NIH requires grantees and investigators to comply with the requirements of 42 CFR Part 50,
Subpart F, “Responsibility of Applicants for Promoting Objectivity in Research for Which PHS
Funding is sought.” That subpart promotes objectivity in research by establishing standards to ensure that the design, conduct, and reporting of research funded under PHS grants or cooperative agreements will not be biased by any conflicting financial interest of an investigator. The signature of the Authorized Organizational Representative on the face page of the application serves as certification of compliance with the requirements of 42 CFR Part 50, Subpart F. Under the requirements the organization will do the following:

-Have an up-to-date, written and enforced administrative process to identify and manage, reduce, or eliminate conflicting financial interests with respect to research projects for which NIH funding is sought.
-Shall promote and enforce Investigator compliance with the regulations.
-Shall manage FCOI and provide initial and ongoing FCOI reports.
-Agrees to make FCOI and SFI information available to HHS, promptly, upon request.
-Before spending any NIH funds awarded under a new award, inform the CGMO of the existence of any conflicting financial interests it identified of the type covered by 42 CFR 50.605.
-When informing the CGMO that a financial conflict of interest has been identified, ensure that the interest has been addressed in accordance with the regulations by indicating whether the conflict has either been managed, reduced, or eliminated.
-Continue to make similar reports on subsequently identified conflicts within 60 days of identifying them.
-Make additional information available to NIH, upon request, as to how it handled conflicting interests in accordance with the regulations.

Aronora’s Training Requirements
Each Investigator will be informed, through the distribution of Aronora’s Policies and Procedures Manual, of Aronora’s FCOI policy as well as the Investigator’s disclosure responsibilities, which mirror the Federal regulation (42 CFR 50.604 (b)). FCOI training will be required for all Investigators 1) prior to engaging in research related to any PHS-funded grant, 2) at least every four years or 3) immediately, if Aronora revises its FCOI policy that affects the Investigator requirements, investigator is new to the Institution, or if an Investigator is not in compliance with the plan. To complete the training, each Investigator will review this document along with the following webinars and tutorials provided through the US Dept. of Health & Human Services OER http://grants.nih.gov/grants/policy/coi/index.htm :

-Financial Conflict of Interest Presentation with Case Studies (06/26/2012)

http://grants.nih.gov/grants/policy/coi/FCOI_NIH_Regional_Seminar-June_22_2012.ppt

-Web based tutorial

http://grants.nih.gov/grants/policy/coi/tutorial2011/fcoi.htm

-NIH FCOI Reporting Requirements and eRA Commons FCOI Module Demonstration:

http://grants.nih.gov/grants/policy/coi/fcoi_webinar_2012/FCOI%208-14-2012_WEBINAR.pdf

-Summary Slide Set for the revised 2011 FCOI Regulation (10/05/2011)

http://grants.nih.gov/grants/policy/coi/FCOI.ppt

All Investigators at Aronora must sign a letter stating that they have reviewed and agree to abide by all FCOI requirements.

Disclosure, Review and Monitoring Requirements
Each Investigator is required to disclose SFIs (and those of the Investigator’s spouse and dependent children) related to the Investigator’s institutional responsibilities that meets the regulatory definition of SFI: 1) no later than at the time of application for PHS-funded research, 2) At least annually during the period of award, 3) within 30 days of discovering or acquiring a new SFI. The 2011 revised regulation that guides Aronora’s policy defines a “Significant Financial Interest” as follows:

