Diseases of Blood Cells. Back to Basics Blood is a liquid tissue A mixture of cells and water The...

Diseases of Blood Cells

Back to Basics

• Blood is a liquid tissue• A mixture of cells and water• The water contains

• Protein, glucose, cholesterol, calcium, hormones, metabolic waste and hundreds of other substances

• Plasma is the liquid portion of the blood containing the blood clotting protein Fibrinogen

• Serum is the fluid remaining after the blood clots• Does not contain Fibrinogen

plasma (55%)

red blood cells(5-6-million /ml)

white blood cells

(5000/ml)platelets

Plasma

liquid part of blood

plasma transports:- soluble food

molecules waste products hormones antibodies

Production of Erythrocytes

• Hematopoiesis – blood cell formation• Occurs in the red bone marrow (myeloid tissue)

• Axial skeleton and girdles• Epiphyses of the humerus and femur• Marrow contains immature erythrocytes• Composed of reticular connective tissue

• Hemocytoblasts give rise to ALL formed elements • Lymphoid stem cells - give rise to lymphocytes• Myeloid stem cells - give rise to all other blood cells

Production of Erythrocytes: Erythropoiesis

Production of Erythrocytes: Erythropoiesis

• A hemocytoblast is transformed into a committed cell called the proerythroblast

• Proerythroblasts develop into early erythroblasts• The developmental pathway consists of three phases

• Phase 1 – ribosome synthesis in early erythroblasts• Phase 2 – hemoglobin accumulation in late erythroblasts and

normoblasts• Phase 3 – ejection of the nucleus from normoblasts and

formation of reticulocytes• Reticulocytes then become mature erythrocytes

• Reticulocytes make up about 1 -2 % of all circulating erythrocytes

• Circulating erythrocytes – the number remains constant and reflects a balance between RBC production and destruction• Too few red blood cells leads to tissue hypoxia• Too many red blood cells causes an undesirable

increase in blood viscosity• Erythropoiesis is hormonally controlled and depends on

adequate supplies of iron, amino acids, and B vitamins

Regulation and Requirements for Erythropoiesis

Hormonal Control of Erythropoiesis

• Erythropoietin (EPO) released by the kidneys is triggered by:• Hypoxia due to decreased RBCs• Decreased oxygen availability• Increased tissue demand for oxygen

• Enhanced erythropoiesis increases the: • RBC count in circulating blood• Oxygen carrying ability of the blood

Erythropoietin MechanismImbalance

Reduces O2 levels in blood

Erythropoietin stimulates red bone marrow

Enhanced erythropoiesis increases RBC count

Normal blood oxygen levels Stimulus: Hypoxia due to decreased RBC count, decreased availability of O2 to blood, or increased tissue demands for O2

Imbalance

Start

Kidney (and liver to a smaller extent) releases erythropoietin

Increases O2-carrying ability of blood

• Erythropoiesis requires:• Proteins, lipids, and carbohydrates• Iron, vitamin B12, and folic acid

• The body stores iron in Hb (65%), the liver, spleen, and bone marrow

• Intracellular iron is stored in protein-iron complexes such as ferritin and hemosiderin

• Circulating iron is loosely bound to the transport protein transferrin

Dietary Requirements of Erythropoiesis

Plateletsif you get cut:- platelets produce tiny fibrin threads these form a web-

like mesh that traps

blood cells. these harden

forming a clot, or "scab."

150,000 to 400,000 per mm3

Thrombopoiesis

• Thrombocytes or platelets• Derived from the megakaryocyte

• Thrombopoietin • Formed in the liver and is similar to erythorpoeitin

• Megakaryocytes fragment to form platelets• The spleen takes up about 1/3 of the platelets

• Forms red plulp

Figure 17.9

Hemostasis

= Opposite of hemorrhage stops bleeding

Too little hemostasis too much bleeding

Too much hemostasis thrombi / emboli

Three major steps:1. Vasoconstriction2. Platelet plug Temporarily blocks the hole

1. Platelet-derived cytokines further the process

3. Coagulation cascade (= clot formation seals hole until tissues repaired)1. Two pathways: Extrinsic and Intrinsic

4. After vessel repair, plasmin dissolves the clot

Steps of Hemostasis

Vessel damage exposes collagen fibers

Platelets adhere to collagen & release factors

local vasoconstriction & platelet aggregation

+ feedback loop

platelet plug formation decreased blood flow

Steps of Hemostasis cont.1. Two coagulation pathways converge onto common

pathway1. Intrinsic Pathway. Collagen exposure. All factors needed are

present in blood. Slower. 2. Extrinsic Pathway. Uses Tissue Factors released by injured cells

and a shortcut.

