Tissue Factor Pathway Inhibitor [Tfpi]: A Natural Coagulation Inhibitor and Potential Therapeutic Agent – A Review

REVIEW ARTICLE

Tissue Factor Pathway Inhibitor [Tfpi]: A Natural Coagulation Inhibitor and Potential Therapeutic Agent – A Review Professor Abdel Galil M Abdel Gader MBBS, PhD, FRCP (London and Edinburgh) Department of Physiology, College of Medicine and Blood Bank King Khalid University Hospital, King Saud University, Riyadh, Saudi Arabia

Abstract

It is now well established that the prime trigger to blood coagulation in vivo is tissue factor (TF) that is exposed on the surface of fibroblasts as a result of vessel wall injury. TF joins activated factor VII (FVIIa) normally present in the circulating blood and the TF-FVIIa complex converts FX to FXa. TF activity and the extrinsic pathway of blood coagulation in general are regulated by the specific and major physiological circulating inhibitor: "tissue factor pathway inhibitor -TFPI”. TFPI binds to factor Xa and, in this combination, binds to and inhibits tissue factor/factor VIIa complex and activated FX (FXa) and thus TFPI is currently being included as a natural coagulation inhibitor. TFPI is synthesized primarily by the vascular endothelium.. TFPI is distributed in three pools in vivo; about 80 to 85% of the total body TFPI is associated with endothelial cell-surface, presumably involving glycosaminoglycans and proteoglycans and 15-20% is blood-born circulating in plasma, of which 80% bound to lipoproteins and the rest is the free form, and a tiny proportion (~3%) is found in platelets. The TFPI that is free in plasma is the physiologically active anticoagulant part of TFPI. The importance of TFPI as a natural coagulation inhibitor is reflected by the role TFPI plays in several diseases, as detected by its plasma levels, presence of TF and TFPI in pathologic specimens as well as the effect of exogenously administered recombinant TFPI (rTFPI) on thrombosis, in both humans and animal models. Recent literature is reviewed on the involvement of TFPI in diseases like: Atherosclerosis, arterial thrombosis, Restenosis following arterial intervention, Stroke and ischemia reperfusion injury, Deep Venous Thrombosis (DVT) and anti-phospholipid antibody syndrome, Acute Lung Injury, Malignancy particularly the metastasis of tumor cell, Chronic renal failure (CRF), nephrotic syndrome, crescentic glomerulonephritis, and thrombosis associated with paroxysmal nocturnal hemoglobinuria (PNH). Lastly, a short account is added on the potential Therapeutic Uses of TFPI.

Conclusion

This review article aims to highlight the importance of yet another natural coagulation inhibitor (TFPI), like earlier inhibitors, its deficiency in numerous disease conditions led to the elaboration of recombinant TFPI (rTFPI) which holds much promise in the future therapy of thrombotic disease.

Keywords: Coagulation pathways, Tissue factor pathway inhibitor, Tissue factor Journal of Taibah University Medical Sciences 2009; 4(1): 1-15 Correspondence to: Professor Abdel Galil M Abdel Gader Department of Physiology Coagulation Laboratory, the Blood Bank College of Medicine, King Khalid University Hospital King Saud University,  7805 Riyadh 11461 Saudi Arabia  [email protected] 1

Abdel Galil M Abdel Gader

Introduction

gradually been realized that the cascade model suffers from many limitations, as it fails to explain convincingly how hemostatic activation occurs in vivo. For example, the model cannot explain why hemophiliacs bleed when they have an intact factor VIIa/TF "extrinsic" pathway. The classical cascade model of the coagulation mechanism is being replaced by the new, Cell-based model of coagulation 1 (Figure 2) which emphasizes the interaction of coagulation proteins with the cell surfaces of platelets, subendothelial cells and the endothelium. According to this model coagulation is initiated (The Initiation Phase) by the formation of a complex between tissue factor (TF) exposed on the surface of fibroblasts as a result of vessel wall injury, and activated factor VII (FVIIa), normally present, in tiny quantities, in the circulating blood. The TF-FVIIa complexes convert FX to FXa on the TF bearing fibroblasts. FXa then activates prothrombin (FII) to thrombin (FIIa). The next phase is the Amplification Phase in which this limited amount of thrombin activates FVIII, FV, FXI and platelets, on the surface of blood platelets. Thrombin-activated platelets change shape and as a result will expose negatively charged membrane phospholipids, which form the perfect template for the assembly of various clotting factors and full thrombin generation, involving FVIIIa and FIXa (The Propagation Phase).

The Coagulation Mechanism

U

nder normal conditions the blood circulates freely within the confines of the vascular system. However, when blood escapes to extravascular sites after blood vessel injury or the vessel wall becomes pathologically challenged by atheroma, haemostasis may be activated ending in the formation of blood (fibrin) clot. This process is finely regulated by positive and negative feedback loops that control fibrin clot formation. For many decades the accepted blood coagulation mechanism has been based on the concept of the coagulation cascade model (Figure 1) that describes the interactions of the coagulation factors along two pathways: the intrinsic pathway which is triggered by the contact of blood with a foreign surface, and the extrinsic pathway which is triggered by exposure of the blood to the transmembrane receptor tissue factor (TF) which binds to clotting factor VIIa to form TF/FVIIa complex. Both pathways meet at the level of clotting factor X after which the common pathway progresses until the generation of the thrombin and the formation of fibrin clot. However, while the cascade model delineates the interactions between the coagulation proteins and provides a framework for interpreting the common screening coagulation tests (particularly the PT and the APTT), it is

Extrinsic pathway

Intrinsic Pathway FXII

FXIIa

FXI

FXIa

FIX

Tissue factor Factor VIIa & Ca ++

FIXa

Tissue Factor pathway Inhibitor (TFPI)

FVIIIa

X

Xa FVa+ Ca+P

Thrombin

Prothrombin

Fibrinogen

Fibrin

Figure 1: The coagulation cascade 2

J T U Med Sc 2009; 4(1)

Tissue Factor Pathway Inhibitor

Figure 2: The coagulation cascade model

Tissue factor + Factor VIIa TFPI

Factor IXa -FVIIIa

Factor Xa +FVa Anti-Thrombin

Protein C

Factor IIa (thrombin)

Factor XIa

Fibrinogen

Fibrin

Figure 3: The Coagulation inhibitors According to this cell-based model the tissue factor (TF) extrinsic pathway is the principal cellular initiator of normal blood coagulation in vivo, and the major regulator of haemostasis and thrombogenesis, with the intrinsic pathway, playing an amplification role 1, 2.

tissue factor/factor VIIa complex 2, 3. Many pieces of recent evidence in human and animal studies2 indicated that the deficiency of this inhibitor can lead not only to a thrombotic tendency but also to the development of atherosclerosis. Thus TFPI is currently being included as a natural coagulation inhibitor. Prior to 1983, two major mechanisms were known for controlling blood coagulation. One is the inhibition of the serine proteases (factors XIa, IXa, Xa and thrombin) by antithrombin and the other is the inactivation of two key cofactors (factors Va and VIIIa) by the activated protein C/protein S complex 4 (Figure 3). Although antithrombin has been

