Denver School of Nursing
Bio 206 / 308 – ch 19 & 20 Hemo PATH
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Chapter 19 & 20
Image Source: http://www.beliefnet.com
Source: Huether, McCance Understanding Pathophysiology 4th Ed. 2008
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Composition of blood
 90% water and 10% solutes
 6 quarts (5.5 L = “about 6 liters”)
 Plasma
▪ 55% to 60% of the blood volume
▪ Organic and inorganic elements

Chief Function
 Delivery of substances needed for cellular
metabolism
 Removal of wastes
 Defense against microorganisms and injury
 Maintenance of acid-base balance
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Composition of blood
 Plasma proteins
▪ Albumins
▪ Function as carriers and control the plasma oncotic pressure
▪ Globulins
▪ Carrier proteins and immunoglobulins (antibodies)
▪ Clotting factors
▪ Mainly fibrinogen
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Composition of blood
 Cellular components
▪ Erythrocytes
▪
▪
▪
▪
Most abundant cell in the body
Responsible for tissue oxygenation
Biconcavity and reversible deformity
120-day life cycle
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Cellular components
 Leukocytes (white blood cells)
▪ Defend the body against infection and remove
debris
▪ Granulocytes
▪ Membrane-bound granules in their cytoplasm
▪ The granules contain enzymes capable of destroying
microorganisms
▪ Inflammatory and immune functions
▪ Capable of ameboid movement (diapedesis)
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After all of your immuno studies what
blood cells would you consider to be
granulocytes??
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Granulocytes
 Neutrophils
▪ Polymorphonuclear neutrophil (PMN)
▪ Phagocytes in early inflammation
 Eosinophils
▪ Eosinophils ingest antigen-antibody complexes
▪ Induced by IgE hypersensitivity
▪ Increase in parasitic infections

Granulocytes- basophils
 Mast cells
▪ Central cell in inflammation
▪ Found in vascularized connective tissue
 Basophils
▪ Structurally and functionally similar to mast cells
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Agranulocytes
 Monocytes and macrophages make up the
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mononuclear phagocyte system (MPS)
Monocytes
Macrophages
Lymphocytes-T & B
Natural killer (NK) cells
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Platelets
 Disk-shaped cytoplasmic fragments
 Essential for blood coagulation and control
of bleeding
 Thrombopoietin
▪ Main regulator of platelets
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Spleen
 Largest secondary lymphoid organ
 Splenic pulp
▪ Masses of lymphoid tissue containing
macrophages and lymphoid tissue
 Venous sinuses
▪ Phagocytosis of old, damaged, and dead
blood cells
▪ Blood storage

Lymph nodes
 Part of the immune and hematologic
systems
▪ Facilitates maturation of lymphocytes
▪ Transports lymphatic fluid back to the circulation
▪ Cleanses the lymphatic fluid of microorganisms
and foreign particles
The MPS consists of a line of cells that
originate in the bone marrow, are
transported into the bloodstream,
differentiate into monocytes, and settle
in the tissues as mature macrophages
 Cells of the MPS ingest and destroy
microorganisms and foreign material
 The MPS is mostly the liver and spleen
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Hematopoiesis is the process of
blood cell production
Two stages
 Mitosis
▪ Mitosis stops before the cell enters the
peripheral blood
 Maturation and differentiation
 Stem
cell system
 Pluripotent stem cells
 Colony-stimulating factors
 Bone
marrow
 Also called myeloid tissue
 Red and yellow bone marrow
 Adult active bone marrow
▪ Pelvic bones, vertebrae, cranium and mandible,
sternum and ribs, humerus, and femur
Source: Huether, McCance Understanding Pathophysiology 4th Ed. 2008
Source: Huether, McCance Understanding Pathophysiology 4th Ed. 2008
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Erythrocytes are derived from
erythroblasts (normoblasts)
Maturation is stimulated by
erythropoietin
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Sequence
 Uncommitted pluripotent stem cell,
committed proerythroblast, normoblast,
basophilic normoblast,
polychromatophilic normoblast,
orthochromic normoblast, reticulocyte
(nucleus is lost), erythrocyte
 In each step the quantity of hemoglobin
increases and the nucleus decreases in
size
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Numbers of circulating red cells in
healthy individuals remain constant
The peritubular cells of the kidney
produce erythropoietin
Hypoxia stimulates the production and
release of erythropoietin