2. Usually both pathways are triggered by same tissue damaging events.

3. The different factors can be subject to a variety of problems

1. Hemophilia2. Hypercoagulable states

Vit K needed for synthesis of several clotting factors

The Role of the Platelet

• VIII – Von Willebrand Factor• vWF can bind to exposed collagen and also to

receptors on the surface of platelets• Platelets are delivered to the damage site and bind to

vWF = platelet activation• Platelet Plug

• Platelets expose receptors• Degranulation – release of ADP to promote platelet

activation (pa)

• Releases Thromboxane A2 to promote pa

Structure of Blood Clot

SEM x 4625

Plasmin, trapped in clot, will dissolve clot by fibrinolysis

Clot formation limited to area of injury: Intact endothelial cells release anticoagulants (heparin, antithrombin III, protein C).

An Electronmicrograph of a Platelet

Clot Busters & Anticoagulants

Dissolve obsolete or unwanted clots

Enhance fibrinolysis

Examples: Urokinase, Streptokinase & t-PA

Prevent coagulation by blocking 1 or more steps in fibrin forming cascade

Inhibit platelet adhesion plug prevention

Examples:

Coumadin (warfarin) blocks Vit K

EDTA chelates Ca2+

Aspirin prevents platelet plug

The Fibrinolytic System

• tPA – tissue plasminogen activator• Activates plasminogen to become plasmin• Plasmin is a proteolytic enzyme

• Degrades fibrinogen, fibrin and several clotting factors

Bleeding Disorders - Terminology

• Petechiae • Pinpoints of hemorrhage seen in the skin, or in a

post-mortem organ section, such as the brain• Purpura

• Larger and sometimes less-regular areas of bleeding in the skin

• Ecchymoses• Still larger (over 2cm) areas of bleeding

• Commonly called bruises• Hematoma

• A large volume of blood trapped in a soft tissue

Petechial Hemorrhages on the Heart found when a coagulopathy is due to a low platelet count. They can also appear following sudden hypoxia.

Ecchymoses are larger than petechiae. In between in size are hemorrhages called purpura.

A localized collection of blood outside the vascular system within tissues is known as a hematoma

Platelet Disorders - Thrombocytopenia

• The inability to mount an adequate hemostatic response• Insufficient platelets

• Under 100,000 mm3

• May result from marrow suppression due to:• Thiazide diuretics, certain anticibiotics, chronic

alcohol abuse, tumor metastases, and dietary deficiencies of folic acid and vitamin B12

• Idiopathic Thrombocytopenia Purpura• Autoimmune disorder

• Petechiae, purpura, often arises after a viral infection

Genetic Clotting Factor Disorders

• Von Willebrand’s Disease• Interferes with platelet binding to the subendothelial

surfaces• Autosomal dominant inheritance• Recurring bouts of gastric and intestinal bleeding• Excessive menstrual hemorrhage

• Transfusion of vWF• Hemophilia

• Defects of factor VIII – Hemophilia A• Defect of factor IX – Hemophilia B

• Both found on X chromosome

Hemophilia and Acquired Clotting Factor Disorders

• Hemophiliacs suffer from bleeding into the larger weight-bearing joints• Ankylosis

• Impaired Hepatic Synthesis• Deficiency of vitamin K

• Produced in the colon by e.coli• Lipid-soluble and absorbed in the bile

• Liver damage may decrease vit K in the blood

Hemophilia• It is sometimes called Christmas disease after

Stephen Christmas, the first patient described with this disease. In addition, the first report of its identification was published in the Christmas edition of the British Medical Journal.

• In more recent history, royal watchers know that Queen Victoria of Britain's son Leopold had hemophilia, and that two of her daughters, Alice and Beatrice, were carriers of the gene. Through them, hemophilia was passed to the royal families in Spain and Russia, leading to one of the most famous young men with the disease, Tsar Nicholas II's only son Alekei.

