Chronic Myelogenous Leukemia:

CML affects all ages, with a median age of 53 years at diagnosis. CML is a clonal disorder resulting in myeloid marrow hyperplasia and myeloid cells in the blood displaying the t(9;22) chromosome translocation.

Risk factors include older age, male gender, and exposure to ionizing radiation and benzene and benzene-containing products.

Gingival enlargement in a 16-year-old white female with undiagnosed acute myelogenous leukemia (AML) who presented to the dentist with gingival swelling, low-grade fever, and fatigue. A, Lower gingiva with leukemic gingival overgrowth. B, Upper gingiva 1 week postgingivectomy with failure to heal and prolonged hemorrhage that led to the AML diagnosis.

CML is typically chronic and indolent for 3 to 5 years in which patients have no symptoms, followed by an accelerated phase and blast crisis, resembling acute leukemia. in the acute or blast phase, the most common presentations are fever, weakness, fatigue, anorexia, weight loss, splenomegaly, anemia, and infection.

Chronic Lymphocytic Leukemia:

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

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

Oral manifestations at presentation of CLL are infrequent and generally related to bleeding.

CLL is a relatively indolent chronic hematologic malignant disease that often has a prognosis compatible with relatively normal dental treatment planning. Patients in late-stage disease, with severe thrombocytopenia (< 50,000 cells/mm3), might require platelet transfusions prior to dental surgery.

Hodgkin’s Lymphoma/Disease:

Approximately 95% of patients with HL will have the classic HL histology, which is characterized by the presence of rare malignant Hodgkin’s reed-Sternberg cells among an overwhelming number of benign reactive cells.

The etiology of HL is unknown; however, both genetic and environmental factors, including EBV, play a role in the pathogenesis of HL.

The first sign of HL is typically an asymptomatic enlargement of a supradiaphragmatic lymph node, often in the neck, which may wax and wane over a period of a few months. mediastinal lymph node involvement is common, occurring in 80% of cases. When mediastinal disease is bulky, patients may complain of chest pain, cough, and dyspnea.

Systemic symptoms of night sweats, fever, and weight loss are reported in approximately 30% of patients. less common symptoms are generalized pruritus and alcohol-induced pain localized over the involved lymph node.

Infradiaphragmatic sites such as the inguinal, pelvic, or retroperitoneal lymph node regions are rare. Physical examination may reveal involvement of the Waldeyer’s ring structures.

Unlike NHLs, HL rarely presents as an extranodal mass in the head and neck region. Waldeyer’s ring involvement by HL tumors is uncommon.

Patients who receive radiation in fields involving the cervical nodes will invariably have their submandibular and sublingual salivary glands in the field and are at risk for temporary, and occasionally permanent, xerostomia.

Because the parotid glands are usually not in the field of radiation for these patients, the risk of radiation-induced caries is minimal; however, topical fluoride varnish, gel, or 1,000 parts per million fluoride toothpaste can be used for caries prevention if the patient’s mouth appears to be dry or the caries rate appears elevated.

The risk of osteoradionecrosis is very low due to low radiation doses delivered (30–40 Gy) and often exclusion of maxilla and mandible from the fields, with the exception of the inferior border and angle of the mandible.

Non-Hodgkin’s Lymphoma:

NHL is known to be associated with chronic inflammatory diseases such as Sjögren’s syndrome, celiac disease, and rheumatoid arthritis and immune suppression from HIV and medications to manage patients who have received solid organ transplantation.

Chronic infection is associated with lymphoma, with an association between Helicobacter pylori infection and mucosa-associated lymphoid tissue (MALT) lymphoma; HTLV-1 and adult T-cell lymphoma; EBV and Burkitt’s lymphoma; Clamydia psittaci and ocular adenexal lymphomas; and hepatitis C and splenic or large cell lymphomas.

Clinical manifestations on presentation usually include lymphadenopathy and sometimes extranodal involvement of the gastrointestinal tract, skin, bone marrow, sinuses, thyroid, or central nervous system.

Splenomegaly is seen in approximately 30 to 40%, but the spleen is rarely the only site of disease involvement at initial presentation.

Diagnosis of NHL in the oral cavity may result from gingival or mucosal tissue swelling or masses, whereas intrabony presentation can mimic tooth- ache. This latter presentation can result in dental extraction and then rapid growth of the tumor from the nonhealing extraction site.

Nerve invasion can lead to paresthesia or anesthesia of related oral mucosal tissue.

Symptoms may include anesthesia or paresthesia. Presentation can also include nonhealing ulceration with ill-defined borders in the surrounding mucosa, benign- appearing gingival lesions, and erosive mucosal lesions resembling a vesiculobullous disease.

Acute complications of chemotherapy include mucositis, viral and bacterial infections, and hemorraghic lesions related to bone marrow suppres- sion.

If radiation therapy is delivered to the mandible/maxilla during tooth formation, the consequences for development include short, blunted, tapered, and V-shaped root malformations, as well as delayed and ectopic eruptions.