Inhibition of the Coagulation System – Tissue Factor Pathway Inhibitor - TFPI In vivo TF activity and the extrinsic pathway of blood coagulation is regulated by the specific and major physiological circulating inhibitor known as "tissue factor pathway inhibitor (TFPI). TFPI binds to factor Xa and, in this combination, binds to and inhibits 3

J T U Med Sc 2009; 4(1)

Abdel Galil M Abdel Gader

shown to inhibit VIIa/TF in vitro 5, 6 it does not appear to play a major role in inhibiting VIIa/TF in vivo 7, 8. Thus neither of the above two mechanisms controls the initiation of TFinduced coagulation. There were earlier indications that an inhibitor of VIIa/TF complex may be present in serum; however, compelling evidence for a third inhibitory mechanisms, eventually identified as TFPI, was not discovered until 1983, in Rapaport’s laboratory 9. This inhibitor which blocks VIIa/TF induced coagulation requires factor X/Xa as a cofactor for its functionality 9, 10.

results in a 2- to 4- fold increase in plasma TFPI levels from the release of the endothelial GPI bound full-length TFPI 23, which is known to have more potent anticoagulant effect than circulating lipoprotein- associated TFPI 24, 25. These observations might account for some of the anticoagulant effect of heparin. There is now convincing evidence from in vitro and in vivo experiments that TFPI plays an important role in regulating the initiation of blood coagulation 7, 8, 26-29. In man, some studies reproted that low levels of TFPI are a weak risk factor for venous thrombosis 30-33. However, manifest TFPI-deficiency, either associated or not with thrombotic disorders, similar to deficiencies of other coagulation inhibitors, have not yet been detected 34. One possible explanation for this apparent discrepancy between the experimental evidence and data in humans could be the available TFPI assays, at the time the studies were undertaken, were technically inadequate to detect the role of TFPI in vivo and thus to detect TFPI deficiency 33, 34.

Synthesis of TFPI TFPI is synthesized primarily by the vascular endothelium under normal physiologic In immunohistochemical conditions 11. analysis of normal human tissues, TFPI was present primarily in the microvascular endothelial surface and megakaryocytes 12,13; but can also located on the surface of monocytes 14 within platelets 15 and circulating in plasma 16,17. Studies of cultured endothelial cells have demonstrated that TFPI associated with the cell surface through a glycophosphatidylinositol (GPI)-anchor 18, in a manner that is not dependant on glycosaminoglycans (GAGs) or altered by heparin 19, 20. These results indicate that TFPI is a GPI-anchored protein. In addition, heparin releasable-TFPI likely represents only a small portion of the total TFPI on endothelium that remains attached to cell surface glycosaminoglycans after cleavage of the GPI-anchor by endogenous enzymes 20.

Role of TFPI in Disease The role TFPI plays in several disease states has been uncovered by measurement of its plasma levels, presence of TF and TFPI in pathologic specimens as well as the effect of exogenously administered recombinant TFPI (rTFPI) on thrombosis in animal models 3. Measurements of TFPI levels in several disease states have demonstrated either a deficiency state due to consumption or elevated levels indicating endothelial injury or inflammation. However, since ~85% of TFPI is bound to the endothelium, the plasma levels of TFPI do not accurately reflect the total body TFPI levels 12.

Distribution of TFPI TFPI is distributed in three pools in vivo; about 80 to 85% of the total body TFPI is bound toendothelial cell-surface, presumably involving glycosaminoglycans and proteoglycans, and 15-20% is blood born, circulating in plasma, of which 80% is bound to lipoproteins and the rest is the free form; a tiny proportion (~3%) is found in platelets 21, 22. The TFPI that is free in plasma (free form) is the physiologically active anticoagulant part of TFPI 2, while the TFPI associated with plasma lipoproteins is C-terminally truncated and is a less efficient anticoagulant 22. Intravenous administration of heparin

TFPI Deficiency and Arterial and Venous Thrombosis TFPI null humans have not been identified suggesting that TFPI is required for human birth and reproduction. However, low plasma levels of TFPI are weakly linked to disease in humans and several studies have suggested that plasma TFPI levels may indicate a “threshold effect”, where patients with free (non-lipoprotein bound) plasma 4

J T U Med Sc 2009; 4(1)

Tissue Factor Pathway Inhibitor

TFPI concentration less than 10% of the normal mean value, are at increased risk (~ 2-fold) for both deep venous thrombosis and myocardial infarction35-38. In other published studies there is a considerable amount of conflicting data about the contribution of plasma TFPI levels and the development of thrombosis39-42. This is likely a result of the wide normal range of plasma TFPI43, the various methods for measurement of plasma TFPI44 and the poor correlation between the soluble circulating plasma TFPI concentration and the amount of cell surface associated endothelial and/or platelet TFPI43.

degree of restenosis at the site of ballooninduced arterial injury was shown following the inhibition of local thrombosis with rTFPI 59, 60. Acute coronary syndromes A hypercoagulable state exists in patients with acute coronary syndrome, whether myocardial infarction (MI) or unstable angina(US), as depicted by the elevated levels of prothrombin fraction 1+2, thrombin antithrombin complexes, and D-Dimer as well as plasminogen activator inhibitor (PAI) and reduced levels of the natural coagulation inhibitors protein C and antithrombin. However, the reduction in the level of these two natural coagulation inhibitors is compensated for by the significant elevation in plasma levels of both total and free plasma TFPI in MI and UA61. This was taken to be a physiological response towards maintaining the balance of procoagulant versus anticoagulant activities that prevents further development of thrombosis.

Atherosclerosis and arterial thrombosis The disruption of atherosclerotic plaque in coronary arteries is usually complicated by acute local thrombosis which leads to unstable angina and myocardial infarction 45. Such event of disruption exposes the monocyte/macrophage TF in these plaques 46, 47 to circulating blood, resulting in the formation of a mural thrombus. However, TFPI colocalized with TF in endothelial cells, macrophages, and vascular smooth muscle cells plays a regulatory role in TF-induced thrombosis in atherosclerotic plaques 48-51. Under culture conditions macrophages exposed to cholesterol and oxidized LDL upregulate TF but not TFPI, create a procoagulant state which may end in thrombus formation52. Some studies have shown that arterial thrombi formed on ruptured atherosclerotic plaques were resistant to heparin and aspirin53, but a beneficial effect of recombinant TFPI on TFinduced arterial thrombosis have been rTFPI demonstrated by others54-57. administered in a model of dog coronary artery with intimal injury, maintained coronary patency following fibrinolysis 55. This finding is of particular interest since the current use of aspirin and heparin after thrombolysis is only partially effective in preventing recurrent thrombosis and leaves a potential useful antithrombotic role for TFPI in the management of coronary thrombosis. In this respect it is worthwhile adding that in rabbits and pigs significant reduction in the

