Blood Functions and Composition

Blood Functions

• Transporting oxygen and nutrients to body cells
• Transporting metabolic wastes to lungs and kidneys for elimination
• Transporting hormones from endocrine organs to target organs
• Protecting against blood loss and infection
• Regulating body temperature
• Maintaining normal pH buffers
• Maintaining adequate fluid volume in the circulatory system

Composition of Blood

• Blood is the only fluid tissue in the body
• Consists of plasma and formed elements (type of connective tissues)
• Cells are suspended in plasma
• Formed elements include erythrocytes, leukocytes, and platelets

Blood Layers

• Erythrocytes (red blood cells) make up 45% of whole blood (47% in males, 42% in females)
• Plasma makes up 55% of whole blood
• White blood cells and platelets in the buffy coat make up less than 1% of whole blood

Physical Characteristics and Volume

• Blood is a sticky, opaque fluid with a metallic taste
• Color varies with oxygen content (scarlet red with high oxygen, dark red with low oxygen)
• pH ranges from 7.35 to 7.45
• Average volume of blood in males is 5-6 liters, and in females is 4-5 liters

Blood Plasma

• Blood plasma is a straw-colored, sticky fluid
• Composed of approximately 90% water
• Contains over 100 dissolved solutes, including nutrients, gases, hormones, wastes, proteins, and inorganic ions
• Proteins produced mainly by the liver, including albumin, which makes up 60% of plasma proteins
• Albumin functions as a carrier of other molecules, blood buffer, and contributes to plasma osmotic pressure

Formed Elements

• Formed elements include red blood cells, white blood cells, and platelets
• White blood cells are the only complete cells, while red blood cells lack nuclei and organelles
• Platelets are cell fragments
• Most formed elements have a short lifespan of only a few days in the blood stream
• Most blood cells originate from bone marrow and do not divide

Erythrocytes (Red Blood Cells)

• Erythrocytes have a diameter of 7.5 micrometers and play a crucial role in gas transport
• They consist of a plasma membrane and spectrin, which allows for flexibility and shape change
• Characteristics include a biconcave shape, 97% hemoglobin content, and lack of mitochondria
• Functions include gas transport, with hemoglobin binding to oxygen
• The red hue of erythrocytes gives blood its red color
• Hemoglobin is composed of 4 polypeptides: 2 alpha and 2 beta
• There are 4-6 million erythrocytes per microliter of blood
• Oxygen loading in the lungs is called oxyhemoglobin, while oxygen unloading in tissues is called deoxyhemoglobin
• 20% of carbon dioxide in the blood binds to hemoglobin, forming carbaminohemoglobin

Hematopoiesis and Hematopoietic Stem Cells

• Hematopoiesis is the formation of all blood cells
• Hematopoietic stem cells, also known as hemocytoblasts, give rise to all formed cells
• Committed cells cannot change their cell type
• New blood cells enter the sinusoids

Erythropoiesis

• Erythropoiesis is the formation of red blood cells, which have a lifespan of 15 days
• The process involves the transformation of a hematopoietic stem cell into a myeloid stem cell, then a proerythroblast, followed by a series of divisions and maturation stages

Maturation Stages

• Proerythroblast divides into basophilic erythroblast, which synthesizes ribosomes and stains blue
• Basophilic erythroblast develops into polychromatic erythroblast, characterized by a red hue with pink and blue areas
• Polychromatic erythroblast matures into orthochromatic erythroblast, which contains hemoglobin and turns pink

Regulation and Requirement of Erythropoiesis

• Too few red blood cells lead to hypoxia
• Too many red blood cells increase blood viscosity
• Approximately 2 million red blood cells are produced every second
• Erythropoiesis is regulated by hormonal controls and dietary requirements

Hormonal Controls

• Erythropoietin is a blood hormone released by the kidney
• Hypoxia-induced factor can be accumulated due to hypoxia and hormonal control
• Causes of hypoxia include hemorrhage, pneumonia, and iron deficiency
• Erythropoietin is inhibited by erythrocytes and high oxygen levels
• Testosterone enhances erythropoietin production

Dietary Requirements for Erythropoiesis

• Amino acids, lipids, and carbohydrates are necessary for erythropoiesis
• Iron is essential, but it needs to bind with protein to avoid toxicity
• Iron is stored in cells called ferritin and hemosiderin
• Transferrin transports iron in the blood

Vitamins and Anemia

• Vitamin B12 and folic acid support rapidly dividing cells
• Anemia can be caused by hemorrhage, iron deficiency, chronic hemorrhagic anemia, pernicious anemia, and renal anemia

Types of Anemia

• Pernicious anemia: an autoimmune disease that destroys the intrinsic factor, leading to the inability to absorb B12
• Renal anemia: occurs when the kidneys fail to produce erythropoietin
• Aplastic anemia: caused by the destruction or inhibition of red bone marrow, often due to drugs, chemicals, radiations, or viruses
• Hemolytic anemias: premature lysis of red blood cells, often caused by incompatible transfusion, infections, or hemoglobin abnormalities

