An Updated Concept of Coagulation With Clinical Implications

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An updated concept of coagulation with clinical implications Gregory Romney, BA; Michael Glick, DMD

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Background. Over the past century, a series of models have been put forth to explain the coagulaN C tion mechanism. The coagulation cascade/waterfall U U IN G ED A model has gained the most widespread acceptance. 4 RT ICLE This model, however, has problems when it is used in different clinical scenarios. A more recently proposed cell-based model better describes the coagulation process in vivo and provides oral health care professionals (OHCPs) with a better understanding of the clinical implications of providing dental care to patients with potentially increased bleeding tendencies. Methods. The authors conducted a literature search using the PubMed database. They searched for key words including “coagulation,” “hemostasis,” “bleeding,” “coagulation factors,” “models,” “prothrombin time,” “activated partial thromboplastin time,” “international normalized ratio,” “anticoagulation therapy” and “hemophilia” separately and in combination. Conclusions. The coagulation cascade/waterfall model is insufficient to explain coagulation in vivo, predict a patient’s bleeding tendency, or correlate clinical outcomes with specific laboratory screening tests such as prothrombin time, activated partial thromboplastin time and international normalized ratio. However, the cell-based model of coagulation that reflects the in vivo process of coagulation provides insight into the clinical ramifications of treating dental patients with specific coagulation factor deficiencies. Clinical Implications. Understanding the in vivo coagulation process will help OHCPs better predict a patient’s bleeding tendency. In addition, applying the theoretical concept of the cell-based model of coagulation to commonly used laboratory screening tests for coagulation and bleeding will result in safer and more appropriate dental care. Key Words. Coagulation; coagulation cascade; cell-based model; hemostasis. JADA 2009;140(5):567-574. T

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lood coagulation is vital in achieving hemostasis after a vascular insult has occurred. The failure of blood to coagulate may lead to consequences associated with morbidity and mortality. Since treating patients with increased bleeding tendencies poses a clinical challenge to oral health care professionals (OHCPs), there is a need to understand how hemostasis is achieved in vivo. Over the past century, as more blood cells and clotting-associated proteins were identified, different models were proposed to explain the coagulation mechanism. The classical model, described by Morawitz in 1905, was based on four coagulation factors1-3 and theorized that fibrinogen (factor I [FI]) was converted to fibrin4-6 by thrombin (Figure 1). This theory remained dominant until additional coagulation factors were discovered and the coagulation cascade/waterfall model was developed in 19647,8 (Figure 2, page 569). The cascade/waterfall model, which was based on in vitro data, proposed that coagulation consisted of an activating sequence in which a proenzyme was converted into an active enzyme. This sequence continued until sufficient thrombin was generated to convert FI to fibrin.

Mr. Romney is a third-year dental student, Arizona School of Dentistry & Oral Health, A. T. Still University, Mesa, Ariz. Dr. Glick is a professor of Oral Medicine, Arizona School of Dentistry & Oral Health, A. T. Still University, 5850 E. Still Circle, Mesa, Ariz. 85206, e-mail “mglick@ atsu.edu”. He also is the editor of The Journal of the American Dental Association. Address reprint requests to Dr. Glick.

