Factor X

Last updated

F10
Protein F10 PDB 1c5m.png
Available structures
PDB Ortholog search: PDBe RCSB
Identifiers
Aliases F10 , FX, FXA, coagulation factor X
External IDs OMIM: 613872; MGI: 103107; HomoloGene: 30976; GeneCards: F10; OMA:F10 - orthologs
Orthologs
SpeciesHumanMouse
Entrez

2159

14058

Ensembl

ENSG00000126218

ENSMUSG00000031444

UniProt

P00742

O88947

RefSeq (mRNA)

NM_000504
NM_001312674
NM_001312675

NM_001242368
NM_007972

RefSeq (protein)

NP_000495
NP_001299603
NP_001299604

NP_001229297
NP_031998

Location (UCSC) Chr 13: 113.12 – 113.15 Mb Chr 8: 13.09 – 13.11 Mb
PubMed search [3] [4]
Wikidata
View/Edit Human View/Edit Mouse

Coagulation factor X (EC 3.4.21.6), or Stuart factor, is an enzyme of the coagulation cascade, encoded in humans by F10 gene. [5] It is a serine endopeptidase (protease group S1, PA clan). Factor X is synthesized in the liver and requires vitamin K for its synthesis.

Factor X is activated, by hydrolysis, into factor Xa by both factor IX with its cofactor, factor VIII in a complex known as intrinsic pathway; and factor VII with its cofactor, tissue factor in a complex known as extrinsic pathway. [6] It is therefore the first member of the final common pathway or thrombin pathway.

It acts by cleaving prothrombin in two places (an Arg-Thr and then an Arg-Ile bond), which yields the active thrombin. This process is optimized when factor Xa is complexed with activated co-factor V in the prothrombinase complex.

Factor Xa is inactivated by protein Z-dependent protease inhibitor (ZPI), a serine protease inhibitor (serpin). The affinity of this protein for factor Xa is increased 1000-fold by the presence of protein Z, while it does not require protein Z for inactivation of factor XI. Defects in protein Z lead to increased factor Xa activity and a propensity for thrombosis. The half life of factor X is 40–45 hours.

Structure

The first crystal structure of human factor Xa was deposited in May 1993. To date, 191 crystal structures of factor Xa with various inhibitors have been deposited in the protein data bank. The active site of factor Xa is divided into four subpockets as S1, S2, S3 and S4. The S1 subpocket determines the major component of selectivity and binding. The S2 sub-pocket is small, shallow and not well defined. It merges with the S4 subpocket. The S3 sub-pocket is located on the rim of the S1 pocket and is quite exposed to solvent. The S4 sub-pocket has three ligand binding domains: the "hydrophobic box", the "cationic hole" and the water site. Factor Xa inhibitors generally bind in an L-shaped conformation, where one group of the ligand occupies the anionic S1 pocket lined by residues Asp189, Ser195, and Tyr228, and another group of the ligand occupies the aromatic S4 pocket lined by residues Tyr99, Phe174, and Trp215. Typically, a fairly rigid linker group bridges these two interaction sites. [7]

Genetics

The human factor X gene is located on chromosome 13 (13q34).

Role in disease

Inborn deficiency of factor X is very rare (1:1,000,000), and may present with epistaxis (nosebleeds), hemarthrosis (bleeding into joints) and gastrointestinal blood loss. Apart from congenital deficiency, low factor X levels may occur occasionally in a number of disease states. For example, factor X deficiency may be seen in amyloidosis, where factor X is adsorbed to the amyloid fibrils in the vasculature.

Deficiency of vitamin K or antagonism by warfarin (or similar medication) leads to the production of an inactive factor X. In warfarin therapy, this is desirable to prevent thrombosis. As of late 2007, four out of five emerging anti-coagulation therapeutics targeted this enzyme. [8]

Inhibiting Factor Xa would offer an alternate method for anticoagulation. Direct Xa inhibitors are popular anticoagulants.