“(1) A financial interest consisting of one or more of the following interests of the Investigator (and those of the Investigator’s spouse and dependent children) that reasonably appears to be related to the Investigator’s institutional responsibilities:
(i) With regard to any publicly traded entity, a significant financial interest exists if the value of any remuneration received from the entity in the twelve months preceding the disclosure and the value of any equity interest in the entity as of the date of disclosure, when aggregated, exceeds $5,000. For purposes of this definition, remuneration includes salary and any payment for services not otherwise identified as salary (e.g., consulting fees, honoraria, paid authorship); equity interest includes any stock, stock option, or other ownership interest, as determined through reference to public prices or other reasonable measures of fair market value;
(ii) With regard to any non-publicly traded entity, a significant financial interest exists if the value of any remuneration received from the entity in the twelve months preceding the disclosure, when aggregated, exceeds $5,000, or when the Investigator (or the Investigator’s spouse or dependent children) holds any equity interest (e.g., stock, stock option, or other ownership interest); or
(iii) Intellectual property rights and interests (e.g., patents, copyrights), upon receipt of income related to such rights and interests.
(2) Investigators also must disclose the occurrence of any reimbursed or sponsored travel (i.e., that which is paid on behalf of the Investigator and not reimbursed to the Investigator so that the exact monetary value may not be readily available), related to their institutional responsibilities; provided, however, that this disclosure requirement does not apply to travel that is reimbursed or sponsored by a federal, state, or local government agency, an Institution of higher education as defined at 20 U.S.C. 1001(a), an academic teaching hospital, a medical center, or a research institute that is affiliated with an Institution of higher education. The Institution’s FCOI policy will specify the details of this disclosure, which will include, at a minimum, the purpose of the trip, the identity of the sponsor/organizer, the destination, and the duration. In accordance with the Institution’s FCOI policy, the institutional official(s) will determine if further information is needed, including a determination or disclosure of monetary value, in order to determine whether the travel constitutes an FCOI with the PHS-funded research.
(3) The term significant financial interest does not include the following types of financial interests: salary, royalties, or other remuneration paid by the Institution to the Investigator if the Investigator is currently employed or otherwise appointed by the Institution, including intellectual property rights assigned to the Institution and agreements to share in royalties related to such rights; any ownership interest in the Institution held by the Investigator, if the Institution is a commercial or for-profit organization; income from investment vehicles, such as mutual funds and retirement accounts, as long as the Investigator does not directly control the investment decisions made in these vehicles; income from seminars, lectures, or teaching engagements sponsored by a federal, state, or local government agency, an Institution of higher education as defined at 20 U.S.C. 1001(a), an academic teaching hospital, a medical center, or a research institute that is affiliated with an Institution of higher education; or income from service on advisory committees or review panels for a federal, state, or local government agency, an Institution of higher education as defined at 20 U.S.C. 1001(a), an academic teaching hospital, a medical center, or a research institute that is affiliated with an Institution of higher education.”
The revised 2011 regulation does not apply to Phase I SBIR/STTR applications but the revised 2011 regulation does apply to Phase II SBIR/STTR applications/awards. As defined in Section 50.603 Definitions, a “Significant Financial Interest” does not include “….any ownership interest in the [applicant or awardee] Institution held by the Investigator, if the Institution is a commercial or for-profit organization;…”. Therefore, the Investigator’s equity interest is excluded from the disclosure requirement when the for-profit company is the Institution that is applying for, or that receives, the PHS research funding in which the Investigator is participating.

The designated institutional official will solicit and review disclosures of SFIs of the Investigator (and those of the Investigator’s spouse and dependent children) related to an Investigator’s institutional responsibilities. The institutional official will determine, using the above guidelines, whether an Investigator’s SFI is related to PHS-funded research and, if so related, whether the SFI is an FCOI. The designated official will review all Investigator SFI disclosures, determine if any SFIs relate to PHS-funded research, determine if an FCOI exists (SFI that could directly and significantly affect the design, conduct, or reporting of the NIH-funded research), develop and implement management plans, as needed to manage FCOIs. The designated official will review disclosures of SFIs, make determination of FCOIs, and implement a management plan when required for an Investigator who is new to participating in the research project or for an existing Investigator who discloses a new SFI. The designated official will review disclosures of SFIs, make determination of FCOIs, and implement a management plan within sixty days whenever an Institution identifies an SFI that was not disclosed timely by an Investigator or not previously reviewed by the Institution. The designated official will take such actions as necessary to manage FCOIs, including any financial conflicts of a subrecipient Investigator, if applicable, and monitor Investigator compliance with management plans until completion of the project.
The President is currently designated as the institutional official, and is responsible for ensuring the proper collection and reporting of all FCOIs according to the above guidelines.