Thalassemias

• A genetic disorder resulting in abnormal globins
• Typically found in people of Mediterranean ancestry
• Characterized by the absence of one globin chain
• Red blood cells are thin and deficient in hemoglobin

Sickle Cell Anemia

• Caused by Hemoglobin S or mutated hemoglobin
• Only one amino acid is incorrect in the beta chain out of 146 amino acids
• Red blood cells become crescent-shaped when oxygen levels are low
• Misshapen red blood cells rupture easily and block small vessels
• More prevalent in black people
• Individuals with 2 copies of Hb-s develop sickle-cell anemia, while those with 1 copy have a milder disease and a better chance of surviving malaria
• Treatments include transfusion, inhaled nitric oxide, stem cell transplants, gene therapy, and hydroxyurea to induce fetal hemoglobin formation

Erythrocyte Disorders

• Polycemia is a condition characterized by an excess of red blood cells and increased blood viscosity, leading to sluggish blood flow.
• Polycythemia vera is a type of bone marrow cancer that causes an overproduction of red blood cells, resulting in a high hematocrit level (up to 80%).
• Therapeutic phlebotomy is a treatment for polycythemia vera.

Causes of Polycemia

• Low oxygen levels can lead to polycemia.
• Increased EPO (erythropoietin) production can also cause polycemia.

Leukocytes

• Leukocytes are complete cells with a shorter lifespan compared to red blood cells.
• There are three main components of leukocytes: basophils, eosinophils, and neutrophils.

Agranulocytes

• Agranulocytes consist of lymphocytes and monocytes.
• Lymphocytes make up 25% of leukocytes and are divided into two types: T-lymphocytes (cell-mediated, originating from the thymus) and B-lymphocytes (antibody-producing, originating from bone marrow).
• Monocytes are rare, making up 3-8% of leukocytes, and have a kidney-shaped nucleus that later develops into macrophages.

Leukopoiesis

• Leukopoiesis is the production of white blood cells from bone marrow, involving the action of interleukins and colony-stimulating factors.

Leukocyte Development

• Leukocytes originate from hemocytoblasts, which give rise to lymphoid stem cells and myeloid stem cells.
• Lymphoid stem cells produce lymphocytes, while myeloid stem cells produce other elements.

Granulocyte Production

• Myeloblasts produce myelocytes.
• Promyelocytes produce lysosomes.
• Myelocytes produce granules.
• Band cells produce nuclei that form a carved arc shape.
• Mature granulocytes have segmented nuclei and are released into the blood, with 10 times more stored in the bone marrow than in the blood.

Agranulocyte Production

• Agranulocyte production occurs in the following stages: monoblast → promonocyte → monocyte
• Monocytes can live up to several months

Hematopoietic Hormones

• EPO (Erythropoietin) and CSF (Colony-Stimulating Factor) are hematopoietic hormones used clinically
• These hormones can stimulate bone marrow in cancer patients receiving chemotherapy or stem cell transplants
• They are also used to increase protective immune responses in AIDS patients

Leukocytes Disorders

• Leukocytes disorders include overproduction of abnormal white blood cells, such as leukemia and infectious mononucleosis.
• Leukopenia is a condition characterized by an abnormally low number of white blood cells, which can be drug-induced.

Leukemia

• Leukemia involves the cloning of white blood cells, with myeloid leukemia involving myeloblast descendants and lymphocytic leukemia involving lymphocytes.
• Acute leukemia derives from stem cells and primarily affects children.
• Chronic leukemia involves the proliferation of later cell stages and is prevalent in older people.
• Without treatment, all leukemia are fatal, with death resulting from internal hemorrhage or overwhelming infections.
• Cancerous cells fill the red bone marrow, leading to leukemia.

Treatment of Leukemia

• Treatments for leukemia include irradiation, antileukemia drugs, and stem cell transplants.

Infectious Mononucleosis

• Infectious mononucleosis is a highly contagious viral disease, usually seen in young adults.
• It is caused by the Epstein-Barr virus and results in high numbers of typical agranulocytes.
• The disease involves lymphocytes that become enlarged, and was originally thought to involve monocytes, hence the name mononucleosis.
• Symptoms of infectious mononucleosis include sore throat, low fever, tiredness, and achy feelings.

Platelets

• Cytoplasmic fragments of megakaryocytes with a blue-staining outer region and purple granules
• Granules contain serotonin, calcium, enzymes, ADP, and platelet-derived growth factor (PDGF), which help in the clotting process
• Normal platelet count is between 150,000 to 400,000 platelets/mcl of blood
• Circulating platelets are kept inactive and mobile by nitric oxide (NO)
• Platelet formation is regulated by thrombopoietin
• Formed in the myeloid line from megakaryoblast (stage I megakaryocyte)

Platelet Formation

• Stage IV megakaryocyte sends cytoplasmic projections into the lumen of a capillary
• Projections then break off into platelet fragments

Hemostasis

• Fast series of reactions to stop bleeding
• Requires clotting factors and substances released by platelets and injured tissues
• Three steps involved in the clotting process: vascular spasm, platelet plug formation, and coagulation