Ischemia-reperfusion injury and stroke Activation of TF-induced coagulation plays an important role in ischemia reperfusion injury which complicates shock, central nervous system thrombosis and following surgery of the liver, spinal cord, brain, lungs, etc. 62, 63. In a study using a rabbit model of ischemia-reperfusion injury of the spinal cord, rTFPI-treated animals showed significant recovery of neurologic function, compared with those treated with heparin alone64. Similarly, rTFPI also protected rats against the hepatic ischemia reperfusion injury65. These observations show clearly that TFPI plays an important potential protective role in ischemia reperfusion injury and stroke. Thrombosis associated with use of oral contraceptives The plasma TFPI concentration decreases about 25% in women using oral contraceptives and this represents increased risk (up to 6-fold) of thrombosis associated with the use of oral contraceptives66-70. In animal models the decreased TFPI in the 5

J T U Med Sc 2009; 4(1)

Abdel Galil M Abdel Gader

Disseminated Intravascular Coagulation (DIC) and Sepsis TF expression of TF on monocytes 78 and endothelium can readily be triggered by endotoxemia 79 which I turn ends in DIC. Considerable variability exists in the reported levels of free TFPI antigen, TFPI activity and Xa-TFPI complex in patients with DIC 80-82, thereby reducing the diagnostic value of measuring these parameters in clinical DIC. In the animal models, inhibition of endotoxin-induced coagulation was demonstrated, including inactivation of factor VIIa, two-domain rTFPI 83. In a model of E coli sepsis with DIC, Creasy et al demonstrated a significant decrease in intravascular coagulation, shock and mortality with the administration of rTFPI 84. The decrease in mortality with rTFPI and inactive VIIa was attributed to the reduction of plasma IL-6 and IL-8 85- 87 levels. This anti-inflammatory effect of rTFPI was attributed, in part, to its ability to prevent binding of endotoxin to its cells surface receptor, CD14 88.

presence of FV Leidin (FVL) enhances further the risk of thrombosis. It has been found that mice with heterozygous deficiency of TFPI develop normally and do not suffer from spontaneous thrombosis 71; however, when the FVL mutation is bred into such mice, the animal develops severe disseminated thrombosis and death 72. These studies in genetically alerted mice support the notion that decreased TFPI contributes to increased risk for thrombosis associated with oral contraceptive use. Deep Venous Thrombosis (DVT) A convincing association between TFPI and venous thrombosis has not been established yet. The plasma TFPI levels reamin unaltered in DVT 73. Also low plasma levels of free TFPI appear to cause a significantly increase in the risk for DVT especially in patients with factor V Leiden mutation 74. In both arterial and venous thrombosis, associated with antiphospholipid syndrome (APS), the free plasma and monocyte TF levels have been found to be elevated 75; however, Amengual et al 75 also found higher plasma TFPI levels in patients with APS. Similarly, in another study, the plasma TFPI activity were found to be higher in patients with APS, both before and after intra-venous heparin injection; however, the TFPI anticoagulant activity was inhibited in the presence of lupus anticoagulants 76. These authors suggest that the increased plasma TFPI levels may be in response to the increased procoagulant TF activity. Since plasma TFPI levels reflect only a small pool of the total TFPI, Mannuci and coworkers measured the larger endotheliumbound and heparin releasable pool of TFPI in patients with arterial and venous thrombosis 77. As compared to normal, the post-heparin TFPI levels were found to be significantly decreased in 12 out of 113 subjects. Since at least one first degree relative had low TFPI levels in six cases, it appears that this defect could have been inherited. However, whether or not low heparin-releasable plasma TFPI plays a definite causative role in arterial or venous thrombosis could not be established.

Acute Lung Injury In acute lung injury (ALI) coagulation was shown in both the intravascular and extravascular compartments in the lung 89, 90. Besides, an increased activity of TF pathway of coagulation has been demonstrated in the alveolar compartment 90. Since endothelial injury with increased vascular permeability is the hallmark of ALI, not surprisingly the plasma levels of plasma TFPI levels in ALI were found to be significantly elevated and this was related to endothelial injury in this disease 91, 92. Malignancy and tumor metastasis It is now well established that venous thromboembolism is a frequent complication of cancer. This appears to be due to the shedding of the procoagulant TF into the circulation 93, 94 from numerous malignant tumors 95, 96 resulting in the activation of the extrinsic pathway of coagulation 97. A hypercoagulable state ensues despite elevations in the plasma TFPI activity and antigen in patients with acute nonlymphocytic leukemias with DIC and 6

J T U Med Sc 2009; 4(1)

Abdel Galil M Abdel Gader

also in solid tumors 98. Besides its procoagulant activity, TF appears to play a new role in tumor metastasis. In melanoma cells, the expression of TF correlates with hematogenous metastasis 99. Also melanoma cells are rendered less invasive by an anti-TF antibody 100. This action of TF is thought to be independent of the role of TF in coagulation 100. In this respect tumor cells adhesion and subsequent migration were found to be enhanced by binding of TFPI to An the extracellular domain of TF101. alternative mechanism by which TFPI may promote invasion and metastasis of cancer cells could involve inhibition of other serine proteases known to help cellular migration on the extra cellular matrix 102. In addition to promoting metastasis, TF has also been implicated the organization and integrity of the vessel wall during angiogenesis in a hemostasis independent manner 103. In this capacity TF has been found to play a significant role in tumor associated angiogenesis 104. This raises the possibility that inhibition of TF via TFPI may help regulate angiogenesis.

were recorded in the steroid-resistant nephrotics. This study concluded that the elevated levels of both total and free TFPI in these phases of nephrotic syndrome, constitutes, besides the already reported elevated levels of proteins C and S 109, additional physiological natural anticoagulant mechanism, which will attenuate the hypercoagulability that characterize childhood nephrotic syndrome and in this way will guard against the thrombosis that is known to be associated with nephrotic syndrome. Treatment of Bleeding in Patients with Haemophilia In the introduction of this review and in relation to the emergence of the cell-based model of coagulation the following question was raised: if TF-FVIIa is the primary initiative of blood clotting in vivo and is a potent activator of FX, why do haemophiliacs bleed? The discovery and characterization of TFPI activity offers new hope for better management of haemophiliacs 110. In vitro evidence has demonstrated that reduction of the inhibitory effect of TFPI is an important step for the prevention of bleeding in patients with haemophilia 111. Besides, anti-TFPI antibody shortens the bleeding time in rabbits with antibody-induced haemophilia A 112. In patients with hemophilia, the success of recombinant FVIIa therapy in those with acquired inhibitors of FVIII or FIX has demonstrated that TF pathway is an important target for treatment, and suggests that therapeutic modulation of TFPI activity could be an attractive therapeutic target of the development of new therapies to prevent bleeding in patients with haemophilia.

