Hematologic Disorders
Hematologic Disorders
Bleeding disorders
Red blood cell disorders
White blood cell disorders
Hemostasis
Bleeding Disorders
• 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
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
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Bleeding Disorders
• Coagulation
– Hemophilia
• Platelet disorders
– Thrombocytopenia
– Thrombasthenia
• Capillary fragility
– Vitamin C deficiency
– Hereditary hemorrhagic telangiectasia
TESTS
TESTS
• Prolonged BT:
• Platelet Count
– Included in the CBC
– Normal level 200,000 – 400,000
• Bleeding Time (BT):
– Time required for bleeding to cease
– Normal bleeding time is between 3-8 minutes
– Congenital or acquired disorders of platelet function
– Drugs that interfere with platelet function
• 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
Tests of Secondary Hemostasis
Prolongation of aPTT
• Activated Partial Thromboplastin Time (aPTT):
Factor deficiency
Factor Inhibition
Anticoagulation with heparin
Contamination of the sample with heparin
– 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
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• 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.
Causes of a prolonged PT and/or a prolonged aPTT
Test Result
Causes of test result pattern
PT
aPTT
Prolonged
Normal
Normal
Prolonged
• 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
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)
Causes of test result
pattern
PT
aPTT
Prolonged
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
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Hemophilia
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
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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
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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)
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
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Causes
• ↓ platelets
– Chemotherapeutic agents, neoplasms
(leukemia), autoimmune
• Increased destruction
– Drugs (heparin), idiosyncratic, TTP
• Sequestration in the spleen
– Portal hypertension, splenic tumor, genetic
Oral Manifestations
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Petechiae: pinpoint
Ecchymoses: >petechiae
Hematoma: the largest
Gingival hemorrhage
Systemic hemorrhage: epistaxis, hematemesis,
hemoptysis, uremia
ITP and TTP
• Idiopathic thrombocytopenic purpura
– Childhood after viral infection
– Resolves spontaneously (most often)
• Thrombotic thrombocytopenic purpura
– Endothelial damage and formation of microthrombi
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Thrombasthenia
Capillary Fragility
• Vitamin C deficiency (scurvy)
• Defective adherence or aggregation of platelets
– Drugs (aspirin), von Willebrand’s disease (mild),
factor VIII
• Petechial hemorrhage; thrombocytopenia
• Platelet count is normal, ↑ bleeding time
• Reversible in ~ 1 week; dipyridamole; infusion
– 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
Red Blood Cell Disorders
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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
Anemia
• Causes
– 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
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Iron deficiency
Pernicious anemia
Aplastic anemia *
Sickle cell anemia
Thalassemia
Clinical Symptoms of Anemia
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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
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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
• Treatment
Antibiotics, transfusions, androgenic steroids,
immunomodulatory therapy, BMT
Sickle Cell Anemia
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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)
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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
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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
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Lymphoid Hyperplasia
Lymphadenopathy
1. Enlargement of lymphoid tissue
• Acute infection
2. Antigenic challenge
• Chronic infection
– Enlarged, tender, relatively soft, freely movable
– Enlarged, rubbery firm, nontender, freely movable
3. Lymph nodes, Waldeyer’s ring, lymphoid
• Neoplasm
– Nontender, progressive enlargement, freely
movable or fixed
aggregates
Lymphoid Hyperplasia
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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
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White Blood Cell Disorders
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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
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Neutropenia
• <1,500 neutrophils/mm3
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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
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Leukocyte adhesion deficiency
Glucose-6-phosphate dehydrogenase deficiency
Myeloperoxidase deficiency
Lazy leukocyte syndrome
Leukocytosis
• Viral infections
– Lymphocytes and monocytes
• Bacteria-associated leukocytosis
– Immature neutrophils (band cells)
– Abscess
– Cellulitis
Neoplasms
• Leukemia
• Hodgkin’s disease
• Non-Hodgkin’s lymphoma
– Mycosis fungoides
– Burkitt’s lymphoma
• 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
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Hodgkin’s Disease
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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%
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Hodgkin’s Disease
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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
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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
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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
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Mycosis Fungoides
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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”
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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
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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
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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
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Midline Lethal Granuloma
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Many disease entities
T-cell lymphoma
Nasal symptoms (stuffiness, epistaxis), hard palate
Deep ulcers and secondary infections
Angiocentricism
Langerhans’ Cell Histiocytosis
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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)
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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
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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
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