Hematopoiesis, Coagulation, and Bleeding
Nancy Munro
The physiological functions of blood include nutrition, oxygenation, respiration, and excretion. These various components of blood accomplish these functions. Approximately 55% of blood volume is composed of plasma, which is a transport medium for ions, proteins, hormones, and end products of cellular metabolism. The most important ions carried in the plasma are sodium, potassium, chloride, hydrogen, magnesium, and calcium. Examples of proteins transported in the plasma are immunoglobulins and the coagulation proteins. Formed elements or cells including red blood cells (RBC; erythrocytes), white blood cells (WBC; leukocytes), and platelets (thrombocytes) constitute the other 45% of blood volume. Erythrocytes transport oxygen to the tissues and carbon dioxide to the lungs for excretion. Leukocytes protect against infection and play a major role in the inflammatory process. Thrombocytes, along with coagulation proteins, protect against blood loss through the formation of blood clots.1
Because these functions are vital, a significant blood loss has devastating consequences for all body tissues. A complex series of events leading to hemostasis achieves protection against such blood losses and potential exsanguination from injuries. The endothelium of the vasculature plays a vital role in the coagulation process and is now considered an organ by the Margaux III Conference on Critical Illness: The Endothelium: An Underrecognized Organ in Critical Illness.2 The endothelial cell participates by releasing mediators that effect coagulation and the role of the vessel’s participation in hemostasis. The equally complex mechanism of fibrinolysis, which dissolves clots, balances this system. Normal blood flow through the vasculature depends partly on the balance of these two systems, hemostasis and fibrinolysis. Recent research has also revealed a link between coagulation and the inflammatory process that has caused the scientific community to re-examine the process of atherosclerosis.3 Knowledge of these normal processes is important as a basis for understanding the many alterations that may result from disease states or drug administration.
HEMATOPOIETIC CELLSHematopoiesis, or the production of blood cells, occurs primarily in the bone marrow. The liver, spleen, lymph nodes, and thymus are involved in hematopoiesis during embryonic life, but after birth extramedullary (outside the bone marrow) hematopoiesis occurs only during abnormal circumstances. If it occurs at all after birth, extramedullary hematopoiesis occurs mainly in the liver and spleen. The hematopoietic stem cell resides mainly in the bone marrow and in small numbers in the peripheral blood. The hematopoietic stem cell is the source of all the types of blood cells: RBC, WBC, and platelets.
The stem cell is an immature (undifferentiated) cell that has the capacity to reproduce itself and to mature (differentiate) into any of the different types of blood cells. As the stem cell divides and matures, it differentiates into one of two committed cell lines: lymphoid or myeloid progenitor cells. The committed lymphoid progenitor cell eventually matures into T and B lymphocytes and natural killer cells. The committed myeloid stem progenitor cell develops into (1) the megakaryocyte-erthrocyte precursors leading to the development of platelets and RBC and (2) the granulocyte-monocyte precursors leading to the development of the granulocyte and monocyte.4 Maturation of these cell lines is influenced by multiple growth factors such as granulocyte colony-stimulating factor, erythropoietin, thrombopoietin, interleukins, interferon, and many others.4 As the various types of blood cells mature, they are released into the peripheral circulation. Figure 6-1 shows a model for hematopoietic cell differentiation.
Red Blood Cells
The major role of the RBC is respiration, which is the exchange of gases. The mature RBC is a biconcave disc filled with hemoglobin but it does not have a nucleus. The lack of a nucleus allows the RBC to change shape and facilitates movement through small capillary beds. Heme, the iron-containing pigment, is the actual oxygen-transporting portion of the hemoglobin molecule. Oxygen diffuses from the alveoli into the alveolar capillaries and binds to each of four to five sites on the heme portion of hemoglobin. One gram of hemoglobin can carry 1.34 to 1.36 milliliters of oxygen. The remarkable oxygen-binding capacity of the RBC is influenced by three factors that affect the oxyhemoglobin dissociation curve: pH, temperature, and the amount of 2,3-diphosphogylcerate (see Chapter 2). Tissue metabolism produces carbon dioxide as a waste product that is also transported from the tissues by the RBC. Carbon dioxide diffuses into the RBC and combines with water to form carbonic acid that further dissociates to the hydrogen and bicarbonate ions. The bicarbonate ion is inactivated when combined with hydrogen ions to again form water and carbon dioxide, which is eliminated at the alveoli.