Erythrocytes (RBCs)• Biconcave disc

• Folding increases surface area (30% more surface area)• Plasma membrane contains spectrin

• Give erythrocytes their flexibility• Anucleate, no centrioles, no organelles

• End result - no cell division• No mitochondria means they generate ATP anaerobically

• Prevents consumption of O2 being transported• Filled with hemoglobin (Hb) - 97% of cell contents

• Hb functions in gas transport• Hb + O2 HbO2 (oxyhemoglobin)

• Most numerous of the formed elements• Females: 4.3–5.2 million cells/cubic millimeter• Males: 5.2–5.8 million cells/cubic millimeter

Erythrocytes (RBCs)

Figure 17.3

Erythrocyte Function• Erythrocytes are dedicated to respiratory gas

transport• Hemoglobin reversibly binds with oxygen and

most oxygen in the blood is bound to hemoglobin

• Composition of hemoglobin• A protein called globin

• made up of two alpha and two beta chains• A heme molecule

• Each heme group bears an atom of iron, which can bind to one oxygen molecule

• Each hemoglobin molecule thus can transport four molecules of oxygen

Structure of Hemoglobin

Figure 17.4

Hemoglobin

• Oxyhemoglobin – hemoglobin bound to oxygen• Oxygen loading takes place in the lungs

• Deoxyhemoglobin – hemoglobin after oxygen diffuses into tissues (reduced Hb)

• Carbaminohemoglobin – hemoglobin bound to carbon dioxide

• Carbon dioxide loading takes place in the tissues

Life Cycle of Red Blood Cells

Fate and Destruction of Erythrocytes

• The life span of an erythrocyte is 100–120 days• Travels about 750 miles in that time (LA to

Albuquerque)

• Old erythrocytes become rigid and fragile, and their hemoglobin begins to degenerate

• Dying erythrocytes are engulfed by macrophages

• Heme and globin are separated • Iron is removed from the heme and salvaged for

reuse• Stored as hemosiderin or ferritin in tissues• Transported in plasma by beta-globulins as transferrin

Fate and Destruction of Erythrocytes

• Heme is degraded to a yellow pigment called bilirubin• Liver secretes bilirubin into the intestines as bile• Intestines metabolize bilirubin into urobilinogen • Urobilinogen leaves the body in feces, in a pigment

called stercobilin

• Globin is metabolized into amino acids which are then released into the circulation

Laboratory Assessment of Blood Cells• Complete Blood Count (CBC) includes

• White Blood Cell Count (WBC)• Red Blood Cell Count (RBC)• Percentage of white cells that are neutrophils,

eosinophis or basophils (white cell differential count)• Amount of hemoglobin• Hematocrit

• Percent of blood volume occupied by red blood cells

ERYTHROCYTE DISORDERS

• Polycythemia• Abnormal excess of erythrocytes

• Increases viscosity, decreases flow rate of blood

• Anemia• Abnormally low hemoglobin in blood

• Caused by decreased numbers of RBC’s, decreased amount of hemoglobin in RBC’s, or both

Erythrocyte Disorders

ANEMIA

• Hemoglobin level falls below normal range: • 14-18 g/dl for males and 12-16 g/dl for females

• Signs and symptoms of hypoxia• Pallor, weakness, lethargy, and exercise intolerance• May affect cardiac rhythms and cause hepatic

necrosis

Red Blood Cell Indices• Mean Corpuscular Volume (MCV)

• Average size of a RBC • Mean Cell Hemoglobin (MCH)

• Average amount of hemoglobin per RBC• Mean Corpuscular Hemoglobin Concentration (MCHC)

• Average concentration of hemoglobin in all RBCs

Red Cell Indices Used to Diagnose Disease• Macrocytic

• Red Blood Cells may be too large• Microcytic

• Red Blood Cells may be too small• Normocytic

• Red Blood Cells are normal size• Normochromic

• Normal amount of hemoglobin• Hypochromic

• Too little hemoglobin

Anemia

Production? Survival/Destruction?

?

