Pathophysiology Lecture

Chapter 21
Alterations in Hematologic
Function
Copyright © 2017, Elsevier Inc. All rights reserved.

Anemia
 Reduction in the total number of erythrocytes

in the circulating blood or in the quality or
quantity of hemoglobin
 Impaired erythrocyte production
 Acute or chronic blood loss
 Increased erythrocyte destruction
 Combination of the above
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Anemia (Cont.)
 Classifications:
 Etiology
 Morphology
• Size
 Identified by terms that end in -cytic
 Macrocytic, microcytic, normocytic
• Hemoglobin content
 Identified by terms that end in -chromic
 Normochromic and hypochromic

Anemia (Cont.)
 Anisocytosis
 Red cells are present in various sizes
 Poikilocytosis
 Red cells are present in various shapes

Anemia (Cont.)
 Physiologic manifestation
 Reduced oxygen-carrying capacity—hypoxemia
 Variable symptoms based on severity and the
ability of the body to compensate
 Classic anemia symptoms:
 Fatigue
 Weakness
 Dyspnea
 Pallor

Macrocytic-Normochromic Anemias
 Also termed megaloblastic anemias

 Characterized by unusually large stem cells
 Result of defective DNA synthesis
 Caused by deficiencies in vitamin B12 or folate
• Coenzymes for nuclear maturation and the DNA
synthesis pathway
 Ribonucleic acid (RNA) processes occur at a
normal rate

(Cont.)
 Pernicious anemia
 Caused by a lack of intrinsic factor from the gastric
parietal cells
• Required for vitamin B12 absorption
• Results in vitamin B12 deficiency

(Cont.)
 Pernicious anemia (Cont.)
 Early symptoms nonspecific and vague
 When hemoglobin at 7-8 g/dl:
• Weakness
• Fatigue
• Paresthesias
• Difficulty walking
• Loss of appetite
• Abdominal pain
• Weight loss
• Sore tongue
 Neurologic manifestations
(Cont.)
 Pernicious anemia (Cont.)
 Treatment
• Parenteral or high oral doses of vitamin B12
• Lifelong

(Cont.)
 Folate deficiency anemia
 Absorption of folate occurs in the upper small
intestine
 Not dependent on any other factor
 Similar symptoms to pernicious anemia except
neurologic manifestations generally not seen
 Treatment requires daily oral administration of
folate

Microcytic-Hypochromic Anemias
 Characterized by red cells that are

abnormally small and contain reduced
amounts of hemoglobin
 Related to:
 Disorders of iron metabolism
 Disorders of porphyrin and heme synthesis
 Disorders of globin synthesis

(Cont.)
 Iron deficiency anemia
 Most common type of anemia worldwide
 Nutritional iron deficiency or blood loss
 Metabolic or functional deficiency
 Manifestations when serum Hgb decreased to 7 or
8 gm/dl
• Early: fatigue; weakness; shortness of breath; pale
earlobes and palms, conjunctiva

(Cont.)
 Iron deficiency anemia (Cont.)
 Progression of iron deficiency causes:
• Brittle, thin, coarsely ridged, and spoon-shaped nails
(koilonychia)
• A red, sore, and painful tongue
• Dry, sore corners of mouth (angular stomatitis)

(Cont.)
 Sideroblastic anemia
 Group of disorders characterized by anemia of
varying severity
 Presence of ringed sideroblasts in the bone
marrow
• Erythroblasts that contain iron-laden mitochondria
arranged in a circle around one third or more of the
nucleus
 Acquired sideroblastic anemias
 Reversible sideroblastic anemias
 Hereditary sideroblastic anemias
 Myelodysplastic syndrome
(Cont.)
 Sideroblastic anemia (Cont.)
 Manifestations:
• Common anemia signs/symptoms
• Hemochromatosis
• Myelodysplastic vs. sideroblastic anemia syndrome in
idiopathic