Q: What must an Investigator disclose for his/her first financial disclosure under the 2011 revised regulation related to intellectual property rights and interests?
Upon the receipt of income, the Investigator is required to disclose the aggregated value of income received in excess of $5,000 from the entity in the twelve months preceding the disclosure. Because this income is subject to the definition of “Significant Financial Interest,” the following disclosure considerations apply:
(1) Investigators who are planning to participate in PHS-funded research must disclose their SFIs over the previous twelve-month period to their Institution no later than at the time of application for PHS-funded research.
(2) Each Investigator who is participating in PHS-funded research must submit an updated disclosure of SFIs at least annually, in accordance with the specific time period prescribed by the Institution, during the period of award.
(3) Each Investigator who is participating in the PHS-funded research must submit an updated disclosure of SFIs within 30 days of discovering or acquiring a new SFI.

Reporting Requirements to NIH
The designated institutional official will send initial, annual (i.e., ongoing) and revised FCOI
reports, including all reporting elements required by the regulation, to the NIH for the Institution and its subrecipients, if applicable, as required by the regulation: 1) prior to the expenditure of funds, 2) within 60 days of identification for an Investigator who is newly participating in the project, 3) within 60 days for new, or newly identified , FCOIs for existing Investigators, 4) at least annually (at the same time as when the Institution is required to submit the annual progress report, multi-year progress report, if applicable, or at time of extention) to provide the status of the FCOI and any changes to the management plan, if applicable, until the completion of the project, 5) following a retrospective review to update a previously submitted report, if appropriate. The designated institutional official will notify NIH promptly if bias is found with the design, conduct or reporting of NIH-funded research and to include the requirement to submit a Mitigation Report in accordance with and including all reporting elements as required by the regulation 42 CFR 50.605(a)(3)(iii). The designated institutional official will notify NIH promptly if an Investigator fails to comply with the Institution’s FCOI policy or a FCOI management plan appears to have biased the design, conduct, or reporting of the NIH-funded research. Aronora will notify NIH promptly and take corrective action for noncompliance with the policy or the management plan.

All FCOI reports will contain a description of the key elements of Aronora’s management plan including the following:
(A) The role and principal duties of the conflicted Investigator in the research project;
(B) Conditions of the management plan;
(C) How the management plan is designed to safeguard objectivity in the research project;
(D) Confirmation of the Investigator’s agreement to the management plan;
(E) How the management plan will be monitored to ensure Investigator compliance; and
(F) Other information as needed.

Updated or annual FCOI reports will include the status of the management plan (i.e., whether the financial conflict is still being managed or explain why the financial conflict no
longer exists) and a description of any changes to the management plan since the last
FCOI report was submitted to the NIH.
REQUIRED FCOI REPORTS TO BE PROVIDED TO NIH THROUGH eRA COMMONS FCOI MODULE
REPORT CONTENT REQUIRED WHEN?
New FCOI Report (Initial submission Grant Number, PI, Name of Entity with FCOI, Nature of FCOI, Value of financial interest (in increments), Description of how FI relates to research, Key Elements of Management Plan.
Prior to expenditure of funds

Within 60 days of any subsequently identified FCOI
Annual FCOI Report
Status of FCOI (i.e., whether FCOI is still being managed or no longer exists) and Changes to Management Plan, if applicable. Annual report due at the same time as when the Institution is required to submit annual progress report, multi-year progress report, or at time of extension.
Revised FCOI Report
If applicable, update a previously submitted FCOI report to describe actions that will be taken to manage FCOI going forward or make changes to originally submitted FCOI report. Following the completion of a retrospective review when there is noncompliance with the regulation, if needed.
Mitigation Report
Project Number, Project Title, Contact PI/PD, Name of Investigator with FCOI, Name of Entity with FCOI, Reason for review, Detail Methodology, Findings and Conclusion. When bias is found as a result of a retrospective review.