Erythropoietin causes an
increase in red cell production and
release from bone marrow
Source: googleimages.com
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Oxygen-carrying protein of the
erythrocyte
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A single erythrocyte contains as many
as 300 million hemoglobin molecules
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Two pairs of polypeptide chains
 Globulins

Four colorful iron-protoporphyrin
complexes
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Adult hemoglobin
 Two alpha chains and two beta chains
Source: Huether: Understanding Pathophysiology, 4th Edition, 2008
Source: Huether: Understanding Pathophysiology, 4th Edition, 2008
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Nutritional requirements
 Building blocks
▪ Proteins
▪ Amino acids
▪ Vitamins
▪ Vitamins B12, B6, B2, E, and C; folic acid; pantothenic acid;
and niacin
▪ Minerals
▪ Iron and copper
▪ Folate
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Iron cycle
 Total body iron is bound to heme or
stored bound to ferritin or hemosiderin
mononuclear phagocytes and hepatic
parenchymal cells
 Less than 1 mg per day is lost in the
urine, sweat, epithelial cells, or from the
gut
 Transferrin
 Apotransferrin-w/o Oxygen
Source: Huether: Understanding Pathophysiology, 4th Edition, 2008
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Aged red cells are sequestered and
destroyed by macrophages of the MPS,
primarily in the spleen
The liver takes over if the spleen is
absent
Globin chains are broken down into
amino acids
Role of B12 & Folate in RBC life span

Porphyrin is reduced to bilirubin,
transported to the liver, and secreted
in the bile

What is the most common cause of
hypocalcemia?
 What is the largest protein molecule in blood?
Source: Robbins Pathologic Basis of Disease 8th Edition 2010
Source: Huether, McCance Understanding Pathophysiology 4th Ed. 2008 (Fig 19-13)
Source: Huether, McCance Understanding Pathophysiology 4th Ed. 2008 (Fig 19-14)
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Leukocytes arise from stem cells
in the bone marrow
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Granulocytes mature in the bone
marrow
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Agranulocytes and monocytes are
released into the bloodstream before
they fully mature

Growth factors and colony-simulating
factors encourage production and
maturation of leukocytes
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Endomitosis
 The megakaryocyte undergoes the
nuclear phase of cell division but fails to
undergo cytokinesis
 The megakaryocyte expands due to the
doubling of the DNA and breaks up into
fragments
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Platelet levels are maintained by
thrombopoietin and IL-11
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Platelets circulate for 10 days
before losing their functional capacity
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Hemostasis means arrest of bleeding
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Requirements
 Platelets
 Clotting factors
 Blood flow and shear forces
 Endothelial cells
 Fibrinolysis
Virchow's Triad - Causes of Thrombosis
1) Changes in the blood vessel wall
2) Changes in blood flow
3) Changes in blood composition
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1. Vasospasm
a)Plug
b)Activate coagulation cascade
2. Initiate repair
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Platelet plug formation
 Activation – Calcium essential for
platelet activation
 Adhesion
▪ von Willebrand factor (vWF)
 Activation (Again)
 Aggregation
 Secretion  granules release…
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Platelet secretion:
Alpha granules have P-selectins on their
membranes and contain fibrinogen, fibronectin,
factors V and VIII, platelet factor 4, platelet-derived
growth factor, and TGFβ.
Delta granules, contain adenine nucleotides ADP
and ATP, ionized calcium, histamine, seratonin, and
epinephrine.
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What are the 4 most important players of
Hemostasis (A&P Review)??
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What are the 4 most important players of
Hemostasis (A&P Review)??
 Thrombinogen
 Thrombin
 Fibrinogen
 Fibrin
 Intrinsic pathway
▪ Activated when factor XII contacts subendothelial
substances exposed by vascular injury
 Extrinsic pathway
▪ Activated when tissue factor (TF) (tissue
thromboplastin) is released by damaged
endothelial cells
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Clot retraction
 Fibrin strands shorten; become denser
and stronger to approximate the edges
of the injured vessel and site of injury
 Facilitated by large numbers of platelets
within the clot and actin-like contractile
proteins in the platelets
Extrinsic Pathway
Intrinsic Pathway
Tissue/Cell Defect
Surface Contact
Collagen
FXII activator
F XII
F XIIa
F XI
Ca2+
F IX
F VIII
F VIIa
F VII
F XIa
Ca2+
F III (Tissue
Thromboplastin)
F IXa
F VIIIa
Platelet Factor 3
Factor F X
Ca2+
Factor F Xa
F Va
Prothrombin I
F XIIIa
Crosslinked
Fibrin Meshwork
Ca2+
Ca2+
Ca2+
Factor F X
FV
Thrombin
F XIII
Fibrin
polymers
Fibrin
monomers
Fibrinogen
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Lysis of blood clots
 Fibrinolytic system
▪ Plasminogen and plasmin
▪ Fibrin degradation products
▪ D-dimers
Clotting
Cascade
Fibrinogen
Fibrin
degradation products
Fibrin-clot
Plasminogen
T-PA
F XIIa
HMWK
Kallikrein
Urokinase
Streptokinase
Plasmin
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Tests of bone marrow function
 Bone marrow aspiration
 Bone marrow biopsy
 Measurement of bone marrow iron stores
 Differential cell count
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Blood tests
 Large variety of tests
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Blood cell counts increase above
adult levels at birth
 Trauma of birth and cutting the umbilical
cord