Polymorphisms in Factor X have been associated with an increased prevalence in bacterial infections, suggesting a possible role directly regulating the immune response to bacterial pathogens. [9]

Therapeutic use

Factor X is part of fresh frozen plasma and the prothrombinase complex. There are two commercially available Factor X concentrates: "Factor X P Behring" manufactured by CSL Behring, [10] and high purity Factor X Coagadex produced by Bio Products Laboratory and approved for use in the United States by the FDA in October 2015, and in the EU in March 2016, after earlier acceptance by CHMP and COMP. [11] [12] [13] [14]

Kcentra, manufactured by CSL Behring, is a concentrate containing coagulation Factors II, VII, IX and X, and antithrombotic Proteins C and S. [15]

Use in biochemistry

The factor Xa protease can be used in biochemistry to cleave off protein tags that improve expression or purification of a protein of interest. Its preferred cleavage site (after the arginine in the sequence Ile-Glu/Asp-Gly-Arg, IEGR or IDGR) can easily be engineered between a tag sequence and the protein of interest. After expression and purification, the tag is then proteolytically removed by factor Xa.

Factor Xa

Blood coagulation pathways in vivo showing the central role played by thrombin Coagulation in vivo.png
Blood coagulation pathways in vivo showing the central role played by thrombin

Factor Xa is the activated form of the coagulation factor X, also known as thrombokinase. Factor X is an enzyme, a serine endopeptidase, which plays a key role at several stages of the coagulation system. Factor X is synthesized in the liver. The most commonly used anticoagulants in clinical practice, warfarin and the heparin series of anticoagulants and fondaparinux, act to inhibit the action of Factor Xa in various degrees.

Traditional models of coagulation developed in the 1960s envisaged two separate cascades, the extrinsic (tissue factor (TF)) pathway and the intrinsic pathway. These pathways converge to a common point, the formation of the Factor Xa/Va complex which together with calcium and bound on a phospholipids surface, generate thrombin (Factor IIa) from prothrombin (Factor II).

A new model, the cell-based model of anticoagulation appears to explain more fully the steps in coagulation. This model has three stages: 1) initiation of coagulation on TF-bearing cells, 2) amplification of the procoagulant signal by thrombin generated on the TF-bearing cell and 3) propagation of thrombin generation on the platelet surface. Factor Xa plays a key role in all three of these stages. [16]

In stage 1, Factor VII binds to the transmembrane protein TF on the surface of cells and is converted to Factor VIIa. The result is a Factor VIIa/TF complex, which catalyzes the activation of Factor X and Factor IX. Factor Xa formed on the surface of the TF-bearing cell interacts with Factor Va to form the prothrombinase complex which generates small amounts of thrombin on the surface of TF-bearing cells.

In stage 2, the amplification stage, if enough thrombin has been generated, then activation of platelets and platelet-associated cofactors occurs.

In stage 3, thrombin generation, Factor XIa activates free Factor IX on the surface of activated platelets. The activated Factor IXa with Factor VIIIa forms the "tenase" complex. This "tenase" complex activates more Factor X, which in turn forms new prothrombinase complexes with Factor Va. Factor Xa is the prime component of the prothrombinase complex which converts large amounts of prothrombin—the "thrombin burst". Each molecule of Factor Xa can generate 1000 molecules of thrombin. This large burst of thrombin is responsible for fibrin polymerization to form a thrombus.

Factor Xa also plays a role in other biological processes that are not directly related to coagulation, like wound healing, tissue remodelling, inflammation, angiogenesis and atherosclerosis.

Inhibition of the synthesis or activity of Factor X is the mechanism of action for many anticoagulants in use today. Warfarin, a synthetic derivative of coumarin, is the most widely used oral anticoagulant in the US. In some European countries, other coumarin derivatives (phenprocoumon and acenocoumarol) are used. These agents known as vitamin K antagonists (VKA), inhibit the vitamin K-dependent carboxylation of Factors II (prothrombin), VII, IX, X in the hepatocyte. This carboxylation after the translation is essential for the physiological activity. [17]

Heparin (unfractionated heparin) and its derivatives low molecular weight heparin (LMWH) bind to a plasma cofactor, antithrombin (AT) to inactivate several coagulation factors IIa, Xa, XIa and XIIa. The affinity of unfractionated heparin and the various LMWHs for Factor Xa varies considerably. The efficacy of heparin-based anticoagulants increases as selectivity for Factor Xa increases. LMWH shows increased inactivation of Factor Xa compared to unfractionated heparin, and fondaparinux, an agent based on the critical pentasacharide sequence of heparin, shows more selectivity than LMWH. This inactivation of Factor Xa by heparins is termed "indirect" since it relies on the presence of AT and not a direct interaction with Factor Xa.