The rate of bone marrow stem cell differentiation into erythrocytes is primarily controlled by erythropoietin. Most of this hormone is produced by the kidney. The creation of RBC is influenced by the oxygen content of the blood as sensed by the kidneys. Production also requires necessary substrates including vitamin B12, vitamin B6, folic acid, and iron. The vitamins and folic acid are obtained from dietary sources, as is iron. However, most iron is gained through the recycling of the RBC in the spleen. RBC production is increased at times of blood loss, at high altitude, and in pulmonary diseases that affect the transport of oxygen from the lungs to the blood. It takes approximately 3 to 5 days for RBC to
mature in the marrow and be released into the peripheral circulation. RBCs live approximately 120 days, at which time they are recycled by the spleen.
mature in the marrow and be released into the peripheral circulation. RBCs live approximately 120 days, at which time they are recycled by the spleen.
 ▪ Figure 6-1 The hematopoietic hierarchy. As hematopoietic stem cells divide, they give rise to common lymphoid and common myeloid precursor cells that eventually generate all mature blood lineages of the body. LT-HSC, long-term hematopoietic stem cells; GMP, granulocyte-monocyte precursors; MEP, megakaryocyte-erythrocyte precursors; NK, natural killer; ST-HSC, short-term hematopoietic stem cells. (Reproduced with permission from Hoffman, R., Benz, E., Shattil, S., et al. (2005). Hematology: Basic principles and practice. Philadelphia: Elsevier-Churchill-Livingstone.) |
White Blood Cells
WBC can be divided into two major categories: phagocytes and lymphocytes. The primary role of phagocytes is to locate and kill invading microorganisms or foreign antigens. The primary role of lymphocytes is to initiate and direct the immune response including the manufacture of antibodies. WBC travel throughout the body and will migrate into different tissues depending on chemical mediators that signal the cells. Phagocytes perform their role primarily out in the tissues, where they travel toward the site of an inflammation (chemotaxis) and kill microbes by engulfing them (phagocytosis). Many substances, including complement fragments and bacterial products, stimulate this chemotactic migration. Phagocytosis is an active process that uses energy derived from anaerobic glycolysis. Phagocytic cells are divided into two subgroups: granulocytes (granular substances within the cell after staining) and monocytes. The granulocytes include neutrophils (“polys”), basophils, and eosinophils. Neutrophils compose 60% to 70% of all WBC. Neutrophil maturation in the marrow takes 7 to 10 days. Their main function is to find and kill bacteria, especially resident microorganisms such as staphylococci and Gram-negative enteric flora.1 They also play an important role in acute inflammatory processes. Neutrophils are one of the first phagocytic cells to appear at the site of an acute inflammation. During severe inflammatory reactions, neutrophils can actually cause damage to surrounding tissues by releasing proteolytic enzymes and oxygen-free radicals. Once in the bloodstream, some of the neutrophils freely circulate while others linger along the blood vessel wall, which is called margination. Adhesion molecules emanating from an injury or from an organism make the blood vessel wall sticky; so that the marginated neutrophils adhere to the vessel walls. The neutrophil releases substances that allow the endothelial cells to separate and permit the neutrophil to crawl into the connective tissue (diapedesis). The neutrophil migrates to the area of injury through chemotaxis. The migration of neutrophils to the tissues takes place rapidly, within 12 hours on entering the bloodstream. Once in the bloodstream, the neutrophil must be able to differentiate cells or substances that are foreign. Opsonization is a process in which molecules in the plasma coat the microorganism, making it more recognizable to the neutrophil.
Esosinophils and basophils are WBC that have specific functions that are also important in the defense of the body. Eosinophils compose approximately 4% of a normal WBC count. Eosinophils have been postulated to play a defensive role against parasites and allergic reactions. Basophils account for only 0.5% to 1% of the total WBC count. Agranular leukocytes are WBC without granular substances within the cells after staining. Monocytes and lymphocytes are agranular leukocytes. Monocytes constitute 4% to 8% of the total WBC count. Within 24 to 36 hours of entering the circulation, they migrate into the tissues where they undergo further maturation and are called macrophages. Hepatic Kupffer cells, alveolar macrophages, and peritoneal macrophages are examples of tissue macrophages. Once lodged in their target organ, macrophages can live for up to 60 days. In the bloodstream, monocytes have similar functions to the neutrophil. However, in addition, monocytes and macrophages play a crucial role in recognizing foreign invaders and presenting foreign antigens to lymphocytes,
thus stimulating the immune response. They are important in killing bacteria, protozoa, cells infected with viruses, and tumor cells. In addition to their phagocytic activity, macrophages secrete biologically active products, including cytokines that modulate the immune response.
thus stimulating the immune response. They are important in killing bacteria, protozoa, cells infected with viruses, and tumor cells. In addition to their phagocytic activity, macrophages secrete biologically active products, including cytokines that modulate the immune response.
