Hematologic Disorders

Hematologic Disorders Hematologic Disorders Bleeding disorders Red blood cell disorders White blood cell disorders Hemostasis • Platelet adhesion, von Willebrand factor and specific adhesion proteins • Deficiency results in pathologic hemorrhage (hemorrhagic diathesis) • Platelet disorders: ↓ number, defective adhesion, defective aggregation • Coagulation factor deficiency: genetic, liver disease, biliary obstruction, steatorrhea, drugs • Vascular wall fragility: scurvy, genetic Bleeding Disorders Hemostasis • Four phases: – Initiation & formation of the platelet plug – Propagation by the coagulation cascade – Termination by antithrombotic control mechanisms – Removal of the clot by fibrinolysis 1 Bleeding Disorders • Coagulation – Hemophilia • Platelet disorders – Thrombocytopenia – Thrombasthenia • Capillary fragility – Vitamin C deficiency – Hereditary hemorrhagic telangiectasia TESTS • Prolonged BT: TESTS – Congenital or acquired disorders of platelet function – Drugs that interfere with platelet function • Platelet Count – Included in the CBC – Normal level 200,000 – 400,000 • Closure time (CT): – Process of platelet adhesion and aggregation following vascular injury is simulated in vitro – Rapid evaluation of platelet function – Time required to obtain full occlusion of the injured site/aperture with a platelet plug – Abnormalities result in prolonged CT > 175 seconds • Bleeding Time (BT): – Time required for bleeding to cease – Normal bleeding time is between 3-8 minutes Tests of Secondary Hemostasis • Activated Partial Thromboplastin Time (aPTT): – Identifies acquired or inherited deficiencies in the activities of Factors XII, XI, IX, and VIII – Assesses reduction in activity of fibrinogen, factors V and X – Monitors heparin anticoagulation – Normal values ~25-35 seconds Prolongation of aPTT Factor deficiency Factor Inhibition Anticoagulation with heparin Contamination of the sample with heparin 2 • Prothrombin Time (PT) – Identifies acquired or inherited deficiencies in the activities of factors VII, X, V, prothrombin, and fibrinogen. – Monitors the activity of warfarin – Normal values: 11-13 seconds – PT shorter than the reference range is not related with any clinical condition and is usually associated with improper procedure or technique. • Prolongation of the PT – Disseminated intravascular coagulation – Increased hematocrit – Liver disease – Vitamin K deficiency – Nephrotic syndrome – Tx with certain antibiotics, chemotherapeutics, or antithrombotic drugs • Thrombin time (TT): – Tests the conversion of fibrinogen to fibrin to cross-linked fibrin. – Monitor anticoagulant therapy with fibrinolytic agents and hirudin. – Screening test for hypo- and hyperfibrinogenemia, abnormalities of the fibrinogen molecule, and inhibitors against thrombin or fibrin. – When modified (using high concentrations of thrombin), this test can be used to measure fibrinogen levels. • TT shorter than reference range – Usually related to improper procedure • Prolongation of the TT occurs when there is: – Contamination with heparin – Afibrinogenemia/Hypofibrinogenemia- acquired (DIC, liver disease) and familial – Interference with fibrinopeptide cleavage Causes of a prolonged PT and/or a prolonged aPTT Test Result Causes of test result pattern Causes of a prolonged PT and/or a prolonged aPTT Test Result Causes of test result pattern PT aPTT Prolonged Normal Inherited VII deficiency Acquired Vitamin K deficiency Liver disease Coumadin Inhibitor of FcVII Inherited vWf or VIII, IX, XI, XII Acquired Heparin administration Inhibitor of vWf or VIII, IX, XI, XII (PT slightly prolonged) PT Prolonged aPTT Prolonged Inherited Def. prothrombin, fibrinogen or V, X Combined factor def Acquired Liver disease DIC Heparin and coumadin Inhibitor of prothrombin, fibrinogen or V, X Normal Prolonged 3 Hemophilia • Three types – A, factor VIII, X-linked recessive, abnormal PTT – B, factor IX, X-linked recessive, abnormal PTT – von Willebrand’s disease; A.D.; abnormal PTT, BT • • • • • • Hemophilia Normal bleeding time (excl. von Willebrand) Normal platelet number Normal prothrombin time Abnormal partial thromboplastin time No petechiae Females can have excessive bleeding (X-linked) Mild, moderate, severe Hemarthrosis ⇒ arthritis and ankylosis Pseudotumor of hemophilia Precautions: Clotting factor replacement, antifibrinolytic agent EACA (ε-aminocaproic acid) • Hemophilia and HIV infection • • • • Platelet Disorders • Thrombocytopenia – ↓ platelets – Increased destruction – Sequestration in the spleen Normal: 200,000-400,000 < 50,000 serious What are platelets ? – Round or oval discs ~2-4 microns in diameter – Formed by fragmentation of megakaryocytes in the BM – 1000-1500 platelets per megakaryocyte – Aged platelets removed by reticuloendothelial system and spleen 4 Causes • ↓ platelets – Chemotherapeutic agents, neoplasms (leukemia), autoimmune Oral Manifestations • • • • • Petechiae: pinpoint Ecchymoses: >petechiae Hematoma: the largest Gingival hemorrhage Systemic hemorrhage: epistaxis, hematemesis, hemoptysis, uremia • Increased destruction – Drugs (heparin), idiosyncratic, TTP • Sequestration in the spleen – Portal hypertension, splenic tumor, genetic ITP and TTP • Idiopathic thrombocytopenic purpura – Childhood after viral infection – Resolves spontaneously (most often) • Thrombotic thrombocytopenic purpura – Endothelial damage and formation of microthrombi 5 Thrombasthenia • Defective adherence or aggregation of platelets – Drugs (aspirin), von Willebrand’s disease (mild), factor VIII Capillary Fragility • Vitamin C deficiency (scurvy) – Impaired collagen fibrillogenesis – Petechiae, ecchymoses, periodontal disease • Hereditary hemorrhagic telangiectasia – Defective vascular walls – Tongue dorsum, lips, epistaxis – Gastrointestinal bleeding⇒iron deficiency – Arteriovenous fistulas, brain abscess – Prophylactic antibiotic treatment • Petechial hemorrhage; thrombocytopenia • Platelet count is normal, ↑ bleeding time • Reversible in ~ 1 week; dipyridamole; infusion Red Blood Cell Disorders 6 Anemia • Deficiency in the transport of oxygen • Microcytic: small cells • Hypochromic: ↓ hemoglobin • Macrocytic-hyperchromic: Total number of RBC ↓ ⇒ BM produces larger cells with increased concentration of hemoglobin • Causes Anemia – Excessive blood loss: trauma, internal hemorrhage, spontaneous hemolysis – Genetic: sickle cell disease, thalassemia – Nutritional deficiency • Laboratory tests – RBC count, hematocrit, hemoglobin evaluation Types of Anemia • • • • • Iron deficiency Pernicious anemia Aplastic anemia * Sickle cell anemia Thalassemia • • • • • • • Clinical Symptoms of Anemia Tiredness Weakness Malaise Increased respiratory rate Headache Pallor (check palbebral conjunctiva) Mucous membranes (mouth) Iron Deficiency Anemia • Inadequate dietary intake of iron • Most common form • Hypochromic, microcytic, ↓ RBC • Oral findings – Bald tongue, atrophic mucosa, angular cheilitis, aphthous stomatitis – Plummer-Vinson syndrome 7 Pernicious Anemia • Impaired RBC maturation secondary to insufficient vitamin B12 (cobalamin) due to a defective intrinsic factor required for its absorption through the intestinal wall. • Autoimmune destruction of parietal cells in the stomach; gastrointestinal by-pass operations • Oral findings – Burning mouth – Atrophic glossitis (Hunter glossitis) – Angular cheilitis • Treatment: cyanocobalamin injections Aplastic Anemia • All types of blood cells affected • Cause: environmental toxins, drugs, viruses, genetic disorders (Fanconi’s anemia, dyskeratosis congenita) • Laboratory values < 500 granulocytes/μl < 20,000 platelets/ μl <10,000 reticulocytes/ μl Aplastic Anemia • Mild to severe • Clinical findings – Symptoms