Blood Lecture

Blood Composition

Blood

Formed elements living blood "cells" suspended in plasma

Erythrocytes (red blood cells, or RBCs)
Leukocytes (white blood cells, or WBCs)
Platelets

Spun tube of blood yields three layers

Hematocrit

47% 5% for males; 42% 5% for females

Physical Characteristics and Volume

Functions of Blood

Distributing substances
Regulating blood levels of substances
Protection

Distribution Functions

Regulation Functions

Protection Functions

Blood Plasma

90% water

Nutrients, gases, hormones, wastes, proteins, inorganic ions

Over 100 dissolved solutes

Plasma proteins most abundant solutes
Remain in blood; not taken up by cells
Proteins produced mostly by liver
60% albumin; 36% globulins; 4% fibrinogen

Albumin

Functions

Formed Elements

Erythrocytes

Erythrocytes

Structural characteristics contribute to gas transport

Biconcave shapehuge surface area relative to volume

Superb example of complementarity of structure and function

>97% hemoglobin (not counting water)

No mitochondria; ATP production anaerobic; do not consume O2 they transport

Erythrocyte Function

RBCs dedicated to respiratory gas transport

Males - 1318g/100ml; Females - 1216 g/100ml

Hemoglobin binds reversibly with oxygen

Normal values

Hemoglobin Structure

Globin composed of 4 polypeptide chains

Two alpha and two beta chains

Heme pigment bonded to each globin chain

Gives blood red color

Heme's central iron atom binds one O2

Each Hb molecule can transport four O2
Each RBC contains 250 million Hb molecules

Hemoglobin (Hb)

O2 loading in lungs

O2 unloading in tissues

CO2 loading in tissues

Hematopoiesis

Hematopoietic stem cells (Hemocytoblasts)

New blood cells enter blood sinusoids

Erythropoiesis: Red Blood Cell Production

Stages

Myeloid stem cell transformed into proerythroblast

Reticulocytes enter bloodstream; in 2 days mature RBC

In 15 days proerythroblasts develop into basophilic, then polychromatic, then

orthochromatic erythroblasts, and then into reticulocytes

Erythropoiesis

As myeloid stem cell transforms

1.
2.
3.

Ribosomes synthesized

Reticulocyte ribosomes degraded; Then become mature erythrocytes

Hemoglobin synthesized; iron accumulates

Ejection of nucleus; formation of reticulocyte (young RBC)
Reticulocyte count indicates rate of RBC formation

Regulation of Erythropoiesis

Hormonal Control of Erythropoiesis

Hormone Erythropoietin (EPO)

Causes of hypoxia

Effects of EPO

Some athletes abuse artificial EPO

Dangerous consequences

Testosterone enhances EPO production, resulting in higher RBC counts in males

Dietary Requirements for Erythropoiesis

Nutrientsamino acids, lipids, and carbohydrates

Iron
Available from diet
65% in Hb; rest in liver, spleen, and bone marrow
Free iron ions toxic
Stored in cells as ferritin and hemosiderin
Transported in blood bound to protein transferrin

Vitamin B12 and folic acid necessary for DNA synthesis for rapidly dividing cells
(developing RBCs)

Fate and Destruction of Erythrocytes

Fate and Destruction of Erythrocytes

Heme and globin are separated

Iron salvaged for reuse

Heme degraded to yellow pigment bilirubin

Liver secretes bilirubin (in bile) into intestines
Degraded to pigment urobilinogen
Pigment leaves body in feces as stercobilin
Globin metabolized into amino acids
Released into circulation

Erythrocyte Disorders

Anemia

Causes of Anemia

Three groups

Blood loss
Low RBC production
High RBC destruction

Causes of Anemia: Blood Loss

Hemorrhagic anemia

Chronic hemorrhagic anemia

Causes of Anemia: Low RBC Production

Iron-deficiency anemia

Pernicious anemia

Renal anemia

Aplastic anemia

Causes of Anemia: High RBC Destruction

Hemolytic anemias

Causes of Anemia: High RBC Destruction

Usually genetic basis for abnormal Hb

Fragile RBCs lyse prematurely

Globin abnormal

Causes of Anemia: High RBC Destruction

Thalassemias

Sickle-cell anemia

Hemoglobin S
One amino acid wrong in a globin beta chain

RBCs crescent shaped when unload O2 or blood O2 low

RBCs rupture easily and block small vessels
Poor O2 delivery; pain

Sickle-cell Anemia

Black people of African malarial belt and descendants

Kills 1 million each year

Sickle-cell gene

Two copies Sickle-cell anemia

Malaria

One copy Sickle-cell trait; milder disease; better chance to survive malaria

Sickle-cell Anemia: Treatments

Acute crisis treated with transfusions; inhaled nitric oxide

Preventing sickling
Hydroxyurea induces fetal hemoglobin (which does not sickle) formation
Blocking RBC ion channels
Stem cell transplants
Gene therapy

