Chapter 19: Blood

The Cardiovascular System• A circulating transport system that consists of:

– a pump (the heart)– a conducting system (blood vessels)– a fluid medium (blood)

Functions of the Cardiovascular System: To transport materials to and from cells:

- O2 & CO2 - nutrients - hormones - immune system components - waste products

• Cells of the body are serviced by 2 fluids

blood• composed of plasma and a variety of cells• transports nutrients and wastes

interstitial fluid• bathes the cells of the body

• Nutrients and oxygen diffuse from the blood → interstitial fluid → cells

• Wastes move in the reverse direction• Hematology is study of blood and blood disorders

Fluids of the Body

• Fluid connective tissue• Functions include

– Transporting dissolved gases, nutrients, hormones, and metabolic wastes

– Regulating pH and ion composition of interstitial fluids– Restricting fluid loss at injury sites– Defending the body against toxins and pathogens– Regulating body temperature by absorbing and redistributing heat

Blood

Physical Characteristics of BloodThicker (more viscous) than water and flows more slowly than waterTemperature of 100.4◦ F (38◦ C)pH 7.4 (7.35-7.45)8 % of total body weightBlood volume : 5 to 6L in average male ; 4 to 5L in average female

: hormonal negative feedback systems maintain constant blood volume and osmotic pressure

Composition of Blood

Blood Plasma

• 0ver 90% water• 7% plasma proteins -created in liver - confined to bloodstream

– Albumin• maintain blood osmotic pressure

– Globulins (immunoglobulins)• antibodies bind to foreign

substances called antigens• form antigen-antibody complexes

Transport globulins (small molecules):– hormone-binding proteins– Metalloproteins & apolipoproteins (lipoproteins)– steroid-binding proteins

– Fibrinogen • Produce fibrinogen for clotting

Other Plasma Proteins• 1% of plasma:

– changing quantities of specialized plasma proteins – enzymes, hormones, and prohormones

Origins of Plasma Proteins :• 90% made in liver• Antibodies made by plasma cells• Peptide hormones made by endocrine organs

Serum -liquid part of a blood sample in which dissolved fibrinogen has converted to solid fibrin ; it is plasma minus clotting proteins

Other Substances– 2% of plasma– electrolytes, nutrients, gases, waste products

Formed Elements of Blood• Red blood cells ( erythrocytes ) – transport oxygen• White blood cells ( leukocytes ) – immune functions

– granular leukocytes : neutrophils, eosinophils, basophils– agranular leukocytes

• lymphocytes = T cells, B cells, and natural killer cells• Monocytes

• Platelets (special cell fragments) – blood clotting

• Only WBCs are complete cells• RBCs have no nuclei or organelles, and platelets are just cell fragments• Most formed elements survive in the bloodstream for only a few days• Most blood cells do not divide but are renewed by cells in bone marrow

Hematocrit

• Percentage of blood occupied by cells • female normal range

• 38 - 46% (average of 42%)– male normal range

• 40 - 54% (average of 46%)• testosterone

• Anemia – not enough RBCs or not enough hemoglobin

• Polycythemia– too many RBCs (over 65%)– dehydration, tissue hypoxia, blood doping in athletes

Erythrocytes (RBCs)

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

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

• Give erythrocytes their flexibility -7.8 µm RBC passes through 4 µm capillary

• 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)

Copyright © 2004 Pearson Education, Inc., publishing as Benjamin Cummings

Hemopoiesis: formation of blood cells

• Also known as hematopoiesis• Occurs in the red marrow (found in spaces of spongy bone):

– In adults, mostly in the proximal epiphysis of femur and bodies of the lumbar vertebrae

– Originally from pluripotent stem cells from mesenchyme– In the fetus, hematopoiesis occurs in the liver, spleen, thymus,

lymph nodes and yolk sac• Erythropoietin from the kidneys stimulates hematopoiesis

Erythrocyte development

Myeloid Stem Cell

Components needed for RBC: -amino acids -iron -vit. B12, B6, and folic acid - carbohydrates - lipids

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 (oxyhemoglobin)• Each RBC contains an average of 250 million Hb molecules• Each Hb molecule has 4 oxygen binding sites• That’s about 1 billion oxygen molecules per RBC!• CO (carbon monoxide) has approximately 200 times the affinity

for Hb than oxygen and it can fool O2 saturation detectors

Hemoglobin Structure

• Complex quaternary structure

Figure 19–3

Fetal Hemoglobin• Strong form of hemoglobin found in embryos• Takes oxygen from mother’s hemoglobin

