Hematologic System Objectives

Clot retraction is the...

"shrinking" of a blood clot over a number of days. In so doing, the edges of the blood vessel wall at the point of injury are slowly brought together again to repair the damage. This involves the shortening of fibrin threads and the squeezing out of excess serum

RBCs

48% (42% in women) of blood cells. Responsible for tissue oxygenation. Contain hemoglobin (carry gases and electrolytes). No nucleus or cytoplasmic organelles (so it can't synthesize protein or carry out oxidative reactions)). Can't undergo mitosis, therefore they only live 120 days before cell death and replacement. Small, bioconcave disc that can be reversibly deformed (allows to assume compact shape to squeeze through microcirculation and then return to normal).

Albumin

60%: serves as a carrier molecule for normal components of blood as well as drugs that have low solubility in water. Its most essential role is regulation of the passage of water and solutes through the capillaries.

plasma proteins

7% of plasma weight. Two groups: Albumin and Globulin

Erythropoiesis cannot proceed in the absence of what vitamins?

B12, folate (folic acid), B6, riboflavin, pantothenic acid, niacin, ascorbic acid, and vitamin E.

Identify sites of active bone marrow in adults.

In adults, active marrow is found primarily in the flat bones of the pelvis (34%), vertebrae (28%), cranium and mandible (13%), sternum and ribs (10%), and in the extreme proximal portions of the humerus and femur (4% to 8%).

WBCs

Leukocytes defend the body against microorganisms that cause infection and remove debris, including dead or injured cells of all kinds. Act primarily in the tissues but are transported in the circulation. The average adult has approximately 5,000 to 10,000 leukocytes/mm3 of blood. Leukocytes are classified according to structure as either granulocytes or agranulocytes and according to function as either phagocytes or immunocytes. The granulocytes, which include neutrophils, basophils, and eosinophils, are all phagocytes. The agranulocytes (monocytes and macrophages) are phagocytes, and lymphocytes are immunocytes (cells that create immunity).

Discuss the processes associated with platelet activation.

Platelet activation is primarily under the control of endothelial cells lining the vessels. • Damage to the vessel initiates a process of platelet activation: o (1) increased platelet adhesion to the damaged vascular wall o (2) activation leading to secretion of chemicals from platelet granules, which stimulate changes in platelet shape and biochemistry o (3) aggregation as platelet-vascular wall and platelet-platelet adherence increases. This process leads to activation of the clotting system and development of an immobilizing meshwork of platelets and fibrin

Characterize the mononuclear phagocyte system (MPS).

The MPS is the main line of defense against bacteria in the bloodstream and cleanses the blood by removing old, injured, or dead blood cells; antigen-antibody complexes; and macromolecules. The MPS is composed of macrophages in tissue and lymphoid organs.

Describe the five stages of the hemostatic mechanism.

The general sequence of events in hemostasis are: o (1) vascular injury leads to a transient arteriolar vasoconstriction to limit blood flow to the affected site o (2) damage to the endothelial cell lining of the vessel exposes prothrombogenic subendothelial connective tissue matrix leading to platelet adherence and activation and formation of a hemostatic plug to prevent further bleeding (primary hemostasis) o (3) tissue factor, produced by the endothelium, collaborates with secreted platelet factors and activated platelets to activate the clotting (coagulation) system to form fibrin clots and further prevent bleeding (secondary hemostasis) o (4) the fibrin/platelet clot contracts to form a more permanent plug, and regulatory pathways are activated (fibrinolysis) to limit the size of the plug o (5) the healing process

Globulin

The globulins are classified by their movement relative to albumin: alpha (α) globulins (those moving most closely to albumin), beta (β) globulins, and gamma (γ) globulins (those with the least movement). They act as antibodies

list the specific granulocytes

There are three types of granulocytes: neutrophils, basophils, and eosinophils.

Dietary vitamin B12

a large molecule that requires a protein secreted by parietal cells into the stomach (intrinsic factor [IF]) for transport across the ileum. Once absorbed, vitamin B12 is stored in the liver and used as needed in erythropoiesis. Defects in IF production lead to decreased B12 absorption and pernicious anemia.