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health care professionals see the cascade as the FIII (tissue factor) model of coagulation and FIV (calcium) physiology. FII (prothrombin) Thrombin Despite the fact that the originators of the model did not “wish to imply a dogmatic view,”8 the use of the coagulation cascade/ waterfall model became FI (fibrinogen) Fibrin more widespread as screening tests for the Figure 1. Classical model. The classical model of coagulation suggests that the coagulation mechanism extrinsic (for example, the could be described through a two-step, four-factor model. In step one, factor II (FII) (prothrombin), actiprothrombin [PT] test) and vated by factor III (FIII) (tissue factor) and factor IV (FIV) (calcium), is converted to thrombin. In the second step, factor I (FI) (fibrinogen) is converted to fibrin by the thrombin produced in the first step. intrinsic (for example, the activated partial thromboAlthough the coagulation cascade/waterfall model plastin time [aPTT] test) pathways were developed was a marked improvement compared with the and used to predict clinical bleeding.10 Although classical model, the sequential activation of facthe coagulation cascade/waterfall model gained tors in a cascade fashion was not able to describe prominence, it failed to explain how the coagulathe coagulation process in vivo. tion mechanism worked in vivo. One example is In this article, we describe the flaws of previthat patients with specific deficiencies in the ously proposed coagulation models and discuss intrinsic arm of the coagulation pathway—for how a cell-based model better describes coagulaexample, of FXII, prekallikrein (PK) and hightion in vivo. molecular-weight kininogen (HMWK)11-14—have a prolonged aPTT without exhibiting increased METHODS bleeding tendencies.15 If the coagulation mechaWe conducted a literature review by using the nism was represented by a step-by-step activating PubMed database and reading additional citacascade, a deficiency in a factor higher in the castions found in the reference section of reviewed cade should result in increased bleeding tendencies articles. We searched for key words including compared with a deficiency in a factor lower in the “coagulation,” “hemostasis,” “bleeding,” “coagulacascade. As this is not the case (a deficiency of FXII tion factors,” “models,” “prothrombin time,” “actiresults in fewer bleeding tendencies than does a vated partial thromboplastin time,” “international deficiency of FVIII), the cascade/waterfall method normalized ratio,” “anticoagulation therapy” and may not represent coagulation in vivo. “hemophilia” separately and in combination. Although FXII, PK and HMWK may not be required, the intrinsic pathway cannot be disrePROBLEMS WITH THE COAGULATION garded entirely, because patients with deficiencies CASCADE/WATERFALL MODEL in other factors associated with the intrinsic The coagulation cascade/waterfall model has formed the basis for our understanding of coagulation for almost the past one-half century. It proABBREVIATION KEY. aPTT: Activated partial thromboplastin time. ATIII: Antithrombin III. FI: Factor I. vides a logical explanation of the clotting reacFII: Factor II. FIII: Factor III. FIV: Factor IV. FIX: tions in vitro.5 The original models often were Factor IX. FIXa: Activated factor IX. FV: Factor V. depicted as a Y-shaped schema with distinct FVa: Activated factor V. FVII: Factor VII. FVIIa: Actiintrinsic and extrinsic pathways converging into a vated factor VII. FVIII: Factor VIII. FVIIIa: Activated common pathway. The intrinsic and extrinsic factor VIII. FX: Factor X. FXa: Activated factor X. FXI: pathways are triggered by factor XII (FXII) and Factor XI. FXIa: Activated factor XI. FXII: Factor XII. the tissue factor/activated factor VII (TF/FVIIa) HMWK: High-molecular-weight kininogen. INR: Intercomplex, respectively. These pathways merge into national normalized ratio. OHCPs: Oral health care the common pathway9 at the activated factor X/ professionals. PK: Prekallikrein. PT: Prothrombin activated factor V (FXa/FVa) complex. Owing to a time. TF: Tissue factor. TFPI: Tissue factor pathway lack of a clear coagulation mechanism, many inhibitor. vWF: von Willebrand factor. 568