Carbaminohemoglobin• With low oxygen (peripheral capillaries):

– hemoglobin releases oxygen– binds carbon dioxide and carries it to lungs

Anemia - Hematocrit or hemoglobin levels are below normal

- Is caused by several conditions

Figure 19–4

Recycling RBCs

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 & fragile, & their Hgb 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

• 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

Stimulating Hormones

• Erythropoietin (EPO) • Also called erythropoiesis-stimulating hormone:

– secreted when oxygen in peripheral tissues is low (hypoxia) – due to disease or high altitude

Diagnosing Disorders

• Hemoglobinuria:– hemoglobin breakdown products in urine due to excess

hemolysis in blood stream• Hematuria:

– whole red blood cells in urine due to kidney or tissue damage

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

Anemia: Decreased Hemoglobin Content● Iron-deficiency anemia results from:

- A secondary result of hemorrhagic anemia

- Inadequate intake of iron-containing foods

- Impaired iron absorption

● Pernicious anemia results from:

- Deficiency of vitamin B12

- Lack of intrinsic factor needed for absorption of B12

→Treatment is intramuscular injection of B12

Anemia: Abnormal Hemoglobin• Thalassemias – absent or faulty globin chain in hemoglobin

– Erythrocytes are thin, delicate, and deficient in hemoglobin• Sickle-cell anemia – results from a defective gene coding for an

abnormal hemoglobin called hemoglobin S (HbS)– HbS has a single amino acid substitution in the beta chain– causes RBCs to become sickle-shaped in low oxygen situations

Sickle Cell

Disease

Polycythemia• Polycythemia – excess RBCs that increase blood viscosity • Three main polycythemias are:

– Polycythemia vera– Secondary polycythemia– Blood doping

RBC homeostasi

s

Erythropoietin Mechanism

Figure 17.6

Imbalance

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

RBC Tests

Table 19–1

• RBC membranes have glycoprotein antigens on their external surfaces• These antigens are:

– Unique to the individual – Recognized as foreign if transfused into another individual– Promoters of agglutination and are referred to as agglutinogens

• Presence or absence of these antigens is used to classify blood groups• Humans have 30 varieties of naturally occurring RBC antigens• The antigens of the ABO and Rh blood groups cause vigorous

transfusion reactions when they are improperly transfused• Other blood groups (M, N, Dufy, Kell, and Lewis) are mainly used for

legalities

Human Blood Groups

• The ABO blood groups consist of:– Two antigens (A and B) on the surface of the RBCs – Two antibodies in the plasma (anti-A and anti-B)

• An individual with ABO blood may have various types of antigens and spontaneously preformed antibodies

• Agglutinogens and their corresponding antibodies cannot be mixed without serious hemolytic reactions

• FOUR BASIC BLOOD TYPES:

ABO Blood Groups

Blood Plasma Antibodies

• Type A: type B antibodies• Type B: type A antibodies• Type O: both A and B antibodies• Type AB: neither A nor B

ABO Blood Groups

Table 17.4

• Also called D antigen• Presence of the Rh agglutinogens on RBCs is indicated as Rh+; 85% of population is +• Lack of antigen indicated as Rh -; 15% of population.• Anti-Rh antibodies are not spontaneously formed • However, if an Rh– individual receives Rh+ blood, anti-Rh antibodies form• A second exposure to Rh+ blood will result in a typical transfusion reaction• Therefore, only sensitized Rh— blood has anti-Rh antibodies • Hemolytic Disease of the Newborn: Rh- mom pregnant with an Rh+ fetus→ mom forms anti-Rh antibodies During next pregnancies: Anti- Rh+ antibodies sensitized Rh– mother cross the placenta and attack and destroy the RBCs of an Rh+ baby The drug RhoGAM can prevent the Rh– mother from becoming sensitized Treatment of hemolytic disease of the newborn involves pre-birth transfusions and exchange transfusions after birth

Rh Blood Groups

Copyright © 2004 Pearson Education, Inc., publishing as Benjamin Cummings

Rh Factor

• Transfusion reactions occur when mismatched blood is infused• Donor’s cells are attacked by the recipient’s plasma agglutinins causing:

– Diminished oxygen-carrying capacity– Clumped cells that impede blood flow– Ruptured RBCs that release free hemoglobin into the bloodstream

• Circulating hemoglobin precipitates in the kidneys and causes renal failure

• Blood Type/ Cross MatchTest – determines blood type & compatibility

Transfusion Reactions/Cross Reactions

Leukocytes/ White Blood Cells (WBCs) Do not have hemoglobin ; Have nuclei & other organelles ; complete cells