Globulins function

about 34% of total plasma protein, antibodies

Fibrinogen function

about 4% of total plasma protein, most plentiful of the clotting factors and is the precursor of the fibrin clot

Albumin function

about 60% of total plasma protein at a concentration of about 4 g/dl, serves as a carrier molecule for normal components of blood as well as drugs that have low solubility in water

what are the three major plasma proteins?

albumin globulin fibrinogen

Hemostasis is defined as

arrest of bleeding.

Folate

deficiency is more common than vitamin B12 deficiency and occurs more rapidly. Folate stores can be depleted within a few months, whereas vitamin B12 depletion can take years. Folate supplements are prescribed for pregnant women because pregnancy increases the demand for folate and may cause anemia.

platelets

disk-shaped cytoplasmic fragments that are essential for blood coagulation and control of bleeding. They are formed by fragmentation of very large cells known as mega-Karyocytes. They lack a nucleus, have no deoxyribonucleic acid (DNA), and are incapable of mitotic division. There are approximately 140,000 to 340,000 platelets/mm3 of circulating blood. An additional one third of the body's available platelets are in a reserve pool in the spleen. A platelet circulates for approximately 10 days, ages, and is removed by macrophages of the MPS, mostly in the spleen.

bone marrow aspiration and biopsy are important in detecting...

hematopoiesis because the cells can be assessed with respect to o (1) relative numbers of stem cells and their developing daughter cells. o (2) morphologic structure

The endothelium is the major site of __________

hemostasis. Despite the continual presence of clotting factors and platelets in the circulation, blood normally remains fluid. Thus the major regulatory factors that control hemostasis reside where the greatest probability of clotting would occur: on the endothelial cell surface

Folate

is the second most important vitamin for erythrocyte production and maturation. Folate is necessary for DNA synthesis, being a component of three of the four DNA bases (thymine, adenine, and guanine), and RNA synthesis. Folate absorption occurs principally in the upper small intestine and is stored in the liver.

list the agranulocytes

lymphocytes and monocytes

Senescent platelets are destroyed by...

mononuclear cell phagocytosis.

role of antithrombin III in hemostasis

o Antithrombin III: a circulating plasma serine protease inhibitor produced by the liver. Specifically, it inhibits thrombin and several activated clotting factors

compare the functions of monocytes, lymphocytes, and natural killer (NK) cells.

o Monocytes migrate from the bloodstream and enter tissue (eating). These mature into macrophages (important germ eating cells). A low number can put you at a high risk of infection, particularly those caused by bacteria. Lymphocytes are the primary cells of the immune response. These include T-cells, B-cells, and natural killer (NK) cells. Viral infections may cause an increase in quantity. T cells are crucial to the immune response because they possess a unique 'memory' system which allows them to quickly identify and destroy pathogens that the body has been previously exposed to. B cells make antibodies that bind to pathogens to enable their destruction Natural killer (NK) cells kill viruses that act on cells (including tumor cells) without being induced by previous exposure.

role of protein C in hemostasis

o Protein C: in the circulation binds to thrombomodulin in a thrombin-dependent manner and is converted to activated protein C Activated protein C, in association with a cofactor (protein S), degrades factors Va and VIIIa. Deficiencies of AT-III, protein C, or protein S are important causes of hypercoagulation (increased clotting).

role of protein S in hemostasis

o Protein S: Cofactor of protein C. Helps degrade factors Va and VIIIa. Deficiency causes hypercoagulation (increased clotting).

role of tissue factor pathway inhibitor (TFPI) in hemostasis

o Tissue factor pathway inhibitor (TFPI): produced by endothelial cells and complexes to, and reversibly inhibits, factor Xa. The resultant TFPI/Xa complex inhibits TF/VIIa, which mediates feedback inhibition of tissue factor as well as factor VIIa. Although the majority of TFPI remains associated with endothelial surfaces, about 20% circulates in plasma with lipoproteins. Heparin increases plasma levels of TFPI, which may contribute to heparin's antithrombotic effects.

