An Overview of Hemostasis PDF

CE Update [coagulation and hematology] An Overview of Hemostasis Henry O. Ogedegbe, PhD, BB(ASCP)SC Department of Environmental Health, Molecular and Clinical Sciences, Florida Gulf Coast University, Fort Myers, FL DOI: 10.1092/50UQGUPFW6XW1X7B After reading this art...

CE Update [coagulation and hematology] An Overview of Hemostasis Henry O. Ogedegbe, PhD, BB(ASCP)SC Department of Environmental Health, Molecular and Clinical Sciences, Florida Gulf Coast University, Fort Myers, FL DOI: 10.1092/50UQGUPFW6XW1X7B After reading this article, the reader should understand the basic principles of hemostasis and the elements of the coagulation cascade. Hematology exam 0202 questions and answer form are located after the “Your Lab Focus” section on p.955. Downloaded from https://academic.oup.com/labmed/article-abstract/33/12/948/2657208 by guest on 05 November 2019 왘 Hemostasis is the physiological hemorrhage as a result of hypercoagula- proteins. The ECs are supported by a col- process that helps to maintain blood tion or hypocoagulation, respectively.1,4 lagen-rich basement membrane and sur- in the fluid state and prevent the Hemostasis is categorized as either a rounding layers of connective tissues.1 A escape of blood from damaged blood primary or secondary process. Primary breakdown in the vascular system is rap- vessels through clot formation. hemostasis involves the response of the idly repaired to maintain blood flow and 왘 Many coagulation proteins are vascular system and platelets to vessel the integrity of the vasculature. The vas- involved in reactions that precipitate injury.4 [F1] It takes place when there are cular system prevents bleeding through the hemostatic process. Deficiencies injuries to small vessels during which the vessel contraction, diversion of blood in any of the coagulation proteins affected vessels contract to seal off the flow from damaged vessels, initiation of may lead to bleeding. wound and platelets are mobilized, aggre- contact activation of platelets with aggre- 왘 Laboratory tests can monitor the gate, and adhere to components of the gation, and contact activation of the coag- hemostatic status of individuals subendothelium of the vasculature. ulation system.2 including the prothrombin time, which Platelet adhesion requires the presence of Platelets are activated by collagen monitors the extrinsic pathways and various factors such as von Willebrand located in the basement membrane. The the activated partial thromboplastin factor (vWF) and platelet receptors ECs secrete vWF, which is needed for time, which monitors the intrinsic (IIb/IIIa and Ib/IX). Additional platelets platelet adhesion to exposed subendothe- pathways. are attracted to the site of injury by the lial collagen in the arterioles. The ECs release of platelet granular contents, such produce a variety of other adhesion mole- Hemostasis is derived from a Greek as adenosine diphosphate (ADP). The cules, which include P-selectin, intercel- word, which means stoppage of blood platelet plug is stabilized by interaction lular adhesion molecules (ICAMs), and flow. The process is a combination of cel- with fibrinogen. Thus a defect in platelet platelet endothelial cell adhesion mole- lular and biochemical events that function function or von Willebrand’s disease cules (PECAMs). The smooth muscle together to keep blood in the liquid state (vWD) may result in debilitating and and fibroblast release tissue factor (TF), within the veins and arteries and prevent sometimes fatal hemorrhage.1 Secondary which activates factor VII (FVII).1 The blood loss following injury through the hemostasis involves the response of the vascular system provides potent anticoag- formation of a blood clot.1,2 It consists of coagulation system to vessel injury.4 [F2] ulant properties, which prevents the initi- a complex regulated system which is de- It is required to control bleeding from ation and propagation of the coagulation pendent on a delicate balance among sev- large wounds and is a continuation of the process. Coagulation is inhibited through eral systems. The systems involved in the primary hemostatic mechanisms. the expression of thrombomodulin (TM), hemostatic process include the vascular Whereas the outcome of primary hemo- which promotes activation of protein C system, coagulation system, fibrinolytic