100 m  1 s 1 mm  100 s distance = time2 Transport System of the Body: 1 cm  10000 s Transport System of the Body: O2 / Energy

O2 Nutrients O2 Nutrients O2 / Energy

CO2 Waste CO2 Waste Diffusion Source Source Cell Cell

TOO MUCH Bulk flow (pressure) TIME

External environment: External environment: Sink CO2 / Waste Sink CO2 / Waste

O2 / Nutrients O2 / Nutrients CO2 / Waste CO2 / Waste

Cardiovascular System – Cardiovascular System: Blood: Blood • Only fluid tissue in body (connective tissue) • pH = 7.35 – 7.45 (slightly alkaline) • Temp. slightly higher than body temp. (38°C / 100.4°F) • ~ 8% body weight (♂ = 5-6 L; ♀ = 4-5 L)

Function (“River of Life”): 1) Distribution • Delivers oxygen / nutrients • Carries away metabolic wastes • Transports hormones 2) Regulation Bloodletting a common medical • Maintains body temperature / pH treatment in the • Maintains fluid volumes Middle Ages 3) Protection • Prevents blood loss (e.g., clot formation) • Prevents infection (e.g., antibodies)

Cardiovascular System – Blood Cardiovascular System – Blood

Blood Components: Blood Components: Serum: Plasma minus 1) Formed Elements (living cells) A) Plasma clotting proteins • Erythrocytes (RBC’s) • Distributes materials / heat • Leukocytes (WBC’s)

• Composition: (precisely maintained)

Plasma A) Water (~ 90%) (Primarily produced : by ) % of whole blood containing formed elements Buffy Coat Males ~ 47% (~ 1%) B) Protein (~ 8%) Females ~ 42% 60% 36% 4%

Formed Albumin Globulins Fibrinogen elements Erythrocytes • Osmotic pressure • Transport ( / ) • Clotting protein (~ 45%) • Transport • Antibodies () 2) Plasma C) Other solutes (~ 2%; >100 different solutes present; Table 17.1) • Non-cellular fluid matrix (dissolved proteins) • Organic nutrients (e.g., glucose) • Electrolytes (e.g., sodium)

• Nitrogenous waste (e.g., urea) • Respiratory gases (e.g., O2)

1 Cardiovascular System – Blood Cardiovascular System – Blood

Blood Components: Blood Components:

B) Erythrocytes (red blood cells – RBCs) B) Erythrocytes (red blood cells – RBCs)

• Small (~ 7 m); biconcave (“certs”) • Anucleate (lacking nucleus); few organelles Structure complements function

• Contain (O2 / CO2 transport protein) Shape maintained by network of proteins (e.g., spectrin) 1) Small size and shape equates to large 250 million / cell surface area / volume

Rapid respiratory gas loading / unloading 4 globins / hemoglobin 2) 97% of cell volume is hemoglobin (2  chains; 2  chains) (~ 250 million hemoglobin) = 4 molecules O2 Mass transport of respiratory gases

Why maintain hemoglobin 3) Lack mitochondria (don’t burn oxygen) in erythrocytes? Efficient transport of respiratory gases 1) Leakage through capillary walls 2) Viscosity / osmotic pressure issues

Heme (O2-binding pigment w/ iron) + Globin (protein)

Marieb & Hoehn ( Anatomy and Physiology, 8th ed.) – Figures 17.3 / 17.14

Cardiovascular System – Blood Cardiovascular System – Blood

Blood Components: Blood Components: Entire process takes ~ 15 days B) Erythrocytes (red blood cells – RBCs) B) Erythrocytes (red blood cells – RBCs)

Erythropoiesis (red formation): ( formation): • ~ 2 million RBCs produced per second (ribosome factory) • Formation occurs in red marrow

High

Hemocytoblast Myeloid Erythroblast (stem cell) Axial skeleton Ribs Femur Count: Provide rough index of RBC Long formation rate Tibia Low (nucleus ejected) Young Old (enters blood stream) 1 – 2 % of RBCs Age (years) Erythrocyte Reticulocyte Normoblast

Cardiovascular System – Blood Cardiovascular System – Blood

Blood Components: Blood Components: Free iron ions toxic! (~ 85%) (~ 15%) • Acts as a catalyst for B) Erythrocytes (red blood cells – RBCs) B) Erythrocytes (red blood cells – RBCs) the formation of Produced by the free radicals and liver Erythropoiesis (red blood cell formation): Erythropoiesis (red blood cell formation): • Regulated hormonally by • Dietary requirements must be met for normal RBC formation 1) RBC loss 2)  hemoglobin Iron: Hypoxia (hemoglobin synthesis) 3) Low O2 • Stored in liver & in protein-iron (-) Normal Blood Oxygen Level complexes ferritin and hemosiderin