Causes of Anemia

Decreased erythrocyte production

• Decreased erythropoietin production

• Inadequate marrow response to erythropoietin

Erythrocyte loss

• Hemorrhage

• Hemolysis

Impaired Erythocyte Production

• Iron Deficiency• Erythrocytes are small (microcytic) and deficient in

hemoglobin (hypochromic)• Low MCV and MCHC values

• Vitamin B12 Deficiency (cobalamin)

• Vit B12 is required for normal DNA synthesis

• May be due to decreased intrinsic factor (IF)• Mitosis in the marrow progenitor lines is suppressed

• RBCs are macrocytic, normochromic• Increased MCV and normal MCHC

Pernicious Anemia

• Pernicious anemia is a decrease in red blood cells that occurs when the body cannot properly absorb vitamin B12 from the GI Tract

• Common causes include:• Weakened stomach lining (atrophic gastritis)• The body's immune system attacking the cells that

make intrinsic factor (autoimmunity against gastric parietal cells) or intrinsic factor (IF) itself

Symptoms

• Diarrhea or constipation• Fatigue• Loss of appetite• Pale skin• Shortness of breath, mostly during exercise• Swollen, red tongue or bleeding gums• Neuropathy

Folic Acid Deficiency

• Produces a megaloblastic anemia similar to cobalamin deficiency• No neuropathy• Due to poor diet/high-demand states

Hemolytic Anemia – RBC Destruction

• Hemolytic anemias are either acquired or congenital.• Hemolytic anemia is a condition in which there are not

enough RBCs in the blood• Due to premature RBC destruction-hemolysis

• Hemolytic anemia can result from: • infection • certain drugs• autoimmune disorders in which the body attacks and

destroys its own red blood cells – abnormal amounts of hemoglobin-Hemoglobinopathies

• Sickle Cell Anemia• Thalassemia

Symptoms of Hemolytic Anemia• Dark Urine• Enlarged spleen• Fatigue• Fever• Pale skins color• Rapid heart rate• Shortness of breath• Yellow skin color (jaundice)• Chills

Sickle Cell Anemia• Normal hemoglobin - HbA• Abnormal hemoglobin - HbS• Single base pair mutation results in a single amino acid

change.• Under low oxygen, HgS becomes insoluble forming long

polymers• Distorts the cell which becomes less flexible and

leads to membrane changes (“sickling”) and vasoocclusion

Sickle Cell Mutation

+O2

-O2

+O2

-O2

5'

3'Chromosome 16

5' 3'Chromosome 11 G A

CCT GAG GAG

-Pro-Glu-Glu-5 6 7

CCT GTG GAG

-Pro-Val-Glu-5 6 7

A S

Normal (HbA) Abnormal (HbS)

*

Red Blood Cells from Sickle Cell Anemia

OXY-STATE DEOXY-STATE

• Deoxygenation of HbS erythrocytes leads to intracellular hemoglobin polymerization, loss of deformability and changes in cell morphology.

Sickle Cell Anemia

• Cells get stuck in the microcirculation• Obstructs flow and

causes ischemic injury

• Sickle cells have a life span of 20 days• Leads to chronic

anemia

• Sickle Cell Crisis:• Acute sickling

episodes that block flow, pose threat of widespread ischemia and organ damage

• Pain is due to bone necrosis caused by blood vessel occlusion

Thalassemia

• Genetic defect in hemoglobin synthesis• synthesis of one of the 2 globin chains ( or )• Imbalance of globin chain synthesis leads to depression of

hemoglobin production and precipitation of excess globin (toxic)

• “Ineffective erythropoiesis”• Ranges in severity from asymptomatic to incompatible with

life (hydrops fetalis)• Found in people of African, Asian, and Mediterranean

heritage

• Dx:• Microcytic/Hypochromic, misshapen RBCs• -thalassemia will have an abnormal Hgb

electrophoresis (HbA2, HbF)

• Fe stores are usually elevated

Thalassemias

Alpha Thalassemia

Thalassemia• The oxygen depletion in the

body becomes apparent within the first 6 months of life.

• If left untreated, death usually results within a few years.

• Note the small, pale (hypochromic), abnormally-shaped red blood cells. The darker cells likely represent normal RBCs from a blood transfusion.

Thalassemia• The only treatments are stem cell transplant and simple

transfusion.• Chelation therapy to avoid iron overload has to be

started early.

Polycythemia

• Primary absolute polycythemia• Marrow stem cell lines proliferate without an

increased EPO• Benign tumor of the marrow

Polycythemia

• Absolute polycythemia (Secondary)• Increased red cell concentration in the blood with

normal plasma volume• Overproduction of erythrocytes by the bone

marrow• Elevated EPO

• May be due to elevation, renal tumors, renal hypoxia due to restricted blood flow

Polycythemia

• Relative polycythemia• Normal RBC numbers suspended in a reduced

plasma volume• Dehydration• Extensive skin burns• Diarrhea or diuresis• Pregnancy

• Used to be referred to as “Preleukemia”• Most commonly in the elderly.