Non-Hodgkin’s lymphoma in a nonhealing extraction site of teeth 30 and 31 that appeared within 1 week of dental extraction in a 31-year-old HIV-infected man.

Burkitt’s Lymphoma:

Burkitt’s lymphoma (BL) is a highly aggressive, that commonly presents as jaw swellings.

Within these lymphomas was found EBV, the first virus identified as involved in the pathogenesis of a tumor in humans.

Endemic (African) BL refers to cases occurring in African children, usually 4 to 7 years old, with a male to female ratio of 2:1, nearly all EBV associated, involving primarily the bones of the jaw and other facial bones, as well as the kidneys, gastrointestinal tract, ovaries, breast, and other extranodal sites.

Sporadic (American) BL, 15 to 30% of which is EBV associated, occurs worldwide and accounts for 1 to 2% of lymphomas in adults.

BL accounts for nearly 30 to 40% of NHLs in HIV-infected patients.

The major sites involved in chil- dren were the jaw (52%), abdomen (25%), combined jaw and abdomen (14%), and other sites (10%). in adults, the involved sites were the jaw (4%), abdomen (43%), combined jaw and abdomen (25%), and other sites (27%). For those with jaw involvement, most were male and younger.

Clinically evident jaw tumors may result in tooth mobility and pain, intraoral swelling of the mandible and maxilla, and anterior open bite. mobile teeth may be present even in the absence of clinically detectable jaw tumors.

Radiographic features on panoramic images include resorption of alveolar bone, loss of teeth lamina dura, enlargement of tooth follicles, destruction of the cortex around tooth crypts, displacement of teeth and tooth buds by the enlarging tumor, resulting in the impression of “teeth floating in air,” and sun-ray spicules as bone forms perpendicular to the mandible from subperiosteal growth.

Multiple Myeloma:

multiple myeloma (MM) is a plasma cell neoplasm that is characterized by a bone marrow plasmacytosis(monoclonal plasma cell), abnormal paraprotein, and complications of bone disease with skeletal destruction, renal insufficiency or failure, anemia, and hypercalcemia.

It is the third most common hematologic malignancy after leukemia and lymphoma.

Symptoms include fatigue, weakness, weight loss, bone pain, and recurrent infections. This disease is characterized by a high capacity to induce focal osteolytic bone lesions, diffuse osteopenia, and pathologic fractures. osteolytic bone lesions in mm result from increased osteoclast formation, osteoblast inhibition induced by MM cells, and activity that occurs in close proximity to myeloma cells.

Patients with MM can manifest soft tissue masses that are extramedullary plasmablastic tumors of the jaws.

Consistent with plasma cell tumor growth in the mandible, initial oral signs of mm may involve pain, paresthesia of the inferior alveolar and mental nerves, swelling, tooth mobility, and radiolucency. radiographic changes in patients with mm include typical “punched-out” lesions in the skull from the focal proliferation of plasma cells inside the bone marrow and mandibular (more so than maxillary) involvement, ranging from asymptomatic osteolytic lesions to pathologic fracture.

Osteonecrosis of the jaw (ONJ), resulting in symptomatic exposed nonhealing areas of the maxilla and mandible, is increasingly recognized as a serious complication of long-term intravenous bisphosphonate therapy, primarily with zoledronic acid and pamidronate.

Management of ONJ focuses on maximizing oral health to prevent its occurrence, conservative management with antiseptic mouthrinses and antibiotics, and avoidance of unnecessary invasive dental procedures.

Odontogenic infections should be treated aggressively with systemic antibiotics, such as amoxicillin and/or clindamycin, with adequate bone penetration and a wide spectrum of coverage.

Another consideration for mm patients requiring dental surgery is the risk of hemorrhage. Patients with mm and other disorders associated with high-titer serum paraproteins can manifest unique hemostatic disorders, predisposing the patient to hemorrhage, especially following surgical procedures.

Predental surgery assessment should include radiographic assessment for plasma cell tumors of the jaw and CBC and coagulation studies.

Prevention of hemorrhage should be managed by consultation with the patient’s hematologist regarding the status of treatment of the underlying disease and, depending on clinical circumstances, the need for additional therapies that might include plasmapheresis with appropriate factor replacement, desmopressin acetate, fibrinolysis inhibitors e-aminocaproic acid and tranexamic acid and splenectomy.

Multiple myeloma of the left mandible of a 58-year-old African American woman. A, Clinical image of a left mandible plasmablastic tumor. B, Panoramic radiographic image with punched-out lesions of the right and left mandible.

Plasmablastic tumor of the right maxilla in a 46-year-old African American woman with multiple myeloma.

Osteonecrosis of the jaw. A 58-year-old African American male with a 2-year history of zoledronic acid use for multiple myeloma who had maxillary tooth extractions 2 months prior to bone necrosis and infection of the bilateral mandible in the molar region.

Sickle cell anemia. A, Leg ulcer, and B, growth deformation of the middle finger from vaso-occlusive attack and dactylitis of the growth plate.