Vascular Spasm

• Vessel responds to injury with vasoconstriction triggered by direct injury to vascular smooth muscle, chemicals released by endothelial cells, and pain reflexes
• Most effective in smaller blood vessels

Platelet Plug Formation

• Platelets stick to collagen fibers exposed when a vessel is damaged
• Prostacyclins and nitric oxide secreted by endothelial cells prevent platelet sticking
• Von Willebrand factor helps stabilize platelet-collagen adhesion
• Activated platelets swell, become spiked and sticky, and release chemical messengers: • ADP causes more platelets to stick and release their contents • Serotonin and thromboxane A2 enhance vascular spasm and platelet aggregation

Coagulation Process

• Coagulation reinforces the platelet plug with fibrin threads, transforming blood from a liquid to a gel-like state.

Coagulation Factors

• There are 13 clotting factors (procoagulants) involved in the coagulation process, numbered I to XIII in the order of their discovery.
• Vitamin K is necessary for the synthesis of four clotting factors.

Phase 1 of Coagulation

• Coagulation can be initiated by either the intrinsic or extrinsic pathway.
• The intrinsic pathway is triggered by negatively charged surfaces, such as activated platelets, collagen, or glass.
• The extrinsic pathway is triggered by exposure to tissue factor (TF) and is a faster pathway.
• Both pathways cascade towards the activation of factor X.

Phase 1 of Coagulation (Factor X Activation)

• Factor X combines with calcium and platelet factor 3 and factor 5 to form prothrombin activator.

Phase 2 of Coagulation

• Prothrombin activator catalyzes the transformation of prothrombin to the active enzyme thrombin.

Phase 3 of Coagulation

• Thrombin converts soluble fibrinogen to fibrin, forming the structural basis of the clot.
• Fibrin makes the plasma become gel-like and traps formed elements passing by.
• Thrombin, along with calcium, activates factor XIII, the fibrin-stabilizing factor, which cross-links fibrin and strengthens the clot.

Anticoagulants and Blood Coagulation

• Anticoagulants are factors that inhibit blood coagulation, and can also refer to drugs that prevent clotting.

Clot Formation and Stabilization

• A clot must be stabilized and removed after the damaged area has been repaired.
• Clot retraction occurs within 30-60 minutes, where actin and myosin in platelets contract, pulling on fibrin strands and squeezing serum from the clot.
• Serum is plasma minus the clotting proteins.

Clot Retraction and Vessel Repair

• Clot retraction draws ruptured blood vessel edges together, preparing for repair.
• Platelet-derived growth factor (PDGF) is released by platelets, stimulating the division of smooth muscle cells and fibroblasts to rebuild the blood vessel wall.

Fibrinolysis and Clot Removal

• Fibrinolysis is the process of removing clots after repair is completed, starting within 2 days and continuing for several days until the clot is dissolved.
• Plasminogen, a plasma protein trapped in the clot, is converted to plasmin, a fibrin-digesting enzyme.
• Tissue plasminogen activator (tPA), factor XII, and thrombin all play a role in the conversion process.

Thromboembolic Disorders

• Undesirable clot formation can lead to tissue death by blocking circulation
• Thrombus: a clot that develops and persists in an unbroken blood vessel
• Embolus: a thrombus that is freely floating in the bloodstream
• Embolism: an embolus that obstructs a vessel

Treatment of Thromboembolic Disorders

• Anti-coagulant drugs are used to prevent undesirable clotting, such as:
  • Aspirin
  • Heparin
  • Warfarin

Bleeding Disorders

• Abnormalities that prevent normal clot formation
• Thrombocytopenia: a deficit of circulating platelets
• Petechiae: a result of spontaneous widespread hemorrhage

Causes of Thrombocytopenia

• Suppression or destruction of red bone marrow, such as:
  • Malignancy
  • Radiation
  • Drugs

Diagnosis and Treatment of Thrombocytopenia

• Platelet count less than 50k/ul is diagnostic
• Treatment: transfusion of concentrated platelets

Impaired Liver Function

• Inability to synthesize procoagulant factors can be caused by vitamin K deficiency, hepatitis, or cirrhosis
• Liver disease can prevent the liver from producing bile, leading to impaired absorption of fat and vitamin K

Hemophilia

• Hemophilia refers to a group of hereditary bleeding disorders
• Hemophilia A: most common type, caused by factor VIII deficiency
• Hemophilia B: caused by factor IX deficiency
• Hemophilia C: milder form, caused by factor XI deficiency
• Symptoms: prolonged bleeding, especially into joint cavities
• Treatment: injection of genetically engineered factors, eliminating the need for plasma transfusion and the risk of contracting hepatitis or HIV

Disseminated Intravascular Coagulation (DIC)

• Involves both widespread clotting and severe bleeding
• Widespread clotting occurs in intact blood vessels, blocking blood flow
• Severe bleeding follows due to depletion of clotting factors
• Can occur in:
  • Septicemia
  • Incompatible blood transfusions
  • Complications in pregnancy