Recently a new series of specific, direct acting inhibitors of Factor Xa has been developed. These include the drugs rivaroxaban, apixaban, betrixaban, LY517717, darexaban (YM150), edoxaban and 813893. These agents have several theoretical advantages over current therapy. They may be given orally. They have rapid onset of action. And they may be more effective against Factor Xa in that they inhibit both free Factor Xa and Factor Xa in the prothrombinase complex. [18]

History

American and British scientists described deficiency of factor X independently in 1953 and 1956, respectively. As with some other coagulation factors, the factor was initially named after these patients, a Mr Rufus Stuart (1921) and a Miss Audrey Prower (1934). At that time, those investigators could not know that the human genetic defect they had identified would be found in the previously characterized enzyme called thrombokinase.

Thrombokinase was the name coined by Paul Morawitz in 1904 to describe the substance that converted prothrombin to thrombin and caused blood to clot. [19] That name embodied an important new concept in understanding blood coagulation – that an enzyme was critically important in the activation of prothrombin. Morawitz believed that his enzyme came from cells such as platelets yet, in keeping with the state of knowledge about enzymes at that time, he had no clear idea about the chemical nature of his thrombokinase or its mechanism of action. Those uncertainties led to decades during which the terms thrombokinase and thromboplastin were both used to describe the activator of prothrombin and led to controversy about its chemical nature and origin. [20]

In 1947, J Haskell Milstone isolated a proenzyme from bovine plasma which, when activated, converted prothrombin to thrombin. Following Morawitz’s designation, he called it prothrombokinase [21] and by 1951 had purified the active enzyme, thrombokinase. Over the next several years he showed that thrombokinase was a proteolytic enzyme that, by itself, could activate prothrombin. Its activity was greatly enhanced by addition of calcium, other serum factors, and tissue extracts, [22] which represented the thromboplastins that promoted the conversion of prothrombin to thrombin by their interaction with thrombokinase. In 1964 Milstone summarized his work and that of others: “There are many chemical reactions which are so slow that they would not be of physiological use if they were not accelerated by enzymes. We are now confronted with a reaction, catalyzed by an enzyme, which is still too slow unless aided by accessory factors.” [23]

Interactions

Factor X has been shown to interact with Tissue factor pathway inhibitor. [24]

Related Research Articles

<span class="mw-page-title-main">Anticoagulant</span> Class of drugs

An anticoagulant, commonly known as a blood thinner, is a chemical substance that prevents or reduces the coagulation of blood, prolonging the clotting time. Some occur naturally in blood-eating animals, such as leeches and mosquitoes, which help keep the bite area unclotted long enough for the animal to obtain blood.

<span class="mw-page-title-main">Coagulation</span> Process of formation of blood clots

Coagulation, also known as clotting, is the process by which blood changes from a liquid to a gel, forming a blood clot. It results in hemostasis, the cessation of blood loss from a damaged vessel, followed by repair. The process of coagulation involves activation, adhesion and aggregation of platelets, as well as deposition and maturation of fibrin.

<span class="mw-page-title-main">Disseminated intravascular coagulation</span> Medical condition where blood clots block small blood vessels

Disseminated intravascular coagulation (DIC) is a condition in which blood clots form throughout the body, blocking small blood vessels. Symptoms may include chest pain, shortness of breath, leg pain, problems speaking, or problems moving parts of the body. As clotting factors and platelets are used up, bleeding may occur. This may include blood in the urine, blood in the stool, or bleeding into the skin. Complications may include organ failure.

<span class="mw-page-title-main">Thrombin</span> Enzyme involved in blood coagulation in humans

Prothrombin is encoded in the human by the F2-gene. It is proteolytically cleaved during the clotting process by the prothrombinase enzyme complex to form thrombin.

<span class="mw-page-title-main">Antithrombin</span> Mammalian protein found in Homo sapiens

Antithrombin (AT) is a small glycoprotein that inactivates several enzymes of the coagulation system. It is a 464-amino-acid protein produced by the liver. It contains three disulfide bonds and a total of four possible glycosylation sites. α-Antithrombin is the dominant form of antithrombin found in blood plasma and has an oligosaccharide occupying each of its four glycosylation sites. A single glycosylation site remains consistently un-occupied in the minor form of antithrombin, β-antithrombin. Its activity is increased manyfold by the anticoagulant drug heparin, which enhances the binding of antithrombin to factor IIa (thrombin) and factor Xa.