TFPI and Renal Disease Both FVIIa and TF were found to be elevated in plasma of patients with chronic renal failure (CRF) 105, 106. This is also accompanied by elevations in plasma TFPI levels, possibly secondary to such factors as administration of heparin during hemodialysis as well as endothelial injury. Both TF and TFPI antigen have been detected in crescentic 107 glomerulonephritis . Also, TFPI has been correlated with chronicity in the crescentic lesions in this study 107. Thus, CRF seems to be associated with increased TF and TFPI in plasma and at the site of inflammation in renal tissue.

Thrombosis Associated with Paroxysmal Nocturnal Haemoglobinuria (PNH) PNH is a disease characterized by lack of glycosyl phosphatidylinositol (GPI)anchored protein expression and patients with PNH have a pronounced predisposition to intravascular thrombosis. The thromboses occur in an organ specific pattern, mostly in the portal circulation (hepatic vein occlusion, also called the Budd-Chaiari Syndrome, or in

Childhood Nephrotic Syndrome In a recent report on childhood nephrotic syndrome 108, both total and free plasma TFPI were found to be significantly elevated in nephrotic children in the relapse of nephrosis with and without steroid treatment as well as in those in remission while on steroid therapy. However, the highest levels of both total and free TFPI 7

J T U Med Sc 2009; 4(1)

Tissue Factor Pathway Inhibitor

the possible future use of rTFPI in the management of acute coronary syndrome, particularly the prevention of restenosis after angioplasty in humans. In a very recent study rTFPI irrigation was shown to inhibit thrombosis and neointimal hyperplasia, and attenuate vascular remodeling and luminal stenosis 118. Recombinant TFPI (rTFPI) which has been employed in various therapeutic trials is available in two forms that differ in their pharmacokinetics 84, 119: a full-length protein as well as a C-terminally truncated twodomain form. A Phase II trial of the efficacy of TFPI in patients with severe sepsis showed a mortality reduction in TFPIcompared to placebo-treated patients and an improvement of organ dysfunctions. High concentrations of TFPI are provided at sites of tissue damage and ongoing thrombosis, either by exogenous administration of rTFPI, or TFPI can be released from intravascular stores by heparin and low molecular weight heparins (LMWH) 116. In a recent study in rabbits and rats, intravenous injection of recombinant TFPI-2 prevented the development of experimentally-induced retinal degenerative diseases, suggesting the potential use of rTFPI in the treatment of retinal degeneration in humans 120. Lastly, a recent review summarized the evidence, drawn from animal models, for the antiangiogenic and antimetastatic effects of TFPI and described its mechanisms of action particularly the potential antitumor properties of rTFPI (TFPI-2), thereby strengthening the rationale for considering TFPI as a future anticancer agent 121. These and other pieces of evidence indicate clearly that it will not be too long before TFPI and its various recombinant forms will undergo further development and improvement and find multiple therapeutic uses in humans.

venous circulation of the brain 113. As stated earlier, TFPI is an endothelial GP-anchored protein and defective expression of TFPI in patients with PNH is believed to contribute to the organ specific thrombosis observed in PNH 114. Pregnancy Hypertension (PH) In a recent study employing precise ELISA assays of total and free plasma TFPI 115, the levels of total plasma TFPI im normal pregnancy was found to be comparable to non-pregnant levels; however, the levels of free TFPI exhibited significant reduction in normal pregnancy as compared to nonpregnant controls. The same study has found a significant increase in the levels of free tissue factor pathway inhibitor (TFPI) in pre-eclampsia and in non-proteinuric hypertension, as compared to normal pregnancy. In pre-eclampsia the elevated levels were maintained after placental delivery. Free protein S levels in preeclampsia, non-proteinuric hypertension and in post-partum pre-eclamptic patients, were significantly higher than in normal pregnant controls. Total TFPI fluctuations were unremarkable. This study concluded that the significant increase in the levels of the physiologically active free forms of the two coagulation inhibitors, TFPI and protein S, in PH, may protect such patients from the risks of haemostatic activation which is a known feature of PH. Potential Therapeutic Uses of TFPI The inhibition of the extrinsic TF-FVIIa by TFPI, as detailed in this review, provided a unique therapeutic approach for prophylaxis and/or treatment in a wide range of pathological conditions. The available experimental and clinical data suggest strongly that TFPI might turn out to be an important treatment for several clinical conditions. In particular, TFPI is expected to inhibit the development of post-injury intimal hyperplasia and thrombotic occlusion in atherosclerotic vessels as well as being effective in acute coronary syndromes, particularly unstable angina and myocardial infarction, sepsis and DIC and many more conditions116, 117. Strong hope is attached to

Acknowledgement The author is grateful to Mrs Farah Chatila for her excellent secretarial work while preparing this review article. 8

J T U Med Sc 2009; 4(1)

Abdel Galil M Abdel Gader

References 1.

Roberts HR, Hoffman M, Monroe DM. A cell-based model of thrombin generation. Semin Thromb Hemost. 2006; 32 Suppl 1: 32-38 2. Bajaj MS, Birktoft JJ, Steer SA, Bajaj SP. Structure and biology of tissue factor pathway inhibitor. Thromb Haemostas 2001; 86: 959-972 3. Rapaport SI. The extrinsic pathway inhibitor. A regulator of tissue factor dependent blood coagulation. Thromb Haemostas 1991; 66: 6-15 4. Rapaport SI. Inhibition of factor VIIa/tissue factor-induced coagulation: with particular emphasis upon a factor Xa-dependent mechanism. Blood 1989; 73: 359-365 5. Lawson JH, Butenas S, Ribarik N, Mann KG. Complex dependent inhibition of factor VIIa by antithrombin and heparin. J Biol Chem 1993; 81: 704-719 6. Rao LVM, Rapaport SI, Hoang AD. Binding of factor VIIa to tissue factor permits rapid antithrombin III/heparin inhibition of factor VIIa. Blood 1993; 81: 2600-2607 7. Sandset PM, Warn-Cramer BJ, Rao LVM, Maki SL, Rapaport SI. Depletion of extrinsic pathway inhibitor (EPI) sensitizes rabbits to disseminated intravascular coagulation induced with tissue factor: evidence supporting a physiologic role for EPI as a natural anticoagulant. Proc Natl Acad Sci USA 1991; 88: 708-712 8. Sandset OM, Warn –Cramer BJ, Maki SL, Rapaport SI. Immunodepletion of extrinsic pathway inhibitor sensitizes rabbits to endotoxin-induced intravascular coagulation and the generalized Schwartzman reaction. Blood 1990; 78: 1496-1502 9. Sanders NL, Bajaj SP, Rapaport SI. A plasma protein that inhibits tissue factorfactor VII activation of factor IX in the presence of factor X. Circulation 1983; 68(Suppl): 1266a (abstr). 10. Sanders NL, Bajaj SP, Zivelin A, Rapaport SI. Inhibition of tissue factor/factor VIIa activity in plasma

11.

12.

13.

14.

15.

16.

17.

18.

19.

