Hematopoietic Flashcards by Samantha Kennedy

Define:
Leukopenia
Granulocytopenia
Aplastic Anemia
Agranulocytosis

Leukopenia - decrease in WBC
Granulocytopenia - low granulocytes
Aplastic Anemia - deficiency in bone marrow maturation of all cell types from stem cells
Agranulocytosis - absence of neutrophils

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Neutropenia: cause

Congenital - alloimmune neonatal neutropenia, cyclic neutropenia, kostmann syndrome

Acquired - secondary to lupus, infection, drug related, radiation therapy, hematologic malignancies

Autoimmune - primary is rare

Neoplasms

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Neutropenia: mechanisms of symptom production

Because neutrophils are the first line of defence

Skin infection, ulcerative necrotizing lesions of the mouth, infection of the respiratory tract

Neutrophils elaborate proteolytic enzymes to liquefy dead cells

No signs of inflammatory response, fever assumed to be infectious in origin, absence of pus

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Infectious Mononucleosis

Self limiting lymphoproliferative disorder caused by Epstein Barr virus
Adolescents and young adults in developed countries
Persists for the life time and invades 90% of people

Spread: oral secretions, close contact, kissing, crowded conditions

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Infectious Mononucleosis: Pathogenesis

Virus penetrates nasopharyngeal, oropharengeal, and salivary epithelial cells
Spreads to underlying oropharyngeal lymphoid tissue and B lymphocytes - receptors for EBV

Infection of the B cells may kill the B cell or may incorporate into the genome
Infected cells proliferate in circulation and produce heterophil antibodies
Virus specific T cells appear as large atypical lymphocytes

Healthy persons response is to control viral shedding by limiting th number of affected cells rather than eliminating them

Infected cells disappear after recovery, but virus remains in transformed B cell and is shed in saliva

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Infectious Mononucleosis: manifestations

Insidious onset - incubation from time of expose to symptoms is 4-8 weeks
Malaise
Anorexia
Chills
 Fever
Pharyngitis
Lymphadenopathy
Enlarged lymph nodes
Hepatitis and splenomegaly are common 
Leukocytosis is common

Acute phase is 2-3 weeks

Complications - rupture of spleen, cranial nerve pansies, encephalitis, meningitis, transverse myelitis, guillain barre syndrome

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Leukemia

Malignant neoplasms of cells derived from the precursor myeloid or lymphoid tissue cells
Reversal of ratio of RBC to WBC
Immature and poorly differentiated

Longer life span
Proliferate rapidly in the blood stream
Abnormal function
Interfere with normal maturation of cells

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Leukemia: Causes

Largely unknown
Radiation exposure
Benzene
Antitumor drugs
Post chemotherapy
Genetic predisposition - Down syndrome, neruorfibromatosis

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Acute Leukemia: manifestations

Cancers of the hematopoietic progenitor cell

Low grade fever
Night sweats
Weight loss
 Infections
Bleeding and easy bruising
Lymphadenopathy
Splenomegaly and hepatomegaly 
Symptoms of depressed bone marrow 
Leukostasis - high number of circulating leukemic blast cells increasing blood viscosity
Hyperuricemia - uric acid accumulation secondary to cell death

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Acute Lymphocytic Leukemia

Common form in children
Immature lymphocytes and their progenitors that originate in bone marrow, but infiltrate spleen, lymph nodes, CNS, etc
Most of B cell origin
Over production of abnormal immune cells and decreased production of other cell types

Chromosomal aberrations dysregulate expression and function of factors of normal hematopoietic cell development

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Acute Myelocytic Leukemia

Disease of older adults
Pluripotent myeloid stem cells in bone marrow and interfere with maturation of all blood cells
Over production of abnormal erythrocytes and granulocytes with a decrease in production of all other cell types
Associated with acquired genetic alterations inhibiting terminal myeloid differentiation - bone marrow is replaced with undifferentiated blast cells
Leading to anemia, neutropenia, thrombocytopenia

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Chronic Leukemia

Affects adults
Insidious onset
Proliferation of more fully differentiated myeloid and lymphoid cells

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Chronic Lymphocytic Leukemia

B lymphocyte malignacy
Adults
Minimal symptoms or rapid and fatal

Often asymptomatic
Elevated lymphocytes
Lymphedema
Hepatosplenomegaly 
Fever
Abdominal pain
Weight loss
Progressive anemia
Thrombocytopenia
Rapid rise in lymphocyte count 
Hypogammaglobulinemia - increased susceptibility to infection

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Chronic Myelogenous Leukemia

Disorder of pluripotent hematopoietic progenitor cell
Excessive proliferation of marrow granulocytes, erythroid precursors and megakaryocytes
Cytogenetic abnormality - Philadelphia chromosome

Phases:
Chronic - slow with non specific symptoms
Leukocytosis with immature granulocytes in peripheral blood
Anemia and thrombocytopenia develop
Typically asymptomatic with splenomegaly common at dx

Short accelerated - enlargement of spleen and progressive symptoms
Feeling of abdominal fullness and discomfort
Increase in basophils count and immature cells in blood or bone marrow
Low grade fever, night sweats, bone pain, weight loss, bleeding, bruising
6-12 months