stasis is the formation of the platelet plug, and heparan sulfate (HS), which activates system, platelets, kinin system, serine the outcome of secondary hemostasis is antithrombin III (AT-III) to accelerate protease inhibitors, and the complement the formation of a thrombus. thrombin inhibition. Endothelial cells also system.3,4 The systems work together release tissue factor pathway inhibitor when the blood vessel endothelial lining The Vascular System (TFPI), which blocks activated factor is disrupted by mechanical trauma, physi- The vascular system has procoagu- VIIa (FVIIa)-TF/factor Xa (FXa) com- 948 cal agents, or chemical trauma to produce lant, anticoagulant, and fibrinolytic prop- plex and annexin V, which prevents bind- clots. The clots stop bleeding and are erties and is made up of blood vessels. ing of coagulation factors.5 eventually dissolved through the The innermost lining of the blood vessels fibrinolytic process. As a result, there is a is made up of endothelial cells (ECs) Coagulation System delicate balance between the production which form a smooth, unbroken surface The coagulation system is where and dissolution of clot during the hemo- that promotes the fluid passage of blood coagulation factors interact to form a static process. A disruption of this bal- and prevents turbulence that may trigger fibrin clot. The coagulation system is ance may precipitate thrombosis or activation of platelets and plasma involved in the conversion of soluble laboratorymedicine> december 2002> number 12> volume 33 © fibrinogen, a major component of the acute inflammatory exudates into fibrin. The fibrin clot reinforces the platelet Vessel Injury Vessel spasm plug formed during primary hemostasis. Various protein factors present in the inactive state in the blood participate in the coagulation system [T1]. The protein Exposed Subendothelium Vessel Constriction factors are designated by Roman numer- vWF,GPIb,receptor,collagen als according to their sequence of dis- covery and not by their point of Downloaded from https://academic.oup.com/labmed/article-abstract/33/12/948/2657208 by guest on 05 November 2019 interaction in the coagulation cascade.2 Some of the coagulation factors such as fibrinogen and prothrombin are referred ADP, TXA2, Colagen, Ca++, Platelet adhesion & serotonin shape change to by their common names, whereas oth- ers such as factors VIII and XI are re- ferred to by their Roman numeral nomenclatures. Activation of a factor is indicated by the addition of low case “a” Thrombin Platelet activation & secretions, next to the Roman numeral in the coagu- change shape (β- TB, PF3, PF4, lation cascade such as VIIa, Xa, XIIa.2 PDGF, thrombospondin) Some of the common names were de- rived from the original patients in whom symptoms leading to the determination of the factor deficiency were found. Ex- Platelet aggregation amples are the Christmas factor and (ATP, Fibrinogen, GPIIb, GPIIIa) Hageman factor. The coagulation factors may be cate- gorized into substrates, cofactors, and enzymes. Fibrinogen is the main sub- strate. The cofactors accelerate the activ- Platelet plug formation ities of the enzymes, which are involved in the coagulation cascade. Examples of cofactors include tissue factor, factor V, Fibrin Meshwork factor VIII, and Fitzgerald factor. With the exception of factor XIII, all the en- Thrombus consolidation zymes are serine proteases when acti- vated.2 The coagulation factors may also Fibrin clot construction be categorized into 3 groups on the basis vWF =von Willebrand’s factor ADP = Adenosine diphosphate of their physical properties. These TXA2 = Thromboxane groups are the contact proteins compris- Fibrin polymerization β-TB = Beta-thromboglobulin ing of factors XII, XI, prekallikrein PF4 = Platelet factor 4 (PK), and high molecular weight kinino- PF3 = Platelet factor 3 gen (HMWK); the prothrombin proteins PDGF = Platelet derived growth factor comprising of factors II, VII, IX, and X; and the fibrinogen or thrombin sensitive [F1] The primary hemostatic plug formation proteins comprising of factors I, V, VIII, and XIII.2 have local effects on vascular permeabil- renin-angiotensin-aldosterone system ity. Plasmin digests fibrin and fibrinogen (RAAS) may participate in the regula- 949 Fibrinolytic System through hydrolysis to produce smaller tion of fibrinolytic function.7 Fibrinolysis