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pathway—factor VIII Intrinsic Pathway Extrinsic Pathway (FVIII) and factor IX (FIX)—have a serious FXII bleeding tendency even PK when the extrinsic Tissue Factor HMWK pathway is functional.10 PT-INR aPTT Test Test Conversely, patients with a deficiency in factor VII FXI FIX (FVII), an extrinsic FVII pathway factor, also have FVIII a bleeding diathesis, even when the intrinsic pathCommon Pathway way is not affected.16 Furthermore, patients with FX deficiencies of factor X FV (FX) and factor V (FV), FII (prothrombin) which are common pathway factors, may Thrombin have impaired hemoFI (fibrinogen) stasis, and patients deficient in factor XI (FXI) may have a bleeding Fibrin Generation diathesis that is much less predictable.17 These patFigure 2. Coagulation cascade/waterfall model. The coagulation cascade/waterfall model consists of the extrinsic, intrinsic and common pathways. The clotting factors are activated sequentially in each terns suggest that the pathway until sufficient thrombin is generated to convert factor I (FI) (fibrinogen) into fibrin. intrinsic and extrinsic According to this model, the pathways are initiated independently and unite only at the factor X pathways are interdepen(FX) and factor V (FV) levels. Activated partial thromboplastin time (aPTT) and prothrombin time– international normalized ratio (PT-INR) tests are used widely to assess the intrinsic and extrinsic pathdent in vivo, instead of ways. PK: Prekallikrein. HMWK: High-molecular-weight kininogen. FXII: Factor XII. FXI: Factor XI. FIX: being separate and funcFactor IX. FVIII: Factor VIII. FVII: Factor VII. 16,18 tionally independent. Studies have attempted to explain the in vivo on the results of in vitro laboratory studies that relationship between the intrinsic and extrinsic often used platelet-poor plasma.26,27 However, cerpathways by demonstrating how the combination tain activations and reactions of clotting factors of TF and FVII becomes a potent activator of that occur on the platelet surface could not be FIX19 and FX.20,21 mimicked by alternative platelet suspensions.28 To compensate for specific factor deficiencies The role of platelets and other cells such as and the findings of research regarding the activamonocytes and fibroblasts in the in vivo coagulation of FIX and FX, it is unlikely that the intrinsic tion mechanism was elucidated and focused and extrinsic pathways operate independently specifically on the function of the cell’s surface from each other in vivo as suggested by the coagumembranes.29 lation cascade/waterfall model. Furthermore, The discovery of the role of cellular surfaces and these pathways appear to act synergistically to TF-bearing cells led to the description of a cellgenerate thrombin, while the TF/FVIIa complex is based model of coagulation.16,18,30,31 This model 22,23 the sole initiator of coagulation in vivo. This has three overlapping phases: initiation, amplificadiffers markedly from the cascade hypotheses in tion and propagation (Figures 3, 4 and 5 [page which in vitro studies have shown that the 571]).10,16,32,33 intrinsic and extrinsic pathways act separately Initiation phase. TF-bearing cells provide the and through an activating sequence until conkey cellular surface in the initiation phase (Figure verging into the common pathway.24,25 3). TF is an important membrane protein that acts as a receptor for FVII.34,35 A break in the vascular CELL-BASED MODEL OF COAGULATION wall allows TF-bearing cells to contact plasma. The coagulation cascade/waterfall model focuses Exposed collagen causes accumulation and activaon an activating sequence of clotting factors based tion of platelets, while exposed TF initiates the JADA, Vol. 140

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TF-Bearing Cell TF

TF/FVIIa

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FIXa Figure 3. Cell-based model initiation phase. A tissue factor– (TF-) bearing cell is the major membrane surface during the initiation phase of the cell-based model. Factor VII (FVII) is activated by TF, resulting in the TF/activated FVII (FVIIa) complex. This complex activates factor IX (FIX) and factor X (FX). FIX is able to migrate to the cellular surfaces, but FX remains on the TF-bearing cell, activating factor V (FV). Activated factor X (FXa) and activated factor V (FVa) form a complex, producing a small amount of thrombin. This thrombin is a key activator in the amplification phase. FIXa: Activated factor IX. TFPI: Tissue factor pathway inhibitor. ATIII: Antithrombin III.

vWF/FVIII TF-Bearing Cell

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Initiation Phase Figure 4. Cell-based model amplification phase. During the amplification phase, thrombin amplifies the coagulation process by activating platelets, factor V (FV), factor VIII (FVIII) and factor XI (FXI). The amplification phase ends with activated FVIII (FVIIIa), activated factor IX (FIXa) and activated factor V (FVa) on the surface of activated platelets. FXIa: Activated factor XI. FIX: Factor IX. TF: Tissue factor. vWF: von Willebrand factor.

