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Aka granulocytopenia

Refers to an absolute neutrophil count of <1800 cells/mL

Agrnulocytosis: severe neutropenia in which both the marginated pool and the bone marrow reserve have been depleted.

Asymptomatic = chronci benign neutropenia.
An increase in the absolute peripheral blood neutrophil count to >7000 cells/ML.

*Leukemoid Reaction: in patients with acute infections, neutrophilia may be so pronounced that it can be mistaken for leukemia.
Chronic Granulomatous Disease (CGD)
Refers to a group of rare, inherited, X-linked or autosomal recessive disorders that are characterized by defects in the bactericidal function of phagocytic cells, including neutrophils and macrophaegs.

Inability of these cells to undergo a respiratory burst and to generate H2O2 upon phagocytosis of microorganism..

Deficiency of membrane-bound NADPH oxidase.
Chediak-Higashi Syndrome
A rare, autosomal recessive condition that is characterized by abnormal, giant lysosomes in leukocytes and numerous cells in other tissues.

Neutropenia, decreased chemotaxis, impaired degranulation, ineffective bactericidal activity.
Indicators of B-lymphocyte immunoreactivity:
hyperplasia of the secondary follicles, or germinal centers, and plasmacytosis of the medullary cords.
Indicators of T-lymphocyte immunoreactivity:
hyperplasia of the deep cortex or paracortex.
Acute suppurative lymphadenitis
occurs in lymph nodes that drain a site of acute bacterial infection.

Lymph nodes enlarge rapidly because of edema and hyperemia, also tender.
Define thrombocytopenia
A decrease in the platelet count to <150,000 cells/ML

<50,000: increase the hazard of bleeding from trauma or surgical procedures.

<20,000: spontaenous bleeding can be expected
Principal causes of thrombocytopenia.
-decreased/infective production of platelets
-increased destruction of platelets
-increased splenic sequestration (splenomegaly-can hold 80% of platelets; hepatic cirrhosis, lymphomas)
-dilution (blood/plasma transfusions)
What would produce decreased production of platelets?
Aplastic anemia
Infiltrative disorders of the marrow
Marrow hypoplasia/damage produced by drugs, radiation, viral infections.
Chemotherapeutic agents
Myelophthisic (cancer of bone marrow)
Abnormal megakaryocytes (megaloblastic anemia)

a aplastic anemia, idiopathic or secondary exposure to radiation or cytotoxic drugs
b. myelophthisic disease (carcinoma, leukemia, etc.)
c. drugs (alcohol, estrogens, thiazides)
d. cyclic thrombocytopenia
e. paroxysmal nocturnal hemoglobinuria
f. congenital thrombocytopenia with skeletal malformations
g. congenital rubella infection
The 2 major mechanisms responsible for an increased destruction of platelets.
-immune-mediated damage + removal of circulating platelets.

-intravascular platelet aggreagation
Idiopathic (Immune) Thrombocytopenic Purpura
ITP is a quantitative disorder of platelets that is caused by antibodies directed against platelet or megakaryocytic antigens.

Antiplatelet IgG, spleen.
20-40 year olds, F>M
Isolated or SLE associated.

Hemorrhages dispersed throughout body, commonly seen on mucosa or serosa.

Acute ITP: children after a viral illness, platelet count <20,000; petechiae and purpura

Chronic ITP: adults, associated with a collagen vascular disease or malignant lymphoproliferative disease. Bleeding episodes (nosebleeds, mehorrhagia, ecchymoses).
Drug-Induced Thrombocytopenia
Drugs include: quinidine, sulfonamides, penicillin, cimetidine, digoxin.

Heparin (an anticoagulant) is a common cause.

Severe and symptomatic.
Thrombotic Thrombocytopenic Purpura
A rare syndrome featuring the pentad of:
-microangiopathic hemolytic anemia
-neurologic symptoms
Hemophilia B
aka Christmas Disease

An X-linked recessive bleeding disorder that results from a deficiency of factor IX activity.