is the physiological fragments. The gradual process occurs at Angiotensin II (Ang II) is the primary process that removes insoluble fibrin the same time that healing is occurring, candidate to mediate this interrelation- clots through enzymatic digestion of the and eventually cells of the mononuclear ship, since this peptide is capable of cross-linked fibrin polymers. Plasmin is phagocytic system phagocytize the par- stimulating plasminogen activator responsible for the lysis of fibrin into ticulate products of the hydrolytic diges- inhibitor-1 (PAI-1) in vitro and in vivo. fibrin degradation products, which may tion.6 Recent evidence suggest that the It has been suggested that aldosterone © laboratorymedicine> december 2002> number 12> volume 33  Coagulation Factors Factor Common Name Function Pathway Participation T1 Factor I Fibrinogen Thrombin substrate, polymerizes Common to form fibrin Factor II Prothrombin Serine protease Common Factor III Tissue factor Cofactor Factor IV Ionic calcium Mineral Downloaded from https://academic.oup.com/labmed/article-abstract/33/12/948/2657208 by guest on 05 November 2019 Factor V Labile factor Cofactor Common Factor VII Stable factor Serine protease Extrinsic Factor VIII Antihemophiliac factor von Willebrand factor (vWF) Cofactor Intrinsic Factor IX Christmas factor Serine protease Intrinsic Factor X Stuart Prower factor Serine protease Common Factor XI Plasma thromboplastin Serine protease Intrinsic antecedent (PTA) Factor XII Hageman factor Serine protease Intrinsic Factor XIII Fibrin stabilizing factor Transglutaminase Common Prekallikrein Fletcher factor Serine protease Intrinsic High molecular weight Fitzgerald factor, HMWK Cofactor Intrinsic kininogen Platelet factor 3 Phospholipids, PF3 Assembly molecule may also modulate fibrinolysis, possibly Platelets environment that support plasma coagu- by interacting with Ang II.7 Platelets are anuclear fragments lation.1 Fibrinolysis is controlled by the plas- derived from the bone marrow Platelets and ECs have biochemical minogen activator system. The proteolytic megakaryocytes. They have a complex pathways involving the metabolism of activity of this system is mediated by internal structure, which reflects their arachidonic acid (AA), which is released plasmin, which is generated from plas- hemostatic functions. The 2 major in- from membrane phospholipids by phos- minogen by 1 of 2 plasminogen activa- tracellular granules present in the pholipase A2. Subsequently, cyclooxyge- tors. Inactive plasminogen circulates in platelets are the α-granules and the nase converts AA to cyclic plasma until such a time that an injury dense bodies. The α-granules contain endoperoxides. The endoperoxides are occurs. Then, plasminogen is activated by platelet thrombospondin, fibrinogen, then converted by thromboxane means of a number of proteolytic fibronectin, platelet factor 4, vWF, synthetase to thromboxane A2. Throm- enzymes known as plasminogen activa- platelet derived growth factor, β-throm- boxane A2 is a potent agonist that induces tors. These activators are present at vari- boglobulin, and coagulation factors V platelet aggregation. Endothelial cells ous sites such as the vascular and VIII. The dense granules contain also contain AA and preferentially con- endothelium. Some of the activators in- ADP, adenosine triphosphate (ATP), vert cyclic endoperoxides to prostacyclin, clude tissue-type plasminogen activator, and serotonin. When stimulated, which is a potent inhibitor of platelet ag- urokinase, streptokinase, and acyl-plas- platelets release both the α-granules gregation.9 During primary hemostasis, minogen streptokinase activator complex. and the dense bodies through the open platelets interact with elements of the Inhibitors of fibrinolysis include α2- plas- canalicular system.14 When platelets damaged vessel wall leading to the initial 950 min inhibitor, tissue plasminogen activa- aggregate, they expend their stored en- formation of the platelet plug. The tor inhibitor, and plasminogen activator ergy sources, lose their membrane in- platelet/injured vessel wall interaction inhibitor-1 (PAI-1).6 Individuals with re- tegrity, and form an unstructured mass involves a series of events that include duced fibrinolytic activity are at increased called a syncytium. In addition to the platelet adhesion to components of the