Normocytic-Normochromic Anemias
 Characterized by red cells that are relatively

normal in size and hemoglobin content but
insufficient in number

Normocytic-Normochromic Anemias
(Cont.)
 Aplastic
 Posthemorrhagic
 Acquired hemolytic
 Hereditary hemolytic
 Anemia of chronic inflammation

Myeloproliferative RBC Disorders
 Polycythemia
 Overproduction of red blood cells
 Relative polycythemia
 Result of dehydration
 Fluid loss results in relative increases of red cell
counts and Hgb and Hct values

(Cont.)
 Absolute polycythemia
 Primary absolute
• Abnormality of stem cells in the bone marrow
• Polycythemia vera (PV)
 JAK2 mutation
 Secondary absolute
• Increase in erythropoietin as a normal response to
chronic hypoxia or an inappropriate response to
erythropoietin-secreting tumors

(Cont.)
 Polycythemia vera
 Abnormal, uncontrolled proliferation of RBCs,
WBCs, and platelets
 Insidious
 Manifestations due to increased red cell mass and
hematocrit
• Increased blood viscosity
• Hypercoagulopathy

Myeloproliferative Disorders
 Iron overload
 Hereditary hemochromatosis
 Autosomal recessive disorder of iron metabolism

1. Which of the following is characteristic of the
megaloblastic anemias?
A. Small cell size

B. Decreased thickness
C. Presence of macrocytes
D. Caused by increased folate

Alterations of Leukocyte Function
 Quantitative disorders:
 Increases or decreases in cell numbers
 Bone marrow disorders or premature destruction
of cells
 Response to infectious microorganism invasion

Quantitative Alterations of
Leukocytes
 Leukocytosis
 Leukocytosis is a normal protective physiologic
response to physiologic stressors, such as
infectious microorganisms
 Leukopenia
 Leukopenia is not normal and not beneficial
 A low white count predisposes a patient to
infections

Granulocytosis (Neutrophilia)
 Neutrophilia is evident in the first stages of an

infection or inflammation
 If the need for neutrophils increases beyond
the supply, immature neutrophils are released
into the blood

Granulocytosis (Neutrophilia) (Cont.)
 This premature release is detected in the

manual WBC differential and is termed a shift
to the left
 When the population returns to normal, it is
termed a shift to the right

Neutropenia
 Reduction in circulating neutrophils

 Causes:
 Prolonged severe infection
 Decreased production
 Reduced survival
 Abnormal neutrophil distribution and sequestration

Granulocytopenia (Agranulocytosis)
 Causes:
 Interference with hematopoiesis
 Immune mechanisms
 Chemotherapy destruction
 Ionizing radiation

Eosinophilia
 Increase in circulating eosinophils

 Hypersensitivity reactions trigger the release
of eosinophilic chemotactic factor of
anaphylaxis from mast cells
 Increased in allergic disorders
 Increased in parasitic invasions

Eosinopenia
 Decrease in circulation numbers of

eosinophils
 Usually caused by migration of cells to
inflammatory sites
 Other causes:
 Surgery
 Shock
 Trauma
 Burns
 Mental distress
Basophils
Basophilia Basopenia
 Increase in circulating  Decrease in circulating
basophils numbers of basophils

 Response to  Occurs in acute
inflammation and infections,

hypersensitivity reactions hyperthyroidism, and
 Seen in myeloproliferative long-term steroid therapy
disorders

Monocytes
 Monocytosis
 Poor correlation with disease
 Usually occurs with neutropenia in later stages of
infections
 Monocytes are needed to phagocytize organisms
and debris
 Monocytopenia
 Very little known about this condition

Lymphocytes
Lymphocytosis Lymphocytopenia
 Increase in the number or  Decrease in the number
proportion of lymphocytes of circulating lymphocytes

in the blood in the blood
 Acute viral infections  Immune deficiencies
 Epstein-Barr virus  Drug destruction
 Viral destruction
 Radiation

2. Which of the following terms best describes
a higher-than-normal white blood cell count?
A. Neutrophilia
B. Leukopenia
C. Leukocytosis
D. Granulocytosis