Q: How should the FCOI report be submitted to NIH?
For awarded grants and cooperative agreements, Institutions must submit all FCOI reports to the NIH through the electronic Research Administration (eRA) Commons FCOI Module. See NIH Guide for Grants and Contracts, Notice No. NOT-OD-09-072.

Maintenance of Records
Aronora will maintain all FCOI-related records for at least 3 years from the date the final expenditures report is submitted to the PHS (NIH).

Enforcement Mechanisms and Remedies and Noncompliance
Sanctions or other administrative actions to ensure Investigator compliance will be fully implemented depending on the nature and severity of the noncompliance. These sanctions may include anything from a written warning to termination of employment. The designated institutional official will complete and document retrospective reviews within 120 days of the Institution’s determination of noncompliance for SFIs not disclosed timely or previously reviewed or whenever an FCOI is not identified or managed in a timely manner and to document the reviews consistent with the regulation. In any case in which the Department of Health and Human Services determines that a PHS-funded research project of clinical research whose purpose is to evaluate the safety or effectiveness of a drug, medical device, or treatment has been designed, conducted, or reported by an Investigator with an FCOI that was not managed or reported by the Institution as required by the regulation, the Institution shall require the Investigator involved to: 1) Disclose the FCOI in each public presentation of the results of the research, and 2) to request an addendum to previously published presentations.

Subrecipient Requirements
When applicable, a written agreement will be implemented that states the subrecipient will follow the FCOI policy of the awardee Institution. If applicable, Aronora will obtain a certification from subrecipient(s) that its FCOI policy complies with the regulation. If applicable, this will include a written subrecipient agreement for the subrecipient to report identified FCOIs for its Investigators in a time frame that allows the awardee Institution to report identified FCOIs to the NIH as required by the regulation. Alternatively, if applicable, included in the written agreement will be a requirement to solicit and review subrecipient Investigator disclosures so as to enable the awardee Institution to identify, manage and report identified FCOIs to the NIH.

Public Accessibility Requirements
Aronora agrees to post this FCOI policy on its public Web site, or if there is no current presence on a publicly accessible Web site, and only in those cases, make FCOI policy available within 5 business days of a request. If a presence on a publicly accessible Web site is acquired, post FCOI
policy within 30 days. Aronora will also make available information concerning identified FCOIs held by senior/key personnel (as defined by the regulation), publicly accessible prior to the expenditure of funds. The information will: 1) Include the minimum elements as provided in the regulation, 2) Be posted on a Public Website or made available within 5 calendar days of a written request, 3) Be updated, at least annually (Web site only but any response to a written request should include the updated information), 4) Be updated, within 60 days of a newly identified FCOI (Web site only but any response to a written request should include the updated information), 5) Remain available for three years from the date the information was most recently updated.

The information that the Institution makes available via a publicly accessible Web site or written response shall include, at a minimum, the following:
i. Investigator’s name;
ii. Investigator’s title and role with respect to the research project;
iii. Name of the entity in which the Significant Financial Interest is held;
iv. Nature of the Significant Financial Interest; and
v. Approximate dollar value of the Significant Financial Interest (dollar ranges are permissible: $0-$4,999; $5,000-$9,999; $10,000-$19,999; amounts between $20,000-$100,000 by increments of $20,000; amounts above $100,000 by increments of $50,000) or a statement that the interest is one whose value cannot be readily determined through reference to public prices or other reasonable measures of fair market value.

PDF DOWNLOAD OF THIS DOCUMENT:
Aronora’s FCOI Policy

READ MORE: http://www.springerlink.com/content/2m5807146453073m/?MUD=MP

Blood. 2012 May 17;119(20):4762-8. Epub 2012 Mar 22.