risk for ischemic cardiovascular events, plug formation, platelet aggregates subendothelium, activation, shape change, and reduced fibrinolysis may underlie release micro-platelet membrane particles release of platelet granules, formation of some of the pathological consequences of rich in phospholipids and various coagu- fibrin stabilized fibrin platelet aggregates, reduced nitric oxide (NO) availability.8 lation proteins which provide localized and clot retraction. In this process, the laboratorymedicine> december 2002> number 12> volume 33 © activation of platelets with exposure of negatively charged phospholipids facili- tates the assembly of coagulation factors Intrinsic System Extrinsic System on the activated platelet membrane, lead- ing to the generation of thrombin and subsequent fibrin deposition.9 Platelet Function In some disorders, platelets may be normal in number, yet hemostatic plugs Downloaded from https://academic.oup.com/labmed/article-abstract/33/12/948/2657208 by guest on 05 November 2019 do not form normally, and therefore, bleeding time will be long. Platelet dys- function may stem from an intrinsic platelet defect or from an extrinsic factor that alters the function of otherwise nor- mal platelets. Defects may be hereditary or acquired. Tests of coagulation phase of hemostasis such as activated partial thromboplastin time (APTT) and prothrombin time (PT) are normal in most circumstances but not all.10 When a patient’s childhood history reveals easy bruising and bleeding after tooth extrac- tion, tonsillectomy, or other surgical pro- cedures, the finding of normal platelet count but a prolonged bleeding time sug- gests a hereditary disorder affecting platelet function. The cause is either HMWK = High Molecular Weight Kininogen vWD (which is the most common cause PF3 = Platelet factor 3 of hereditary hemorrhagic disease) or a PL = Phospholipids hereditary intrinsic platelet disorder. Whatever the cause of platelet dysfunc- tion, drugs that may further impair [F2] The secondary hemostasis platelet function should be avoided such as aspirin and other non-steroidal anti- idiopathic thrombocytopenic puerperal dures or childbirth will be increased.11 inflammatory drugs (NSAIDs). (ITP) usually results from development of When the platelet count reaches 10,000 to an antibody directed against a structural 20,000/µL, the risk of spontaneous and Thrombocytopenia platelet antigen. In childhood ITP, viral serious bleeding rises.11 This includes Thrombocytopenia may be the con- antigen is thought to trigger synthesis of strokes, GI bleeding, and prolonged nose sequence of failed platelet production, an antibody that may react with viral anti- bleeds. When these conditions develop, splenic sequestration of platelets, gen associated with the platelet surface. platelet transfusions are often used to stop increased platelet destruction, or dilution Platelet count is usually maintained in a the bleeding. Unfortunately, transfused of platelets. Regardless of the cause, se- range of 150,000 to 400,000/µL and platelets are short-lived and cannot be vere thrombocytopenia usually results in counts of 100,000 to 150,000/µL are re- used indefinitely as antibodies may de- a typical pattern of bleeding such as mul- garded as borderline for thrombocytope- velop against the platelets. Platelet trans- tiple petechiae in the skin, scattered small nia while counts that are less than fusions are most appropriate when the ecchymoses at the sites of minor trauma, 100,000/µL are considered abnormal.11 cause of thrombocytopenia is a temporary mucosal bleeding, and excessive bleeding Symptoms do not usually develop lack of production such as after intensive 951 after surgery. Heavy gastrointestinal (GI) until the platelet count is less than chemotherapy. bleeding and bleeding into the central 50,000, at which time easy bruising may nervous system (CNS) may be life threat- be evident and petechiae may appear on Kinin System ening. However, thrombocytopenia does the skin. Surgeons usually do not perform The kinins are peptides of 9 to 11 not cause massive bleeding into tissues, routine surgery on patients whose platelet amino acids of which the most important which is characteristic of bleeding sec- counts are december 2002> number 12> volume 33  coagulation factor XII. Bradykinin is also Antithrombin has been shown in