Terminal - evolution to acute leukemia
Increasing number of myeloid precursors, blast cells
Constitutional symptoms become more pronounced and splenomegaly increases significantly
Isolated infiltrates can involve skin, lymph nodes, bone, and CNS
Very high blast counts - leukostasis
Median survival 3months

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Non-Hodgkin Lymphoma

Originates in lymphatic tissue or nodes (T and B lymphocytes)

Slow growing painless lymphadenopathy
May transform into more aggressive forms of lymphoma or leukemia

Indolent:
Painless; can be isolated or widespread
Involved lymph nodes may present in the retroperiotneum, mesentry, and pelvis
Disseminated at the time of dx and bone marrow involvement is common

Aggressive:
Accompanying constitutional symptoms
Fever, drenching night sweats, weight loss
Increase susceptibility to bacterial, viral, and fungal infections associated with hypogammaglobulinemia and poor humoral antibody response NOT cellular

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Hodgkin Lymphoma

Lymph node enlargement above diaphragm
Night sweats
Pruritus
Fever
Chills
Weight loss
 Fatigue 
Anemia
Susceptibility to infection

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Multiple Myeloma:

Plasma cell dyspraxia in bone marrow and osteolytic bone lesions throughout the body
Main sites are bone and bone marrow

Abnormal proliferation of marrow plasma cells
Activation of osteoclasts leading to bone reabsorption and destruction and prone to infection due to impaired cell production

B cell malignancy of terminal differentiated plasma cells

Multiple Myeloma: manifestations

Bone reabsorption - fractures and hypercalcemia
High concentrations of paraproteins - hyperviscosity of blood
Paraprotiens breakdown into amyloid - HF and nephropathy
Myeloma nephrosis
Normal immunoglobulin depression - bacterial infections
Plasma cell tumors - bone destruction and bone pain
Anemia and suppression of cell production
Symptoms of bone marrow suppression
Weight loss and weakness

Hemostasis and coagulation cascade

Vessel Spasm
Injury to blood vessel causes vascular smooth muscle contraction to reduce blood flow
Both local and neural reflexes and local humoral factors released from platelets contributing to vasoconstriction
Formation of platelet plug
Von willebrand factor is released from endothelium and bonds to platelet receptor causes adhesion to exposed collagen
Adherence causes activation and release of ADP and TXA2 to attract more platelets leading to aggregation

3.Blood coagulation
Sequential activation of factors in blood
A) intrinsic - initiated by activation of factors XII
B) extrinsic - activated by tissue factor that is exposed on tissue injury
Both pathways lead to activation of factor X and the conversion of prothrombin II to thrombin IIa and the conversion of fibrinogen I into insoluble fibrin Ia

Clot retraction
Actin and myosin contract pulling platelets and squeezing out plasma causing shrinkage
Clot dissolution or FIbrinolysis

FIbrinolysis

Plasminogen is converted by plasminogen activators into plasmin
Plasmin digest fibrin strands and certain clotting factors
Tissue type plasminogen activator tPA - endothelial cells - active when attached to fibrin
Urokinase type plasminogen activator uPA - present in tissues - activates plasminogen in the fluid phase
Excess circulating plasmin is inactivated by a2-antiplasmin limiting fibrinolytic process to the local clot
Endothelial cells modulate coagulation and anticoagulation by releasing PA inhibitors which block FIbrinolysis and confer overal procoagulation

Coagulation Factors

Vitamin K - synthesized in liver - needed for synthesis of VII IX and X, prothrombin and proteins C and S
Calcium (factor IV) is required in all by the first two steps

Circulate as inactive factors

Hypercoaguability: Increased Platelets (thrombocytosis)

Predisposes to platelet adhesion, formation of platelet clots, and disruption of blood flow

Increase in platelet count, disturbances in blood flow, damage to vascular endothelium, increased sensitivity of platelets to factors that cause adhesion

Reactive disorder - associated with iron deficiency anemia, splenectomy, cancer, chronic inflammatory conditions

Myeloproliferative Disorders - excess platelets that predispose to thrombosis or bleeding when the rapidly produced platelets are defective
Acquired genetic anomaly, polycythemia Vera

Hypercoaguability: Increased Clotting Activity

Thrombus formation due to activation of the coagulation system can result form disorders affecting coagulation

Primary. - mutations in factor V and prothrombin predisposing to venous thrombosis and elevated prothrombin levels

Secondary - Stasi of blood and accumulation of platelets in persons with bedrest, sickle cell disease, oral contraceptives, pregnancy, malignancies

Hypercoaguability: endothelial damage

Hypercoaguability: decreased anticoagulation factors

Platelet adherence due to elevated lipids, smoking

Atherosclerotic plaques disturb blood flow causing endothelial damage and promoting platelet adherence

Hemophilia A

Mutation of factor VIII gene = defective Bleeding can be spontaneous and severe Bound to Von Willebrand Factor until an injury damages blood vessels In response to injury, coagulation factor VIII is activated and separates from vWF Active factor interacts to turn X into Xa = formation of a stable clot