Low-molecular-weight heparin (LMWH) is a class of anticoagulant medications. They are used in the prevention of blood clots and, in the treatment of venous thromboembolism, and the treatment of myocardial infarction.

<span class="mw-page-title-main">Partial thromboplastin time</span> Test for coagulation of blood

The partial thromboplastin time (PTT), also known as the activated partial thromboplastin time, is a blood test that characterizes coagulation of the blood. A historical name for this measure is the Kaolin-cephalin clotting time (KCCT), reflecting kaolin and cephalin as materials historically used in the test. Apart from detecting abnormalities in blood clotting, partial thromboplastin time is also used to monitor the treatment effect of heparin, a widely prescribed drug that reduces blood's tendency to clot.

<span class="mw-page-title-main">Factor VII</span> Mammalian protein found in humans

Coagulation factor VII is a protein involved in coagulation and, in humans, is encoded by gene F7. It is an enzyme of the serine protease class. Once bound to tissue factor released from damaged tissues, it is converted to factor VIIa, which in turn activates factor IX and factor X.

<span class="mw-page-title-main">Draculin</span> Glycoprotein found in the saliva of vampire bats

Draculin is a glycoprotein found in the saliva of vampire bats. It is a single-chain polypeptide protein composed of 708 amino acids, weighing about 88.5 kDa when reduced and 83 kDa when non-reduced, and selectively inhibits FIXa and FXa. It functions as an anticoagulant, inhibiting coagulation factors IX (IXa) and X (Xa) by establishing rapid equilibrium with factor Xa, and is the first natural polypeptide which has been described to show immediate anti-IXa and anti-Xa properties. In addition, Draculin inhibits the conversion of prothrombin to thrombin, preventing fibrinogen from converting to fibrin. These two processes inhibit blood coagulation thus keeping the blood of the bitten victim from clotting while the bat is drinking. The activation of factor X is a common point between the intrinsic and extrinsic pathway of blood coagulation. Activated factor X (FXa) is the sole enzyme that catalyzes the conversion of prothrombine into thrombin, which is vital in the coagulation cascade. Draculin is a member of the Lactoferrin family of proteins that functions as an antibacterial protein in other mammals, but has been co-opted in bat evolution to function as an anticoagulant.

<span class="mw-page-title-main">Protein C</span> Mammalian protein found in Homo sapiens

Protein C, also known as autoprothrombin IIA and blood coagulation factor XIV, is a zymogen, that is, an inactive enzyme. The activated form plays an important role in regulating anticoagulation, inflammation, and cell death and maintaining the permeability of blood vessel walls in humans and other animals. Activated protein C (APC) performs these operations primarily by proteolytically inactivating proteins Factor Va and Factor VIIIa. APC is classified as a serine protease since it contains a residue of serine in its active site. In humans, protein C is encoded by the PROC gene, which is found on chromosome 2.

<span class="mw-page-title-main">Thrombophilia</span> Abnormality of blood coagulation increasing the risk of blood clotting (thrombosis)

Thrombophilia is an abnormality of blood coagulation that increases the risk of thrombosis. Such abnormalities can be identified in 50% of people who have an episode of thrombosis that was not provoked by other causes. A significant proportion of the population has a detectable thrombophilic abnormality, but most of these develop thrombosis only in the presence of an additional risk factor.

<span class="mw-page-title-main">Factor V</span> Mammalian protein found in humans

Coagulation factor V, also less commonly known as proaccelerin or labile factor, is a protein involved in coagulation, encoded, in humans, by F5 gene. In contrast to most other coagulation factors, it is not enzymatically active but functions as a cofactor. Factor V deficiency leads to predisposition for hemorrhage, while some mutations predispose for thrombosis.

<span class="mw-page-title-main">Factor XI</span> Mammalian protein found in Homo sapiens

Factor XI, or plasma thromboplastin antecedent, is the zymogen form of factor XIa, one of the enzymes involved in coagulation. Like many other coagulation factors, it is a serine protease. In humans, factor XI is encoded by F11 gene.

<span class="mw-page-title-main">Hirudin</span> Chemical compound in leeches

Hirudin is a naturally occurring peptide in the salivary glands of blood-sucking leeches that has a blood anticoagulant property. This is essential for the leeches' habit of feeding on blood, since it keeps a host's blood flowing after the worm's initial puncture of the skin.