Lymphocytes are essential components of the immune system. They recognize and are instrumental in the elimination of foreign proteins, pathogens, and tumor cells. Lymphocytes control the intensity and specificity of the immune response. There are two general types of lymphocytes, T lymphocytes (or T cells), which provide cell-mediated and B lymphocytes (B cells), which produce the antibodies of humoral immunity. Stem cell differentiation for the production of lymphocytes occurs in the bone marrow. It is in the thymus that T cells learn to differentiate self from nonself. There are four separate subsets of T cells: helper T cells, suppressor T cells, cytotoxic T cells, and memory T cells. Cell-mediated activities are of great importance in delayed hypersensitivity reactions; graft rejection; graft-versushost disease; and in defense against fungal, protozoal, and most viral infections. Another important function of T cells is to regulate immune activities through the secretion of lymphokines.
B lymphocytes mature into cells that respond to stimulation from foreign proteins by differentiating into memory cells and plasma cells. The plasma cells produce specific antibodies that inactivate or destroy foreign proteins and pathogens. These antibodies are particularly effective against bacterial infections, especially encapsulated bacteria, such as pneumococci, streptococci, meningococci, and hemophilus influenzae, as well as certain viruses. The helper cells of the T cells stimulate B cells to produce antibodies. Natural killer cells, another subset of lymphocytes, kill tumor cells and cells infected by viruses. They play an important role in tumor surveillance. The activities of phagocytes and immune cells overlap in numerous mutually beneficial ways. For example, immune cells often participate in chronic inflammatory reactions. Conversely, engulfment of foreign protein by macrophages is a preparatory step leading to antibody production. Table 6-1 summarizes the WBC and their function.
Table 6-1 ▪ WHITE BLOOD CELLS | ||||||||||||||||||
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Because blood cells have a limited lifespan, they need to be replaced constantly. Usually, the number of cells produced is fairly constant, but depending on environmental stimuli such as bleeding, infection, or inflammation various cells may be needed in larger than normal quantities at times. Thus, each of these cell lines is regulated by cytokines that influence the rate of growth and differentiation of the stem cells in the marrow. Cytokines are proteins that are made by cells of the immune system and regulate the immune response. Some examples of cytokines are granulocyte-macrophage colony-stimulating factor, which stimulates the growth of granulocytes and macrophages, and interleukin-3 (IL-3), which stimulates the stem cell. Cytokines also stimulate the function of mature immune cells.
Platelets
Platelets are small cell fragments that are produced by the disintegration of megakaryocytes in the bone marrow, producing several thousand platelets that are released into the circulation. They are tiny, disc-shaped fragments that are capable of changing shape and have a high metabolic rate. It takes approximately 5 days for a stem cell to differentiate along the megakaryocyte line and produce platelets. Under normal circumstances, platelets circulate in the bloodstream for approximately 10 days. The production of platelets is regulated by thrombopoietin, which is a humoral hormone-like substance. Platelets are also called thrombocytes, which means clot cell. They play a major role in hemostasis by adhering to a damaged blood vessel wall and aggregating together to form a mechanical barrier to the flow of blood thereby preventing blood loss. Platelets will then release various mediators to attract other cells and components to the site so that fibrin formation can start. There are three storage granules in the platelets: alpha granules, dense bodies, and lysomes. Alpha granules contain and release fibrinogen. Dense bodies release adenine nucleotides, serotonin, and platelet factor 4 (PF4). Lysomes contain degradative acid hydrolases.1 Platelets are sequestered in the spleen and are released as needed to combat bleeding. Their function is vital to the coagulation process, so much so that many cardiac interventions are now aimed at disabling platelet function.
Coagulation Factors
The major component of blood, plasma, contains many particles including proteins (clotting factors) that are involved in coagulation. To standardize the identification of these proteins, an international committee assigned a nomenclature for these proteins using Roman numerals listed in order of their discovery. However, the order does not refer to the sequence of reactions in the coagulation cascade. A lowercase “a” is also used to indicate the activated form of a clotting factor. Table 6-2 lists these clotting factors. The liver plays a significant role in maintaining adequate amounts of these clotting factors, because it is the primary site of protein synthesis. Tissue thromboplastin, or tissue factor (III), is an exception that can be found in most body tissues, especially around vessels and organs. Antihemophilic factor (VIII) is a factor that is synthesized in the endothelial cells. It is also important to recognize that there are multiple enzymes and mediators that play key roles in the activation of these clotting factors. Synthesis of factors II, VII, IX, and X requires vitamin K to be present, and these are known as vitamin K-dependent factors. Calcium is also a coagulation factor
whose role can be underestimated. To balance the coagulation process, there are also a number of proteins and systems that will inhibit coagulation including antithrombin III, proteins C and S, as well as components of the fibrinolytic cascade. The interaction of all these proteins in a chemical sequence will produce a clot to repair blood vessels and then dissolve the clot so that normal flow can be restored.