• Occurs when something goes wrong in your bone marrow

Marrow Production - Myelodysplasia

Signs and Symptoms of Myelodysplasia

• Fatigue• Shortness of breath• Unusual paleness (pallor) due to anemia• Easy or unusual bruising or bleeding• Pinpoint-sized red spots just beneath your skin caused

by bleeding (petechiae)• Frequent infections

Causes

• Caused by poorly formed or dysfunctional blood cells due to either• Unknown causes• Chemical exposure

• Myelophthisic anemia is a normocytic-normochromic anemia that occurs when normal marrow space is infiltrated and replaced by nonhematopoietic or abnormal cells.

• Causes:• Most often due to replacement of the bone marrow by

metastatic cancers such as breast or prostate; less often, kidney, lung, adrenal, or thyroid.

• Marrow fibrosis often occurs. • Splenomegaly may develop.

Marrow Production - Myelophthisic

Marrow Production - Aplastic Anemia

The body stops producing enough new blood cells. • Signs and symptoms may include:

• Fatigue• Shortness of breath with exertion• Rapid or irregular heart rate• Pale skin• Frequent or prolonged infections• Unexplained or easy bruising• Nosebleeds and bleeding gums• Prolonged bleeding from cuts• Skin rash• Dizziness• Headache

NORMAL BONE MARROW

Here we see a sample of bone marrow in a patient with Aplastic Anemia. Notice there are very few cells except for the fat cells

Factors that can temporarily or permanently injure bone marrow and affect blood cell production include:

Acquired• Radiation and chemotherapy treatments• Exposure to toxic chemicals. • Exposure to benzene• Use of certain drugs even some antibiotics. • Autoimmune disorders• Viral infections

• Epstein Barr, CMV, Parvovirus B19, HIV• Pregnancy. • Unknown factors. This is called idiopathic

aplastic anemia.

Hereditary• Fanconi

• a rare, inherited blood disorder that leads to bone marrow failure.

• Diamond-Shwachman• a rare autosomal recessive disorder characterized

by exocrine pancreatic insufficiency, bone marrow dysfunction

Marrow Production - Aplastic Anemia

Treatment• Most patients require red cell transfusions.• Bone MarrowTransplant when possible.• Stem Cell Transplant• Medication: Bone Marrow Stimulants

• Sargramostim (Leukine)• Filgrastim (Neupogen) • Pegfilgrastim (Neulasta)• Epoetin alfa (Epogen, Procrit)

Marrow Production - Aplastic Anemia

Leukocyte Disorders

Leukemia• Primary malignant tumors of leukocyte precursors in the

marrow• Proliferating cells in the marrow in varying degrees of

differentiation spill over into the blood• Signs include:

• Susceptibility to infection• Neutropenia and agranulocytosis• Failure of normal hemostasis = blood loss• Thrombocytopenia• Metasasis to the spleen, liver, meninges and lymph

nodes is common

Acute Lymphocytic Leukemia (ALL)

• Predominantly seen in children and adolescents• Anemias due to inadequate erythropoiesis• Progressive weakness and lethargy• Throbocytopenia• Bone pain• Infection• Cerivcal Lymphadenopathy

• Treated with chemotherapy and bone marrow transplants

Acute Myeloblastic Leukemia (AML)

• ALL and AML are clinically similar• Prognosis is more optimistic for AML

Chronic Lymphocytic Leukemia (CLL)

• The most common of the leukemias• Above 50 years of age• Onset is gradual

• Fatigue, weight loss, anorexia• B lymphocytes most involved – very high but

nonfunctional• Deficiency in antibody production

• Chemotherapy prolongs survivals

Chronic Myeloblastic Leukemia (CML)

• 25 to 60 years of age• Granulocytes are very high• Liver and spleen infiltration – massive splenomegaly• Blast Crisis:

• Large number of leukocytes enter the blood stream• Rapid patient deterioration• Damaged chromosome 22

• The Philadelphia chromosome• No therapeutic intervention

Lymphoma• Solid malignant tumors arising in the cells of lmphoid

tissue• The tumor replaces marrow and lymphoid tissue• Invasive• Immune deficiencies…infections• Anemia• Lymphadema• Splenomegaly