The prothrombinase enzyme complex consists of factor Xa (a serine protease) and factor Va (a protein cofactor). The complex assembles on negatively charged phospholipid membranes in the presence of calcium ions. The prothrombinase complex catalyzes the conversion of prothrombin (factor II), an inactive zymogen, to thrombin (factor IIa), an active serine protease. The activation of thrombin is a critical reaction in the coagulation cascade, which functions to regulate hemostasis in the body. To produce thrombin, the prothrombinase complex cleaves two peptide bonds in prothrombin, one after Arg271 and the other after Arg320. Although it has been shown that factor Xa can activate prothrombin when unassociated with the prothrombinase complex, the rate of thrombin formation is severely decreased under such circumstances. The prothrombinase complex can catalyze the activation of prothrombin at a rate 3 x 105-fold faster than can factor Xa alone. Thus, the prothrombinase complex is required for the efficient production of activated thrombin and also for adequate hemostasis.

<span class="mw-page-title-main">Heparin cofactor II</span> Protein-coding gene in the species Homo sapiens

Heparin cofactor II (HCII), a protein encoded by the SERPIND1 gene, is a coagulation factor that inhibits IIa, and is a cofactor for heparin and dermatan sulfate.

<span class="mw-page-title-main">Thrombin time</span>

The thrombin time (TT), also known as the thrombin clotting time (TCT), is a blood test that measures the time it takes for a clot to form in the plasma of a blood sample containing anticoagulant, after an excess of thrombin has been added. It is used to diagnose blood coagulation disorders and to assess the effectiveness of fibrinolytic therapy. This test is repeated with pooled plasma from normal patients. The difference in time between the test and the 'normal' indicates an abnormality in the conversion of fibrinogen to fibrin, an insoluble protein.

Prothrombin complex concentrate (PCC), also known as factor IX complex, sold under the brand name Kcentra among others, is a combination medication made up of blood clotting factors II, IX, and X(3-factor PCC) or, when also containing factor VII as does Kcentra, 4-factor PCC. It is used to treat and prevent bleeding in hemophilia B if pure factor IX is not available. It may also be used for reversal of warfarin therapy. It is given by slow injection into a vein. Another product, activated prothrombin complex concentrate or FEIBA, may be used for acquired hemophilia.

Four drugs from the class of direct Xa inhibitors are marketed worldwide. Rivaroxaban (Xarelto) was the first approved FXa inhibitor to become commercially available in Europe and Canada in 2008. The second one was apixaban (Eliquis), approved in Europe in 2011 and in the United States in 2012. The third one edoxaban was approved in Japan in 2011 and in Europe and the US in 2015. Betrixaban (Bevyxxa) was approved in the US in 2017.

Prothrombin fragment 1+2 (F1+2), also written as prothrombin fragment 1.2 (F1.2), is a polypeptide fragment of prothrombin generated by the in vivo cleavage of prothrombin into thrombin by the enzyme prothrombinase. It is released from the N-terminus of prothrombin. F1+2 is a marker of thrombin generation and hence of coagulation activation. It is considered the best marker of in vivo thrombin generation.