WBC Functions:•Defend against pathogens•Remove toxins and wastes•Attack abnormal cells

Most WBCs are in connective tissue proper & lymphatic system organs

Small numbers in blood: 6000 to 9000/microliter→ Circulating WBCs

- Migrate out of bloodstream via diapedesis

- Move through tissues via amoeboid movement

- Attracted to chemical stimuli (positive chemotaxis)

- Some are phagocytic: neutrophils, eosinophils, and monocytes

Leukocytosis – WBC count over 11,000/mm3

- Normal response to bacterial or viral invasion

Leukopenia - a decrease in WBC count below 4,800/mm3

Leukemia - a cancer of WBC

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Emigration & Phagocytosis in WBCs

• WBCs roll along endothelium, stick to it & squeeze between cells.– adhesion molecules

(selectins) help WBCs stick to endothelium

• displayed near site of injury

– molecules (integrins) found on neutrophils assist in movement through wall

• Neutrophils & macrophages phagocytize bacteria & debris– chemotaxis of both

• kinins from injury site & toxins

Figure 19–9

5 Types of WBCs

Granulocytes:Neutrophils, Eosinophils, BasophilsAgranulocytes: Monocytes, Lymphyocytes

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lymphocyte basophil

monocyte neutrophileosinophil

Granulocytes – neutrophils, eosinophils, basophils

• Contain cytoplasmic granules that stain specifically (acidic, basic, or both) with Wright’s stain– Are larger and usually shorter-lived than RBCs– Have lobed nuclei– Are all phagocytic cells

Neutrophils – Polymorphonuclear Leukocytes (PMNs)

• 50–70% of circulating WBCs• Nuclei = 2 to 5 lobes connected by thin strandsNuclei = 2 to 5 lobes connected by thin strands

– older cells have more lobesolder cells have more lobes– young cells called band cells because of horseshoe shaped nucleus young cells called band cells because of horseshoe shaped nucleus

(band)(band)• Pale cytoplasm granules (lilac shade) with:

– lysosomal enzymes- bactericides (hydrogen peroxide and superoxide)- Fastest response of all WBC to bacteria; 1st to attack bacteria– Engulf pathogens– Digest pathogens– Release prostaglandins and leukotrienes– Form pus

Degranulation - removing granules from cytoplasm– Defensins: peptides from lysosomes :attack pathogen membranes

Eosinophils/Acidophils

• 2–4% of circulating WBCs• Attack large parasites• Excrete toxic compounds:

– nitric oxide– cytotoxic enzymes

• Eosinophils account for 1–4% of WBCs – Have red-staining, bilobed nuclei connected via a broad band of nuclear

material (but can be 3 lobes)– Have red to crimson (acidophilic) large, coarse, lysosome-like granules– Granules do not obscure the nucleus– Lead the body’s counterattack against parasitic worms– Lessen the severity of allergies by phagocytizing Ag-Ab complexes

• Leave capillaries to enter tissue fluid• Release histaminase

– slows down inflammation caused by basophils

Basophils • Are less than 1% of circulating WBCs (usually 0.5%)

– Have U- or S-shaped bilobed nuclei with two or three conspicuous constrictions

– Have large, purplish-black (basophilic) granules that obscure the nucleus• Accumulate in damaged tissue

Basophil Actions :

• Involved in inflammatory and allergy reactions

• Leave capillaries & enter connective tissue as mast cells

• Release heparin, histamine & serotonin

– heighten the inflammatory response and account for hypersensitivity (allergic) reaction

• Histamine: – inflammatory chemical that acts as a vasodilator and attracts other WBCs

(antihistamines counter this effect)• Heparin:

– prevents blood clotting

• Lymphocytes and Monocytes:– Lack visible cytoplasmic granules– Are similar structurally, but are functionally distinct and unrelated

cell types– Have spherical (lymphocytes) or kidney-shaped (monocytes)

nuclei

Agranulocytes

Monocytes

– 2–8% of circulating WBCs– They are the largest leukocytes– They have purple-staining, U- or kidney-shaped nuclei– They leave the circulation, enter tissue, and differentiate into

macrophages

Macrophage Actions :• Take longer to get to site of infection, but arrive in larger numbers• Become wandering macrophages, once they leave the capillaries• Destroy microbes and clean up dead tissue following an infection• Engulf large particles and pathogens• Secrete substances that attract immune system cells and

fibroblasts to injured area

Lymphocytes• 20–30% of circulating WBCs• Are larger than RBCs• Migrate in and out of blood• Mostly in connective tissues and lymphatic organs Lymphocyte Actions :• Are part of the body’s specific defense system• Generally increased in levels during viral infection • THREE CLASSES OF LYMPHOCYTES:

1. T cells - Cell-mediated immunity →Attack foreign cells directly2. B cells - Humoral immunity→Differentiate into plasma cells that synthesize antibodies3. Natural killer (NK) cells -Detect and destroy abnormal tissue cells (ex. Cancers)

The Differential Count of Circulating WBCs

• Detects changes in WBC populations• Infections, inflammation, and allergic reactions

WBC Disorders• Leukopenia:

– abnormally low WBC count• Leukocytosis:

– abnormally high WBC count• Leukemia:

– extremely high WBC count

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Differential WBC Count

• Detection of changes in numbers of circulating WBCs (percentages of each type)– indicates infection, poisoning, leukemia, chemotherapy, parasites or

allergy reaction• Normal WBC counts

– neutrophils 60-70% (up if bacterial infection)– lymphocyte 20-25% (up if viral infection)– monocytes 3 -- 8 % (up if fungal/viral infection)– eosinophil 2 -- 4 % (up if parasite or allergy reaction)– basophil <1% (up if allergy reaction or hypothyroid)

WBC Disorders• Leukopenia: abnormally low WBC count• Leukocytosis: abnormally high WBC count• Leukemia: extremely high WBC count

Figure 19–10

WBC Production

WBC Production• All blood cells originate from hemocytoblasts:

– which produce myeloid stem cells and lymphoid stem cells• Myeloid Stem Cells• Differentiate into progenitor cells:

– which produce all WBCs except lymphocytes• Lymphocytes are produced by lymphoid stem cells• Lymphopoiesis: the production of lymphocytes• WBCs, except monocytes, develop fully in bone marrow• Monocytes develop into macrophages in peripheral tissues

Other Lymphopoiesis• Some lymphoid stem cells migrate to peripheral lymphoid tissues

(thymus, spleen, lymph nodes) • Also produce lymphocytes

4 Colony-Stimulating Factors (CSFs)

• Hormones that regulate blood cell populations:

1. M-CSF-stimulates monocyte production

2. G-CSF-stimulates granulocyte production• neutrophils, eosinophils, and basophils

3. GM-CSF- stimulates granulocyte & monocyte production

- neutrophils, eosinophils, basophils, monocytes

4. Multi-CSF- accelerates production of granulocytes, monocytes,

platelets & RBCs

Table 19–3

Platelets• Cell fragments involved in human clotting system• Nonmammalian vertebrates have thrombocytes (nucleated cells) • Flattened discs• Circulate for 9-12 days before being removed by phagocytes in spleen• 2/3 are reserved for emergencies• Thrombocytopoiesis – platelet production ; occurs in bone marrow

• Myeloid stem cells→ megakaryocyte-colony forming cells→ megakaryoblast→ megakaryocytes whose cell fragments form platelets

• Rate of platelet formation is stimulated by thrombopoietin, thrombocyte-stimulating factor, interleukin-6, and Multi-CSF

PLATELET FUNCTIONS:1. Release important clotting chemicals2. Temporarily patch damaged vessel walls3. Actively contract tissue after clot formationPLATELET COUNT:• 150,000 to 500,000/ microliter - normal Thrombocytopenia vs. Thrombocytosis

Complete Blood Count

• Screens for anemia and infection• Total RBC, WBC & platelet counts; differential WBC; hematocrit

and hemoglobin measurements• Normal hemoglobin range

– infants have 14 to 20 g/100mL of blood– adult females have 12 to 16 g/100mL of blood– adult males have 13.5 to 18g/100mL of blood

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What mechanisms control blood loss after injury,

and what is the reaction sequence in blood clotting?