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process of generating thrombin32 through binding to FVII, creating the TF/FVIIa complex. During the initiation phase, the TF/VIIa complex activates FIX and FX.36,37 Activated FIX (FIXa) migrates and binds to a platelet surface, and FXa remains on the TFbearing cell. FXa is not able to transfer successfully to the platelet because TF pathway inhibitor (TFPI) and antithrombin III (ATIII) rapidly inhibit it. FIXa is not inhibited by TFPI, but it is inhibited slowly by ATIII.38 On the TF-bearing cell, FXa activates FV.39 FXa then combines with FVa on the cellular membrane to produce small amounts of thrombin. FIXa does not act on the TF-bearing cells or play a significant role during the initiation phase.10 The small quantity of thrombin generated during this phase is the key factor for further thrombin and subsequent fibrin production.32 Amplification phase. The initiation and amplification phases occur on different cell membrane surfaces to limit the coagulation mechanism when it is not needed. The amplification phase occurs mainly on platelets (Figure 4).18,32 The small amount of thrombin generated during the initiation phase activates platelets, FV, FVIII and FXI.18,40-42 Thrombin activates FVIII by cleaving and releasing it from the von Willebrand factor. When thrombin activates FXI,43,44 it enables it to bind to the platelet’s surface. Thrombin acts as an amplifier of the coagulation mecha-

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nism and activates several factors, including FV, FVIII FVIIIa and FXI, that will participate in generating large amounts Activated of thrombin in the next Platelet FVa phase. The amplification Thrombin FIXa Generation phase ends with FVa and activated FVIII (FVIIIa) bound to the surfaces of activated platelets. Propagation phase. In the propagation phase, the Prothrombin tenase (FVIIIa/FIXa) and FXa prothrombinase18,45 (FVa/ FXa) complexes are formed Tenase Activated Complex: on the platelet surface Platelet Activated Prothrombinase FVIIIa/FIXa (Figure 5). FIXa originates Complex:FVa/FXa Platelet FVa from TF-bearing cells and migrates to the platelet surFX face. In addition, activated factor XI (FXIa) may provide Figure 5. Cell-based model propagation phase. As the propagation phase begins, activated additional FIXa directly on factor VIII (FVIIIa) and activated factor IX (FIXa) may be found on the membrane of the platelet. These activated factors form the tenase complex (FVIIIa/FIXa) and activate factor X (FX) on the the platelet surface. The surface. Activated factor X (FXa) subsequently binds with activated factor V (FVa), cretenase complex activates FX, platelet ating the prothrombinase complex (FXa/FVa). The prothrombinase complex converts prothrombin which then binds with its to thrombin. More thrombin is formed in this phase compared with the thrombin generated in cofactor, FVa. The prothrom- the initiation phase. binase complex on the surface of the platelet initiates a burst of thrombin plasma.18 FXa in plasma—activated by TF/FVIIa that brings about the conversion of FI to or provided as a treatment—is not as effective at fibrin.18,30,46-48 Thrombin produced in this phase generating thrombin as is FXa on a platelet suralso activates factor XIII, which stabilizes the face. FX activated on the platelet is able to remain fibrin clot by catalyzing covalent crosslinkages.49,50 localized to the platelet’s surface and is protected Hemophilia and FXI. The cell-based model of from plasma inhibition.31 According to the cellcoagulation explains why the FXa generated by based model, the end result of nonfunctional comthe extrinsic pathway is insufficient to compenplexes on the platelet surfaces is the insufficient sate for a deficiency in FVIII or FIX, resulting in generation of thrombin, which causes the clinical hemophilia. According to the cell-based model, in bleeding tendencies seen in hemophilia.51 normal coagulation it is important that both the The cell-based model also may provide a tenase complex (FVIIIa/FIXa) and the prothromhypothesis to explain the role of FXI in coagulabinase complex (FVa/FXa) be functional. In hemotion. FXI can be activated by the small amount of philia, the tenase complex is deficient owing to thrombin that is generated during the initiation the lack of FVIIIa or FIXa. Without an adequate phase, which in turn activates additional FIX.15 tenase complex, FX is not activated on the Additional FXa may then be manufactured by the platelet surface, effectively impairing the protenase complex, leading to increased thrombin thrombinase complex. The prothrombinase comgeneration. FXIa has been described as a possible plex is responsible for converting prothrombin thrombin mechanism booster.9 The clinical repre(factor II [FII]) to thrombin. sentation of FXI deficiency is variable because Logic would suggest that hemophilia could be even in the absence of FXI, the tenase treated by providing FXa, thus bypassing the (FVIIIa/IXa) and prothrombinase (FXa/FVa) comtenase complex. However, similar to FXa proplexes are formed on the platelet surface and are duced in the initiation phase, FXa used to treat a functional. For this reason, the lack of FXI results patient is not able to migrate to the platelet surin a mild or absent bleeding tendency, because face because it is inhibited by TFPI and ATIII in the coagulation mechanism still may produce sufJADA, Vol. 140