Pernicious anemia. This 38-year-old man shows premature graying and has blue eyes and vitiligo— three features that are more common in patients with pernicious anemia than in control subjects.

Smooth red tongue and angular cheilitis in a patient found to have iron deficiency anemia.

Periapical radiograph of the mandible in a patient with sickle cell anemia. Note the prominent horizontal trabeculations and the dense lamina dura.

Skull film in a patient with hemolytic anemia shows new bone formation on the outer table, producing perpendicular radiations or “hair on end” appearance.

A, Acute myeloid leukemia presenting as bleeding and ecchymosis of the tongue in a 14-year-old. B, Gingival leukemia infiltrate in a patient with acute myeloid leukemia.

Non-Hodgkin’s lymphoma presenting as (A)a gingival enlargement that also

involvedthe underlying alveolar bone and

(B) an osteolytic lesion of the mandible.

Multiple myeloma. Punched-out lytic lesions in the skull containing malignant plasma cells.

Oral ulcers due to neutropenia.

Leukemic gingival enlargement in a patient who has acute myeloid leukemia. Enlargement is due to leukemic infiltrations in the gingival tissue.

Hemostasis can be divided into four general phases: the vascular phase; the platelet phase; the coagulation cascade phase, consisting of intrinsic, extrinsic, and common pathways; and the fibrinolytic phase.

The first three phases are the principal mechanisms that prevent or diminish the loss of blood following vascular injury.

Briefly, when vessel integrity is disrupted, platelets are activated, adhere to the site of injury, and form a platelet plug that reduces or temporarily arrests blood loss.

The exposure of collagen and activation of platelets also initiates the coagulation cascade, which leads to fibrin formation and the generation of an insoluble fibrin clot that strengthens the platelet plug.

Fibrinolysis is the major means of disposing of fibrin after its hemostatic function has been fulfilled, and it can be considered the rate-limiting step in clotting. it leads to fibrin degradation by the proteolytic enzyme plasmin.

The coagulation cascade is under way within 10 to 20 seconds of injury, an initial hemostatic plug is formed in 1 to 3 minutes, and fibrin has been generated and added to stabilize the clot by 5 to 10 minutes.

Vascular Phase:

After tissue injury, there is an immediate reflex vasoconstriction that may alone be hemostatic in small vessels.

Reactants such as serotonin, histamine, prostaglandins, and other products are vasoactive and produce vasoconstriction of the microvascular bed in the area of the injury.

Platelet Phase:

When circulating platelets are exposed to damaged vascular surfaces (in the presence of functionally normal VWF, endothelial cells, collagen or collagen-like materials, basement membrane, elastin, microfibrils, and other cellular debris), platelets are activated to experience physical and chemical changes.

These changes produce an environment that causes the platelets to undergo the aggregation and release phenomenon and form the primary vascular plug that reduces blood loss from small blood vessels and capillaries.

These platelet plugs adhere to exposed basement membranes. as this reaction is occurring, the release reaction is under way, involving the intracellular release of active components for further platelet aggregation as well as promotion of the clotting mechanism.

Coagulation Phase:

The generation of thrombin and fibrin is the end product of the third phase of hemostasis, the coagulation phase. this process involves multiple proteins, many of which are synthesized by the liver (fibrinogen; prothrombin; Fs v, vii, iX, X, Xi, Xii, and Xiii) and are vitamin K dependent (Fs ii, vii, iX, and X). the process of coagulation essentially involves three separate pathways. it initially proceeds by two separate pathways (intrinsic and extrinsic) that converge by activating a third (common) pathway.

The intrinsic pathway is initiated when F Xii is activated by surface contact (eg, with collagen or subendothelium), and it involves the interaction of F Xii and F Xi. the next step of intrinsic coagulation, the activation of F iX to F Xia, requires a divalent cation. Once activated, F iXa forms a complex with F viii, in a reaction that requires the presence of both calcium ions and phospholipid, which, in turn, converts F X to an activated form—F Xa.

The extrinsic pathway is initiated by the release of tissue thromboplastin, also called tissue factor, and does not require contact activation. tissue thromboplastin binds to F vii in the presence of calcium, and this complex is capable of activating Fs iX and X, linking the intrinsic and extrinsic pathways.

It is the activation of FX that begins the common pathway.

Once activated, F Xa converts prothrombin to thrombin in a reaction similar to the activation of F X by F iXa. the activation of prothrombin by F Xa requires the presence of calcium ions and phospholipid as well as F v, a plasma protein cofactor. Once formed, thrombin converts fibrinogen, a soluble plasma protein, to insoluble fibrin.

Fibrinolytic phase: Once the microvascular bed is sealed and primary

hemostasis is complete, the secondary hemostasis pathway has already commenced in parallel. as the monomeric fibrin is cross-linked with the aid of F Xiii (fibrin stabilizing factor), the propagation of the formed clot is limited by several interactions.

Kallikrein, which is an intrinsic activator of plasminogen, is generated when prekallikrein is bound to kininogen, thereby becoming a substrate for F Xiia. tissue plasminogen activator (TPA) is released from the endothelial cells and converts plasminogen to plasmin that degrades fibrinogen and fibrin into fibrin degradation products (FDPs).