9

requires factor X and an additional plasma component. Blood 1985; 66: 204212 Bajaj MS, Kuppuswamy MN, Saito H, Spitzer SG, Bajaj SP. Cultured normal human hepatocytes do not synthesize lipoprotein-associated coagulation inhibitor: Evidence that endothelium is the principal site of its synthesis. Proc Natl Acad Sci USA 1990; 8869-8873 Werling RW, Zacharski LR, Kisiel W, Bajaj SP, Memoli VA, Rousseau SM. Distribution of tissue factor pathway inhibitor in normal and malignant human tissues. Thromb Haemost 1993; 69: 366-369 Ameri A, Kuppuswamy MN, Basu S, Bajaj SP. Expression of tissue factor pathway inhibitor by cultured endothelial cells in response to inflammatory mediators. Blood 1992; 79: 3219-3226 Ott I, Andrassy M, Zieglgansberger D et al. Regulation of monocyte procoagulant activity in acute myocardial infarction: role of tissue factor and tissue factor pathway inhibitor-1. Blood 2001; 97: 3721-3726 Novotny WF, Girard TJ, Miletich JP, Broze GJ Jr. Platelets secrete a coagulation inhibitor functionally and antigenically similar to the lipoprotein associated coagulation inhibitor. Blood 1988; 72: 2020-2025 Broze GJ Jr, Lange GW, Duffin KL, MacPhail L. Heterogeneity of plasma tissue factor pathway inhibitor. Blood Coagul Fibrinolysis 1994; 5: 551-559 Novotny WF, Girard TJ, Miletich JP, Broze GJ Jr. Purification and characterization of the lipoproteinassociated coagulation inhibitor from human plasma. J Biol Chem 1989; 264: 18832-18837 Maroney SA, Mast AE. Expression of tissue factor pathway inhibitor by endothelial cells and platelets. Transfus Apher Sci 2008; 38: 9-14 Sevensky JR, Rao LV, Ruf W. Liganinduced protease receptor translocation into caveolae: a mechanism for regulating cell surface proteolysis of the J T U Med Sc 2009; 4(1)

Tissue Factor Pathway Inhibitor

20.

21.

22.

23.

24.

25.

26.

27.

28.

29.

tissue factor-dependant coagulation pathway. J Cell Biol 1996; 133: 293-304 Ott I, Miyagi U, Miyazaki K, et al. Reversible regulation of tissue factorinduced coagulation by glycosyl phosphatidylinositol-anchored tissue factor pathway inhibitor. Arterioscler Thromb Vasc Biol 2000; 20: 874-882 Bajaj MS, Ameri A, Bajaj SP. Tissue factor pathway inhibitor – A regulator of tissue factor-induced coagulation. In: Anticoagulants: physiologic, pathologic and pharmacologic. Green D, ed. Florida: CRC Press 1994; 41-65 Broze GJ JR, Lange GW, Duffin KL, MacPhail L. Heterogeneity of plasma tissue factor pathway inhibitor. Blood Coagul Fibrinolysis 1994; 5: 551-559 Sandset PM, Abidgaard U, Larsen ML. Heparin induces release of extrinsic coagulation pathway inhibitor (EPI). Thromb Res 1988; 50: 803-813 Nordfgang O, Bjorn SE, Valentin S, Nielsen LS, Wildgoose O, Beck TC, Hedner U. The C-terminus of tissue factor pathway inhibitor is essential to its anticoagulant activity. Biochemisty 1991; 30: 10371-10376 Wesselschmidt R, Likert K, Girard T, Wun T-C, Broze GJ Jr. Tissue factor pathway inhibitor: the carboxy-terminus is required for optimal inhibition of factor Xa. Blood 1992;79: 2004-2010 Holst J, Londblad B, Bergqvist D, Nordgang O, Ostergaard PB, Petersen JL, Nielsen G, Hedner U. Antithrombotic properties of a truncated recombinant tissue factor pathway inhibitor in an experimental venous thrombosis model. Haemostasis 1993; 23 (Suppl 1): 112-117 Kaiser B, Fareed J. Recombinant fulllength tissue factor pathway inhibitor (TFPI) prevents thrombus formation and rethrombosis after lysis in a rabbit model of jugular vein thrombosis. Thromb Haemost 1996; 76: 615-620 Bajaj MS, Bajaj SP. Tissue factor pathway inhibitor: potential therapeutic applications. Thromb Haemost 1997; 78: 471-477 Huang ZF, Higuchi D, Lasky N, Broze GJ Jr. Tissue factor pathway inhibtor gene

30.

31.

32.

33.

34.

35.

36.

37.

38.

39.

10

disruption produces intrauterine lethality in mice. Blood 1997; 90: 944-951 Van Dreden P, Grosly M, Cost H. Total nad free levels of tissue factor pathway inhibitor: arisk factor in patients with factor V Leiden? Blod Coagul Fibrinolysis 1999; 10: 115-116 Ariens RA, Alberio G, Moia M, Mannucci OM. Low levels of heparinreleasable tissue factor pathway inhibitor in young patients with thrombsosis. Thromb haemost 1999; 81: 203-207 Amini-Nekoo A, futers TS, Moia M, Mannucci OM, Grant PJ, Ariens RA. Analysis of the tissue factor pathway inhibitor gene and antigen levels in relation to venous thrombosis. Br J Haematol 2001; 113: 537-547 Dahn A, van Hylckama Vlieg A, Bendz B, Rosendaal F, Bertina RM, Sandset PM. Low levels of tissue factor pathway inhibitor (TFPI) increase the risk of venous thrombosis. Blood 2003; 101: 4387-4392 Sandset PM, Bendz B. Tissue factor pathway inhibitor: clinical deficiency states. Thromb Haemost 1997; 78: 467470 Dahm A, Van HV, Bendz B et al. Low levels of tissue factor pathway inhibitor (TFPI) increase the risk of venous thrombosis. Blood 2003; 101: 4387-4392 Golino P, Ravera A, Ragni M et al. Involvement of tissue factor pathway inhibitor in the coronary circulation of patients with acute coronary syndromes. Circulation 2003; 108: 2864-2869 Morange PE, Simon C, Alessi MC et al. Endothelial cell markers and the risk of coronary heart disease: the prospective epidemiological study of myocardial infarction (PRIME) study. Circulation 2004; 109: 1343-1348 Duering C, Kosch A, Langer C, Thedieck S, Nowak-Gottl U. Total tissue factor pathway inhibitor is an independent risk factor for symptomatic paediatric venous thromboembolism and stroke. Thromb Haemsot 2004; 92: 707-712 Ariens RA, Alberio G, Moia M, Mannucci PM. Low levels of heparinreleasable tissue factor pathway inhibitor J T U Med Sc 2009; 4(1)

Abdel Galil M Abdel Gader

40.

41.

42.

43.

44.

45.

46.

47.

48.