vitro tial role as mediators of both immune a chemical mediator of pain, which is a to increase prostacyclin responses and and allergic reactions. Complement cardinal feature of acute inflammation. activated protein C has been shown to protein are involved in reactions which Therefore, bradykinin is capable of repro- inhibit a variety of cellular responses lead to the lysis of cells. This is due to ducing many of the characteristics of an including endotoxin induced calcium the production of the membrane attack inflammatory state, such as changes in fluxes in monocytes, a key step in the complex (MAC). The activation of local blood pressure, edema, and pain, generation of the inflammatory complement may follow the classical resulting in vasodilation and increased response.14 pathway or the alternative pathway. microvessel permeability.12 Human Serine proteases (such as thrombin, Complement is activated by plasmin HMWK, a single-chain protein with a FXa, elastase, trypsin) are implicated in through the cleavage of C3 into C3a Downloaded from https://academic.oup.com/labmed/article-abstract/33/12/948/2657208 by guest on 05 November 2019 molecular weight of 120,000 daltons, is many clinical disorders such as emphy- and C3b. C3a is an anaphylotoxin that cleaved by human urinary kallikrein sema, arthritis, and cardiovascular dis- causes increased vascular permeability (HUK) to release kinin from within a eases. Naturally occurring serine via degranulation of mast cells leading disulfide loop and form a 2-chain protein protease inhibitors (such as antithrom- to the release of histamine. C3b is an that retains all the procoagulant activity bin) which are involved in thrombin opsonin that causes immune of the native molecule.13 It is a multifunc- inhibition regulate these enzymes in adherence.2 During reperfusion, com- tional protein, a parent protein of normal physiological conditions. Serine plement may be activated by exposure bradykinin, and serves as a cofactor for protease inhibitors attach to various en- to intracellular components such as mi- FXI and PK assembly on biologic mem- zymes and inactivate them. Antithrom- tochondrial membranes or intermediate branes. The docking of HMWK to bin was the first of the plasma filaments. In order to protect platelet and EC membranes requires its coagulation regulatory protein to be themselves from the complement binding by regions on both its heavy and identified and the first to be assayed attack, cells express several regulatory light chains. routinely in the clinical laboratory. molecules including the terminal com- Other members of the serine protease plex regulator CD59 that inhibits Serine Protease Inhibitors inhibitor family are heparin cofactor II, assembly of the large MACs by inhibit- It is becoming increasingly clear α1-antitrypsin, and α2-macroglobulin.1 ing the insertion of additional C9 mole- that coagulation augments inflamma- More than 90% of the antithrombin ac- cules into the C5b-9 complex.17 tion and that anticoagulants, tivity of normal plasma is derived from particularly natural anticoagulants, can AT-III.2 Antithrombin-III has been Activated Partial limit the coagulation induced increases shown to exert marked anti-inflamma- Thromboplastin Time in the inflammatory response. The latter tory properties and proven to be effica- Activated partial thromboplastin time control mechanisms appear to involve cious in experimental models of sepsis, was developed from the observation that not only the inhibition of the coagula- septic shock, and disseminated intravas- hemophiliacs have prolonged clotting tion proteases but interactions with the cular coagulation (DIC).15 Antithrom- time. However, when tissue thromboplas- cells that either generate anti-inflamma- bin-III also inhibits factors XIIa, XIa, tin is added, the plasma clots as normal tory substances or limit cell activation. IXa, protein S, protein C, plasmin, and plasma does.4 Thromboplastins are Recent studies have demonstrated a va- kallikrein. lipoproteins. They may be classified as riety of mechanisms by which coagula- either complete or partial, which means tion, particularly the generation of Complement System that they consist of only phospholipids. thrombin, FXa, and the TF/FVIIa com- Complement has an important role Addition of negatively charged activators plex, can augment acute inflammatory