Lymphomas

• Hodgkin’s Lymphoma• Most often in young

adults• Single, painless,

cervical lymph node• Spreads to adjacent

nodes and then to lymphoid organs

• Reed-Sternberg (RS) cell

• Large, multinucleate cell

• Genetics vs Epstein Barr Virus

Lymphoma

• Non-Hodgkin’s Lymphoma• These tumors arise in B and T lymphocyte lines in

particular• Lymph nodes are primary site

• Hereditary spherocytosis• Hereditary elliptocytosis• Hereditary pyropoikilocytosis• Southeast Asian ovalocytosis

Red cell destruction – membrane disorders

Review red blood cell disordersRed cell destruction – membrane disorders

• G6PD deficiency• Pyruvate kinase deficiency• Other very rare deficiencies

Review red blood cell disordersRed cell destruction – enzymopathies

Deoxyhemoglobin S Polymer Structure

A) Deoxyhemoglobin S 14-stranded polymer (electron micrograph)

D) Charge and size prevent 6b Glu from binding.

C) Hydrophobic pocket for 6b Val

B) Paired strands of deoxyhemoglobin S (crystal structure)

Dykes, Nature 1978; JMB 1979Crepeau, PNAS 1981 Wishner, JMB 1975

• In severely anemic patients, simple transfusions should be used.

• Common causes of acute anemia: • acute splenic sequestration• transient red cell aplasia • Hyperhemolysis (infection, acute chest

syndrome, malaria).• If the patient is stable and the reticulocyte

count high, transfusions can (and should) be deferred.

Transfusion in Sickle Cell

• A comprehensive transfusion protocol should include accurate records of the patient’s red cell phenotype, alloimmunization history, number of units received, serial Hb S percentages, and results of monitoring for infectious diseases and iron overload.

• Transfusions are used to raise the oxygen-carrying capacity of blood and decrease the proportion of sickle red cells.

Transfusion in Sickle Cell(exchange transfusion)

• Transfusions usually fall into two categories: episodic, acute transfusions to

stabilize or reverse complications. long-term, prophylactic transfusions to

prevent future complications.

Transfusion in Sickle Cell(exchange transfusion)

• episodic, acute transfusions to stabilize or reverse complications.

Limited studies have shown that aggressive transfusion (get Hgb S < 30%) may help in sudden severe illness.

May be useful before general anesthesia.

Vichinsky et al., NEJM 1995

Transfusion in Sickle Cell(exchange transfusion)

Inappropriate uses of transfusion:• Chronic steady-state anemia• Uncomplicated pain episodes• Infection• Minor surgery• Uncomplicated pregnancies• Aseptoic necrosis

Transfusion in Sickle Cell

• Except in severe anemia, exchange transfusion offers many benefits and is our first choice

• Phenotypically matched, leukodepleted packed cells are the blood product of choice.

• A posttransfusion hematocrit of 36 percent or less is recommended.

• Avoid hyperviscosity, which is dangerous to sickle cell patients.

Transfusion in Sickle Cell(exchange transfusion)

Iron overload and chelation

• Can occur in any patient requiring chronic transfusion therapy or in hemochromatosis.

• Liver biopsy is the most accurate test though MRI is being investigated.

• Ferritin is a good starting test.• 120 cc of red cells/kg of body weight is an approximate

point at which to think about iron overload

• Chelator, deferoxamine• 25 mg/kg sq per day over 8 hours.• Supplementation with vitamin C may aid excretion.• Otooxicity, eye toxicity, allergic reactions.• Discontinue during an infection.

• Oral chelators are in development.

Iron overload and chelation

Conclusions

• Transfuse for any severe anemia with physiologic compromise.

• Decide early whether transfusion will be rare or part of therapy.

• Avoid long-term complications by working with your blood bank and using chelation theraoy.

Anemia: Insufficient Erythrocytes

• Hemorrhagic anemia – result of acute or chronic loss of blood

• Hemolytic anemia – prematurely ruptured erythrocytes• Aplastic anemia – destruction or inhibition of red bone

marrow

Physical Characteristics of Blood

• Average volume of blood:– 5–6 L for males; 4–5 L for females (Normovolemia)– Hypovolemia - low blood volume– Hypervolemia - high blood volume

• Viscosity (thickness) - 4 - 5 (where water = 1)• The pH of blood is 7.35–7.45; x = 7.4• Osmolarity = 300 mOsm or 0.3 Osm