Accounts for 10% of all cases of hemophilia.
Von Willebrand Disease
The common name for a heterogenous complex of hereditary coagulation disorders related to a deficiency or abnormality of von Willebrand factor (vWf).

After endothelial injury, subendothelial vWf binds to platelet glycoprotein receptors, promoting adherence of platelets and sealing off the endothelial injury.

vWf binds to and protects factor VIII.
Vitamin K deficiency
Necessary cofactor for activation of prothrombin, factors VII, IX, and X, and the anticoagulant protein C.

Patients with liver disease: deficiency of vitamin K-dependent factors results from inadequate hepatic synthesis of the factors themselves.
Define Disseminated Intravascular Coagulation (DIC)
An acquired disorder that is characterized by consumption of platelets and coagulation factors, thereby resulting in a serious hemorrhagic diathesis.

Accompanied by widespread ischemic changes secondary to microvascular fibrin thrombi.
The central event in the initiation of DIC is....
activation of the intrinsic and extrinsic clotting cascades within the vascular compartment by tissue injury, damage to the endothelium, or both.

Procoagulant tissue factor is released into the circulation following trauma; bacterial endotoxin stimulates mac's to release tissue factor; certain neoplasms release tissue factor.

Endothelial injury plays an important role: the anticoagulant properties of the endothelium are impaired in the setting of widely varying injuries.
Clinical factors of DIC
-arterioles, capillaries, venules are occluded by MICROTHROMBI --> widespread ischemic changes.

-erythrocytes become fragmented by passing through webs of intravascular fibrin strands --> MICROANGIOPATHIC HEMOLYTIC ANEMIA.

Ischemic changes in brain --> seizures/coma

Mild azotemia, acute renal failure, acute respiratory distress syndrome may supervene, acute ulcers of GI tract may cause hemorrhage.
Chronic Myeloproliferative Syndromes
Comprise a group of interrelated, neoplastic disorders of multipotential hemopoietic stem cells.

All cell lineages are involved.

4 Subtypes:
-polycythemia vera
-chronic myelogenous leukemia
-idiopathic thrombocythemia
-myelofibrosis with myeloid metaplasia
Polycythemia Vera
A neoplastic disorder of multipotential hemopoietic stem cells in which the total body erythrocyte mass is markedly increased.

Erythroid precursor cells predominate.
Series of phases of polycythemia vera
Proliferative Phase: usually prolonged, dominated by erythroid poliferation and increased erythrocyte mass.

Spent phase: stable or decreased erythrocyte mass.

Postpolycythemic Myelofibrosis with Myeloid Metaplasia: prognosis poor

Acute Myelogenous Leukemia (AML)
Chronic Myelogenous Leukemia
A neoplastic disorder of multipotential hemopoietic stem cells that principally involves the granulocytic cell lineage.

In 2/3 of the cases, the chronic stable phase is terminated by blast crisis, either abruptly or after an accelerated phase.
Myelofibrosis with Myeloid Metaplasia (MMM)
An uncommon neoplastic proliferation of multipotential hemopoietic stem cells in which the proliferation of all hemopoietic cell lineages stimulates a reactive fibrosis of the bone marrow.
Acute Myelogenous Leukemia
Consists of a heterogenous gropu of interrelated disorders in which the neoplastic transformation of a multipotential hemopoietic stem cell results in the accumulation of granulocytes, monocytes, erythrocytes, or megakaryocytes.
Risk factors for Acute Myelogenous Leukemia
-myelotoxic agents: benzene
-radiation: doses >100 rads
-genetic abnormalities: trisomy 21
-hematologic disorders
Chronic Lymphocytic Leukemia
CLL is a neoplastic disorder that is characterized by the clonal proliferation of immunologically immature and functionally incompetent small lyphocytes.