The role of platelets is to:

o contribute to regulation of blood flow into a damaged site by induction of vasoconstriction o initiate platelet-to-platelet interactions resulting in formation of a platelet plug to stop further bleeding o activate the coagulation cascade to stabilize the platelet plug o initiate repair processes including clot retraction and clot dissolution. The state of platelet activation is primarily under the control of endothelial cells lining the vessels. Damage to the vessel initiates a process of platelet activation

Normal development of erythrocytes and synthesis of hemoglobin depends on adequate supplies of what necessary building blocks?

protein, vitamins, and minerals. If these components are lacking for a prolonged time, erythrocyte production slows and anemia may result.

Maintenance of optimal levels of granulocytes and monocytes in the blood depends on...

the availability of pluripotent stem cells in the marrow, induction of these into committed stem cells, timely release of new cells from the marrow, and mobilization of the granulocyte reserve pool.

Three equally important components of hemostasis are:

the vasculature (endothelial cells and subendothelial matrix), platelets, and blood proteins (clotting factors).

Erythrocytes are primarily responsible for _______ ________

tissue oxygenation

Describe the structure of the hemoglobin molecule.

• A hemoglobin molecule is composed of two pairs of polypeptide chains (the globins) and four colorful complexes of iron plus protoporphyrin (the hemes). • Hemoglobin molecules carry gases and electrolytes that diffuse through a cell's plasma membrane

As a result of hemostasis, damaged blood vessels maintain a relatively steady state of...

blood volume, pressure, and flow. The importance of hemostasis clearly varies with vessel size. Damage to large vessels cannot easily be controlled by hemostasis but requires vascular contraction and dramatically decreased blood flow into the damaged vessels.

formed elements

consist of RBCs, WBCs, and platelets

Describe the sequence of destruction for senescent erythrocytes.

• After about 100 to 120 days in the circulation, old erythrocytes are removed by tissue macrophages, primarily in the spleen. • Because they do have cytoplasmic enzymes capable of glycolysis (which provides the energy needed to maintain cell function and membrane pliability) metabolic processes diminish as the erythrocyte ages, so less ATP is available to maintain plasma membrane function. • The senescent red cell becomes increasingly fragile and loses its reversible deformability, becoming susceptible to rupture while passing through narrowed regions of the microcirculation. • Plasma membrane of senescent red cells undergo phospholipid rearrangement that is recognized by receptors on macrophages (primarily in the spleen) that selectively remove and sequester the red cells. o If the spleen is dysfunctional or absent, macrophages in the liver (Kupffer cells) take over. • The erythrocytes are digested by proteolytic and lipolytic enzymes in the phagolysosomes (digestive vacuoles) of the macrophage. • The heme and globin of methemoglobin dissociate easily, and the globin is broken down into its component amino acids. • The iron in hemoglobin is oxidized, forming Fe+3 (methemoglobin), and recycled. • Porphyrin is reduced to bilirubin, which is transported to the liver, conjugated, and finally excreted in the bile as glucuronide

Name structure and function of an agranulocyte;

• Agranulocytes (monocytes and macrophages) are phagocytes, and lymphocytes are immunocytes (cells that create immunity). • Agranulocytes differ from the granulocytes in that they contain relatively fewer granules in their cytoplasm. • Agranulocytes co-ordinate immune response

what are the structural characteristics and values of RBCs?

• An RBC is a small disk with two unique properties: (1) a biconcave shape and (2) the capacity to be reversibly deformed • Most abundant cells of the blood, occupying approximately 48% of the blood volume in men and about 42% in women.

Describe the role of transferrin, apotransferrin, ferritin, apoferritin, and hemosiderin in the iron cycle.

• Apotransferrin: a glycoprotein synthesized primarily by hepatocytes in the liver but also produced in small quantities by tissue macrophages, submaxillary and mammary glands, and ovaries or testes. Iron from either dietary sources or erythrocyte catabolism is transported in the blood bound to apotransferrin, which is then called transferrin. • Ferritin: the major intracellular iron storage protein. • Hemosiderin: Apoferritin is ferritin without attached iron. It can store thousands of atoms of iron. Several (24) apoferritin complexes combine to form ferritin micelles, known as hemosiderin.

Describe changes that occur within the hematologic system with aging.