49.

in young patients with thrombosis. Thromb Haemost 1999; 81: 203-207 Asakura H, Ontachi Y, Mizutani T et al. Elevated levels of free tissue factor pathway inhibitor antigen in cases of disseminated intravascular coagulation caused by various underlying diseases. Blood Coagul Fibrinolysis 2001; 12: 1-8 Velasco F, Lopez-Pedrera C, Borrell M, Fontcuberta J, Torres A. Elevated levels of tissue factor pathway inhibitor in actue non-lymphoblastic leukemia patients with disseminated intravascular coagulation. Blood Coagul Fibrinolysis 1997; 8: 70-72 Adams MJ, Cardigan RA, Marchant WA et al. Tissue factor pathway inhibitior antigen and activity in 96 patients’ receivingheparin for cardiopluymonary bypass. J Cardiothoracic Vascul Anesthesia 2002; 16: 59-63 Novotny WF, Brown SG, Miletich JP, Rader DJ, Broze GJ Jr. Plasma antigen levels of the lipoprotein-associated coagulation inhibitor in patient samples. Blood 1991; 78: 387-393 Ariens RAS. The Quest for the Holy Grail of tissue factor pathway inhibitor deficiency has just begun. J Thromb Haemos 2005; 3: 649-650 Fuster V. Mechanisms leading to myocardial infarction: insights from studies of vascular biology. Circulation 1994; 90: 2126-2146 Wilcox JN, Smith KM, Schwartz SM, Gordon D. Localization of tissue factor in the normal vessel wall and in the atherosclerotic plaque. Proc Natl Acad Sci USA 1989; 86: 2839-2843 Tipping PG, Malliarors J, Holdsworth SR. Procoagulant activity expression by macrophages from atheromatous vascular plaques. Atherosclerosis 1989; 79: 237-243 Drew AF, Davenport P, Apostolopoulos J, Tipping PG. Tissue factor pathway inhibitor expression in atherosclerosis. Lab Invest 1997; 77: 291-298 Caplice N, Mueske CS, KLeppe LS, Simari RD. Presence of tissue factor pathway inhibitor in human atherosclerotic plaques is associated with

50.

51.

52.

53.

54.

55.

56.

57.

11

reduced tissue factor activity. Circulation 1998; 98: 1051-1057 Kaikita K, Takeya M, Ogawa H, Suefuji H, Yasue H, Takahashi K. Colocalization of tissue factor and tissue factor pathway inhibitor in coronary atherosclerosis. J Pathol 1999; 188: 180188 Crawley J, Lupu F, Westmuckett AD, Severs NJ, Kakkar VV, Lupu C. Expression, localization and activity of tissue factor pathway inhibitor in normal and atherosclerotic human vessels. Arterioscler Thromb Vasc Biol 2000; 20: 1362-1673 Petit L, Lesnik P, Dachet C, Morequ M, Chapman MJ. Tissue factor pathway inhibitor is expressed by human monocyte-derived macrophages: relationship to tissue factor induction by choelsteroal and oxidized LDL. Arterioscler Thromb Vasc boil 1999; 19: 309-315 Chesebro JH, Toschi V, Lettino M, Gallo R, Badimon JJ, Fallon JT, Fuster V. Evolving concepts in the pathogenesis and treatment or arterial thrombosis (Grand rounds). Mt Sinai J Med 1995; 62: 275-286 Haskel EJ, Torr SR, Day KC, Palmier MO, Wun TC, Sobel BE, Abendschein DR. Prevention of arterial re-occlusion after thrombolysis with recombinant lipoprotein-associated coagulation inhibitor. Circulation 1991; 84: 821-827 Abendschein DR, Meng YY, Torr-Brown S, Sobel BE. Maintenance of coronary patency after fibrinolysis with tissue factor pathway inhibitor. Circulation 1995; 92: 944-949 Badimon JJ, Lettino M, Toschi V, Furster V, Berrozpe M, Chesebro JH, Badimon L. Local inhibition of tissue factor reduces the thrombogenicity of disrupted human atherosclerotic plaques: effects of tissue factor pathway inhibitor on plaque thrombogenicity under flow conditions. Circulation 1999; 99: 1780-1787 Roque M, Resi ED, Fuster V., Padureau A, Fallon JT, Taubman MB, Gchesebro JH, Badimon JJ. Inhibition of tissue factor reduces thrombus formation and J T U Med Sc 2009; 4(1)

Tissue Factor Pathway Inhibitor

58.

59.

60.

61.

62.

63.

64.

65.

intimal hyperplasia after porcine coronary angioplasty. J Am Coll Cardiol 2000; 36: 2303-2310 Shantsila E, Watson T, Lip GYH. Aspirin resistance: what, shy and when? Editorial – Thrombosis Research 2007; 119: 551-554 Jang Y, Guzman LA, Lincoff M, Gottsauner WM, Forudi, F, Hart CE, Courtman DW, Exban M, Ellis SG, Topol EJ. Influence of blockade at specific levels of the coagulation cascade on restenosis in a rabbit atherosclerotic femoral artery injury model. Circulation 1995; 92: 3041-3050 St.Pierre J, Yang LY, Tamirisia K, Scherrer D, De Ciechi P, Eisenberg P, Tolunay E, Abendschein D. Tissue factor pathway inhibitor attenuates procoagulant activity and upregulation of tissue factor at the site of ballooninduced arterial injury in pigs. Arterioscler Thromb Vasc Biol 1999; 19: 2263-2269 Al-Nozha MM, Abdel Gader AM, Arafah M, Al Maatouq M, Al Shahid M , Al Harthi S, Khan N, Abdullah M. Tissue factor pathway inhibitor (TFPI), natural coagulation inhibitors and haemostatic activation markers in patients with acute coronary syndromes. Ann Saudi Medicine 2005; 25: 937-942 Del Zoppo GJ, Copeland BR, Harker LA, Waltz TA, Zyroff J, Hanson ST, Batenberg E. Experimental acute thrombotic stroke in baboons. Stroke 1986; 17: 1254-265 Kobayashi Y, Yoshimura N, Nakamura K, Yamagishi H, Oka T. Expression of tissue factor in hepatic ischemiareperfusion injury of the rat. Transplantation 1998; 66: 708-716 Koudsi B, Chatman DM, Ballinger BA, Fergusson EW, Kraemer BA, Miller GA, Wun TC, Farr G, Money SRT. Tissue factor pathway inhibitor protects the ischemic spinal cord. J Surg Res 1996; 63: 174-178 Yoshimura N, Kobayashi Y, Nakamura K, Yamagishi H, Oka T. The effect of tissue factor pathway inhibitor on hepatic ischemia reperfusion injury of