Increased O2 Reduced O2 Ferritin level in blood level in blood (24 protein subunits)

• Transported in blood bound to transferrin

Vitamin B12 and folic acid RBCs mature Erythropoietin stimulates Kidney releases necessary for proper DNA synthesis Transferrin more rapidly erythropoietin (; 2 binding sites)

2 Cardiovascular System – Blood Cardiovascular System – Blood Pathophysiology: Blood Components: Jaundice: Blood Components: Yellowing of skin due to B) Erythrocytes (red blood cells – RBCs) bilirubin deposition B) Erythrocytes (red blood cells – RBCs) ( oxygen carrying capacity of blood)

Destruction of Erythrocytes

Decreased • Lose flexibility number of RBCs Hemorrhagic anemia Hemolytic anemia Aplastic anemia (blood loss) (RBC rupture) (red marrow destruction)

Microcytes • Iron salvages; stored for re-use Decreased • Heme group degraded to bilirubin hemoglobin content Macrocytes

(captured by liver; Iron-deficiency anemia Pernicious anemia Bilirubin (yellow pigment) released via gallbladder) (inadequate intake of iron) (deficiency of vitamin B12)

(metabolized in Urobilinogen large Intestine) • “Old” RBCs engulfed by Abnormal in spleen / liver (exits in feces) Stercobilin (brown pigment) hemoglobin • Globins recycled to amino acids Sickle-cell anemia Thalassemias (genetic mutation – abnormal globin) (genetic mutation – missing globin)

Cardiovascular System – Blood Cardiovascular System – Blood Pathophysiology: Blood Components: Blood Components:

B) Erythrocytes (red blood cells – RBCs) C) Leukocytes (white blood cells – WBCs) ( red blood cell number) • Only complete cell in blood (e.g., nucleus / organelles)

Polycythemia increases blood viscosity, • Function in defense against disease ~ 4800 – 10,800 WBCs / l causing it to flow sluggishly • ONLY utilize blood for transport Whole blood EPO Rolling Margination Migration Diapedesis

Polycythemia vera Artificial polycythemia (bone marrow cancer) () Amoeboid Tight movement adherence “leaping across” Secondary polycythemia Inflamed endothelial cells sprout (high altitude living) cell-adhesion molecules (CAMs)

Carman, C.V., Journal of Cell Science. 2009;122:3025-3035

Cardiovascular System – Blood Cardiovascular System – Blood

Blood Components: Blood Components:

C) Leukocytes (white blood cells – WBCs) C) Leukocytes (white blood cells – WBCs)

Categories of Leukocytes: Categories of Leukocytes:

Granulocytes (contain granules) (lack granules)

1) (50 – 70%) 2) (2 – 4%) 3) (< 1%) 1) Lymphocytes (15 – 45%) 2) Monocytes (3 – 8%) • Small granules • Large granules • Large granules • Large nucleus (spherical) • Largest of WBCs (hydrolytic enzymes/defensins) (lysosomes) (histamines) • Function in immunity • U-shaped nucleus • Multi-lobed nucleus • Bi-lobed nucleus • U-shaped nucleus T • Function as macrophages • Engulfs bacteria / fungi • Kills parasitic worms • Vasodilator / attracts WBCs B lymphocytes (differentiate in tissues)

Lifespan = hours – decades Lifespan = hours – months Lifespan = hours – days

3 Cardiovascular System – Blood Cardiovascular System – Blood Mononucleosis: Blood Components: Blood Components:

C) Leukocytes (white blood cells – WBCs) C) Leukocytes (white blood cells – WBCs)

Hormones: ( formation): Epstein-Barr Interleukins Pathophysiology: virus Colony-stimulating factors migrate to Excessive number of lymphoid tissue Leukemia: agranulocytes Lymphoblast • Uncontrolled proliferation of WBCs (cancerous)

Lymphoid • Named according to abnormal (+) stem cell cell line involved

Granules appear Nuclei arc Acute leukemia: Chronic leukemia: Derived from blast-type cells Derived from later cell stages Neutrophilic Neutrophilic • Rapid advancement • Slow advancement Hemocytoblast • Often observed in children • Often observed in elderly (stem cell) Lymphocytic leukemia Basophilic Basophilic Symptoms: Treatment: myelocyte band cell • Anemia / problems • Irradiation Myeloid • Fever / weight-loss • Chemotherapy stem cell Eosinophilic Eosinophilic • Frequent infections • Bone marrow transplant myelocyte band cell Myelocytic leukemia

Cardiovascular System – Blood Cardiovascular System – Blood

Blood Components: (“stoppage of bleeding”):

D) Platelets (thrombocytes) • Series of fast, localized reactions to halt blood loss

• Cytoplasmic fragments (anucleate) Phase 1: Phase 2: • Function in blood clotting (contain clotting chemicals) Vascular spasm plug formation