Infectious Mononucleosis
 Acute, self-limiting infection of B lymphocytes

transmitted by saliva through personal
contact
 Commonly caused by the Epstein-Barr virus
(EBV)—85%
 B cells have an EBV receptor site
 Others viral agents resembling IM:
• Cytomegalovirus (CMV)
• Hepatitis
• Influenza
• HIV
Infectious Mononucleosis (Cont.)
 Symptoms:
 Fever
 Sore throat
 Swollen cervical lymph nodes
 Increased lymphocyte count
 Atypical (activated) lymphocytes
 Serious complications are rare

 Splenic rupture is the most common cause of
death

Infectious Mononucleosis (Cont.)
 >50% lymphocytes and at least 10% atypical

lymphocytes
 Diagnostic test
 Monospot qualitative test for heterophilic
antibodies
 Treatment: symptomatic

Leukemias
 Malignant disorder of the blood and blood-

forming organs
 Excessive accumulation of leukemic cells
 Pancytopenia if cells crowd bone marrow
 Acute leukemia
 Presence of undifferentiated or immature cells,
usually blast cells
 Chronic leukemia
 Predominant cell is mature but does not function
normally
Leukemias (Cont.)
 Signs and symptoms of leukemia

 Fatigue  Liver, spleen, and lymph
 Bleeding node enlargement
• Petechiae  Infections
• Ecchymosis  Neurologic
 Fever manifestations
 Weight loss
 Bone pain
 Elevated uric acid

Acute Leukemias
 Acute lymphocytic leukemia (ALL)

 Too many lymphoblasts
 Mostly occurs in children
 Acute myelogenous leukemia (AML)

 Too many myeloblasts
 Most common adult leukemia
 Manifested by bone marrow depression
signs/symptoms, fever, anorexia, and
neurologic symptoms
 Treated with chemotherapy
Chronic Leukemias
 Chronic myelogenous leukemia (CML)

 Too many blood cells made in bone marrow
 Chronic lymphocytic leukemia (CLL)
 Too many immature lymphocytes
 Most common adult leukemia in western world
 Slow progression
 Lymphadenopathy

Lymphadenopathy
 Enlarged lymph nodes that become palpable

and tender
 Local lymphadenopathy
 Drainage of an inflammatory lesion located near
the enlarged node
 General lymphadenopathy
 Occurs in the presence of malignant or
nonmalignant disease

Malignant Lymphomas
 Diverse group of neoplasms that develop

from the proliferation of malignant
lymphocytes in the lymphoid system
 REAL classification
 Two major categories:
 Hodgkin lymphoma
 Non-Hodgkin lymphoma

Hodgkin Lymphoma
 Characterized by the presence of Reed-

Sternberg cells in the lymph nodes
 Reed-Sternberg cells are necessary for diagnosis,
but they are not specific to Hodgkin lymphoma
 Classical Hodgkin lymphoma
 Nodular lymphocyte predominant Hodgkin
lymphoma

Hodgkin Lymphoma (Cont.)
 Physical findings
 Adenopathy, mediastinal mass, splenomegaly,
and abdominal mass
 Symptoms
 Fever, weight loss, night sweats, pruritus
 Adult Hodgkin lymphoma can usually be
cured with early diagnosis and treatment
 Chemotherapy
 Radiation
 Surgery

Non-Hodgkin Lymphoma
 Generic term for a diverse group of

lymphomas
 New classification based on cell type
(T, B, NK)
 Differentiated based on etiology, unique
features, and response to therapies

Non-Hodgkin Lymphoma (Cont.)
 Non-Hodgkin lymphomas are linked to

chromosome translocations
 Risk factors include being older, male, or
white, having certain immune disorders,
HIV/AIDS, immunosuppression, a variety of
environmental exposures, certain viruses,
and a diet high in meats and fat