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ficient thrombin on the cellular surface.18 PT and aPTT tests. A cell-based model demonstrates the clinical shortcomings of standard coagulation tests such as PT and aPTT. PT and aPTT tests often are used clinically to evaluate bleeding abnormalities and monitor anticoagulant therapy.52 The results of both PT and aPTT tests measure the time it takes to form an in vitro fibrin clot after a blood sample has been recalcified in the presence of appropriate reagents.53 Although these tests attempt to evaluate bleeding risk, their results do not always represent the ability of a patient’s blood to coagulate in vivo. The PT test was first used to describe bleeding associated with hemophilia and obstructive jaundice. Owing to its sensitivity to extrinsic (FVII) and common (FI, FII, FV and FX) pathway factors, PT became an important test used to examine congenital or acquired coagulopathies and to monitor vitamin K antagonist treatment.54-56 Coagulation times obtained by PT tests may vary depending on the reagent used, which can lead to poor interlaboratory comparisons. In the 1980s, a method was developed that allowed for comparisons between laboratories, and it is known as the international normalized ratio (INR) scale.55,57 Although the PT-INR test has been prominent in clinical practice for the past three decades, it has two important limitations to consider. First, the PT test when converted to the INR scale is valid only for patients taking vitamin K antagonists, such as warfarin.55 The calibration of PT to the INR is done by association between the plasma PT of healthy subjects and that of patients treated with vitamin K antagonists. Owing to this association, the INR is inherently related to vitamin K antagonists. The result of this relationship suggests that the INR may be considered accurate only when it is being used in patients who are undergoing oral anticoagulant therapy. The second limitation of the PT-INR test is that it monitors only procoagulant factors and disregards changes in anticoagulant agents. The coagulation process is a balance between procoagulants, such as clotting factors, and anticoagulant agents, including the aforementioned TFPI and ATIII. Each of these substances plays a role in the in vivo coagulation mechanism. By excluding anticoagulant agents’ impact on the balance of coagulation, the PT-INR test becomes an in vitro test of coagulation and solely indicates a deficiency in procoagulant proteins. These two limita572