TPA has been used with great success in therapeutic doses to lyse thrombi in individuals with thromboembolic disorders associated with myocardial infarction. the effectiveness of this drug is limited to the first 6 hours postinfarction.

Activation of the fibrinolytic system can be turned off by inhibition of plasmin activity (eg, by a2-antiplasmin) or inhibition of plasminogen activators (eg, plasminogen activator inhibitor).

Mechanisms of hemostasis following vascular injury.

The coagulation cascade.

The fibrinolytic system.

Individuals with mild disease may present with no clinical signs, whereas individuals with severe coagulopathies may have definite stigmata.

When skin and mucosa are involved, individuals may present with petechiae, ecchymoses, spider angiomas, hematomas, or jaundice. deep dissecting hematomas and hemarthroses of major joints may affect severe hemophiliacs and result in disability or death.

Disorders of platelet quantity may result in hepatosplenomegaly, spontaneous gingival bleeding, and risk of hemorrhagic stroke.

The two clinical tests used to evaluate primary hemostasis are the platelet count and platelet function tests such as bleeding time (BT).

Tests to evaluate the status of other aspects of hemostasis include prothrombin time (PT)/international normalized ratio (INR), activated partial thromboplastin time (aPTT), thrombin time (TT), FDPs, specific coagulation factor assays (especially Fs vii, viii, and iX and fibrinogen), and coagulation factor inhibitor screening tests (blocking antibodies).

Normal platelet counts are 150,000 to 450,000/mm3. spontaneous clinical hemorrhage is usually not observed with platelet counts above 10,000 to 20,000/mm3. many hospitals have established a critical value of 10,000/mm3 platelets, below which platelets are transfused to prevent serious bleeding sequelae, such as hemorrhagic stroke. surgical or traumatic hemorrhage is more likely with platelet counts below 50,000/mm3.

BT is determined from a standardized incision on the forearm. BT is usually considered to be normal between 1 and 6 minutes (by modified ivy’s test) and is prolonged when greater than 15 minutes. the skin BT test, thought to identify qualitative or functional platelet defects, is a poor indicator of clinically significant bleeding at other sites, and its use as a predictive screening test for oral surgical procedures has been discouraged.

The normal range of PT is approximately 11 to 13 seconds. because of individual laboratory reagent variability and the desire to be able to reliably compare the PT from one laboratory with that from another, the PT test is now commonly reported with its INR.

Normal coagulation profile is reported as an INR of 1.0.

This test evaluates the extrinsic coagulation system and measures the presence or absence of clotting Fs i, ii, v, vii, and X. its most common use is to measure the effects of coumarin anticoagulants and reduction of the vitamin K–dependent Fs ii, vii, iX, and X.

Since the extrinsic system uses only Fs i, ii, vii, and X, it does not measure the reduction of Fs viii or iX, which characterizes hemophilias a and b. additionally, the PT is used to measure the metabolic aspects of protein synthesis in the liver.

The aPTT is considered normal if the control aPTT and the test aPTT are within 10 seconds of each other. Control aPTT times are usually 15 to 35 seconds.

It is used to evaluate the intrinsic cascade and measure the functional levels of Fs viii, iX, Xi, and Xii.

The TT is used specifically to test the ability to form the initial clot from fibrinogen and is considered normal in the range of 9 to 13 seconds.

Vessel Wall disorders:

Scurvy: vitamin C is necessary for the synthesis of hydroxyproline, an essential constituent of collagen. One of the first clinical signs is petechial hemorrhages at the hair follicles and purpura on the back of the lower extremities that coalesce to form ecchymoses. hemorrhage can occur in the muscles, joints, nail beds, and gingival tissues. gingival involvement may include swelling, friability, bleeding, secondary infection, and loosening of teeth. scurvy results when dietary vitamin C falls below 10 mg/d. implementation of a diet rich in vitamin C and administration of 1 g/d of vitamin C supplements provide rapid resolution.

Cushing’s syndrome, resulting from excessive exogenous or endogenous corticosteroid intake or production, leads to general protein wasting and atrophy of supporting connective tissue around blood vessels. patients may show skin bleeding or easy bruising.

Aging causes similar perivascular connective tissue atrophy and lack of skin mobility. tears in small blood vessels can result in irregularly shaped purpuric areas on arms and hands, called purpura senilis.

Ehlers-danlos syndrome is an autosomal dominant inherited disorder of connective tissue matrix, generally resulting in fragile skin blood vessels and easy bruising. it is characterized by hyperelasticity of the skin and hypermobile joints.

Rendu-Osler-weber syndrome, also called hereditary hemorrhagic telangiectasia (HTT), is a group of autosomal dominant disorders with abnormal telangiectatic capillaries, frequent episodes of nasal and gastrointestinal bleeding, and associated brain and pulmonary lesions. perioral and intraoral angiomatous nodules or telangiectases are common with progressive disease, involving areas of the lips, tongue, and palate that may bleed upon manipulation during dental procedures.