in inflammation and in the normal to the system results in significantly responses.14 Many of these responses function of the immune system. Acti- shorter clotting times. It is the most are due to the activation of 1 or more of vated complement fragments have the widely used test for screening for factor the protease activated receptors. Activa- capacity to bind and damage self-tis- deficiencies in the intrinsic and common tion of these receptors on endothelium sues. On their surfaces, cells express pathways. The APTT reflects the activity can lead to the expression of adhesion regulators of complement activation of PK, HMWK, and factors XII, XI, VIII, molecules and platelet activating factor, that protect the cell from the deleterious X, V, II, and I. The APTT may be pro- 952 thereby facilitating leukocyte effects of cell-bound complement frag- longed due to either a factor decrease or activation.14 Therefore, anticoagulants ments. Abnormalities in these regula- the presence of circulating anticoagulants. that inhibit any of these factors would tors may participate in the pathogenesis The normal APTT is less than 35 be expected to dampen the inflamma- of autoimmune diseases and inflamma- seconds.6 tory response. The 3 major natural anti- tory disorders.16 The complement sys- coagulant mechanisms seem to exert a tem consists of approximately 22 serum Prothrombin Time further inhibition of these processes by proteins, which together with antibodies Prothrombin time is the routine test impacting cellular responses. and clotting factors perform an essen- used to screen for deficiencies of factors laboratorymedicine> december 2002> number 12> volume 33 © I, II, V,VII, and X. It is the test of choice gen degradation products (FDPs) is 2. Harmening DM. Clinical Hematology and Fundamentals of Hemostasis. 3rd ed. for monitoring anticoagulant therapy by commonly used in conjunction with Philadelphia: F.D. Davis; 1997:481-508. vitamin K antagonists. Three of the 5 other hemostatic test abnormalities to 3. Hoffmeister HM. Overview of the relevant aspects factors measured by PT (II, VII, X) are identify patients with DIC. of the blood coagulation system-focus and sensitive to and depressed by these anti- cardiovascular hemostasis. Kongressbd Dtsch Ges Chir Kongr. 2001;118:572-575. coagulants.4 Prothrombin time is widely Investigation of Disseminated 4. Stiene-Martin EA, Lotspeich-Steininger CA, utilized for evaluation of diseases with Intravascular Coagulation Koepke JA. Clinical Hematology. Principles, single or multiple coagulation factors A variety of tests are used to detect Procedures, Correlations. 2nd ed. Philadelphia: disorders, such as severe liver dysfunc- DIC. The most sensitive tests are mark- Lippincott; 1998:599-611. tion and DIC. However, its standardiza- ers of endogenous thrombin generation. 5. Bombeli T, Karsan A, Tait JF, et al. Apoptotic Downloaded from https://academic.oup.com/labmed/article-abstract/33/12/948/2657208 by guest on 05 November 2019 vascular endothelial cells become procoagulant. tion of reagents and method is not In the practical management of patients, Blood. 1997;89:2429-2442. established yet for universal purpose ex- cruder measures of DIC are often used. 6. Turgeon ML. Clinical Hematology, Theory and cept International Normalized Ratio Some of these tests include screening Procedures 3rd ed. Lippincott Williams and Wilkins, Philadelphia 1999:398-422 (INR) for control of oral anticoagulant tests such as PT and APTT, which may 7. Lottermoser K, Hertfelder HJ, Wehling M, et al. therapy (OAT).18 Oral anticoagulants be prolonged reflecting consumption of Effects of the mineralocorticoid fludrocortisone on have been widely employed to decrease many coagulation proteins. Plasma con- fibrinolytic function in healthy subjects. J Renin thrombotic risk by reducing the levels of centrations of coagulation proteins con- Angiotensin Aldosterone Syst. 2000;1:357-360. vitamin K-dependent clotting factors. sumed in DIC, such as fibrinogen, FV, 8. Vaughan DE. Angiotensin and vascular fibrinolytic balance. Am J Hypertens. 