whose role can be underestimated. To balance the coagulation process, there are also a number of proteins and systems that will inhibit coagulation including antithrombin III, proteins C and S, as well as components of the fibrinolytic cascade. The interaction of all these proteins in a chemical sequence will produce a clot to repair blood vessels and then dissolve the clot so that normal flow can be restored.
Table 6-2 ▪ BLOOD COAGULATION PROTEINS | ||||||||||||||||||||||||||||
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HEMOSTASISThe normal hemostatic system is designed to protect against bleeding from injured blood vessels. Hemostasis is usually accomplished by a sequence of interrelated processes involving blood vessels and endothelial activity, platelets, and coagulation proteins. This complex system is highly regulated to ensure that clotting occurs only at a site of injury and only as long as the integrity of the vessel is compromised. The process of hemostasis consists of several components: (1) blood vessel spasm; (2) formation of a platelet plug; (3) contact between damaged blood vessel, blood platelet, and coagulation proteins; (4) development of a blood clot around the injury; and (5) fibrinolytic removal of excess hemostatic material to reestablish vascular integrity.5 Coagulation proteins make up the coagulation cascade. The coagulation cascade consists of three components: the intrinsic pathway (vascular trauma), the extrinsic pathway (tissue trauma), and the common pathway leading to fibrin formation. The clotting processes are balanced by the complex mechanism of fibrinolysis, which breaks down clots and maintains or re-establishes blood flow once the vessel damage has healed. The balance between these two mechanisms and their activators and inhibitors is vital. An imbalance in one direction leads to excessive bleeding; whereas an imbalance in the other direction leads to excessive clotting. The following sections present the normal sequence of coagulation and fibrinolysis, as well as selected coagulation disorders most commonly associated with the patient experiencing cardiovascular disease.
Vascular Spasm
The sympathetic nervous system is automatically stimulated when a blood vessel is injured. Epinephrine and norepinephrine are released causing contraction of the vascular smooth muscle and vasoconstriction. Endothelin I, which is a peptide produced by the endothelial cell, angiotensin II, and vasoconstrictor prostaglandins are additional agents that contribute to vasoconstriction.5 The vasoconstriction of arterioles may be sufficient to decrease blood flow and close disrupted capillaries. Larger vessels may require longer periods of more intense vasoconstriction to assist with hemostasis, but may ultimately require surgical intervention.
Role of the Endothelium in Hemostasis
The endothelial cell was once thought to be inert and have no specific role in maintaining vascular integrity. Research over the years has proven this hypothesis to be incorrect. The endothelial cell is a vital component of normal homeostasis. Under normal conditions, the endothelium surface is intact and there is minimal interaction with platelets or the coagulation proteins. The function of the endothelium is to promote blood flow. The endothelial cell inhibits blood coagulation by: (1) expressing thrombomodulin, a clotting enzyme that binds thrombin; (2) changing the specificity of thrombomodulin from fibrin to protein C, which blocks the ability to convert fibrinogen to fibrin; (3) using proteoglycans on their surfaces to bind and potentiate the coagulation inhibitors antithrombin III and tissue factor pathway inhibitor; (4) releasing small amounts of plasminogen activator tissue-type plasminogen activator (tPA); (5) inhibiting platelet aggregation by producing prostacyclin and nitric oxide, which vasodilates the microcirculation; and (6) inhibiting adherence of peripheral blood cells.6 These interactions maintain the anticoagulant properties of the endothelium by keeping platelets inactive and inhibiting key coagulation proteins such as tissue factor and thrombin.
Once the endothelial surface is disrupted by various factors, including physical injury or circulating mediators, it will develop procoagulant properties. When the endothelium is stimulated by inflammatory cytokines such as ILα-, ILβ-, or tumor necrosis factor α, it is referred to as activated endothelium. Once the subendothelial connective tissue is exposed and activated, it will lose thrombomodulin and heparin sulfate and begin to synthesize tissue factor (factor III). Factor III interacts with factor VII to start the extrinsic pathway. Therefore, protein C is not activated and the action of clotting inhibitor systems will be lost. This activation of the cascade will further incite the endothelial cell to produce more inflammatory mediators (cytokines and chemokines) that will start the expression of adhesion molecules. Leukocytes will adhere to the endothelial cell and become activated by the production of leukocyte agonists such as platelet activating factor.6 Platelets are now attracted to the site and augment the coagulation process.