Erythrocyte Disorders

Polycythemia vera

Secondary polycythemia

Leukocytes

Make up <1% of total blood volume

4,800 10,800 WBCs/l blood

Function in defense against disease

Can leave capillaries via diapedesis

Move through tissue spaces by ameboid motion and positive chemotaxis

Leukocytosis: WBC count over 11,000/mm3

Normal response to infection

Leukocytes: Two Categories

Granulocytes Visible cytoplasmic granules

Neutrophils, eosinophils, basophils

Agranulocytes No visible cytoplasmic granules

Lymphocytes, monocytes

Decreasing abundance in blood

Never let monkeys eat bananas

Granulocytes

Granulocytes

Neutrophils

Eosinophils

Basophils

Agranulocytes

Agranulocytes

Lymphocytes

Lymphocytes

Two types

T lymphocytes (T cells) act against virus-infected cells and tumor cells

B lymphocytes (B cells) give rise to plasma cells, which produce antibodies

Monocytes

Monocytes

Leave circulation, enter tissues, and differentiate into macrophages

Actively phagocytic cells; crucial against viruses, intracellular bacterial parasites,

and chronic infections

Activate lymphocytes to mount an immune response

Leukopoiesis

Production of WBCs

Stimulated by 2 types of chemical messengers from red bone marrow and mature
WBCs

Interleukins (e.g., IL-3, IL-5)

Colony-stimulating factors (CSFs) named for WBC type they stimulate (e.g.,

granulocyte-CSF stimulates granulocytes)

All leukocytes originate from hemocytoblasts

Myeloblast promyelocyte myelocyte band mature cell

Granulocytes stored in bone marrow

Shorter life span; die fighting microbes

Progression of agranulocytes differs

Share common precursor with neutrophils

Lymphocytes live few hours to decades

Lymphoid stem cells lymphocytes

Myeloid stem cells all others
Progression of all granulocytes

3 times more WBCs produced than RBCs

Monocytes live several months

Monoblast promonocyte monocyte

Lymphoid stem cell T lymphocyte precursors (travel to thymus) and B

lymphocyte precursors

Leukocyte disorders

Leukopenia
Abnormally low WBC countdrug induced
Leukemias all fatal if untreated
Cancer overproduction of abnormal WBCs
Named according to abnormal WBC clone involved
Myeloid leukemia involves myeloblast descendants
Lymphocytic leukemia involves lymphocytes
Acute leukemia derives from stem cells; primarily affects children
Chronic leukemia more prevalent in older people

Leukemia

Infectious Mononucleosis

Platelets

Cytoplasmic fragments of megakaryocytes

Mitosis but no cytokinesis megakaryocyte - large cell with multilobed nucleus

Formation regulated by thrombopoietin

Derive from megakaryoblast

Hemostasis

Fast series of reactions for stoppage of bleeding

1.
2.

Vascular spasm

Requires clotting factors, and substances released by platelets and injured tissues
Three steps
Platelet plug formation

3.

Coagulation (blood clotting)

Hemostasis: Vascular Spasm

Hemostasis: Platelet Plug Formation

Hemostasis: Coagulation

Coagulation: Overview

Three phases of coagulation

Prothrombin activator formed in both intrinsic and extrinsic pathways

Prothrombin converted to enzyme thrombin
Thrombin catalyzes fibrinogen fibrin

Coagulation Phase 1: Two Pathways to Prothrombin Activator

Initiated by either intrinsic or extrinsic pathway (usually both)

Triggered by tissue-damaging events

Factor X complexes with Ca2+, PF3, and factor V to form prothrombin activator

Involves a series of procoagulants

Each pathway cascades toward factor X

Coagulation Phase 1: Two Pathways to Prothrombin Activator

Intrinsic pathway

Triggered by negatively charged surfaces (activated platelets, collagen, glass)

Uses factors present within blood (intrinsic)

Extrinsic pathway

Triggered by exposure to tissue factor (TF) or factor III (an extrinsic factor)

Bypasses several steps of intrinsic pathway, so faster

Coagulation Phase 2: Pathway to Thrombin

Prothrombin activator catalyzes transformation of prothrombin to active enzyme

thrombin

Once prothrombin activator formed, clot forms in 1015 seconds

Coagulation Phase 3: Common Pathway to the Fibrin Mesh

Thrombin converts soluble fibrinogen to fibrin

Cross-links fibrin

Fibrin strands form structural basis of clot

Fibrin causes plasma to become a gel-like trap for formed elements
Thrombin (with Ca2+) activates factor XIII which:
Strengthens and stabilizes clot

Clot Retraction

Vessel Repair

Fibrinolysis


Factors Limiting Clot Growth or Formation

Two mechanisms limit clot size

Swift removal and dilution of clotting factors

Thrombin bound onto fibrin threads

Inhibition of activated clotting factors

Antithrombin III inactivates unbound thrombin
Heparin in basophil and mast cells inhibits thrombin by enhancing antithrombin

III
Factors Preventing Undesirable Clotting

Platelet adhesion is prevented by

Smooth endothelium of blood vessels prevents platelets from clinging

Antithrombic substances nitric oxide and prostacyclin secreted by endothelial

cells

Vitamin E quinone acts as potent anticoagulant

Disorders of Hemostasis

Thromboembolic disorders: undesirable clot formation

Involves both types of disorders

Bleeding disorders: abnormalities that prevent normal clot formation

Disseminated intravascular coagulation (DIC)