Platelet disorders:

platelet disorders may be divided into two categories by etiology—congenital and acquired—and into two additional categories by type—thrombocytopenias and thrombocytopathies.

Thrombocytopenias occur when platelet quantity is reduced and are caused by one of three mechanisms: decreased production in the bone marrow, increased sequestration in the spleen, or accelerated destruction.

Thrombocytopathies, or qualitative platelet disorders, may result from defects in any of the three critical platelet reactions: adhesion, aggregation, or granule release.

Coagulation disorders:

Coagulation disorders may be either congenital or acquired secondary to drugs or disease processes.

Hemophilia A:

A deficiency of F viii, the antihemophilic factor, is inherited as an X-linked recessive trait that affects males (hemizygous). the trait is carried in the female (heterozygous) without clinical evidence of the disease, although a few do manifest mild bleeding symptoms. individuals with hemophilia exhibit bleeds into more deep-seated spaces. the more common signs include hematomas, hemarthroses, hema- turia, gastrointestinal bleeding, and bleeding from lacerations or head trauma or spontaneous intracranial bleeding that require factor replacement therapy. retroperitoneal and central nervous system bleeds, occurring spontaneously or induced by minor trauma, can be life threatening. severe hemorrhage leads to joint synovitis and hemophilic arthropathies, intramuscular bleeds, and pseudotumors.

Hemophilia B: F iX (Christmas factor) deficiency is found in hemophilia

B. F XI deficiency: Plasma thromboplastin antecedent deficiency: Bleeding

symptoms do occur but are usually mild. in the event of major surgery or trauma, hemorrhage can be controlled with infusions of fresh frozen plasma (FFp).

F XII deficiency: hageman factor deficiency is another rare disease that

presents in the laboratory with prolonged PT and PTT. Clinical symptoms are nonexistent. treatment is therefore contraindicated.

F X deficiency: stuart factor deficiency, also a rare bleeding diathesis, is

inherited as an autosomal recessive trait.

Von Willebrand’s disease: Inherited defects in the concentration, structure, or

function of von willebrand’s factor (vwF), a multimeric high molecular weight glycoprotein.

The clinical features of the disease are usually mild and include mucosal bleeding, soft tissue hemorrhage, menorrhagia in women, and rare hemarthrosis.

▼ antiCoagulant-related Coagulopathies: Heparin: Intentional anticoagulation is induced acutely with

heparin or as chronic oral therapy with coumarin drugs. indications for heparin therapy include prophylaxis or treatment for venous thromboembolism, including prophylaxis in medical and surgical patients. the major bleeding complications from heparin therapy are bleeding at surgical sites and bleeding into the retroperitoneum.

Heparin has a relatively short duration of action of 3 to 4 hours and so is typically used for acute anticoagulation, whereas chronic therapy is initiated with coumarin drugs.

Coumarin:

Coumarin anticoagulants, which include warfarin and dicumarol are used for anticoagulation to prevent recurrent thromboembolic events, such as pulmonary embolism, venous thrombosis, stroke, and myocardial infarction; to treat atrial fibrillation; and in conjunction with prosthetic heart valves.

Medically indicated target ranges vary from a pt of 18 to 30 seconds/inr of 1.5 to 4.0 but are seldom above 3.5. daily doses of 2.5 to 7.5 mg coumarin typically are required to maintain adequate anticoagulation.

Patients with paroxysmal atrial fibrillation and porcine heart valves require minimal anticoagulation (INR target 1.5–2.0), and venous thrombosis is managed with intermediate-range coagulation (INR 2.0–3.0), whereas mechanical prosthetic heart valves and hypercoagulable states require more intense anticoagulation (INR target 3.0–4.0).

Coumarin therapy can result in bleeding episodes that are sometimes fatal. intramuscular injections are avoided in anticoagulated patients because of increased risk of intramuscular bleeding and hematoma formation.

Coumarin drugs are particularly susceptible to drug inter- actions. drugs that potentially increase coumarin potency (ie, elevate the INR) include metronidazole, penicillin, erythromycin, cephalosporins, tetracycline, fluconazole, ketoconazole, chloral hydrate, and propoxyphene; those that reduce its potency (ie, decrease the INR) include barbiturates, ascorbic acid, dicloxacillin, and nafcillin. additive hemostatic effect is seen when coumarin drugs are used in combination with aspirin or nsaids.

▼ disease-related Coagulopathies: liver disease: Owing to impaired protein synthesis, important factors

and inhibitors of the clotting and the fibrinolytic systems are markedly reduced. additionally, abnormal vitamin K–dependent factor and fibrinogen molecules have been encountered. thrombocytopenia and thrombocytopathy are also common in severe liver disease. acute or chronic hepatocellular disease may display decreased vitamin K–dependent factor levels, especially Fs ii, vii, iX, and X and protein C, with other factors still being normal.