B-cell lineage is demonstrated in >95% of cases (B-CLL).
Hairy Cell Leukemia
HCL is a type of chronic lymphocytic leukemia that is named for the membranous filamentous projections, or "hairs" on the surface of the neoplastic cells.
Acute Lymphoblastic Leukemias
ALL comprise a heterogenous group of clonal disorders of lymphopoietic stem cells that are characterized by accumulation of lymphoblasts.

Terminal deoxynucleotidyl transferase (Tdt), a nuclear DNA polymerizing enzyme, is demonstrated in almost all cases of B-ALL and T-ALL.
Subtypes of ALL (acute lymphoblastic leukemias)
-2 subtypes are composed of B-cell precursors: pre-pre-B cell ALL (L1) and pre-B cell ALL (L2).
-1 subtype composed of more mature B cells (L3).
o T-ALL (morphologically L2)
o Null Cell ALL: lack distinguishing B- or T-lymphocyte lineage markers.
Define malignant lymphomas
a heterogeneous group of solid tumors that are composed of neoplastic lymphoid cells.

Called non-Hodgkin’s lymphomas

Congenital and acquired immunodeficiency disorders are particularly associated with an increased risk for the development of aggressive B-cell immunoblastic lymphomas.
Classification of lymphomas
1) Low grade or clinically indolent
2) Intermediate grade
3) High grade or clinically aggressive
Small Lymphocytic Lymphoma
o SLL is a diffuse lymphoma in which the neoplastic cells resemble normal small lymphocytes but are immunologically incompetent.

Cells of SLL are closely related to those of CLL—only difference: presence of the adhesion molecule LFA-1
Small lymphocytic lymphoma with plasmacytoid differentiation
A diffuse lymphoma of small- to medium-size B lymphocytes that exhibit variable plasmacytoid differentiation, eccentric nuclei, and a moderate amount of purple cytoplasm and that secrete a monoclonal IgM.

Hyperviscosity syndrome

Heavy-Chain Diseases
Follicular Small Cleaved Cell Lymphoma
characterized by cohesive aggregates or follicles of neoplastic lymphocytes.

A translocation involving the long arms of chromosomes 14 and 18 is identified in every case of follicular lymphoma.

14: immunoglobulin heavy-chain locus
18: proto-oncogene bcl-2

The oncogene prevents the programmed apoptosis of B lymphocytes.
Name the intermediate-grade malignant lymphomas
-follicular large cell lymphoma
-diffuse small cleaved cell lymphoma
-diffuse, mixed, small & large cell lymphoma
-diffuse large cleaved and noncleaved cell lymphoma.
Name the high-grade malignant lymphomas
-large cell immunoblastic lymphoma
-lymphoblastic lymphoma
-diffuse small noncleaved cell lymphoma (Burkitt Lymphoma)
-Endemic Burkitt Lymphoma
-Sporadic Burkitt Lymphoma
Cutaneous T-Cell LYmphoma (Mycosis Fungoides)
CTCL is a primary lymphoma of the skin that is composed of mature, postthymic T-helper (CD4+) lymphocytes.

3 stages:
-premycotic or eczematous stage
-plaque stage: mycosis cells
-tumor stage
-sezary syndrome: the leukemic variant
Adult T-cell Leukemia/Lymphoma (ATL)
The only human cancer throught to result from a retrovirus, namely HTLV-1.
Hodgkin's Disease
HD is a unique, malignant neoplasm originated in the lymphoid tissue that features characteristic Reed-Sternberg cells in association with an appropriate cellular background.

Bimodal age distribution

most cases are neoplasms of B lymphocytes.
Classification of Hodgkin's Disease
1. lymphocyte-predominant HD
2. mixed cellularity HD
3. lymphocyte-depletion HD
4. nodular sclerosis HD
Cure rates for the different kinds of Hodgkin's disase
Lymphocyte-predominant: >90%

mixed-cellularity: 75%

lymphocyte-depletion: 40-50%

nodular sclerosis: 80-85%
Plasma Cell Neoplasia
Comprises a group of related, malignant disorders of terminally differentiated B lymphocytes (plasma cells).