Thromboembolic Conditions

Thrombus: clot that develops and persists in unbroken blood vessel

May block circulation leading to tissue death

Embolus: thrombus freely floating in bloodstream

E.g., pulmonary and cerebral emboli

Embolism: embolus obstructing a vessel

Risk factors atherosclerosis, inflammation, slowly flowing blood or blood stasis

from immobility

Anticoagulant Drugs

Aspirin

Antiprostaglandin that inhibits thromboxane A2

Heparin

Anticoagulant used clinically for pre- and postoperative cardiac care

Warfarin (Coumadin)

Used for those prone to atrial fibrillation

Dabigatran directly inhibits thrombin

Interferes with action of vitamin K

Bleeding Disorders

Thrombocytopenia: deficient number of circulating platelets

Petechiae appear due to spontaneous, widespread hemorrhage

Platelet count <50,000/l is diagnostic

Due to suppression or destruction of red bone marrow (e.g., malignancy,

radiation, drugs)
Treated with transfusion of concentrated platelets

Bleeding Disorders

Impaired liver function

Inability to synthesize procoagulants

Causes include vitamin K deficiency, hepatitis, and cirrhosis

Impaired fat absorption and liver disease can also prevent liver from producing
bile, impairing fat and vitamin K absorption

Bleeding Disorders

Hemophilia includes several similar hereditary bleeding disorders

Hemophilia A: most common type (77% of all cases); factor VIII deficiency
Hemophilia B: factor IX deficiency
Hemophilia C: mild type; factor XI deficiency

Symptoms include prolonged bleeding, especially into joint cavities

Treated with plasma transfusions and injection of missing factors

Increased hepatitis and HIV risk

Disseminated Intravascular Coagulation (DIC)

Clotting causes bleeding

Widespread clotting blocks intact blood vessels

Severe bleeding occurs because residual blood unable to clot

Occurs as pregnancy complication; in septicemia, or incompatible blood

transfusions

Transfusions

Human Blood Groups

RBC membranes bear 30 types of glycoprotein antigens

Anything perceived as foreign; generates an immune response
Promoters of agglutination; called agglutinogens

Mismatched transfused blood perceived as foreign

May be agglutinated and destroyed; can be fatal

Presence or absence of each antigen is used to classify blood cells into different

groups
Blood Groups

Antigens of ABO and Rh blood groups cause vigorous transfusion reactions

Other blood groups (MNS, Duffy, Kell, and Lewis) usually weak agglutinogens

ABO Blood Groups

Rh Blood Groups

Homeostatic Imbalance: Hemolytic Disease of the Newborn

Also called erythroblastosis fetalis

Only occurs in Rh mom with Rh+ fetus

Rh mom exposed to Rh+ blood of fetus during delivery of first baby baby

healthy

Mother synthesizes anti-Rh antibodies

Second pregnancy

Mom's anti-Rh antibodies cross placenta and destroy RBCs of Rh+ baby

Homeostatic Imbalance: Hemolytic Disease of the Newborn

Baby treated with prebirth transfusions and exchange transfusions after birth

RhoGAM serum containing anti-Rh can prevent Rh mother from becoming

sensitized
Transfusion Reactions

Occur if mismatched blood infused

Donor's cells

Result in

Symptoms

Treatment

Transfusions

Type O universal donor

No A or B antigens

Type AB universal recipient

No anti-A or anti-B antibodies

Misleading - other agglutinogens cause transfusion reactions

Patient predonates

Autologous transfusions

Before Transfusion

Blood typing

Mixing RBCs with antibodies against its agglutinogen(s) causes clumping of

RBCs

Done for ABO and for Rh factor

Cross matching

Mix recipient's serum with donor RBCs

Mix recipient's RBCs with donor serum

Restoring Blood Volume

Death from shock may result from low blood volume

Volume must be replaced immediately with

Normal saline or multiple-electrolyte solution (Ringer's solution) that mimics

plasma electrolyte composition

Plasma expanders (e.g., purified human serum albumin, hetastarch, and dextran)

Mimic osmotic properties of albumin

More expensive and may cause significant complications

Diagnostic Blood Tests

Hematocrit test for anemia

Differential WBC count

Blood glucose tests diabetes

Microscopic examination reveals variations in size and shape of RBCs,

indications of anemias
Prothrombin time and platelet counts assess hemostasis
SMAC, a blood chemistry profile liver and kidney disorders

Complete blood count (CBC) checks formed elements, hematocrit,

hemoglobin

Developmental Aspects

Fetal blood cells form in fetal yolk sac, liver, and spleen

Blood diseases of aging

Chronic leukemias, anemias, clotting disorders

Red bone marrow is primary hematopoietic area by seventh month

Blood cells develop from mesenchymal cells called blood islands

The fetus forms Hemoglobin F, which has higher affinity for O2 than hemoglobin
A formed after birth

Usually precipitated by disorders of heart, blood vessels, or immune system