The hypoxic intrauterine environment
stimulates erythropoietin production
 Results in polycythemia

Children tend to have more atypical
lymphocytes as a result of frequent viral
infections
Source: Huether, McCance Understanding Pathophysiology 4th Ed. 2008
Source: Huether, McCance Understanding Pathophysiology 4th Ed. 2008
Source: Huether, McCance Understanding Pathophysiology 4th Ed. 2008
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Classifications
 Etiology
 Morphology
▪ Based on MCV, MCH, and MCHC values
▪ Size
▪ Identified by terms that end in “-CYTIC
▪ Macrocytic, microcytic, normocytic
▪ Hemoglobin content
▪ Identified by terms that end in “-CHROMIC
▪ Normochromic and hypochromic
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Anisocytosis
 Red cells are present in various sizes
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Poikilocytosis
 Red cells are present in various shapes
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Physiologic manifestation
 Reduced oxygen-carrying capacity
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Variable symptoms based on severity
and the ability for the body to
compensate
Classic anemia symptoms
 Fatigue, weakness, dyspnea, and
pallor
Does anyone know what this condition
of “spoon nails” is called?
Source: Huether, McCance Understanding Pathophysiology 4th Ed. 2008
Koilonychia = spooned nails
Source: Huether, McCance Understanding Pathophysiology 4th Ed. 2008
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Also termed megaloblastic anemias
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Characterized by defective DNA
synthesis
 Caused by deficiencies in vitamin B12 or
folate
▪ Coenzymes for nuclear maturation and the DNA
synthesis pathway
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Pernicious anemia
 Caused by a lack of intrinsic factor
from the gastric parietal cells
 Required for vitamin B12 absorption
 Results in vitamin B12 deficiency
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Pernicious anemia
 Typical anemia symptoms
 Neurologic manifestations
▪ Nerve demyelination
▪ Absence of intrinsic factor
 Others
▪ Loss of appetite, abdominal pain, beefy red
tongue (atrophic glossitis), icterus, and splenic
enlargement
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Pernicious anemia
 Treatment
▪ Parenteral or high oral doses of vitamin B12
Source: Lippincott Pathophysiology, Williams & Wilkins 2003
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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
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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
Source: Lippincott Pathophysiology, Williams & Wilkins 2003
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Iron deficiency anemia
 Most common type of anemia worldwide
 Nutritional iron deficiency
 Metabolic or functional deficiency
 Progression of iron deficiency causes:
▪ Brittle, thin, coarsely ridged, and spoon-shaped
nails
▪ A red, sore, and painful tongue
Source: Lippincott Pathophysiology, Williams & Wilkins 2003
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Sideroblastic anemia
 Group of disorders characterized by anemia
 Altered mitochondrial metabolism
causing ineffective iron uptake and resulting
in dysfunctional hemoglobin synthesis
 Ringed sideroblasts within the bone
marrow are diagnostic
▪ Sideroblasts are erythroblasts that contain iron
granules that have not been synthesized into
hemoglobin