the rat. Transplantation 1999; 67: 45-53 66. Harris GM, Stendt CL, Vollenhoven BJ, Gan TE, Tipping PG. Decreased plasma tissue factor pathway inhibitor in women taking combined oral contraceptives. Am J Haematol 1999; 60: 175-180 67. Bladbjerg EM, Kouby SO, Andersen LF, Jespersen J. Effects of different progrestin regiments in hormone replacement therapy on blood coagulation factor VIII and tissue factor pathway inhibitor. Hum Reprod 2002; 17: 3235-3241 68. Luyer MDP, Khosla S, Owen WG, Miller VM. Prospective randomized study of effects of unopposed estrogen replacement therapy on markers of coagulation and inflammatory in postmenopausal women. J Clin Endocrinol Metab 2001; 86: 3629-3634 69. Shirk RA, Zhang Z, Winneker RC. Differential effects of estrogens and progestins on the anticoagulant tissue factor pathway inhibitor in the rat. J Steroid Biochem Molecul Biol 2005; 94: 361-368 70. Peverill RE, Teede HJ, Smolieh JJ et al. Effects of combined oral hormone replacement therapy on tissue factor pathway inhibitor and factor VII. Clin Sci 2001; 101: 93-99 71. Huang ZF, Higuchi D, Lasky N, Broze GJ Jr. Tissue factor pathway inhibitor gene disruption produces intrauterine lethality in mice. Blood 1997; 90: 994-951 72. Eitzman DT, Westrick RJ, Bi X et al. Lethal perinatal thrombosis in mice resulting from the interaction of tissue factor pathway inhibitor deficiency and factor V Leiden. Circulation 2002; 105: 2139-2142 73. Arcelus JI, Caprini JA,, Hoffman KN, Fink N, Size GP, Fareed J, Hoppensteadt D. Laboratory assays and duplex scanning outcomes after symptomatic deep vein thrombosis: preliminary results. J Vasc Srug 1996; 23: 616-621 74. Dahm A, Vlieg AvH, Bendz B, Rosendall F, Bertina RM, Sandset PM. Low levels of tissue factor pathway 12

J T U Med Sc 2009; 4(1)

Abdel Galil M Abdel Gader

75.

76.

77.

78.

79.

80.

81.

82.

83.

inhibitor (TFPI) increase the risk of venous thrombosis. Blood 2003; 101: 4387-4392 Amengual O, Atsumi T, Khamashta MA, Hughes GR. The role of the tissue factor pathway in the hypercoagulable state in patients with the antiphospholipid syndrome. Thromb Haemost 1998; 79: 276-281 Jacobsen EM, Sandset PM, Wisloff F. Do antiphospholipid antibodies interfere with tissue factor pathway inhibitor? Thromb Res 1999; 94: 213-220 Ariens RA, Alerio G, Moia M, Mannucci PM. Low levels of heparin-releasable tissue factor pathway inhibitor in young patients with thrombosis. Thromb Haemost 1999; 81: 203-207 Osterud B, Glaegstad T. Increased thromboplastin activity in monocytes of patients with meningococcal infection: related to an unfavorable prognosis. Thromb Haemsot 1983; 49: 5-7 Taylor FB Jr. Studies in the inflammatory-coagulant axis in the baboon response to E. coli: regulatory roles of proteins C, S, C 4b , BP and of inhibitors of tissue factor. Prog Clin Biol Res 1994; 388: 175-194 Shimura M, Wada H, Nakasaki T, Hiyoyama K, Mori Y, Nishikawa M, Deguchi H, Deguchi K, Gabazza EC, Shiku H. Increased truncated form of plasma tissue factor pathway inhibitor levels in patients with disseminated intravascular coagulation. Am J Hematol 1999; 60: 94-98 Iversen N, Strekerud FG, Abildgaard U. Tissue factor pathway inhibitor (TFPI) in disseminated intravascular coagulation: low levels of the activated factor X-TFPI complex. Blood Coagul Fibrinolysis 2000; 11: 591-598 Asakura H, Ontachi Y, Mizutani T, Kato M, Saito M, Morishita E, Yamazaki M, Suga Y, Takami A, Miyamoto K, Nakao S. Elevated levels of free tissue factor pathway inhibitor antigen in cases of disseminated intravascular coagulation caused by various underlying diseases. Blood Coagul Fibrinolyiss 2001; 12: 1-8 Bajaj MS, Bajaj SP. Tissue factor pathway

84.

85.

86.

87.

88.

89.

90.

91.

13

inhibitor: Potential therapeutic applications. Thromb Haemost 1997; 78: 471-477 Creasy AA, Chang ACK, Feigen L, Wun TC, Taylor FB Jr, Hishaw Lb. Tissue factor pathway inhibitor reduced mortality from Escherichia coli septic shock. J Clin Invest 1993; 91: 2850-2860 Taylor FB, Chang AC, Peer G, Li A, Exban M, Hedner U. Active site inhibited factor VIIa (DEGR VIIa) attenuates the coagulant and interleukin6 and -8, but not tumor necrosis factor, responses of the baboon to LD100 Escherichia coli. Blood 1998; 91: 16091615 Carr C, Bild GS, Chang ACK, Peer GT, Palmier MO, Frazier RB, Gustafson ME, Wun TC, Creasey AA, Hinshaw LB, Taylor FB Jr, Galluppi GR. Recombinant E. Coli-derived tissue factor pathway inhibitor reduces coagulopathic and lethal effects in the baboon gramnegative model of septic shock. Circ Shock 1995; 44: 126-137 Johnson K, Aarden L, Choi Y, de Groot E, Creasey A. The proinflammatory cytokine response to coagulation and endotoxin in whole blood. Blood 1996; 87: 5051-5060 Park CT, Creasey AA, Wright SD. Tissue factor pathway inhibitor blocks cellular effects of endotoxin by binding to endotoxin and interfering with transfer to CD14. Blood 1997; 89: 4268-4274 Bone RC, Grancis BP, Pierce AK. Intravascular coagulation associated with the adult respiratory distress syndrome. Am J Med 1976; 61: 585-589 Idell S, James KK, Levin EG, Schwartz BS, Manchanda N, Maunder RJ, Martin TR, MacLarty J, Fair DS. Local abnormalities in coagulation and flibrinlytci pathways predispose to alveolar fibrin deposition in the adult respiratory distress syndrome. J Clin Invest 1989; 84: 695-705 Sabharwal AK, Bajaj SP, AMeri A, Tricomi SM, Hyers TM, Dahms TE, Talylor FB, Bajaj MS. Tissue factor pathway inhibitor and von Willebrand factor antigen levels in adult respiratory J T U Med Sc 2009; 4(1)