-multiple myeloma: bence-jones protein
-solitary osseous myeloma
-extramedullary plasmacytoma

*M-component or paraprotein
Risk factors for plasma cell neoplasia
GEnetic predisposition

Ionizing radiation

Chronci antigenic stimulation

Chromosomal abnormalities
Hemophilia A
Factor VIII deficiency

An X-linked, recessive disorder of blood clotting that results in spontaneous bleeding, particularly into the joints, muscles, and internal organs.
Heparin-Induced Thrombocytopenia
3-5% of patients treated with unfractionated heparin

IgG autoantibodies to PF-4/heparin

Platelets activated and aggregate -> thrombosis

Tx: cease heparin
Suspect when patient has abnormal skin or mucosal bleeding, prolonged bleeding time, but normal platelet count

Drug induced: aspirin, prostaglandin -- inhibits release reaction

Hypergammaglobulinemia- coat platelets, failure to adhere.

Inherited – von Willebrand’s disease
Clinical manifestations of COAGULATION disorders
abnormal bleeding involving larger blood vessels, subcutaneous ecchymoses, hemarthroses, intramuscular hematomas, bleeding from superficial wounds delayed, bleeding time normal, PT or PTT abnormal.
ACQUIRED coagulation disorders
1.Vitamin K deficiency-prothrombin, factors VII, IX and X, normal levels of proteins (biologically inactive)

2. Liver disease- cirrhosis, decreased levels of coagulation factors, portal hypertension, congestive splenomegaly, thrombocytopenia, PT, PTT, bleeding time- all prolonged

3. Disseminated Intravascular Coagulation (DIC)
INHERITED coagulation disorders
Hemophilias – A (factor VIII) Classic, B (factor IX) Christmas disease, X linked recessive, deep bleeding –Hemarthoses – joint deformity
PTT prolonged

von Willebrand’s disease:
Autosomal dominant most common, Binds factor VIII – PTT, bleeding time prolonged
Management of dental patients with bleeding diatheses
Disease specific

Hemophilias - hematology consult, replacement therapy

von Willebrand - mild or moderate disease, DDAVP (vasopressin)

Thrombocytopenia - platelet transfusions

Any of the above - AMICAR, fibrin glue

Future - Gene therapy
List the hemostatic tests (5)
bleeding time

blood smear + platelet count

thrombin time

prothrombin time

partial thromboplastic time
Bleeding time
Hemostatic plug formation

Normal: 1-8 minutes,
assesses vascular and platelet disorders

normal in pure coagulatin defects
Abnormal thrombin time means what
low or absent fibrinogen, inhibitors of fibrinogen
Abnormal prothrombin time means what
deficiencies in factors V, VII, X, prothrombin, and fibrinogen
Abnormal thromboplastic time means what
deficiencies of factors V, VIII, IX, X, XI, XII, prothrombin and fibrinogen
Spontaneous bleeding
normal platelet count and function
normal bleeding time
normal coagulation times

easy bruising, spontaneous bleeding, bleeding NOT severe, mainly bleeding into skin and mucosa
Hereditary Hemorrhagic Telangiectasia

-Autosomal dominent- Endoglin or ALK1 gene
-abnormal dilated blood vessels
-Lesions: red macules or papules, face, chest, nasal and oral mucosa, lips, tongue, buccal, and palate
List acquired vascular defects
-local infections: vasculitis, strep, staph, fungi
-autoimmune diseases: Rheumatic Arthritis, Sjogrens syndrome, SLE
-drugs: antibiotics (penicillin), ibuprofen, NSAIDS, diuretics
-systmic amyloidosis
-Vitamin C deficiency
Petechiae and ecchymoses

Normal coagulation time

Bleeding time PROLONGED.

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