Platelet Phase
The platelet phase refers to the formation of a soft mass of aggregated platelets that provides a temporary patch over the injured vessel. Almost immediately after vascular injury, platelets begin to adhere to the exposed subendothelial basement
membrane and collagen fibers. Adherent platelets release adenosine diphosphate, which causes platelets to change from their normal disc shape into a spherical form with pseudopods that attach along the surface and allow platelets to clump to-gether.5 During activation, the platelets become sticky when bridges formed by fibrinogen in the presence of calcium cause platelets to adhere to each other, increasing the size of the platelet plug. Adenosine diphosphate and collagen also trigger formation of arachidonic acid from phospholipids in the platelet membrane. Arachidonic acid leads to the formation of thromboxane A2, a substance that induces further platelet aggregation. Thromboxane A2 causes conformational changes in glycoprotein IIb/IIIa, a receptor on the platelet surface, which exposes fibrinogen-binding sites. Fibrinogen builds bridges to adjacent platelets, a process called platelet adhesion, which advances platelet aggregation. When these aggregates are reinforced with fibrin, they are referred to as a thrombus.5 Ultimately, aggregated platelets plug the injured vessel.
membrane and collagen fibers. Adherent platelets release adenosine diphosphate, which causes platelets to change from their normal disc shape into a spherical form with pseudopods that attach along the surface and allow platelets to clump to-gether.5 During activation, the platelets become sticky when bridges formed by fibrinogen in the presence of calcium cause platelets to adhere to each other, increasing the size of the platelet plug. Adenosine diphosphate and collagen also trigger formation of arachidonic acid from phospholipids in the platelet membrane. Arachidonic acid leads to the formation of thromboxane A2, a substance that induces further platelet aggregation. Thromboxane A2 causes conformational changes in glycoprotein IIb/IIIa, a receptor on the platelet surface, which exposes fibrinogen-binding sites. Fibrinogen builds bridges to adjacent platelets, a process called platelet adhesion, which advances platelet aggregation. When these aggregates are reinforced with fibrin, they are referred to as a thrombus.5 Ultimately, aggregated platelets plug the injured vessel.
Coagulation Cascade
The final phase of hemostasis is the formation of a fibrin blood clot. The coagulation process is most commonly viewed as a series of enzymatic reactions in which clotting factors are sequentially activated. This process is known as the coagulation cascade. The clotting factors are all present in the circulating blood in their inactive form until a stimulus for clot formation occurs. Twelve different substances have been officially designated as clotting factors (see Table 6-2). As studied in the laboratory, the coagulation process can be initiated by two different pathways: the extrinsic pathway and the intrinsic pathway. Although differentiating between them is helpful for understanding pathologic mechanisms, medication actions, and coagulation tests, these two pathways are functionally inseparable in vivo. The extrinsic pathway, whose major mediators are rapidly inactivated, is the primary initiator of the clotting cascade. The intrinsic pathway, whose major mediators are more slowly degraded, is thought to be important for maintenance and amplification of the clotting cascade. Both extrinsic and intrinsic mechanisms eventually lead to the activation of factor X, with the remaining steps of the coagulation sequence being identical and referred to as the common pathway. The sequence of the coagulation process is shown in Figure 6-2.