Tissue Factor Pathway Inhibitor

distress syndrome and in a primate model of sepsis. Am J Respir Crit Care Med 1995; 151: 758-767 92. Bajaj MS, Tricomi SM. Plasma levels of the three endothelial-specific proteins von Willebrand factor, tissue factor pathway inhibitor, and thrombomodulin do not predict the development of acute respiratory distress syndrome. Intensive Care Med 1999; 25: 1259-1266 93. Rao Lv. Tissue factor as a tumor procoagulant. Cancer Metastasis Rev 1992; 11: 249-266 94. Lindahl AK, Sandset PM, Abildgarrd U. Indices of hyper-coagulation in cancer as compared with those in acute inflammation and acute infarction. Haemostasis 1990; 20: 253-262 95. Werling RW, Zacharski LR, Kisiel W, Bajaj SP, Memoli VA, Rousseau SM. Distribution of tissue factor pathway inhibitor in normal and malignant human tissues. Thromb Haemost 1993; 69: 366-369 96. Callander NS, Varki N, Rao LV. Immunohistochemical indentification of tissue factor in solid tumors. Cancer 1992; 70: 1194-1201 97. Kakkar AK, DeRuvo N, Chinswangwatanakul V, Tebbutt S, Williamson RC. Extrinsic-pathway activation in cancer with high factor VIIa and tissue factor. Lancet 1995; 346: 10041005 98. Iversen N, Lindahl AK, Abildgaard U. Elevated TFPI in malignant disease; relation to cancer type and hypercoagulation. Br J Haematol 1998; 102: 889-895 99. Mueller BM, Resifild RA, Edgninton TS, Ruf W. Expression of tissue factor by melanoma cells promotes efficient hematogenous matastasis. Proc Natl Acad Sci USA 1992; 89: 11832-11836 100. Bromberg ME, Knosberg WH, Madison JF, Pawashe A., Garen A. Tissue factor promotes melanoma metastasis by a pathway independent of blood coagulation. Proc Natl Acad Sci USA 1995; 92: 8205-8209 101. Fischer EG, Riewald M, Huang HY, Miyagi YU, Kubota Y, Mueller BM, Ruf

W. Tumor cell adhesion and migration supported by interaction of a receptorprotease complex with its inhibitor. J Clin Invest 1999; 104: 1213-1221 102. Rao CN, Gomez DE, Woodely DT, Throrgeirson UP,. Partial characterization of novel serine proteinase inhibitors from human unbilical vein endothelial cells. Arch Biochem Biophys 1995; 319: 55-62 103. Carmeliet P, Mackman N, Moons L, Luther T, Gressens P, Van Vlaenderen I, Demunck H, Kasper M, Brierr G, Evrared P, Muller M, Risau W, Edginogton T, Collen D. Role fo tissue factor in embryonic blood vessel fevelolent. Nature 1996; 383: 73-75 104. Zhang Y, Deng Y, Luther T, Muller M, Zeigler R, Waldherr R, Stern DM, Nawroth PP. Tissue factor controls the balance of angiogenic and antiangiogenic properties of tumor cells in mice. J Clin Invest 1994; 94: 1320-1327 105. Matsuo T, Doide M, Kario K, Suzuki S, Matsuo M. Extrinsic coagulation factors nad tissue factor pathway inhibitor in end-stage chronic renal failure. Haemostasis 1997; 24: 163-167 106. Inoue a, Wada H, Takagi M, Yamamuro M, Mukai K, Nakasaki T, Shimura M, Hiyaama K, Deguchi Hk, Gabazza EC, Mori Y, Mishikawa M, Deguchi K, Shiku H. Hemostatic abnormalities in patients with thrombotic complications on maintenance hemodialysis. Clin Appl Thromb Hemost 2000; 6: 100-103 107. Cunningham MA, Ono T, Heweiston TD, Tipping PG, Becker GJ, Holdsworth SR. Tissue factor pathway inhibitor expression in human crescentic glomerulonephritis. Kideny Int 1999; 55: 1311-1318 108. Al-Mugeiren MM, Gader AMA, AlRasheed SA, Al-Salloum AA. Tissue factor pathway inhibitor in childhood nephrotic syndrome. Pediat Nephrol 2006; 21: 771-777 109. Al-Mugeiren MM, Gader AMA, Al-Rasheed SA, Bahakim HM, Al-Momen AK, Al-Salloum A. The coagulopathy of childhood nephrotic syndrome- A reappraisal of the role 14

J T U Med Sc 2009; 4(1)

Abdel Galil M Abdel Gader

natural anticoagulants and fibrinolysis. Haemostasis 1996; 26: 304-310 110. Nordfang O, Valentin S, Beck TC, Hedner U. Inhibition of extrinsic pathway inhibitor shortens the coagulation time of normal plasma and of hemophilia plasma. Thromb Haemost 1991; 66: 464-467 111. Welsch DJ, Novotny WF, Wun TC. Effect of lipoprotein-associated coagulation inhibitor (LACI) on thromboplastin-induced coagulation of normal and hemophilia plasmas. Thromb Res 1991; 64: 213-222 112. Erhardtsen E, Ezban M, Madsen MT et al. Blocking of tissue factor pathway inhibitor (TFPI) shortens the bleeding time in rabbits with antibody induced haemophilia A. Blood Coagul Fibrinolysis 1995; 6: 388-394 113. Rosse WF, Nishimura J. Clinical manifestations of paroxysmal nocturnal hemoglobinuria: present state and future problems. Int J hematol 2003; 77: 113120 114. Maroney SA, Cunningham AC, Ferrel J et al. A GPI-anchored co-receptor for tissue factor pathway inhibitor controls its intracellular trafficking and cell surface expression. J Thromb Hemostasis 2006; 4: 1114-1124 115. Gader A.M.A, Al-Mishari AA, Awadallah SA, Buyoumi NM, Khashoggi T, Al-Hakeem M. Total and free tissue factor pathway inhibitor in pregnancy hypertension. Int J Gyn Obstet 2006; 95: 248-253

116. Kaiser B, Hoppensteadt DA, Fareed J. Tissue factor pathway inhibitor: an update of potential implications in the treatment of cardiovascular disorders. Expert Opin Investig Drugs 2001; 10: 1925-1935 117. Lwaleed BA, Bass PS. Tissue factor pathway inhibitor: structure, biology and involvement in disease. J Pathol. 2006; 208: 327-339 118. Yin X, Fu Y, Yutani C, Ikeda Y, Enjyoji K, Kato H. HVJ-AVE liposome-mediated Tissue Factor Pathway Inhibitor (TFPI) gene transfer with recombinant TFPI (rTFPI) irrigation attenuates restenosis in atherosclerotic arteries. Int J Cardiol. 2008; doi: 1010.1016/j.ijcard.2008.02.2009 119. Girard TJ. Tissue Factor Pathway Inhibitor. In: Novel Therapeutic Agents in Thrombosis and Thrombolysis. Sasahara A., Lascalzo J, eds. New York: Marcel Dekker 1997; 225-260 120. Obata R, Yanagi Y, Tamaki Y, Hozumi K, Mutoh M, Tanaka Y. Retinal degeneration is delayed by tissue factor pathway inhibitor-2 in RCS rats and a sodium-iodate-induced model in rabbits. Eye.2005; 19: 464-468 121. Amirkhosravi A, Meyer T, Amaya M, Davila M, Mousa SA, Robson T, Francis JL. The role of tissue factor pathway inhibitor in tumor growth and metastasis. Semin Thromb Hemost. 2007; 33: 643-652

15

J T U Med Sc 2009; 4(1)