Sideroblastic anemia
 Dimorphism
 Myelodysplastic syndrome
 Erythropoietic hemochromatosis
 Mito becomes not so mighty…
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Characterized by red cells that are
relatively normal in size and
hemoglobin content but insufficient in
number
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Aplastic anemia
 Pancytopenia
 Pure red cell aplasia
 Fanconi anemia
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Posthemorrhagic anemia
 Acute blood loss from the vascular space
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Hemolytic anemia
 Accelerated destruction of red blood cells
 Autoimmune hemolytic anemias
 Immunohemolytic anemia
 Warm antibody immunohemolytic anemia
 Drug-induced hemolytic anemia
 Cold agglutinin immunohemolytic anemia
 Cold hemolysin hemolytic anemia
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Sickle cell anemia
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Anemia of chronic inflammation
 Mild to moderate anemia seen in:
▪ AIDS, rheumatoid arthritis, lupus erythematosus,
hepatitis, renal failure, and malignancies
Source: Lippincott Pathophysiology,
Williams & Wilkins 2003
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Anemia of chronic inflammation
 Pathologic mechanisms
▪ Decreased erythrocyte life span
▪ Ineffective bone marrow response to
erythropoietin
▪ Altered iron metabolism
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Polycythemia
 Overproduction of red blood cells
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Relative polycythemia
 Result of dehydration
 Fluid loss results in relative increases of
red cell counts and Hgb and Hct values
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Absolute polycythemia
 Primary absolute
▪ Abnormality of stem cells in the bone marrow
▪ Polycythemia vera (PV)
 Secondary absolute
▪ Increase in erythropoietin as a normal response
to chronic hypoxia or an inappropriate response
to erythropoietin-secreting tumors
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Leukocytosis
 Leukocytosis is a normal protective
physiologic response to physiologic
stressors
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Leukopenia
 Leukopenia is not normal and not beneficial
 A low white count predisposes a patient to
infections
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Acute, self-limiting infection of Blymphocytes transmitted by saliva
through personal contact
Commonly caused by:
 Epstein-Barr virus (EBV)—85%
 B cells have an EBV receptor site
 Others viral agents resembling IM
▪ Cytomegalovirus (CMV), hepatitis, influenza, HIV

Symptoms: fever, sore throat, swollen
cervical lymph nodes, increased
lymphocyte count, and atypical
(activated) lymphocytes
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Serious complications are infrequent
(<5%)
 Splenic rupture is the most common cause
of death
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Malignant disorder of the blood and
blood-forming organs
Excessive accumulation of leukemic
cells
Acute leukemia
 Presence of undifferentiated or
immature cells, usually blast cells
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Chronic leukemia
 Predominant cell is mature but does not
function normally
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Acute lymphocytic leukemia (ALL)
Acute myelogenous leukemia (AML)
Chronic myelogenous leukemia
(CML)
Chronic lymphocytic leukemia (CLL)

Signs and symptoms of leukemia
 Anemia, bleeding purpura, petechiae,
ecchymosis, thrombosis, hemorrhage,
DIC, infection, weight loss, bone pain,
elevated uric acid, and liver, spleen, and
lymph node enlargement
chronic myelogenous leukemia (CML)
chronic myelogenous leukemia (CML)
CML accounts for about 15% of all leukemia cases in the
United States, 4,570 new cases diagnosed in 2007.
The Leukemia & Lymphoma Society estimates that over
21,500 people are living with CML. It can occur at any age,
but most often occurs in people over age 50. Only 10% of
people diagnosed with CML are under the age of 20.
Source: NIH.gov
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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 transformation of a
lymphocyte and proliferation of
lymphocytes, histiocytes, their
precursors, and derivatives in lymphoid
tissues
 Two major categories
 Hodgkin lymphoma
 Non-Hodgkin lymphomas
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Hodgkin Lymphoma
 Characterized by:
▪ 1) Progression from one group of lymph nodes to another
▪ 2) The development of systemic symptoms
▪ 3) Presence of Reed-Sternberg (RS) cells

Non-Hodgkin Lymphoma
 Characterized by two different types:
▪ 1) B-Cell Neoplasms – Includes myelomas orginating from B cells
at multiple stages of differentiation.
▪ 2) T & NK cell Neoplasms – originating from T and NK cells.
▪ Unlike HL both types lack RS cells and have different systemic symptoms
Source: Huether, McCance Understanding Pathophysiology 4th Ed. 2008
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Characterized by the presence of ReedSternberg 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
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Physical findings
 Adenopathy, mediastinal mass,
splenomegaly, and abdominal mass