Vitamin K deficiency: vitamin K is a fat-soluble vitamin that is absorbed in the

small intestine and stored in the liver. it plays an important role in hemostasis. vitamin K deficiency is associated with the production of poorly functioning vitamin K–dependent Fs ii,vii, iX, and X.

Deficiency is rare but can result from inadequate dietary intake, intestinal malabsorption, or loss of storage sites due to hepatocellular disease. biliary tract obstruction and long-term use of broad-spectrum antibiotics, particularly the cephalosporins, can cause vitamin K deficiency.

Disseminated Intravascular Coagulation: DIC is triggered by potent stimuli that activate both F Xii

and tissue factor to initially form microthrombi and emboli throughout the microvasculature. thrombosis results in rapid consumption of both coagulation factors and platelets while also creating FDPs that have antihemostatic effects.

The most frequent triggers for DIC are obstetric complications, metastatic cancer, massive trauma, and infection with sepsis. Clinical symptoms vary with disease stage and severity. most patients have bleeding at skin and mucosal sites.

Fibrinolytic disorders: disorders of the fibrinolytic system can lead to hemorrhage when

clot breakdown is enhanced or excessive clotting and thrombosis when clot breakdown mechanisms are retarded. primary fibrinolysis typically results in bleeding and may be caused by a deficiency in a2-antiplasmin or plasminogen activator inhibitors, natural proteins that turn off activation of the fibrinolytic system. laboratory coagulation tests are normal with the exception of decreased fibrinogen and increased Fdp levels.

Past history of bleeding following surgical procedures, including dental extractions, can help identify a risk. surveying the patient for current medication use is important. identification of medications with hemostatic effect, such as coumarin anticoagulants, heparin, aspirin, nsaids, and cytotoxic chemotherapy, is essential. active medical conditions, including hepatitis or cirrhosis, renal disease, hematologic malignancy, and thrombocytopenia, may predispose patients to bleeding problems. additionally, a history of heavy alcohol intake is a risk factor for bleeding consequences.

The thrombocytopenias are primarily managed acutely with transfusions of platelets to maintain the minimum level of 10,000 to 20,000/mm3 necessary to prevent spontaneous hemorrhage.

Therapy for hemophilias a and b is dependent upon the severity of disease, type and site of hemorrhage, and presence or absence of inhibitors. Commercially prepared Fs viii and iX complex concentrates, desmopressin acetate, and, to a lesser extent, cryoprecipitate and FFp are replacement options.

Therapy for vwd depends on the type of vwd and the severity of bleeding. type i is treated preferentially with ddavp. intermediate-purity F viii concentrates, FFp, and cryoprecipitate are held in reserve for ddavp nonresponders.

Hepatic disease that results in bleeding from deficient vitamin K–dependent clotting factors (Fs ii, vii, iX, and X) may be reversed with vitamin K injections for 3 days, either intravenously or subcutaneously. however, infusion of FFp may be employed when more immediate hemorrhage control is necessary, such as prior to dental extractions.

Patients with moderate thrombocytopenia and functional platelet defects may benefit from ddavp therapy. antifibrinolytic drugs, if used cautiously, have markedly reduced bleeding and thus reduced need for blood and blood product substitution.

In uremic patients, dialysis remains the primary preventive and therapeutic modality used for control of bleeding.

▼ Oral health Considerations:

Platelet deficiency and vascular wall disorders result in extravasation of blood into connective and epithelial tissues of the skin and mucosa, creating small pinpoint hemorrhages, called petechiae, and larger patches, called ecchymoses. platelet or coagulation disorders with severely altered hemostasis can result in spontaneous gingival bleeding, as may be seen in conjunction with hyperplastic hyperemic gingival enlargements in leukemic patients. Continuous oral bleeding over long periods of time fosters deposits of hemosiderin and other blood degradation products on the tooth surfaces, turning them brown.

Hemarthrosis is a common complication in hemophiliacs’ weight-bearing joints, yet it rarely occurs in the TMJ.

▼ Dental management:

Dental modifications required for patients with bleeding disorders depend on both the type and invasiveness of the dental procedure and the type and severity of the bleeding disorder.

For reversible coagulopathies (eg, coumarin anti- coagulation), it may be best to remove the causative agent or treat the primary illness or defect in order to allow the patient to return to a manageable bleeding risk for the dental treatment period.

For irreversible coagulopathies, the missing or defective element may need to be replaced from an exogenous source to allow control of bleeding (eg, coagulation factor concentrate therapy for hemophilia).

Assessment of the coagulopathy and delivery of appropriate therapy prior to dental procedures are best accomplished in consultation with a hematologist and may involve treatment either in specialized hospital facilities or the local general dentist’s office.

When medical management is unable to restore platelet counts to above the level of 50,000/mm3 required for surgical hemostasis, platelet transfusions may be required prior to dental extractions or other oral surgical procedures. the therapeutically expected increment in platelet count from infusion of one unit of platelets is approximately 10,000 to 12,000/mm3. six units of platelets are commonly infused at a time.