References

  1. 1 2 3 GRCh38: Ensembl release 89: ENSG00000126218 – Ensembl, May 2017
  2. 1 2 3 GRCm38: Ensembl release 89: ENSMUSG00000031444 – Ensembl, May 2017
  3. ↑ "Human PubMed Reference:". National Center for Biotechnology Information, U.S. National Library of Medicine.
  4. ↑ "Mouse PubMed Reference:". National Center for Biotechnology Information, U.S. National Library of Medicine.
  5. ↑ "F10 gene: MedlinePlus Genetics". medlineplus.gov.
  6. ↑ Camire RM (August 2021). "Blood coagulation factor X: molecular biology, inherited disease, and engineered therapeutics". Journal of Thrombosis and Thrombolysis. 52 (2): 383–390. doi:10.1007/s11239-021-02456-w. PMC   8531165 . PMID   33886037.
  7. ↑ "Presentation on Direct Factor Xa Inhibitors". Archived from the original on 2016-03-03. Retrieved 2010-04-08.
  8. ↑ Ron Winslow, Avery Johnson (2007-12-10). "Race Is on for the Next Blood Thinner". The Wall Street Journal . p. A12. Archived from the original on 2016-03-10. Retrieved 2008-01-06. The flurry of interest reflects increasing understanding of what doctors call the coagulation cascade... Four new blood thinners target an enzyme called factor Xa, one of several enzymes that play an important role in the cascade.
  9. ↑ Choby JE, Monteith AJ, Himmel LE, Margaritis P, Shirey-Rice JK, Pruijssers A, et al. (March 2019). "A Phenome-Wide Association Study Uncovers a Pathological Role of Coagulation Factor X during Acinetobacter baumannii Infection". Infection and Immunity. 87 (5): IAI.00031–19. doi:10.1128/IAI.00031-19. PMC   6479028 . PMID   30782860.
  10. ↑ Brooker M (April 2008). Registry of Clotting Factor Concentrates (Eighth ed.). World Federation of Hemophilia.
  11. ↑ "FDA approves first Factor X concentrate to treat patients with rare hereditary bleeding disorder" (Press release). US FDA. October 20, 2015. Archived from the original on October 21, 2015. Retrieved October 21, 2015. Until today's orphan drug approval, no specific coagulation factor replacement therapy was available for patients with hereditary Factor X deficiency.
  12. ↑ "Coagadex". U.S. Food and Drug Administration. 28 June 2017. Archived from the original on 22 July 2017. Retrieved 2 April 2020.{{cite web}}: CS1 maint: unfit URL (link)
  13. ↑ "Coagadex". U.S. Food and Drug Administration. 21 September 2018. Archived from the original on 17 December 2019. Retrieved 2 April 2020.
  14. ↑ "Coagadex EPAR". European Medicines Agency (EMA). 17 September 2018. Archived from the original on 30 December 2019. Retrieved 21 April 2020.
  15. ↑ "Kcentra- prothrombin, coagulation factor vii human, coagulation factor ix human, coagulation factor x human, protein c, protein s human, and water kit". DailyMed. 22 October 2018. Archived from the original on 25 March 2021. Retrieved 21 April 2020.
  16. ↑ Hoffman M, Monroe DM (February 2007). "Coagulation 2006: a modern view of hemostasis". Hematology/Oncology Clinics of North America. 21 (1): 1–11. doi:10.1016/j.hoc.2006.11.004. PMID   17258114.
  17. ↑ Golan DE (2012). Principles of Pharmacology The Pathophysiologic Basis of Drug Therapy. Philadelphia: Lippincott Williams & Wilkins. p. 387. ISBN   978-1-4511-1805-6.
  18. ↑ Turpie AG (June 2007). "Oral, direct factor Xa inhibitors in development for the prevention and treatment of thromboembolic diseases". Arteriosclerosis, Thrombosis, and Vascular Biology. 27 (6): 1238–1247. CiteSeerX   10.1.1.536.872 . doi:10.1161/ATVBAHA.107.139402. PMID   17379841. S2CID   2998452.
  19. ↑ Morawitz P. "Beitrage zur Kenntnis der Blutgerinnung". Deutsches Archiv für Klinische Medizin. 79: 432–442.
  20. ↑ Milstone JH (December 1952). "On the evolution of blood clotting theory". Medicine. 31 (4): 411–447. doi: 10.1097/00005792-195212000-00004 . PMID   13012730.
  21. ↑ Milstone JH (December 1947). "Prothrombokinase and the Three Stages of Blood Coagulation". Science. 106 (2762): 546–547. Bibcode:1947Sci...106..546M. doi:10.1126/science.106.2762.546-a. PMID   17741228. S2CID   35643683.
  22. ↑ Milstone LM (August 2021). "Factor Xa: Thrombokinase from Paul Morawitz to J Haskell Milstone". Journal of Thrombosis and Thrombolysis. 52 (2): 364–370. doi:10.1007/s11239-021-02387-6. PMID   33484373. S2CID   231682954.
  23. ↑ Milstone JH, Oulianoff N, Milstone VK (November 1963). "Thrombokinase as prime activator of prothrombin: historical perspectives and present status". The Journal of General Physiology. 47 (2): 315–327. doi:10.1085/jgp.47.2.315. PMC   2195336 . PMID   14080818.
  24. ↑ Broze GJ, Warren LA, Novotny WF, Higuchi DA, Girard JJ, Miletich JP (February 1988). "The lipoprotein-associated coagulation inhibitor that inhibits the factor VII-tissue factor complex also inhibits factor Xa: insight into its possible mechanism of action". Blood. 71 (2): 335–343. doi: 10.1182/blood.V71.2.335.335 . PMID   3422166.

Further reading

Further reading

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