of anemia – Thrombocytopenia – Retinal & cerebral hemorrhage – Neutropenia, leukopenia, granulocytopenia Sickle Cell Anemia • • • • • • A/T mutation: valine instead of glutamic acid RBCs have are sickle-shaped Trait is AD; disease is AR Tissue ischemia, infarction and tissue death Sickle cell crisis: long bones, lungs, abdomen Infections: Hem. influenza, Strept. pneumoniae, (due to spleen infarction), Salmonella (osteomyelitis) • Treatment Antibiotics, transfusions, androgenic steroids, immunomodulatory therapy, BMT 8 Sickle Cell Anemia Delayed growth Impaired kidney function Stroke Oral findings Reduced trabeculation of mandible “Hair-on-end” appearance of calvaria Thalassemia • Alpha and Beta types • 2 genes for B; 4 genes for Alpha • Hemolytic disorder: spleen hemolysis B-Thalassemia • One defective gene: thalassemia minor • Two genes: thalassemia major (Colley’s dz. or Mediterranean fever) • Detected during 1st year of life, usually after fetal hemoglobin synthesis ceases • Extremely fragile RBCs • Extramedullary hematopoiesis • Hepatomegaly, splenomegaly 9 B-Thalassemia • Painless enlargement of mandible and maxilla • “Chipmunk” facies • “Hair-on-end” appearance of calvaria A-Thalassemia • One gene affected ⇒no disease • Two genes affected ⇒trait • Three genes affected ⇒Hb H disease – Hemolytic anemia, splenomegaly • Four genes affected ⇒hydrops fetalis – Fatal within hours of birth Polycythemia Vera • Rare idiopathic hematologic disorder • ↑ RBC, also uncontrolled production of platelets and granulocytes • Abnormal proliferation uncontrolled be regulatory hormones such as erythopoietin • Older patients Polycythemia Vera • Initially, nonspecific clinical symptoms, 40% of patients report pruritus • CVA, MI • Erythromelalgia: burning sensation & erythema • Hemorrhage (Gingiva) • Increased risk for leukemia due to chemotherapy White Blood Cell Disorders 10 Lymphoid Hyperplasia 1. Enlargement of lymphoid tissue 2. Antigenic challenge 3. Lymph nodes, Waldeyer’s ring, lymphoid aggregates Lymphadenopathy • Acute infection – Enlarged, tender, relatively soft, freely movable • Chronic infection – Enlarged, rubbery firm, nontender, freely movable • Neoplasm – Nontender, progressive enlargement, freely movable or fixed Lymphoid Hyperplasia Can occur intraorally Tonsils, lateral tongue, floor mouth Premasseteric lymph node Color: normal, pink, yellow-orange Microscopy: Lymphoid aggregates, germinal centers, macrophages • No treatment usually necessary • • • • • 11 White Blood Cell Disorders • • • • Leukopenia Neutrophil Function Disorders Leukocytosis Neoplasms Leukopenia Normal number of WBC: 6,000-9,000 WBC/mm3 • Agranulocytosis: ↓ granulocytes Chemotherapy drugs, congenital Malaise, sore throat, fever, infections Oral: Ulcers, ANUG-like gingivitis TX: G-CSF • Cyclic neutropenia Idiopathic, A.D. form 21-day cycle Fever, anorexia, lymphadenopathy, malaise Oral and other mucosal ulcerations TX: G-CSF, improvement with age 12 Neutropenia • <1,500 neutrophils/mm3 • • • • Congenital, drugs, infections, autoimmune Staph. aureus, gram(-) bacteria Middle ear, oral cavity, perirectal area Gingival ulcers without erythematous periphery Neutrophil Function Disorders • Chronic granulomatous disease – X-linked, opportunistic infections, candidiasis, gingivitis, periodontitis • • • • Leukocyte adhesion deficiency Glucose-6-phosphate dehydrogenase deficiency Myeloperoxidase deficiency Lazy leukocyte syndrome Leukocytosis • Viral infections – Lymphocytes and monocytes Neoplasms • Leukemia • Hodgkin’s disease • Non-Hodgkin’s lymphoma – Mycosis fungoides – Burkitt’s lymphoma • Bacteria-associated leukocytosis – Immature neutrophils (band cells) – Abscess – Cellulitis • Multiple myeloma & plasmacytoma Leukemia • Acute or chronic • Myeloid or lymphocytic • Certain syndromes are associated with increased risk • Chromosomal abnormalities • Chemicals, radiation, viruses • • • • • • Leukemia Males ≥ females Myeloid: more adults CLL elderly; ALL children Myelophthisic anemia Reduction in oxygen-carrying capacity, thrombocytopenia Infections (candidiasis, herpes), ulcerations, hemorrhage, chloroma, periapical lesions • Biopsy, peripheral blood and marrow 13 Hodgkin’s Disease • • • • • Less common than non-Hodgkin’s lymphoma Reed-Sternberg cells Males>Females Between 15-35 and then after 50-years of age Almost always begins in the lymph nodes – Cervical and supraclavicular 70-75% – Axillary and mediastinal 5-10% – Abdominal and inguinal <5% 14 Hodgkin’s Disease • • • • • Matted and fixed nodes Spleen, bone, liver and lung Weight loss, fever, night sweats, pruritus No systemic signs: A; Systemic signs: B Staging: # of lymph node regions; affected extralymphatic organ or site; diaphragm, systemic signs • • • • • • Hodgkin’s Disease Lymphocyte predominant: 2-10% Nodular sclerosis: 40-80% females>males Mixed cellularity: 20-40% Lymphocyte depletion: 2-15%, most aggressive Prognosis according to stage TX: M(etchlorethamine)O(oncovin)P(rocarbazine)P(rednisone) Non-Hodgkin’s Lymphoma • • • • • Lymph nodes, extranodal, solid masses B-cell (most common), T-cell, histiocytic Low, intermediate and high grades Non-tender mass, slowly enlarging Oral involvement – Buccal vestibule, gingiva, palate, jaws – Erythematous, purplish, yellowish, ulcerated or not, toothache, paresthesia, irregular radioluncies • Histologic types 15 Mycosis Fungoides T-helper cell lymphoma Epidermotropism Male:Female=2:1 Eczematous stage, plaque stage, tumor stage Oral involvement Sézary syndrome: dermatopathic T-cell leukemia, systemic involvement • Atypical lymphocytes, “Pautrier’s microabscesses” • • • • • • 16 Burkitt’s Lymphoma • B-cell lymphoma • EBV-virus, chromosomal translocation (8;14 or 8;22), malaria • American type • Jaw involvement: Max:Mand.=2:1 • Histology: “Starry sky” pattern • Treatment: cyclophosphamide Multiple Myeloma • Plasma cell origin • 1% of all malignancies, 10-15% of hematopoietic malignancies, 50% of all malignancies affecting bone (excluding metastasis) • Older men • Bone pain, anemia, hemorrhage, hypercalcemia • Multiple “punched out” radiolucencies • Renal failure, Bence Jones proteins, amyloid, Mprotein • Amyloidosis 17 Myeloma-associated amyloidosis • AL type; light chains (λ) • Older individuals • Fatigue, weight loss, paresthesia, hoarseness, edema orthostatic hypotension • Macroglossia • Eyelids, retroauricular region, neck, lips • Petechiae, ecchymoses • Xerostomia and xerophthalmia Plasmacytoma • • • • • • Solitary neoplastic proliferation of plasma cells Can be extramedullary May ultimately give rise to multiple myeloma Male:female=3:1 Spine Jaws, tonsils, sinus, parotid gland 18 Midline Lethal Granuloma • • • • • Many disease entities T-cell lymphoma Nasal symptoms (stuffiness, epistaxis), hard palate Deep ulcers and secondary infections Angiocentricism Langerhans’ Cell Histiocytosis • • • • Dendritic mononuclear cells Antigen-processing and presenting (T cells) cells Neoplastic process Monostotic or polyostotic eosinophilic granuloma – May have lymph node involvement • Chronic disseminated disease (Hand-SchülerChristian) • Acute disseminated disease (Letterer-Siwe) 19 Langerhans’ Cell Histiocytosis • Hand-Schüler-Christian – Bone lesions, exophthalmos, diabetes insipidus • More than 50% in children (<10 years) • Skull, ribs, vertebrae, mandible • Jaws – Dull pain, tenderness – Punched-out radiolucencies – Scooped-out appearance, teeth “floating in air” – Sometimes only soft tissues 20 Langerhans’ Cell Histiocytosis • Histopathology – Pale-staining mononuclear cells (histiocytes) • Birbeck granules – Eosinophils • Treatment – Curettage – Low dose radiation – Intralesional injection of steroids – Spontaneous regression – Children do worse than adults 21