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tions suggest that PT-INR test results obtained from patients with conditions, such as liver disease, who have not received anticoagulant therapy may not always be clinically relevant. Like the PT-INR test, the clinical use of the aPTT58 test has limitations.10,53 The aPTT test often is used to determine deficiencies of coagulation factors in the intrinsic (FXII, PK, HMWK, FXI, FIX and FVIII) and common (FII, FV and FX) pathways. A study of the cell-based model of hemostasis indicates that deficiencies in FXII, HMWK and PK do not result in increased bleeding tendencies. Deficiencies in FXI may result in variable levels of bleeding tendencies, while deficiencies of FVIII and FIX result in significant potential for impaired hemostasis. Yet, a deficiency in each of these factors yields a prolonged aPTT. The cell-based model provides an explanation as to why these varied manifestations of clinical bleeding tendency cannot always be predicted by a prolonged aPTT. DISCUSSION

Coagulation in a patient requires generation of thrombin, resulting in a meshwork of insoluble fibrin and platelets. The understanding of how the coagulation mechanism works is evolving continuously. Although the traditional coagulation cascade/waterfall model was able to portray the interaction among coagulation factors in vitro, it inadequately described how the coagulation mechanism worked in vivo. The cell-based model better explains the coagulation mechanism, the limitations of tests commonly used for the evaluation of bleeding tendencies and when to anticipate clinical bleeding. OHCPs who treat patients with impaired hemostasis need to understand the cell-based model and coagulation. The ability of a patient to have blood that clots is one of the major issues that needs to be assessed when evaluating a patient’s likelihood of experiencing an adverse event during dental treatment.59 OHCPs can use the cell-based model to understand why deficiencies in FII, FV, FVIII, FIX and FX may result in severe bleeding after invasive dental procedures, while deficiencies in FXII, PK, HMWK and FXI may result in little or no bleeding. OHCPs often provide care to patients taking anticoagulant and antiplatelet medications. Each of these drugs may result in abnormal bleeding after surgical interventions, although each drug affects distinct aspects of the cell-based

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model. For example, warfarin inhibits vitamin K–dependent factors such as FII, FVII, FIX and FX,60 causing a quantitative change in the amount of procoagulant proteins available for coagulation.61 Aspirin and clopidogrel inhibit platelet aggregation, but according to the cellbased model, it is possible that these types of drugs also may affect thrombin and fibrin production. This theoretical concept is supported by a possible diminished inflammatory response in patients who take these medications that may be caused by the reduced activation of inflammatory cells by the less available amounts of thrombin. Having an understanding of the cell-based model can help OHCPs anticipate possible adverse clinical outcomes suggested by PT-INR and aPTT test results. For example, a PT-INR test result may be relevant only if it is being used to monitor a patient taking anticoagulant agents, since its calibration is based on patients taking vitamin K antagonists. Thus, the results of a PTINR test of a patient in the dental clinic should be questioned if the test was conducted to assess a condition other than one associated with a patient’s anticoagulation therapy. A prolonged aPTT result always should be assessed in conjunction with a thorough medical history, as the risk of bleeding after a dental procedure depends on the underlying medical condition. Patients with FXII deficiencies do not require modifications to established dental protocols, but patients with FXI deficiencies may elicit some concerns, and patients with FVIII and FIX deficiencies need to be cared for according to specific treatment protocols. Yet, all of these patients may have a prolonged aPTT test result. CONCLUSIONS

OHCPs have a responsibility to understand the coagulation mechanism, its relation to laboratory tests results, and how different coagulation disorders may affect treatment and the patient’s health. By understanding the underlying mechanism of the development of potential bleeding tendencies, or lack thereof, OHCPs will be able to render more appropriate and safer dental care. ■ Disclosure. Neither of the authors reported any disclosures. 1. Key NS, Geng JG, Bach RR. Tissue factor; from Morawitz to microparticles. Trans Am Clin Climatol Assoc 2007;118:165-173. 2. Owen CA Jr. Hemostasis: past, present, and future. Mayo Clinic Proc 1980;55(8):505-508. 3. Morawitz P. Die chemie der blugerinnung. Ergebnisse der Physiologie 1905;4:307-423. Cited by: Beck EA. The chemistry of blood coagulation: a summary by Paul Morawitz (1905). Thromb Haemost

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