 ▪ Figure 6-2 The intrinsic, extrinsic, and common coagulation pathways. Lower case “a” denotes an activated factor. The protime (PT) measures the function of the extrinsic and common pathways; the partial thromboplastin time (PTT or aPTT) measures the activity of the intrinsic and common pathways. HMWK, high-molecular-weight kininogen and KAL, kallikrein. (Reproduced with permission from Dipiro, J. T., Talbert, R. L., Yee, G. C., et al. [2006]. Pharmacotherapy: A pathophysiologic approach [6th ed.]. New York: McGraw-Hill.) |
Extrinsic Pathway
The extrinsic pathway is initiated by the combination of tissue factor with factor VIIa and ionized calcium, which together convert factor X to its activated form, factor Xa. The function of the extrinsic pathway is tested in the laboratory by the prothrombin time (PT). Tissue factor, also called tissue thromboplastin
(formerly factor III), is a membrane glycoprotein that is particularly prevalent in tissues, where it plays a vital role in the prevention of hemorrhage. Tissue factor is exposed to and binds to factor VII, which is activated to factor VIIa. Factor VIIa is a potent enzyme that activates factor X to Xa. The reactions from this step on are referred to as the common pathway. Calcium plays a significant role in each step leading to the formation of thrombin.5
(formerly factor III), is a membrane glycoprotein that is particularly prevalent in tissues, where it plays a vital role in the prevention of hemorrhage. Tissue factor is exposed to and binds to factor VII, which is activated to factor VIIa. Factor VIIa is a potent enzyme that activates factor X to Xa. The reactions from this step on are referred to as the common pathway. Calcium plays a significant role in each step leading to the formation of thrombin.5
Intrinsic Pathway
Because the intrinsic pathway is initiated by a separate set of factors that is not degraded by rapid-acting inhibitors, the process may proceed more slowly and the results may last longer and be more pronounced than those initiated by the extrinsic pathway. The function of the intrinsic pathway is commonly analyzed by the partial thromboplastin time (PTT). Intrinsic activation is initiated when blood is exposed to a negatively charged surface, such as the site of blood vessel injury. The negative charge, along with collagen and endotoxin, attracts factor XII, which binds to the surface and autoactivates to factor XIIa. Factor XIIa converts prekallikrein to kallikrein, which in turn converts circulating factor XII to its activated form, XIIa. Both the activated form of factor XII and kallikrein catalyze the activation of factor XI into XIa. Factor XIa, together with ionized calcium, cleaves factor IX at two sites to produce factor IXa. Factor IXa, together with factor VIII, phospholipid, and ionized calcium convert factor X to its activated form, factor Xa. As discussed previously, factor X can also be activated through the extrinsic pathway. From here, the coagulation process proceeds along the common pathway, regardless of whether initiation was extrinsic or intrinsic.5
Common Pathway and Fibrin Formation
The final common sequence involves the combination of factors Xa and V, phospholipid, and ionized calcium into a complex that converts prothrombin to thrombin. The thrombin formed subsequently cleaves the long molecule fibrinogen to fibrin. The fibrin monomer is able to polymerize spontaneously to form a loose web of fibers that is capable of stopping the bleeding in small- and medium-sized arteries and veins. The fibrin clot is eventually stabilized and thickened by the action of factor XIII, which is activated by the presence of ionized calcium and thrombin. Fibrin forms a loose covering over the injured area and reinforces the platelet plug. After a short period of time, the clot begins to retract. This process is thought to be a reaction of the platelets, which send out cytoplasmic processes that attach to the fibrin and pull the fibers closer.5 Plasminogen and other components of the fibrinolytic mechanism are incorporated into the fibrin clot as it solidifies.
Fibrinolysis
The removal of clots when the site of vessel injury has healed is as important as the formation of the clot itself. Fibrinolysis is the physiological process that removes insoluble fibrin deposits by enzymatic digestion of the stabilized fibrin polymers.5 The process of fibrinolysis re-establishes blood flow. Plasmin dissolves clots by digesting fibrin and fibrinogen using hydrolysis. Plasminogen is a glycoprotein and an inactive form of plasmin, which is synthesized by the liver. It is activated to plasmin by the activity of proteolytic enzymes, the kinases that cleave a bond on the plasminogen molecule. Activators of plasminogen are found in various tissues, blood, and urine. The best-known endogenous activators are tPA and urokinase, which is a urinary activator of plasminogen. Some exogenous plasminogen activators are related to types of bacteria such as streptokinase and staphylokinase.5 Drugs have been developed to mimic the activity of these kinases to dissolve clots. Fragments of the fibrin clot, known as fibrin degradation products (FDP), are released into the circulation as the clot is broken down. FDP are potent inhibitors of coagulation. They act by binding to thrombin, thus inhibiting its action, and by interfering with the binding of fibrin threads to form the fibrin clot. Except in some abnormal situations, FDP are present in such small numbers that their anticoagulant effect is not clinically important. Plasminogen is then converted back to plasmin and neutralized by a number of antiplasmin and inhibitor systems. All these reactions that occur in the coagulation cascade and fibrinolytic system are time dependent and can be monitored using laboratory testing as listed in Table 6-3.
Natural Anticoagulant Systems
Coagulation is regulated by three major mechanisms: the elimination of activated clotting factors, the protease inhibitors (inhibitors of coagulation), and the destruction of the fibrin clot. There must be a balance between coagulation and anticoagulation processes in the body to maintain homeostasis. The natural anticoagulant systems include antithrombin III, heparin cofactor II, and protein C and its cofactor, protein S.
Antithrombin III is an α2-globulin glycoprotein, which is considered the major inhibitor of coagulation. It slowly inactivates thrombin as well as factors Xa, IXa, XIa, and XIIa. In the presence of heparin, antithrombin III-thrombin binding is increased significantly. This is thought to be the main mechanism for heparin’s anticoagulation ability and its interaction with antithrombin III and tissue factor pathway inhibitor.