2002;15:3S- The use of oral anticoagulants also de- and FVIII, all show decreases in concen- 8S. creases the levels of natural anticoagu- tration. Fibrinogen/FDPs or D-dimers (a 9. Triplett DA. Coagulation and bleeding disorders: lants such as protein C and protein S. fragment from fibrin alone) are both in- Review and update. Clin Chem. 2000;46:1260- 1269. The PT test investigates the production creased in concentration and fibrin 10. Platelet Dysfunction. Available at: of thrombin and the formation of fibrin monomer may be present. The thrombin http://www.merck.com/pubs/mmanual/section11/c via the extrinsic and common pathway. clotting time may be prolonged reflect- hapter133/133c.htm. Accessed March 10, 2002. In the presence of calcium ions, tissue ing hypofibrinogenemia and the pres- 11. Inherited platelet disorders: Thrombocytopenia thromboplastin complexes with and acti- ence of FDPs.20 (low platelet numbers). Available at: http://www.familygenetics.net/disorders/thromboc vates FVII. This provides surfaces for ytopenia.htm. Accessed March 10, 2002. the attachment and activation of factors Conclusion 12. Colman RW, Schmaier AH. Contact system: A X, V, and II. Normal values for PT range Hemostasis involves the stoppage of vascular biology modulator with anticoagulant, profibrinolytic, antiadhesive, and proinflammatory from 10 to 13 seconds.6 bleeding following an injury to the vascu- attributes. Blood. 90:1997;3819-3843. Values for the INR are preferable to lature. The various systems work together 13. Maier M, Austen KF, Spragg J. Characterization the PT because different thromboplastin to maintain the integrity of this process of the procoagulant chain derived from human reagents have different sensitivities to and prevent what would otherwise be a high molecular weight kininogen (Fitzgerald factor) by human tissue kallikrein. Blood. warfarin-induced changes in levels of traumatic reaction. A delicate balance is 1983;62:457-463. clotting factors. The INR corrects for maintained between all of the systems 14. Esmon CT. Role of coagulation inhibitors in most but not all of the reagent differences that are involved in the hemostatic inflammation. Thromb Haemost. 2001;86:51-56. expressed as international sensitivity process. A derangement of this delicate 15. Oelschlager C, Romisch J, Staubitz A, et al. index (ISI), which is a correction factor balance may result in adverse outcomes Antithrombin III inhibits nuclear factor kappa B activation in human monocytes and vascular assigned by the manufacturer of the for the patient. For centuries, there have endothelial cells. Blood. 2002;99:4015-4020. thromboplastin reagent. The problems been conceited efforts to understand the 16. Molina H. The murine complement regulator associated with the INR are that the con- coagulation process and design accurate Crry: New insights into the immunobiology of complement regulation. Cell Mol Life Sci. cept and reasons for use are poorly under- methods for evaluation and monitoring of 2002;59:220-229 stood and the value is generally misused.6 this complex process. New understanding 17. Farkas I, Baranyi L, Ishikawa Y, et al. CD59 has been acquired, and today clinical lab- blocks not only the insertion of C9 into MAC but Fibrinogen and Fibrinogen oratories provide physicians with very inhibits ion channel formation by homologous C5b-8 as well as C5b-9. J Physiol. 2002;539:537- Degradation Products useful information with which to diag- 545. Fibrinogen levels are useful in de- nose cases of coagulation derangement. It 18. Kagawa K, Fukutake K. Prothrombin time and its tecting deficiencies of fibrinogen and is hoped that the clinical laboratory will standardization: A potentiality to introduce INR 953 method in criteria for disseminated intravascular alterations in the conversion of fibrino- continue to be at the forefront in the elu- coagulation. Rinsho Byori. 2002;50:277-282. gen to fibrin. The normal value for fib- cidation of the intricate processes that 19. Lozier JN, Metzger ME, Donahue RE, et al. The rinogen ranges from 200 to 400 mg/dL. constitute hemostasis. rhesus macaque as an animal model for This may be decreased in liver disease hemophilia B gene therapy. Blood. 1999;93:1875- 1881. or the consumption of fibrinogen due to 1. Rodak BF. Hematology, Clinical Principles and 20. Disseminated intravascular coagulation. Available accelerated intravascular coagulation.19 Applications. 2nd ed. Philadelphia: W.B Saunders; at: http://rnbob.tripod.com/dic.htm. Accessed An increased concentration of fibrino- 2002:609-753. March 9, 2002. © laboratorymedicine> december 2002> number 12> volume 33