• Blood composition changes little with age. • A delay in erythrocyte replenishment may occur after bleeding, presumably because of iron deficiency. • Lymphocyte function appears to decrease with age. Particularly affected is a decrease in cellular immunity. • Platelet adhesiveness probably increases with age.

Describe and identify the effects of colony-stimulating factors; identify the specific colony-stimulating factors for neutrophils, macrophages, and erythrocytes.

• Colony-stimulating factors (CSF) are glycoproteins that regulate the generation and the functions of various blood cells. • Specific colony-stimulating factors o Neutrophils: G-CSF o Macrophages: GM-CSF, M-CSF o Erythrocytes: erythropoietin

Describe the maturation sequence for platelets (thrombocytes).

• During thrombopoiesis, the megakaryocyte progenitor is programmed to undergo endomitotic cell cycle during which DNA replication occurs, but anaphase and cytokinesis are blocked. Therefore, the nucleus enlarges and becomes polyploidy with no cellular division. • The number of cytoplasmic organelles increase and the cell develops elongations and branches that fragment into platelets. • Platelets lack a nucleus. • About two thirds enter circulation, the rest remain in the splenic pool. • Platelets circulate for ten days before losing ability to carry out thrombogenic activity.

Describe the association of fibrin degradation products (FDPs) and D-dimers to the fibrinolytic system.

• Fibrin degradation products: Product of fibrinolysis • D-dimers: A major fibrin degradation product. Two D domains from adjacent fibrin monomers that are cross-linked by factor XIIIa. Measurement used for diagnosis of deep venous thrombosis or pulmonary embolism

Describe the locations and process of hematopoiesis.

• Hematopoiesis, or blood cell production, occurs in the liver and spleen of the fetus and in the bone marrow after birth. • Hematopoiesis involves two stages: (1) proliferation and (2) maturation. The bone marrow contains multiple populations of stem cells; mesenchymal stem cells develop into fibroblasts, osteoclasts, and adipocytes; and hematopoietic stem cells develop into blood cells.

Characterize the cellular changes that take place in red blood cell maturation.

• In the bone marrow, erythroid progenitor cells proliferate and differentiate into large, nucleated proerythroblasts. • The proerythroblast synthesizes hemoglobin and eliminates most intracellular structures (including the nucleus) then becomes a normoblast. • The red blood cell becomes a reticulocyte when it leaves the bone marrow and enters the blood stream. • The reticulocyte matures into an erythrocyte within 24 to 48 hours. During this period, mitochondria and ribosomes disappear and the cell becomes smaller and more disk-like.

Compare and contrast the development of granulocytes, monocytes, macrophages, and lymphocytes.

• Most leukocytes develop from stem cells in the bone marrow. Depending on the type, they can live in the body for years. • Hematopoietic stem cells differentiate into two populations of progenitor cells: common lymphoid progenitors and common myeloid progenitors. o Lymphoid progenitors that remain in the bone marrow undergo differentiation into the B-cell lineage, after which they are released into the circulation and undergo further maturation in the secondary lymphoid organs. o Myeloid progenitors futher differentiate into progenitors for basophils, mast cells, eosinophils, and megakaryocytes, and granulocyte/monocyte progenitors. o The granulocyte/monocyte progenitors further differentiate into monocyte progenitors and granulocyte progenitors, which develop into monocytes/macrophages and neutrophils. • Monocytes mature into various forms of macrophages, which is usually complete within 1 or 2 days after release. • Progenitor cells for granulocytes normally fully mature in the bone marrow into neutrophils, eosinophils, and basophils. • Granulocytes are released into the blood within 14 days of development. The bone marrow selectively retains immature granulocytes as a reserve pool that can be rapidly mobilized in response to the body's needs.

plasmin

• Plasmin: is a serine protease that degrades fibrin polymers in clots .

plasminogen activator

• Plasminogen activator: Serine protease that reaches maximum enzymatic activity after binding to fibrin and proteolytically activates plasminogen to plasmin.

plasminogen

• Plasminogen: Inactive precursor of plasmin. Produced in the liver.

Describe the development of platelets (thrombocytes).