Thrombocytopenia: manifestations

Decrease in the number of circulating platelets Spontaneous bleeding Bruising Purpura - cutaneous bleeding Petechiae - pin point hemorrhage

Von Willebrand Disease

Deficiency or defect in vWF = defect in platelet function and coagulation pathway Alters platelet receptors to stimulate adhesion to collagen and attraction of more platelets = platelet plug Normal platelet count Alters platelet receptors to stimulate adhesion to collagen and attraction of more platelet

Vascular Disorder Bleeding

Weak vessel walls or damage to vessel walls leads to Easy bruising Petechiae and purpura Vitamin C deficiency - poor collagen synthesis and failure of capillary beds to be cemented together Cushing - protein wasting and loss of blood vessel tissue support because of excess cortisol

Acute Disseminated Intravascular Coagulation

Activation of coagulation sequence from other disorder Massive activation leads to fibrin deposits and thrombus formation Leading to ischemia, hemolytic anemia from fragmented RBC Consumption of platelet and coagulation factors and activation of plasminogen Leads to hemorrhagic diathesis Trauma, sepsis, cancer, endothelial damages and activation of factor XII (stasis, temperature extremes, virus, infection, immune), reduced antithrombin and protein C Bleeding and microemboli

Anemia: Causes

Blood loss Hemolysis Deficient RBC production - bone marrow deficiency, lack of nutritional elements

Blood Loss Anemia: mechanisms of blood loss and manifestations

Rapid: Symptoms initially due to loss of intravascular volume, CV collapse, hypoxemia, shock Fall in RBC count caused by hemodilution resulting from movement of fluid in the vascular compartment Fatigue, altered mentation, Tachypnea, SOB ,dyspnea, tachycardia, BP changes, chest pain, oliguria, pale cool skin, cyanosis Slow/Chronic: Results from deficiency in iron with depleted iron stores Often due to GI bleeding, mensutral disorders Doesn't affect blood volume Often asymptomatic

Hemolytic Anemia: mechanisms of blood loss and manifestations

Premature destruction, retention of iron and compensatory increase in erythropoiesis Normocytic and mormochromic Intrinsic to RBC - sickle cell, thalassemia External to RBC - toxin, infection, trauma Destruction in vascular compartment - mechanical injury due to defective valves Destruction in phagocytic cells of reticuloendothelial system - within phagocytic cells of spleen and liver Fatigue, dyspnea, signs of impaired oxygen transport, jaundice, pigment gall stones, splenic sequestration

Sickle Cell Anemia

Inherited Abnormal hemoglobin leads to chronic hemolytic anemia, pain, and organ failure Mutation in the beta chain of the hemoglobin molecule with the abnormal substitution of amino acid ``` Predisposing factors African Cold Stress Physical exertion Infection Illness causing hypoxia, dehydration, acidosis ``` ``` Results in::: Chronic hemolytic anemia Blood vessel occlusion Sickle cell crisis Pulmonary infection Cerebral infection Splenic sequestering crisis ```

Deficient production of RBC: Iron deficiency Anemia

Deficiency leads to increased hemoglobin synthesis Causes Dietary deficiency, increased demands (pregnancy), blood loss Symptoms Pallor, fatiguability, dyspnea, tachycardia, brittle hair and nails, smooth tongue, sores in corner of mouth, dysphagia, decrease in acid secretion Pica - abnormal eating of ice, dirt, etc (neurological or chemical imbalance)

Deficient Production of RBC: Megaloblastic Anemia

Deficiencies in vit b12 or folic acid Causes Inflammation, neoplasms, gastric issues, dietary deficiency Vitamin B12 deficiency anemia - pernicious anemia resulting from strophic gastritis: immunologically mediated destruction of gastric mucosa preventing B12 absorption Folic acid deficiency anemia - megaloblastic RBC changes Lost in cooking, malnutrition, dietary lack, alcoholism

Relationship of folic acid and vitamin b12 to megaloblastic Anemia

Without vit b12 and folic acid DNA cannot be synthesized and nuclear maturation leading to RBC maturation and division cannot occur

Aplastic Anemia

``` Causes: Radiation, chemical, toxins Chemo Virus Idiopathic anemia ```

Chronic Diseases Associated with Anemia

Infections - AIDS, osteomyelitis Cancers Autoimmune - RA, LUpus, IBS Chronic Kidney Disease - erythropoietin deficiency

Polycythemia: manifestations

Abnormally high total RBC count with hematocrit greater than 50% Related to increases in blood volume and viscosity that lead to HTN and stagnation of blood flow

Polycythemia: relative and absolute

Relative - hematocrit rises because of loss of plasma volume without a corresponding increase in RBC Water deprivation, excess use of diuretics, GI losses Absolute - rise in hematocrit due to increase in total RBC mass

Polycythemia: primary vs secondary

Primary - Neoplastic disease of pluripotent stem cells of bone marrow charecteristics by increase in total RBC mass accompanies by elevated WBC and platelet counts Secondary - results from physiologic increase in the level of erythropoietin compensatory to hypoxia Living at high altitudes, chronic heart and lung disease, smoking, erythropoietin secreting neoplasms