Patients who have received multiple transfusions may be refractory to random donor platelets as a result of alloimmunization. these individuals may require single-donor apheresis or leukocyte-reduced platelets. local hemostatic measures are also important.

The thrombasthenic patient needing dental extractions may be successfully treated with the use of hemostatic measures such as microfibrillar collagen and antifibrinolytic drugs.

Since the antiplatelet activity of aspirin remains for the 8- to 10-day lifetime of the affected platelets, avoidance of aspirin is recommended, when possible, for 1 week prior to extensive oral surgical procedures. aspirin is rarely withheld, however, prior to minor oral surgical procedures such as dental extractions.

Other NSAIDs and antiplatelet agents have a similar but less pronounced antiplatelet effect. adjunctive local hemostatic agents are useful in preventing postoperative oozing when aspirin therapy is in use at the time of minor oral surgery.

Hemophilias A and B and vWD: To make certain that preoperative factor levels of at least 40

to 50% of normal activity have been obtained, transfusion recommendations generally aim for replacement of missing coagulation factors to levels of 50 to 100% when single-bolus infusion is used for outpatient treatment.

Additional postoperative factor maintenance may be indicated for extensive surgery. this can be accomplished by infusion of factor concentrates, ddavp, cryoprecipitate, or FFp, depending on the patient’s deficiency state.

When postsurgical bleeding occurs due to fibrinolysis, it commonly starts 3 to 5 days after surgery and can usually be controlled by local measures and use of antifibrinolytics.

Continual oozing from unstable fibrinous clots may require their removal and the repacking of the extraction socket with hemostatic agents.

Local hemostatic agents and techniques include pressure, surgical packs, vasoconstrictors, sutures, surgical stents, topical thrombin, and use of absorbable hemostatic materials. although having no direct effect on hemostasis, primary wound closure aids patient comfort, decreases blood clot size, and protects clots from masticatory trauma and subsequent bleeding. sutures can also be used to stabilize and protect packing.

Microfibrillar collagen acts to attract platelets, causing the release phenomenon to trigger aggregation of platelets into thrombi in the interstices of the fibrous mass of the clot.

Topical thrombin, which directly converts fibrinogen in the blood to fibrin, is an effective adjunct when applied directly to the wound or carried to the extraction site in a nonacidic medium on oxidized cellulose.

Surgifoam is an absorbable gelatin sponge with intrinsic hemostatic properties.

Surgical acrylic stents may be useful if carefully fabricated to avoid traumatic irritation to the surgical site.

Diet restriction to full liquids for the initial 24 to 48 hours, followed by intake of soft foods for 1 to 2 weeks, will further protect the clot by reducing the amount of chewing and resultant soft tissue disturbances.

Antifibrinolytic drugs such as eaCa (amicar 25% syrup, Xanodyne pharmacal inc, Florence, Ky) and tranexamic acid (amCa; Cyclokapron, pharmacia Corp, peapack, nJ) inhibit fibrinolysis by blocking the conversion of plasminogen to plasmin, resulting in clot stabilization.

Systemic antifibrinolytic therapy can be given orally or intravenously as eaCa 75 mg/kg (up to 4 g) every 6 hours or amCa 25 mg/kg every 8 hours until bleeding stops.

For the treatment of acute bleeding syndromes due to elevated fibrinolytic activity, it is suggested that 10 tablets (5 g) or 4 teaspoons of 25% syrup (5 g) of amicar be administered during the first hour of treatment, followed by a continuing rate of 2 tablets (1 g) or 1 teaspoon of syrup (1.25 g) per hour. this method of treatment would ordinarily be continued for about 8 hours or until the bleeding situation has been controlled.

Pain Control:

Intravenous sedation with diazepam, and nitrous oxide/oxygen analgesia, used as adjuncts to control anxiety, drastically reduce or totally eliminate the need for local anesthesia. intrapulpal anesthesia is safe and effective following access for pulp extirpation. periodontal ligament and gingival papillary injections can be accomplished with little risk when delivered slowly with minimal volume.

Although oral endotracheal intubation pro- vides access challenges for the dental operator, it is preferred over nasal endotracheal intubation, which carries the risk of inducing a nasal bleed that can be difficult to control. the use of aspirin and other nsaids for pain management is con- traindicated in patients with bleeding disorders due to their inhibition of platelet function and potentiation of bleeding episodes. intramuscular injections should also be avoided due to the risk of hematoma formation.

Periodontal health is of critical importance for the hemophiliac for two principal reasons: (1) hyperemic gingiva contributes to spontaneous and induced gingival bleeding and (2) periodontitis is a leading cause of tooth morbidity, necessitating extraction.

Periodontal probing and supragingival scaling and polishing can be done routinely. Careful subgingival scaling with fine scalers rarely warrants replacement therapy. severely inflamed and swollen tissues are best treated initially with chlorhexidine oral rinses or by gross débridement with a cavitron or hand instruments to allow gingival shrinkage prior to deep scaling.

Deep subgingival scaling and root planing should be performed by quadrant to reduce gingival area exposed to potential bleeding. locally applied pressure and post-treatment antifibrinolytic oral rinses are usually successful in controlling any protracted oozing.