Symptoms
 Fever, weight loss, night sweats, pruritus

Laboratory findings
 Thrombocytosis, leukocytosis, eosinophilia,
elevated ESR, and elevated alkaline
phosphatase
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Paraneoplastic syndromes
There are two broad types of Burkitt’s lymphoma – the sporadic and the endemic
varieties. There is a very high incidence of this disease in equatorial Africa, and disease in
this region is called endemic Burkitt’s lymphoma. Disease in other regions of the world is
much less common, and is called sporadic Burkitt’s lymphoma. Though they are the
same disease, the two forms are different in many ways.
Source: Huether, McCance Understanding Pathophysiology 4th Ed. 2008 + http://lymphoma.about.com
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Thrombocytopenia
 Platelet count <150,000/mm3
▪ <50,000/mm3—hemorrhage from minor trauma
▪ <15,000/mm3—spontaneous bleeding
▪ <10,000/mm3—severe bleeding

Essential (primary) thrombocythemia
 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 occurs

Qualitative alterations in platelet
function demonstrate an increased
bleeding time in the presence of a
normal platelet count

Platelet function disorders result from
platelet membrane glycoprotein and
von Willebrand factor deficiencies

Manifestations
 Petechiae, purpura, mucosal bleeding,
gingival bleeding, and spontaneous
bruising

Disorders can be congenital or acquired

Vitamin K deficiency
 Vitamin K is necessary for synthesis and
regulation of prothrombin, the
prothrombin factors (II, VII, IX, X), and
proteins C and S (anticoagulants)

Liver disease
 Liver disease causes a broad range of
hemostasis disorders
▪ Defects in coagulation, fibrinolysis, and
platelet number and function

Hemophilia A
-1/5000
-sex linked : Xp28
-loss of factor VIII
-female : modest reduction…X
inactivation (Lyon Hypothesis)

Hemophilia B
-loss of factor IX, Xp27…
disease

Intrinsic Pathway
-initiated: negatively charged surface
a. damaged endothelium
b. surface contact with foreign
substances
c. PTT

Extrinsic Pathway
-initiated: activation tissue thromboplastin
a. cell injury endothelium/others
b.PT
PTT = Partial Thromboplastin Time
The PTT test is used to investigate unexplained bleeding or clotting.
Specific evaluation of the coagulation factors XII, XI, IX, VIII, X, V, II
(prothrombin), and I (fibrinogen) as well as prekallikrein (PK) and high
molecular weight kininogen (HK)
PT = Prothrombin time
PT evaluates hemostasis, the process that the body uses to form blood clots
to help stop bleeding. A PT test evaluates the coagulation factors VII, X, V, II,
and I (fibrinogen).
INR
INR (International Normalized Ratio) is also used for patients on what TX??
Extrinsic Pathway
Intrinsic Pathway
Tissue/Cell Defect
Surface Contact
Collagen
FXII activator
F XII
F XIIa
F XI
Ca2+
F IX
F VIII
F VIIa
F VII
F XIa
Ca2+
F III (Tissue
Thromboplastin)
F IXa
F VIIIa
Platelet Factor 3
Factor F X
Ca2+
Factor F Xa
F Va
Prothrombin I
F XIIIa
Crosslinked
Fibrin Meshwork
Ca2+
Ca2+
Ca2+
Factor F X
FV
Thrombin
F XIII
Fibrin
polymers
Fibrin
monomers
Fibrinogen
Hemophilia A – Genetic deficiency in Clotting factor VIII
Hemophilia B – Genetic deficiency in Clotting factor IX
(Christmas Disease)
Transmission of A & B is via recessive X linked inheritance however 1/3 of cases
occur due to spontaneous mutations.
Incidence
All forms of hemophilia are relatively rare. It affects ALL racial groups and is
found worldwide.
 Estimated 10,000 individuals with Hemophila in the UK
 Hemophilia A affects 1 in 5,000 to 10,000 males in the UK
 Hemophila B affects 1 in 30,000 males in the UK
Source: National Center for Biotechnology Information - http://www.ncbi.nlm.nih.gov
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Complex, acquired disorder in which
“clotting and hemorrhage
simultaneously occur”
DIC is the result of increased
protease activity in the blood caused
by unregulated release of thrombin
with subsequent fibrin formation and
accelerated fibrinolysis
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Endothelial damage is the primary
initiator of DIC
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By activating the fibrinolytic system
(plasmin), the patient’s fibrin
degradation product (FDP) and Ddimer levels will increase
Because of the patient’s clinical state,
the disorder has a high mortality rate
Treatment is to remove the stimulus

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