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
Bleeding Disorders (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:
Congenital or acquired disorders of platelet function
Platelet Count Drugs that interfere with platelet function
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
Bleeding Time (BT): Rapid evaluation of platelet function
Time required for bleeding to cease Time required to obtain full occlusion of the injured
Normal bleeding time is between 3-8 minutes 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
Identifies acquired or inherited deficiencies in the
Factor Inhibition
activities of Factors XII, XI, IX, and VIII
Assesses reduction in activity of fibrinogen, factors Anticoagulation with heparin
V and X Contamination of the sample with heparin
Monitors heparin anticoagulation
Normal values ~25-35 seconds

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 Prothrombin Time (PT)
Identifies acquired or inherited deficiencies in Prolongation of the PT
the activities of factors VII, X, V, prothrombin, Disseminated intravascular coagulation
and fibrinogen. Increased hematocrit
Monitors the activity of warfarin Liver disease
Normal values: 11-13 seconds Vitamin K deficiency
PT shorter than the reference range is not Nephrotic syndrome
related with any clinical condition and is usually
Tx with certain antibiotics, chemotherapeutics,
associated with improper procedure or
or antithrombotic drugs
technique.

Thrombin time (TT):

Tests the conversion of fibrinogen to fibrin to
cross-linked fibrin. TT shorter than reference range
Monitor anticoagulant therapy with fibrinolytic Usually related to improper procedure
agents and hirudin.
Prolongation of the TT occurs when there is:
Screening test for hypo- and hyper-
fibrinogenemia, abnormalities of the fibrinogen Contamination with heparin
molecule, and inhibitors against thrombin or Afibrinogenemia/Hypofibrinogenemia- acquired
fibrin. (DIC, liver disease) and familial
When modified (using high concentrations of Interference with fibrinopeptide cleavage
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
Causes of a prolonged PT and/or a prolonged aPTT

PT aPTT Test Result Causes of test result

pattern
Prolonged Normal Inherited
VII deficiency
Acquired
PT aPTT
Vitamin K deficiency Prolonged Prolonged Inherited
Def. prothrombin,
Liver disease
fibrinogen or V, X
Coumadin
Combined factor def
Inhibitor of FcVII
Acquired
Normal Prolonged Inherited
vWf or VIII, IX, XI, XII
Liver disease
DIC
Acquired
Heparin and coumadin
Heparin administration
Inhibitor of prothrombin,
Inhibitor of vWf or VIII,
fibrinogen or V, X
IX, XI, XII (PT slightly
prolonged)

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 Hemophilia
Three types Hemophilia
A, factor VIII, X-linked recessive, abnormal PTT
B, factor IX, X-linked recessive, abnormal PTT Normal bleeding time (excl. von Willebrand)
von Willebrands disease; A.D.; abnormal PTT, BT Normal platelet number
Mild, moderate, severe Normal prothrombin time
Hemarthrosis arthritis and ankylosis Abnormal partial thromboplastin time
Pseudotumor of hemophilia No petechiae
Precautions: Clotting factor replacement, Females can have excessive bleeding (X-linked)
antifibrinolytic agent EACA (-aminocaproic acid)
Hemophilia and HIV infection

Platelet Disorders What are platelets ?

Thrombocytopenia
Round or oval discs ~2-4 microns in
platelets diameter
Increased destruction Formed by fragmentation of
Sequestration in the spleen megakaryocytes in the BM
Normal: 200,000-400,000 1000-1500 platelets per megakaryocyte
< 50,000 serious Aged platelets removed by
reticuloendothelial system and spleen

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 Causes Oral Manifestations
platelets Petechiae: pinpoint
Chemotherapeutic agents, neoplasms
(leukemia), autoimmune
Ecchymoses: >petechiae
Hematoma: the largest
Increased destruction
Gingival hemorrhage
Drugs (heparin), idiosyncratic, TTP
Systemic hemorrhage: epistaxis, hematemesis,
Sequestration in the spleen
hemoptysis, uremia
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

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Thrombasthenia
Defective adherence or aggregation of platelets
Drugs (aspirin), von Willebrands disease (mild),
factor VIII
Petechial hemorrhage; thrombocytopenia
Platelet count is normal, bleeding time
Reversible in ~ 1 week; dipyridamole; infusion
Red Blood Cell Disorders
Capillary Fragility
Vitamin C deficiency (scurvy)
Impaired collagen fibrillogenesis
Petechiae, ecchymoses, periodontal disease
Hereditary hemorrhagic telangiectasia
Defective vascular walls
Tongue dorsum, lips, epistaxis
Gastrointestinal bleedingiron deficiency
Arteriovenous fistulas, brain abscess
Prophylactic antibiotic treatment
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 Anemia Anemia
Deficiency in the transport of oxygen Causes
Microcytic: small cells Excessive blood loss: trauma, internal
hemorrhage, spontaneous hemolysis
Hypochromic: hemoglobin
Genetic: sickle cell disease, thalassemia
Macrocytic-hyperchromic: Total number of Nutritional deficiency
RBC BM produces larger cells with Laboratory tests
increased concentration of hemoglobin
RBC count, hematocrit, hemoglobin evaluation