Burkitt Lymphoma
 Most common type of non-Hodgkin

lymphoma in children
 Burkitt lymphoma is a very fast-growing tumor
of the jaw and facial bones
 All endemic Burkitt lymphomas are latently
infected with EBV

Lymphoblastic Lymphoma (LL)
 Clone of immature T cells that become

malignant in the thymus
 Painless lymphadenopathy of the neck,
possible chest (mediastinal mass)

Multiple Myeloma (MM)
 Malignant proliferation of plasma cells

 Infiltrate bone marrow and aggregate into
tumor masses in skeletal system
 M-proteins
 Bence Jones protein
 Hypercalcemia, renal failure, bone lesions

Alterations of Splenic Function
 Splenomegaly
 Hypersplenism
 Congestive splenomegaly
 Infiltrative splenomegaly

Disorders of Platelets
 Thrombocytopenia
 Platelet count <150,000/mm3
• <50,000/mm3: hemorrhage from minor trauma
• <15,000/mm3: spontaneous bleeding
• <10,000/mm3: severe bleeding

Disorders of Platelets (Cont.)
 Thrombocytopenia (Cont.)
 Causes:
• Hypersplenism
• Autoimmune disease
• Hypothermia
• Viral or bacterial infections that cause disseminated
intravascular coagulation (DIC)
• Heparin-induced thrombocytopenia (HIT)

 Heparin-induced thrombocytopenia (HIT)

 IgG antibodies target heparin-platelet factor 4
complex
 Typically causes 50% drop in platelet count

 Immune (idiopathic) thrombocytopenic

purpura (ITP)
 The chronic form has IgG autoantibody that
targets platelet glycoproteins
• Antibody-coated platelets are sequestered and removed
from the circulation
 The acute form of ITP that often develops after a
viral infection is one of the most common
childhood bleeding disorders

 Immune (idiopathic) thrombocytopenic

purpura (ITP) (Cont.)
 Manifestations:
• Petechiae and purpura
• Progressing to major hemorrhage

 Thrombotic thrombocytopenic purpura (TTP)

 A thrombotic microangiopathy
• Platelets aggregate, form microthrombi, and cause
occlusion of arterioles and capillaries
 Chronic relapsing TTP
 Acute idiopathic TTP

 Essential (primary) thrombocythemia

(thrombocytosis)
 Thrombocythemia is characterized by platelet
counts >400,000/mm3
 Myeloproliferative disorder of platelet precursor
cells
• Megakaryocytes in the bone marrow are produced in
excess
 Microvasculature thrombosis or hemorrhage
occurs

Alterations of Platelet Function
 Qualitative alterations in platelet function

demonstrate an increased bleeding time in
the presence of a normal platelet count
 Manifestations:
 Petechiae
 Purpura
 Mucosal bleeding
 Gingival bleeding
 Disorders can be congenital or acquired

Alterations of Coagulation
 Vitamin K deficiency
 Vitamin K is necessary for synthesis and
regulation of prothrombin, the procoagulant factors
(VII, XI, X), and proteins C and S (anticoagulants)
 Liver disease
 Liver disease causes a broad range of hemostasis
disorders:
• Defects in coagulation
• Fibrinolysis
• Platelet number and function

Disseminated Intravascular
Coagulation (DIC)
 Complex, acquired disorder in which clotting
and hemorrhage simultaneously occur
 Possible cause
 DIC is the result of increased protease activity in
the blood caused by unregulated release of
thrombin with subsequent fibrin formation and
accelerated fibrinolysis

Coagulation (DIC) (Cont.)
 Endothelial damage/tissue factor is the
primary initiator of DIC
 Sepsis is the most common condition
associated with DIC
 Usually gram negative

 Results from abnormally widespread and
ongoing activation of clotting in small and
midsize vessels that alter the microcirculation,
leading to ischemic necrosis in various
organs, particularly the kidney and lung
 Can be caused by the imbalance between the
coagulant system and the fibrinolytic system