Severe bacterial sepsis often leads to a systemic procoagulant and proinflammatory condition that can manifest as disseminated intravascular coagulation, septic shock, and multiple organ failure. Because activation of the contact proteases factor XII (FXII), prekallikrein, and factor XI (FXI) can trigger coagulation and inflammatory responses, the contact factors have been considered potential targets for the treatment of sepsis. However, the pathogenic role of contact activation in severe infections has not been well defined. We therefore investigated whether an anticoagulant antibody (14E11) that selectively inhibits prothrombotic FXI activation by activated FXII (FXIIa) modifies the course of bowel perforation-induced peritoneal sepsis in mice. Early anticoagulation with 14E11 suppressed systemic thrombin- antithrombin complex formation, IL-6, and TNF-α levels, and reduced platelet consumption in the circulation and deposition in the blood vessels. Treatment with 14E11 within 12 hours after bowel perforation significantly improved survival compared with vehicle treatment, and the saturating dose did not increase tail bleeding. These data suggest that severe polymicrobial abdominal infection induces prothrombotic FXI activation, to the detriment of the host. Systemic anticoagulation by inhibitingFXI activation or FXIIa procoagulant activity during sepsis may therefore limit the development of disseminated intravascular coagulation without increasing bleeding risks.

READ MORE: http://www.ncbi.nlm.nih.gov/pubmed/22442348

J Thromb Haemost. 2010 Nov;8(11):2349-57. doi: 10.1111/j.1538-7836.2010.04031.x.

Coagulation factor (F)XI was first described as a member of the contact pathway of coagulation. However, the ‘classic’ theory of the extrinsic and intrinsic pathway has been revised and FXI was found to be activated by thrombin and to play a role in sustained thrombin generation and fibrinolysis inhibition. Recent studies have pointed to a disproportionate role of FXI in thrombosis and hemostasis. The observations that human congenital FXI deficiency is generally accompanied by mild and injury-related bleeding, and that experimental, provoked bleeding in animals is unaffected by FXI deficiency or FXI inhibition, suggest that the FXI amplification pathway is less important for normal hemostasis in vivo. In contrast, elevated plasma levels of FXI may contribute to human thromboembolic disease and the antithrombotic efficacy of FXI inhibition has been demonstrated in numerous animal models of arterial, venous and cerebral thrombosis. Whether severe FXI deficiency in humans protects against thromboembolic events remains unclear, although some evidence exists that the occurrence of ischemic stroke or venous thrombosis is low in severely FXI-deficient patients. Because of its distinctive function in thrombosis and hemostasis, FXI is an attractive target for the treatment and prevention of thromboembolism. A novel strategy for FXI inhibition is the use of antisense technology which has been studied in various thrombosis and bleeding animal models. The results are promising and support the concept that targeting FXI might serve as a new, effective and potentially safer alternative for the treatment of thromboembolic disease in humans.

READ MORE:  http://www.ncbi.nlm.nih.gov/pubmed/20727068

J Mol Med (Berl). 2012 Feb;90(2):119-26. Epub 2011 Sep 10.

Ischemic stroke is a devastating disease which, in most cases, is caused by thrombotic occlusion of brain arteries. The molecular mechanisms involved in microvascular thrombus formation during focal cerebral ischemia are not well understood. As a consequence, the current antithrombotic drugs used to treat acute stroke or prevent stroke recurrence either show limited efficacy or put patients at risk for serious bleeding complications. The serine protease blood coagulation factor XII (FXII) initiates the intrinsic pathway of coagulation which, together with the extrinsic pathway, culminates in the formation of fibrin. A physiological function of FXII in clot formation and hemostasis in vivo has been questioned for more than 50 years. This was mainly due to the fact that hereditary FXII deficiency does not induce any bleeding phenotype in humans. However, recent studies in transgenic mice challenged this concept by demonstrating that FXII deficiency prevents pathological thrombus formation, but does not affect regular hemostasis. These findings entailed investigations in relevant disease models of thromboembolism including ischemic stroke. The present review summarizes the pathophysiological role of FXII in experimental cerebral ischemia and highlights novel therapeutic strategies based on FXII inhibition.