Thrombopoiesis (platelet formation): Hormone: Thrombopoietin (+)

Myeloid stem cell Hemocytoblast (stem cell) • ~ 150,000 – 400,000 / l • Lifespan = ~ 10 days of damaged vessel Temporarily seals vessel break

Repeat mitosis; (significantly reduces blood loss) (positive feedback loop) no cytokinesis Activated by: Intact endothelial cells release 1) Direct injury to smooth muscle and which prevent platelet aggregation in undamaged tissue 2) Chemical release (endothelial cells) Platelets 3) Nociceptors Marieb & Hoehn (Human Anatomy and Physiology, 8th ed.) – Figures17.13

Cardiovascular System – Blood Cardiovascular System – Blood Step 1: Hemostasis (“stoppage of bleeding”): Hemostasis (“stoppage of bleeding”): Formation of prothrombin • Series of fast, localized reactions to halt blood loss activator Platelet plug formation:

Phase 3: Rupture of vessel (blood clotting)

: Large plasma protein; links platelets to fibers Collagen exposed Platelets swell and form spiked processes

Attracts more (+) Platelets stick to collagen Vascular spasms platelets

Blood converted from liquid to gel Platelets release contents (3 – 6 minutes)

• Requires clotting factors (procoagulants) Aspirin Activation turns clotting factors into Adenosine Thromboxane enzymes diphosphate A (ADP) 2

Marieb & Hoehn (Human Anatomy and Physiology, 8th ed.) – Figures17.14

4 Cardiovascular System – Blood Cardiovascular System – Blood Step 1: : Factors that inhibit clotting Hemostasis (“stoppage of bleeding”): Formation of prothrombin Hemostasis (“stoppage of bleeding”): (e.g., heparin) • Series of fast, localized reactions to halt blood loss activator • Series of fast, localized reactions to halt blood loss

(all factors found within blood) (requires factor outside blood) Intrinsic pathway: Step 2: • triggered by negatively charged surfaces Formation of (platelets / collagen / glass) • Inactivated by antithrombin III • Slow due to many intermediate steps Step 3: Extrinsic pathway: Formation of mesh • triggered by factor found in tissues under the damaged () • Rapid due to few intermediate steps Severe trauma: 15 seconds

Both pathways cascade to activation of Factor X which combines with Platelet ++ Factor 3 (PF3), Ca , and Factor V to form Activation turns Prothrombin Activator clotting factors into Factor XIII (fibrin stabilizing factor): enzymes Cross-linking enzyme that binds fibrin Found on surface strands together of platelets

Marieb & Hoehn (Human Anatomy and Physiology, 8th ed.) – Figures17.14 Marieb & Hoehn (Human Anatomy and Physiology, 8th ed.) – Figures17.14

Cardiovascular System – Blood Cardiovascular System – Blood = requires vitamin K Hemostasis (“stoppage of bleeding”): for synthesis Hemostasis (“stoppage of bleeding”): • Series of fast, localized reactions to halt blood loss (2 days following damage) Clot Retraction / Repair: Fibrinolysis:

(30 – 60 minutes following damage) • Process of removing clot once healing has occurred

• Platelets contain actin / myosin fibers; contract in manner of muscle fibers (draws ruptured edges of closer together) Plasmin: Fibrin-digesting enzyme (‘clot buster’)

(incorporated into clot) Platelet-derived growth factor: Plasminogen Plasmin Released by platelets; stimulates smooth tissue plasminogen activator (tPA) muscle cells and fibroblasts to divide and rebuild vessel wall (released by endothelial cells) Marieb & Hoehn (Human Anatomy and Physiology, 8th ed.) – Table 17.3

Cardiovascular System – Blood Cardiovascular System – Blood

Hemostasis (“stoppage of bleeding”): Hemophilia:

Disorders of Hemostasis:

Thromboembolic Disorders Bleeding Disorders (undesirable clot formation) (abnormal bleeding due to inability to clot)

Petechiae (less severe) Hemophilia C Factor XI deficiency Symptoms: Hemophilia B • Prolonged bleeding Factor IX deficiency Hemophilia A • Disabled / painful joints : Embolus: Thrombocytopenia Impaired Liver Function Factor VIII deficiency A clot develops in an A free-floating clot in • Deficiency in platelets • Vitamin K deficiency 77% of cases unbroken blood vessel the bloodstream • Marrow destruction • Cirrhosis / hepatitis (may lead to )

Causes: • Roughened endothelium (e.g., atherosclerosis) Hemophilia • Slowly flowing blood Treatment: (e.g., airlines - economy class) • Missing clotting factor(s) • Genetic (e.g., X-linked) • Plasma transfusions • Injection of clotting factor(s)

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