 Widespread deposition of fibrin in the
microcirculation that leads to ischemia,
microvascular thrombotic obstruction, and
organ failure
 Involves both widespread clotting and
bleeding because of simultaneous
procoagulant activation, fibrinolytic activation,
and consumption of platelets and coagulation
factors that results directly in serious bleeding

 Clinical signs and symptoms demonstrate
wide variability:
 Bleeding from venipuncture sites
 Bleeding from arterial lines
 Purpura, petechiae, and hematomas
 Symmetric cyanosis of the fingers and toes

Thromboembolic Disorders
 Arterial or venous thrombi

 Virchow triad
• Injury to vessel
• Abnormal blood flow
• Hypercoagulopathy

Hereditary Thrombophilias
 Most autosomal dominant

 Increase risk of thrombosis
 More than 100 different known mutations

Acquired Hypercoagulability
 Deficiencies in proteins S and C and AT III

 Antiphospholipid syndrome

3. Thrombocytopenia commonly is seen with
which condition?
A. Multiple myeloma
B. Hemolytic anemia
C. Non-Hodgkin lymphomas
D. Disseminated intravascular coagulation
(DIC)

Case Study
 A 63-year-old woman with diabetes notes that she has a

general feeling of tiredness and a loss of appetite. For
several months, while on her daily 2-mile walks, she has
heard her heartbeat in her ears as a whooshing sound.
Very knowledgeable about her disease and compliant with
diet and medications, she waits until she sees her
endocrinologist for her yearly examination. In the office,
she explains her symptoms, and the physician collects a
CBC in addition to normal diabetic laboratory tests. The
results indicate an anemia, and she is referred to a
hematologist. The hematologist reviews her laboratory
findings and begins to explain her diagnosis of
megaloblastic anemia.

Case Study
Discussion Question
 Further testing indicates that the woman
suffers from a vitamin B12 deficiency or PA.
This condition is often associated with:
A. Chronic gastritis
B. Thalassemia
C. Excessive blood loss
D. Inadequate dietary intake

Case Study
 The woman is treated with replacement cobalamin (vitamin B12)

over several weeks until the deficiency is corrected. Monthly
injections for the remainder of the woman’s life are explained,
and she acknowledges the importance of treatment. One year
later, the hematologist sees the woman for follow-up laboratory
testing. The woman again complains of fatigue. Part of her
health screening indicates that she has elevated serum iron and
ferritin levels. Confused, the hematologist reviews her
medications. She states that she has been taking several iron
supplements and a multivitamin with iron daily after reading
online that anemia should be treated with iron administration.
Discussion with her friends further convinced her that iron was
the treatment of choice for anemia. The physician again
explains the patient’s initial diagnosis and now informs the
woman that she additionally suffers from secondary iron
overload. Copyright © 2017, Elsevier Inc. All rights reserved. 72
Case Study
Discussion Question
 The treatment for iron overload is:
A. Vitamin C supplements
B. Phlebotomy
C. Aspirin
D. Plasmapheresis

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Chapter 21

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 Reduction in the total number of erythrocytes

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 Also termed megaloblastic anemias

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 Characterized by red cells that are

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 Characterized by red cells that are relatively

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A. Small cell size

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 Neutrophilia is evident in the first stages of an

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 This premature release is detected in the

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 Reduction in circulating neutrophils

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 Increase in circulating eosinophils

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 Decrease in circulation numbers of

basophils numbers of basophils

inflammation and infections,

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proportion of lymphocytes of circulating lymphocytes

 Epstein-Barr virus  Drug destruction

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 Acute, self-limiting infection of B lymphocytes

 Serious complications are rare

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 >50% lymphocytes and at least 10% atypical

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 Malignant disorder of the blood and blood-

 Signs and symptoms of leukemia

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 Acute lymphocytic leukemia (ALL)

 Acute myelogenous leukemia (AML)

 Chronic myelogenous leukemia (CML)

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 Enlarged lymph nodes that become palpable

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 Diverse group of neoplasms that develop

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 Characterized by the presence of Reed-

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