READ MORE: http://www.ncbi.nlm.nih.gov/pubmed/21909687

Infect Immun. 2012 Jan;80(1):91-9. Epub 2011 Oct 17.

In mice infected sublethally with Listeria monocytogenes, fibrin is deposited at low levels within hepatic tissue, where it functions protectively by limiting bacterial growth and suppressing hemorrhagic pathology. Here we demonstrate that mice infected with lethal doses of L. monocytogenes produce higher levels of fibrin and display evidence of systemic coagulopathy (i.e., thrombocytopenia, fibrinogen depletion, and elevated levels of thrombin-antithrombin complexes). When the hepatic bacterial burden exceeds 1×10(6) CFU, levels of hepatic fibrin correlate with the bacterial burden, which also correlates with levels of hepatic mRNA encoding the hemostatic enzyme factor XI (FXI). Gene-targeted FXI-deficient mice show significantly improved survival upon challenge with high doses of L. monocytogenes and also display reduced levels of hepatic fibrin, decreased evidence of coagulopathy, and diminished cytokine production (interleukin-6 [IL-6] and IL-10). While fibrin limits the bacterial burden during sublethal listeriosis in wild-type mice, FXI-deficient mice display a significantly improved capacity to restrain the bacterial burden during lethal listeriosis despite their reduced fibrin levels. They also show less evidence of hepatic necrosis. In conjunction with suboptimal antibiotic therapy, FXI-specific monoclonal antibody 14E11 improves survival when administered therapeutically to wild-type mice challenged with high doses of L. monocytogenes. Together, these findings demonstrate the utility of murine listeriosis as a model for dissecting qualitative differences between protective and pathological host responses and reveal novel roles for FXI in exacerbating inflammation and pathogen burden during a lethal bacterial infection.

READ MORE: http://www.ncbi.nlm.nih.gov/pubmed/22006565

Thromb Res. 2011 Dec 22. [Epub ahead of print]

Coagulation factor FXI (FXI), a plasma serine protease zymogen, has important roles in both intrinsic and extrinsic coagulation pathways and bridges the initiation and amplification phases of plasmatic hemostasis. Recent studies have provided new insight into the molecular structure and functional features of FXI and have demonstrated distinct structural and biological differences between activated factor XII (FXIIa)-mediated FXI activation and tissue factor/thrombin-mediated FXI activation. The former is important in thrombosis; the latter is more essential in hemostasis. Activated partial thromboplastin tine (aPTT) artificially reflects FXIIa-initiated intrinsic coagulation pathway in vitro. Conversely, FXIIa-inhibited diluted thromboplastin time assay may reflect tissue factor/thrombin-mediated FXI activation in vivo. Further explication of the genetic mutations of FXI deficiency has improved the understanding of the structure-function relationship of FXI. Besides its procoagulant activity, the antifibrinolytic activity of FXI was well documented in a wealth of literature. Finally, the new emerging concept of inhibiting FXI as a novel antithrombotic approach with an improved benefit-risk ratio has been supported through observations from human FXI deficiency and various animal models. Large- and small-molecule FXI inhibitors have shown promising antithrombotic effects. The present review summarizes the recent advancements in the molecular physiology of FXI and the molecular pathogenesis of FXI deficiency and discusses the evidence and progress of FXI-targeting antithrombotics development.

Thromb Res. 2011 Dec 16.

The thrombin mutant W215A/E217A (WE thrombin) has greatly reduced procoagulant activity, but it activates protein C in the presence of thrombomodulin and inhibits binding of platelet glycoprotein Ib to von Willebrand factor and collagen under flow conditions. Both thrombomodulin-dependent protein C activation and inhibition of platelet adhesion could contribute to the antithrombotic activity of WE thrombin.