Hemostasis

• Stoppage of bleeding in a quick & localized fashion when blood vessels are damaged

• Prevents hemorrhage (loss of a large amount of blood)• Three Phases:

– vascular phase– platelet phase– coagulation phase

Figure 19–11a

The Vascular Phase• Damage to blood vessel stimulates

pain receptors• Reflex contraction of smooth muscle

of small blood vessels• Can reduce blood loss for 30 min. to

several hours until other mechanisms can take over

• Only for small blood vessel or arteriole

THREE STEPS:1. Endothelial cells contract→expose basal lamina to bloodstream2. Endothelial cells release: chemical factors: ADP, tissue factor, and prostacyclin local hormones: endothelins→ stimulate smooth muscle contraction and cell division3. Endothelial cell membranes become “sticky”: seal off blood flow

Copyright © 2004 Pearson Education, Inc., publishing as Benjamin Cummings Figure 19.13

Platelet Phase - within 15 seconds of injury

• Platelets store a lot of chemicals in granules needed for platelet plug formation– alpha granules

• clotting factors • platelet-derived growth factor– cause proliferation of vascular endothelial cells, smooth muscle & fibroblasts to repair damaged vessels

– dense granules• ADP, ATP, Ca+2, serotonin, fibrin-stabilizing factor, & enzymes that produce thromboxane A2

• Steps in the process– (1) platelet adhesion (2) platelet release reaction (3) platelet aggregation 65

Platelet Adhesion (Attachment)Platelets adhere to sticky endothelial surfaces, to basal lamina & to exposed collagen fibers underlying damaged endothelial cells in vessel wall

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Platelet Release Reaction• Platelets activated by adhesion extend projections to make contact with

each other • Release thromboxane A2 & ADP activating other platelets• Serotonin & thromboxane A2 are vasoconstrictors decreasing blood flow

through the injured vessel

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Platelet Aggregation • Activated platelets stick together and activate new platelets to form a

mass called a platelet plug→ closes small breaks• Plug reinforced by fibrin threads formed during clotting process

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Platelet Plug: Size Restriction

• Prostacyclin:– released by endothelial cells– inhibits platelet aggregation

• Inhibitory compounds:– released by other white blood cells

• Circulating enzymes:– break down ADP

• Negative (inhibitory) feedback:– from serotonin

• Development of blood clot:– isolates area

Coagulation Phase (begins about 30 sec. after injury)

• Blood drawn from the body thickens into a gel– gel separates into liquid (serum) and a clot of insoluble fibers (fibrin) in

which the cells are trapped• If clotting occurs in an unbroken vessel → thrombosis• Substances required for clotting are Ca+2, enzymes synthesized by liver

cells and substances released by platelets or damaged tissues• Clotting is a cascade of reactions in which each clotting factor activates

the next in a fixed sequence resulting in the formation of fibrin threads– prothrombinase & Ca+2 convert prothrombin into thrombin– thrombin converts fibrinogen into fibrin threadsBlood Clot :– Fibrin network– Covers platelet plug– Traps blood cells– Seals off area

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Figure 19–12a

Overview of the Clotting Cascade

• Prothrombinase is formed by either the intrinsic or extrinsic pathway

• Final common pathway produces fibrin threads

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______________

Extrinsic Pathway

• Begins in vessel wall outside bloodstream

• Damaged tissues leak tissue factor (thromboplastin) into bloodstream

• Prothrombinase forms in seconds

• In the presence of Ca+2, clotting factor X combines with V to form prothrombinase

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Intrinsic Pathway

• Begins with coagulating enzymes within bloodstream– endothelium is damaged

& platelets come in contact with collagen of blood vessel wall

– platelets damaged & release phospholipids

• Requires several minutes for reaction to occur

• Substances involved:

- Ca+2

- clotting factors XII, X, V

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Final Common Pathway ( Extrinsic & Intrinsic pathways converge)

• Prothrombinase and Ca+2

– catalyze the conversion of prothrombin to thrombin

• Thrombin

– in the presence of Ca+2 converts soluble fibrinogen to insoluble fibrin threads

– activates fibrin stabilizing factor XIII

– positive feedback effects of thrombin

• accelerates formation of prothrombinase

• activates platelets to release phospholipids

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Copyright © 2004 Pearson Education, Inc., publishing as Benjamin Cummings

Plasma Clotting Factors (Procoagulants)

Table 19–4

They are proteins or ions in plasma required for normal clotting **note: Calcium & vit. K are both essential to clotting process**

Clot Retraction & Blood Vessel Repair

• Clot plugs ruptured area of blood vessel

• Platelets pull on fibrin threads causing clot retraction – trapped platelets release

factor XIII stabilizing the fibrin threads

• Edges of damaged vessel are pulled together

• Fibroblasts & endothelial cells repair the blood vessel

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Clot Retraction

• After clot has formed:– Platelets contract and pull torn area together

• Takes 30–60 minutes

FibrinolysisSlow process of dissolving clot:

thrombin and tissue plasminogen activator (t-PA)→ activate plasminogen

Plasminogen produces plasmin→ digests fibrin strands