Heparin cofactor II is a heparin-dependent thrombin inhibitor whose activity is also accelerated by the presence of heparin. This cofactor not only inhibits thrombin but also thrombin-induced platelet aggregation and release.5
Protein C and protein S are major natural anticoagulants in the body and have a powerful role in anticoagulation. Deficiency in either of these proteins can lead to the development of thrombus. Protein C is a vitamin K-dependent protein, which is synthesized in the liver and circulates as a zymogen, an inactive precursor form in the blood. Activation occurs faster when thrombin, in the presence of thrombomodulin, assists with proteolytic cleavage that converts protein C to its active enzymatic form, activated protein C (APC). Protein S must also be present to help APC proteolytically cleave factors Va and VIIIa, which will decrease the conversion of prothrombin to thrombin, and acts as a regulatory feedback loop to balance coagulation. The dual role of thrombin in both coagulation and anticoagulation is exemplified here. Protein C also has a function in promoting fibrinolysis by neutralizing the inhibitors of tPA, which allows the conversion of plasminogen to plasmin. Inactivation of APC is a slower process with a plasma protease inhibitor that has a short half-life intimating that other unidentified direct cell mechanisms. 5 The properties of protein C have been applied clinically with the development of the medication, Drotrecogin alfa. Drotrecogin alfa is a recombinant intravenous (IV) form of APC, which is used in severely ill patients with sepsis to decrease
microemboli formation and inhibit immune function. Activated protein C has a major role as an agent that suppresses inflammation and prevents microvascular coagulation. Initial studies had shown the efficacy and safety of APC for severe sepsis.7,8 However, current research has demonstrated variable results and the 2008 Surviving Sepsis guidelines list the use of APC as a weak recommendation.7
microemboli formation and inhibit immune function. Activated protein C has a major role as an agent that suppresses inflammation and prevents microvascular coagulation. Initial studies had shown the efficacy and safety of APC for severe sepsis.7,8 However, current research has demonstrated variable results and the 2008 Surviving Sepsis guidelines list the use of APC as a weak recommendation.7
Table 6-3 ▪ COAGULATION LABORATORY TESTS | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
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COAGULATION-INFLAMMATION LINKThe role of the inflammatory process has become a major focus of study in many areas of medicine, especially inflammation’s role in the atherosclerostic process. The study of the relationship between coagulation and inflammation is focused on the integrity of the endothelium and the recruitment of leukocytes.3 Normally, the endothelium does not encourage the binding of WBC to the wall. However, with elevated levels of low-density lipoproteins, the excess low-density lipoproteins molecules will begin to infiltrate the endothelial wall and experience oxidation and glycation.9 These chemical changes will cause the endothelial cell to express an adhesion molecule, vascular cell adhesion molecule I, which will bind various types of leukocytes, especially monocytes and T lymphocytes. This process occurs especially at arterial branch points where the endothelial cells are exposed to abnormal laminar flow. This abnormal laminar flow decreases the endothelial cells protective ability to secrete nitric oxide and to limit the expression of vascular cell adhesion molecule I.3
Once the monocyte is attached to the endothelial wall, it releases monocyte chemoattractant protein-1, which will help the migration of the monocyte into the intima. With the assistance of macrophage colony-stimulating factor, the monocyte starts to ingest the excess lipids and transform itself into a macrophage foam cell. The macrophage foam cells are the trigger for activating the coagulation system. They release proteolytic enzymes that degrade the collagen fibers that compose the fibrous cap, so that it weakens and can rupture. The macrophage foam cell also produces tissue factor (Factor III) and once the plaque cap ruptures and exposes the tissue factor to the circulating blood, coagulation will ensue.3 The T cells also release cytokines such as tumor necrosis factor β, which stimulates the macrophages, endothelial cells, and the smooth muscles. Peptide growth factors are released that promote the replication of smooth muscle cells into an extracellular matrix, which is characteristic of an atherosclerotic lesion.3
However, this link between coagulation and inflammation may not only be limited to the atherosclerosis process. Hypertension
may also be linked to inflammation because angiotensin II not only may be a vasoconstrictor but also may cause intimal inflammation by stimulating the smooth muscle and endothelial cells to express proinflammatory cytokines such as IL-6 and monocyte chemoattractant protein-1.3 Hyperglycemia associated with diabetes can lead to the formation of advance glycation end products that may augment the secretion of proinflammatory cytokines.3 Even chronic extravascular infections such as gingivitis, prostatitis, bronchitis, etc., can augment extravascular production of inflammatory cytokines, which can accelerate the evolution of atherosclerotic lesions.3 This new scientific insight into the role of inflammation in the development of atherosclerosis has led to using new markers to determine the degree of inflammation. Findings of a relationship between increased C-reactive protein levels and unfavorable cardiovascular outcomes have led to new therapeutic considerations for acute coronary syndrome.3