Materials & Methods:

To assess the role of thrombomodulin, we administered WE thrombin to thrombomodulin-deficient (TM(Pro/Pro)) mice and measured the time to occlusive thrombus formation in the carotid artery after photochemical injury of the endothelium.

RESULTS AND CONCLUSIONS:

Doses of WE thrombin ≥10μg/kg prolonged the thrombosis time of wild-type mice (>1.6-fold), while doses ≥100μg/kg only slightly prolonged the thrombosis time of TM(Pro/Pro) mice. We conclude that thrombomodulin plays a predominate role in mediating the antithrombotic effect of WE thrombin in the arterial circulation of mice after endothelial injury. Thrombomodulin-independent effects may occur only when high doses of WE thrombin are administered.

Prog Mol Biol Transl Sci. 2011;99:145-84.

Thrombosis is the most prevalent cause of fatal diseases in developed countries. An antithrombotic agent that can be administered to patients with severe acute thrombotic diseases without the risk of causing hemorrhage, as experienced with antithrombotic/thrombolytic therapy in the treatment of acute ischemic stroke or systemic anticoagulants like heparin, would likely revolutionize the treatment of cardiovascular and cerebrovascular diseases. Thrombin remains at the forefront of cardiovascular medicine and a major target of antithrombotic and anticoagulant therapies, due to its involvement in thrombotic deaths. Heparins and direct thrombin inhibitors currently used in the treatment of acute thrombotic complications, especially in the venous circulation, are plagued by complications related to dosage and bleeding. A new strategy of intervention has been proposed in recent years aiming at modulating, rather than inhibiting, thrombin function. Specifically, efforts have been directed toward finding ways of exploiting the anticoagulant function of thrombin unleashed by the activation of protein C, either using small modulators or protein engineering. The ability of thrombin to activate protein C coexists with its procoagulant and prothrombotic functions, mediated respectively by cleavage of fibrinogen and the protease-activated receptor 1 (PAR1). A strategy that inhibits thrombin at the active site abrogates the procoagulant and prothrombotic functions, but also shuts down activity toward the anticoagulant protein C. On the other hand, a strategy that selectively compromises fibrinogen and PAR1 recognition may take advantage of the anticoagulant and cytoprotective functions of activated protein C and prove of interest for in vivo applications. This chapter summarizes current protein engineering efforts to convert thrombin into a potent and safe anticoagulant for in vivo applications.

READ MORE: http://www.ncbi.nlm.nih.gov/pubmed/21238936

Curr Opin Hematol. 2011 Sep;18(5):349-55.

Arterial and venous thrombosis are major causes of morbidity and mortality, and the incidence of thromboembolic diseases increases as a population ages. Thrombi are formed by activated platelets and fibrin. The latter is a product of the plasma coagulation system. Currently available anticoagulants such as heparins, vitamin K antagonists and inhibitors of thrombin or factor Xa target enzymes of the coagulation cascade that are critical for fibrin formation. However, fibrin is also necessary for terminating blood loss at sites of vascular injury. As a result, anticoagulants currently in clinical use increase the risk of bleeding, partially offsetting the benefits of reduced thrombosis. This review focuses on new targets for anticoagulation that are associated with minimal or no therapy-associated increased bleeding.

Data from experimental models using mice and clinical studies of patients with hereditary deficiencies of coagulation factors XI or XII have shown that both of these clotting factors are important for thrombosis, while having minor or no apparent roles in processes that terminate blood loss (hemostasis).

Hereditary deficiency of factor XII (Hageman factor) or factor XI, plasma proteases that initiate the intrinsic pathway of coagulation, impairs thrombus formation and provides protection from vascular occlusive events, while having a minimal impact on hemostasis. As the factor XII-factor XI pathway contributes to thrombus formation to a greater extent than to normal hemostasis, pharmacological inhibition of these coagulation factors may offer the exciting possibility of anticoagulation therapies with minimal or no bleeding risk.