General restorative and prosthodontic procedures do not result in significant hemorrhage. rubber dam isolation is advised to minimize the risk of lacerating soft tissue in the operative field and to avoid creating ecchymoses and hematomas with high-speed evacuators or saliva ejectors.

Care is required to select a tooth clamp that does not traumatize the gingiva. matrices, wedges, and a hemostatic gingival retraction cord may be used with caution to protect soft tissues and improve visualization when subgingival extension of cavity preparation is necessary. removable prosthetic appliances can be fabricated without complications.

Endodontic therapy is often the treatment of choice for a patient with a severe bleeding disorder, especially when an inhibitor is present because extraction carries a high risk of hemorrhage, and treatment is expensive.

Generally, there are no contraindications to root canal therapy, provided that instrumentation does not extend beyond the apex.

Filling beyond the apical seal also should be avoided. application of epinephrine intrapulpally to the apical area is usually successful in providing hemostasis. endodontic surgical procedures require the same factor replacement therapy as do oral surgical procedures.

The pediatric dental patient occasionally presents with prolonged oozing from exfoliating primary teeth. administration of factor concentrates and extraction of the deciduous tooth with curettage may be necessary for patient comfort and hemorrhage control.

Pulpotomies can be performed without excessive pulpal bleeding. stainless steel crowns should be prepared to allow minimal removal of enamel at gingival areas. topical fluoride treatment and use of pit-and-fissure sealants are important noninvasive therapies to decrease the need for extensive restorative procedures.

Orthodontic treatment can be provided with little modification. Care must be observed to avoid mucosal laceration by orthodontic bands, brackets, and wires. bleeding from minor cuts usually responds to local pressure. properly managed fixed orthodontic appliances are preferred over removable functional appliances for the patient with a high likelihood of bleeding from chronic tissue irritation. the use of extraoral force and shorter treatment duration further decrease the potential for bleeding complications.

Management of the dental patient on anticoagulant therapy involves consideration of the degree of anticoagulation achieved as gauged by the pt/inr, the dental procedure planned, and the level of thromboembolic risk for the patient.

No surgical treatment is recommended for those with an inr of >3.5 to 4.0 without coumarin dose modification. with an inr <3.5 to 4.0, minor surgical procedures with minimal anticipated bleeding require local measures but no coumarin modification. at an inr of <3.5 to 4.0, when moderate bleeding is expected (multiple extractions or removal of wisdom teeth), local measures should be used, and inr reduction should be considered. when significant bleeding is anticipated, as from full-mouth or full-arch extractions, local measures are combined with reduction of anticoagulation to an inr of <2.0 to 3.0. extensive flap surgery or multiple bony extractions may require an inr of <1.5.

When the likelihood of sudden thrombotic and embolic complications is small and hemorrhagic risk is high, coumarin therapy can be discontinued briefly at the time of surgery, with prompt reinstitution postoperatively.

Coumarin’s long half- life of 42 hours necessitates dose reduction or withdrawal 2 days prior to surgery in order to return the patient’s pt/inr to an acceptable level for surgery.

For patients with moderate thromboembolic and hemorrhagic risks, coumarin therapy can be maintained in the therapeutic range with the use of local measures to control postsurgical oozing.

High-risk cardiac patients undergoing high-bleeding-risk surgical procedures may be managed most safely with a com- bination unfractionated heparin–coumarin method, which allows maximal hemostasis with minimal nonanticoagulated time (14 to 18 hours for a 2-hour surgery, as opposed to 3 to 4 days with the coumarin discontinuation method).

Coumarin is withheld 24 hours prior to admission. heparin therapy, instituted on admission, is stopped 6 to 8 hours preoperatively.

Coumarin is reinstituted on the night of the procedure and may require 2 to 4 days to effectively reduce the patient’s procoagulant levels to a therapeutic range.

Heparin is reinstituted 6 to 8 hours after surgery when an adequate clot has formed.

Use of additional local hemostatic agents such as microfibrillar collagen, oxidized cellulose, or topical thrombin is recommended for anticoagulated patients.

Susceptibility to infection among patients with congenital bleeding disorders is not a significant concern. however, due to bleeding into weight-bearing joints, hemophiliacs may have had joint replacement.

For these patients, antibiotic prophylaxis should be considered. should a hematoma form as a result of an anesthetic injection or other dental trauma or spontaneously, use of a broad-spectrum antibiotic is indicated to prevent infection during resolution.

If bleeding results from bone marrow–suppressive systemic disease or chemotherapeutic drug use, antibiotics may be required to prevent infection from bacteremia-inducing dental procedures when production of mature functional neutrophils is substantially diminished.

Spontaneous gingival bleeding between the upper left lateral incisor and canine and labial petechiae in a 38-year-old white male with idiopathic thrombocytopenic purpura.

A 46-year-old male with severe liver cirrhosis due to hepatitis C infection. Shown is purpura of facial skin 1 week after full-mouth extractions.