– This value reflects the concentration of solutes in the plasma

• Salinity = 0.85%– Reflects the concentration of NaCl in the blood

• Temperature is 38C, slightly higher than “normal” body temperature

• Blood accounts for approximately 8% of body weight

Composition of Blood2 major components

– Liquid = plasma (55%)– Formed elements (45%)

• Erythrocytes, or red blood cells (RBCs)• Leukocytes, or white blood cells (WBCs)• Platelets - fragments of megakaryocytes in

marrow

Hematocrit

Blood Plasma• Blood plasma components:

– Water = 90-92%– Proteins = 6-8%

• Albumins; maintain osmotic pressure of the blood• Globulins

– Alpha and beta globulins are used for transport purposes– Gamma globulins are the immunoglobulins (IgG, IgA, etc)

• Fibrinogen; a clotting protein– Organic nutrients – glucose, carbohydrates, amino

acids– Electrolytes – sodium, potassium, calcium,

chloride, bicarbonate – Nonprotein nitrogenous substances – lactic acid,

urea, creatinine– Respiratory gases – oxygen and carbon dioxide

Anemia• Anemia – blood has abnormally low oxygen-carrying

capacity• It is a symptom rather than a disease itself

• Due to some underlying condition• Blood oxygen levels cannot support normal

metabolism• Signs/symptoms include fatigue, paleness, shortness

of breath, and chills

Morphological Approach(big versus little)

First, measure the size of the RBCs:• Use of volume-sensitive automated blood cell

counters, such as the Coulter counter. The red cells pass through a small aperture and generate a signal directly proportional to their volume.

• Other automated counters measure red blood cell volume by means of techniques that measure refracted, diffracted, or scattered light

• By calculation from an independently-measured red blood cell count and hematocrit:

• MCV  (femtoliters) = 10 x HCT(percent) ÷ RBC (millions/µL)

Diagnosis of Anemia

CBC and Determination of Red Blood Cell Indices• Different types of Anemia are generally characterized

by red blood cells of a certain size• For Example, small (microcytic, low MCV) RBCs

occur with iron deficiency• RBCs contain less hemoglobin and are pale

(hypochromic, low MCHC)

Underproduction (morphological approach)

MCV>115• B12, Folate

• Drugs that impair DNA synthesis (AZT (Zidovudine, chemo)

• MDS (myelodysplastic syndromes)• Ineffective production

(or dysplasia) of the myeloid class of blood cells

MCV = 100 - 115• Ditto• Endocrinopathy

(hypothyroidism)• Reticulocytosis

• Increased number of immature RBCs

Underproduction

Normocytic• Anemia from a

chronic disease• Renal failure

Microcytic• Iron deficiency• Thalassemia trait

• abnormal form of hemoglobin

• Anemia due to chronic disease (30-40%)

• Sideroblastic anemia• bone marrow

produces ringed sideroblasts rather than healthy RBCs

Transfusion in Sickle Cell(Controversy!)

• Used correctly, transfusion can prevent organ damage and save the lives of sickle cell disease patients.

• Used unwisely, transfusion therapy can result in serious complications.

http://www.nhlbi.nih.gov/health/prof/blood/sickle/index.htm

• Simple transfusion – give blood • Partial exchange transfusion - remove

blood and give blood• Erythrocytapheresis – use apheresis to

maximize blood exchange

• When to use each method?

Transfusion in Sickle Cell(Controversy!)

• In general, patients should be transfused if there is sufficient physiological derangement to result in heart failure, dyspnea, hypotension, or marked fatigue.

• Tends to occur during an acute illness or when hemoglobin falls under 5 g/dL.

Transfusion in Sickle Cell

Exchange transfusion:

1. Bleed one unit (500 ml), infuse 500 ml of saline

2. Bleed a second unit and infuse two units.

3. Repeat. If the patient has a large blood mass, do it again.

Transfusion in Sickle Cell(exchange transfusion)

• Stroke• Chronic debilitating pain• Pulmonary hypertension• Setting of renal failure and heart failure

Transfusion in Sickle Cell(chronic transfusion therapy)

Controversial uses:• Prior to contast media exposure• Sub-clinical neurological damage• Priapism• Leg Ulcers• Pregnancy

Transfusion in Sickle Cell(chronic transfusion therapy)

Review red blood cell disorders

Marrow production• Thalassemias• Myelodysplasia• Myelophthisic• Aplastic anemia• Nutritional deficiencies

Red cell destruction• Hemoglobinopathies• Enzymopathies• Membrane disorders• Autoimmune