• Platelets are derived from stem cells and progenitor cells that differentiate into megakaryocytes. During thrombopoiesis, the megakaryocyte progenitor is programmed to undergo an endomitotic cell cycle during which DNA replication occurs, but anaphase and cytokinesis are blocked .Thus the megakaryocyte nucleus enlarges and become extremely polyploidy without cellular division. Concurrently, the numbers of cytoplasmic organelles (e.g., internal membranes, granules) increase, and the cell develops cell surface elongations and branches that progressively fragment into platelets. A single megakaryocyte may produce thousands of platelets. Like erythrocytes, platelets released from the bone marrow lack nuclei. About two thirds of platelets enter the circulation, and the remainder reside in the splenic pool. • Platelets circulate in the bloodstream for about 10 days before losing their ability to carry out thrombogenic activity. Senescent platelets are sequestered and destroyed in the spleen by mononuclear cell phagocytosis.

Describe the mechanism and function of clot retraction.

• Retraction is facilitated by fibrinogen bridges between receptors on the platelets. The GPIIb-IIIa-fibrinogen pathway is essential for the formation of a thrombus and as such is an important therapeutic target for blockage by antiplatelet drugs. • Fibrin strands within the clot shorten, becoming denser and stronger, helping the clot to approximate the edges of the injured vessel wall and sealing the site of injury.

Characterize the coagulation cascade.

• The coagulation cascade is a series of reactions by which a small stimulus is amplified to produce rapid coagulation • The coagulation cascade is composed of intrinsic and extrinsic pathways, with the extrinsic pathway being dominant. • The intrinsic pathway is initiated by TF that forms a complex with TF/VIIa complex. It is activated when Hageman factor (factor XII) in plasma contacts negatively charged subendothelial substances exposed by vascular injury. • The extrinsic pathway is activated when membrane-bound or soluble tissue factor (TF) a substance released by damaged endothelial cells, reacts with a high affinity with activated factor VII (TF/VIIa). The resultant complexes of both pathways are enzymatically active with factor X as the substrate.

Name structure and function of a granulocyte

• The granulocytes include neutrophils, basophils, and eosinophils • Granulocytes have many membrane bound granules in their cytoplasm. • Granulocytes are phagocytes. The granules contain enzymes capable of killing microorganisms and catabolizing debris ingested during phagocytosis. The granules also contain powerful biochemical mediators with inflammatory and immune functions.

Compare the activation of the intrinsic and extrinsic pathways.

• The intrinsic pathway is initiated by TF that forms a complex with TF/VIIa complex. It is activated when Hageman factor (factor XII) in plasma contacts negatively charged subendothelial substances exposed by vascular injury. • The extrinsic pathway is activated when membrane-bound or soluble tissue factor (TF) a substance released by damaged endothelial cells, reacts with a high affinity with activated factor VII (TF/VIIa). The resultant complexes of both pathways are enzymatically active with factor X as the substrate.

Identify and describe the primary and secondary lymphoid organs.

• The lymphoid organs are sites of residence, proliferation, differentiation, and function of lymphocytes and mononuclear phagocytes. • The lymphoid organs are classified as primary (thymus and bone marrow) or secondary (spleen, lymph nodes, tonsils, and Peyer patches of the small intestine).

Identify and describe the system responsible for lysis of blood clots; discuss the roles of tissue plasminogen activator, plasminogen, plasmin, and urokinase type PA.

• The primary mechanism for lysis (breakdown) of blood clots is the fibrinolytic system (plasminogen-plasmin system) that produces plasmin.

urokinase type PA

• Urokinase type PA: Serine protease that binds to a specific cellular u-PA receptor causing activation of plasminogen resulting in plasmin generation. Major activator of fibrinolysis in the extravascular or tissue compartment, whereas t-PA is largely involved in intravascular fibrinolysis. Several cancers are membrane bound to u-PA.

Describe the clinical use of a bone marrow aspiration and biopsy to evaluate hematopoiesis.

• Usually taken from sternum or pelvis using a needle (in children, use the vertebrae or femur). • Aspirate/biopsy tissue is examined microscopically and cultured if infected. • Bone marrow is the immediate source of iron destined for RBC production. • Aspiration is safer and less painful and expensive than a bone marrow biopsy.