may also be linked to inflammation because angiotensin II not only may be a vasoconstrictor but also may cause intimal inflammation by stimulating the smooth muscle and endothelial cells to express proinflammatory cytokines such as IL-6 and monocyte chemoattractant protein-1.3 Hyperglycemia associated with diabetes can lead to the formation of advance glycation end products that may augment the secretion of proinflammatory cytokines.3 Even chronic extravascular infections such as gingivitis, prostatitis, bronchitis, etc., can augment extravascular production of inflammatory cytokines, which can accelerate the evolution of atherosclerotic lesions.3 This new scientific insight into the role of inflammation in the development of atherosclerosis has led to using new markers to determine the degree of inflammation. Findings of a relationship between increased C-reactive protein levels and unfavorable cardiovascular outcomes have led to new therapeutic considerations for acute coronary syndrome.3
BLEEDING DISORDERSBleeding can occur when the intricate relationship between the various elements of the hemostatic system is disturbed. Bleeding defects in the hemostatic system can be categorized into three areas: vascular issues, platelet dysfunction, or coagulation dysfunction. Vascular issues generally cause endothelial damage by an autoimmune process (allergy induced), endotoxins from infections, or abnormal vascular structure. Platelet dysfunction can present as thrombocytopenia (low platelet count) or thrombocytosis (high platelet count). Thrombocytopenia can result from decreased production, decreased distribution, or increased destruction of platelets. Thrombocytosis can result from either a primary or a secondary cause. Coagulation dysfunction can be either congenital or acquired deficiencies in the coagulation factors (Display 6-1). In each case, bleeding is the primary manifestation. The bleeding may be minor, such as petechiae and easy bruising of the skin, or major, with massive hemorrhage.
DISPLAY 6-1 Conceptual Etiology of Bleeding Disorders
The focus of cardiac interventions today emphasizes maintaining blood flow with percutaneous interventions (vascular injury) and anticoagulation to prevent thrombus formation. This intentional disruption of the coagulation system can potentially lead to bleeding disorders or even shock with excessive blood loss from percutaneous interventions and/or thrombolysis. Shock can lead to hypoperfusion and decreased oxygen delivery, which can trigger the intrinsic and extrinsic pathways simultaneously. Disseminated intravascular coagulation (DIC) is a complication of shock. Although DIC is actually a disorder of coagulation, it is discussed as a bleeding disorder because its major manifestation is bleeding.
Disseminated Intravascular Coagulation
DIC is a pathological syndrome resulting in the indiscriminate formation of fibrin clots throughout all or most of the microvasculature. Paradoxically, diffuse bleeding occurs as a result of the consumption of clotting factors and is usually the hallmark sign of the syndrome. It is a disorder in which the coagulation cascade has been “pathologically activated” either by the extrinsic pathway releasing tissue factor or by the intrinsic pathway with endothelial injury.1 It is considered a complication of many different diseases and is known as a consumptive coagulopathy or defibrination syndrome.5 Successful treatment of DIC must include treatment of the primary cause of the disorder as well as the hematologic consequences. (See Display 6-2 for diseases associated with disseminated intravascular coagulation.)
DISPLAY 6-2 Diseases Associated with Disseminated Intravascular Coagulation
Etiology
Inappropriate coagulation results from the presence of thromboplastic substances in the bloodstream. These thromboplastic substances stimulate clotting despite the lack of actual bleeding. Tissue thromboplastin (tissue factor) is released into the circulation by damaged cells in massive burns, injuries, and systemic infections. DIC is a common complication of serious infections, especially Gram-negative sepsis. The fetus, placenta, and amniotic fluid contain thromboplastic substances that are released into the maternal circulation during obstetric complications such as abruptio placentae and amniotic fluid embolism. Certain malignant tumors release small amounts of thromboplastic substances into the circulation. Chemotherapy or radiation treatment can cause tumor cells to die and release massive amounts of thromboplastin into the circulation.10 In the patient with cardiovascular disease, DIC is most likely to develop as a result of cardiogenic, septic, or hemorrhagic shock; acidosis; or extracorporeal circulation, which can all lead to cellular death and thromboplastin release. Figure 6-3 provides a conceptual model of the cause of DIC.
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