Types of Anemia Clinical Symptoms of Anemia

Iron deficiency Tiredness
Pernicious anemia Weakness
Aplastic anemia * Malaise
Sickle cell anemia Increased respiratory rate
Thalassemia 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 (Fanconis anemia,
dyskeratosis congenita)
Laboratory values
< 500 granulocytes/l
< 20,000 platelets/ l
<10,000 reticulocytes/ l

Aplastic Anemia
Sickle Cell Anemia
Mild to severe A/T mutation: valine instead of glutamic acid
Clinical findings RBCs have are sickle-shaped
Symptoms of anemia
Trait is AD; disease is AR
Thrombocytopenia
Retinal & cerebral hemorrhage
Tissue ischemia, infarction and tissue death
Neutropenia, leukopenia, granulocytopenia Sickle cell crisis: long bones, lungs, abdomen
Treatment Infections: Hem. influenza, Strept. pneumoniae,
Antibiotics, transfusions, androgenic steroids, (due to spleen infarction), Salmonella
immunomodulatory therapy, BMT
(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 (Colleys 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
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
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
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
1. Enlargement of lymphoid tissue
2. Antigenic challenge
3. Lymph nodes, Waldeyers 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
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 Leukopenia
White Blood Cell Disorders Normal number of WBC: 6,000-9,000 WBC/mm3
Agranulocytosis: granulocytes
Leukopenia Chemotherapy drugs, congenital
Malaise, sore throat, fever, infections
Neutrophil Function Disorders
Oral: Ulcers, ANUG-like gingivitis
Leukocytosis TX: G-CSF
Neoplasms 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 Neutrophil Function Disorders
<1,500 neutrophils/mm3 Chronic granulomatous disease
Congenital, drugs, infections, autoimmune X-linked, opportunistic infections, candidiasis, gingivitis, periodontitis

Staph. aureus, gram(-) bacteria Leukocyte adhesion deficiency

Middle ear, oral cavity, perirectal area
Gingival ulcers without erythematous
periphery
Glucose-6-phosphate dehydrogenase deficiency
Myeloperoxidase deficiency
Lazy leukocyte syndrome

Leukocytosis Neoplasms
Viral infections Leukemia
Lymphocytes and monocytes Hodgkins disease
Bacteria-associated leukocytosis Non-Hodgkins lymphoma
Immature neutrophils (band cells) Mycosis fungoides
Abscess Burkitts lymphoma
Cellulitis Multiple myeloma & plasmacytoma

Leukemia Leukemia
Acute or chronic Males females
Myeloid: more adults
Myeloid or lymphocytic CLL elderly; ALL children
Certain syndromes are associated with Myelophthisic anemia
increased risk Reduction in oxygen-carrying capacity, thrombocytopenia
Chromosomal abnormalities Infections (candidiasis, herpes), ulcerations, hemorrhage,
chloroma, periapical lesions
Chemicals, radiation, viruses Biopsy, peripheral blood and marrow

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 Hodgkins Disease
Less common than non-Hodgkins 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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 Hodgkins Disease Hodgkins Disease
Matted and fixed nodes Lymphocyte predominant: 2-10%
Spleen, bone, liver and lung Nodular sclerosis: 40-80% females>males
Mixed cellularity: 20-40%
Weight loss, fever, night sweats, pruritus
Lymphocyte depletion: 2-15%, most aggressive
No systemic signs: A; Systemic signs: B
Prognosis according to stage
Staging: # of lymph node regions; affected TX: M(etchlorethamine)O(oncovin)P(rocarbazine)P(rednisone)
extralymphatic organ or site; diaphragm,
systemic signs

Non-Hodgkins 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

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 Mycosis Fungoides
T-helper cell lymphoma
Epidermotropism
Male:Female=2:1
Eczematous stage, plaque stage, tumor stage
Oral involvement
Szary syndrome: dermatopathic T-cell leukemia,
systemic involvement
Atypical lymphocytes, Pautriers microabscesses

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 Burkitts 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, M-
protein
Amyloidosis

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Myeloma-associated amyloidosis
AL type; light chains ()
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

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 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-Schler-
Christian)
Acute disseminated disease (Letterer-Siwe)

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 Langerhans Cell Histiocytosis
Hand-Schler-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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