Tissue Factor in the Heart: Multiple Roles in Hemostasis, Thrombosis, and Inflammation

Tissue factor (TF) is the primary cellular initiator of the coagulation protease cascade. It plays an essential role in hemostasis to limit hemorrhage in the event of vascular injury. Indeed, loss of TF is incompatible with life. Recent studies have suggested that TF also plays non-hemostatic roles in blood vessel development, tumor angiogenesis, tumor metastasis, cell migration, and inflammation. This review discusses the roles of TF in hemostasis, thrombosis, and inflammation in the heart as well as other potential roles of TF in the maintenance of cardiac muscle.     

Tissue factor: (patho)physiology and cellular biology.

The transmembrane glycoprotein tissue factor (TF) is the initiator of the coagulation cascade in vivo. When TF is exposed to blood, it forms a high-affinity complex with the coagulation factors factor VII/activated factor VIIa (FVII/VIIa), activating factor IX and factor X, and ultimately leading to the formation of an insoluble fibrin clot. TF plays an essential role in hemostasis by restraining hemorrhage after vessel wall injury. An overview of biological and physiological aspects of TF, covering aspects consequential for thrombosis and hemostasis such as TF cell biology and biochemistry, blood-borne (circulating) TF, TF associated with microparticles, TF encryption-decryption, and regulation of TF activity and expression is presented. However, the emerging role of TF in the pathogenesis of diseases such as sepsis, atherosclerosis, certain cancers and diseases characterized by pathological fibrin deposition such as disseminated intravascular coagulation and thrombosis, has directed attention to the development of novel inhibitors of tissue factor for use as antithrombotic drugs. The main advantage of inhibitors of the TF*FVIIa pathway is that such inhibitors have the potential of inhibiting the coagulation cascade at its earliest stage. Thus, such therapeutics exert minimal disturbance of systemic hemostasis since they act locally at the site of vascular injury.     

Complications from vascular disrupting agents and angiogenesis inhibitors: aberrant control of hemostasis and thrombosis

PURPOSE OF REVIEW: To discuss thrombotic and hemorrhagic complications from angiogenesis inhibitors and vascular disrupting agents, pathogenesis, and recommendations for prophylaxis and management of those complications. RECENT FINDINGS: Venous thromboembolism has been a significant complication of the angiogenesis inhibitors thalidomide and lenalidomide. Prophylaxis with aspirin, low-molecular-weight heparin, or warfarin has been shown to decrease rates of venous thromboembolism in patients treated with these agents. Life-threatening hemorrhage and arterial thromboembolism have been observed in patients using treatments that inhibit the vascular endothelial growth factor signaling pathway. Patients should be screened for arterial thromboembolism and hemorrhage risk prior to using vascular endothelial growth factor signal inhibitors. It is not known how angiogenesis inhibitors and vascular disrupting agents upset normal hemostasis. It is likely that disruption of the function and/or integrity of vascular endothelium leads to an increased risk for thrombosis and/or hemorrhage. SUMMARY: New angiogenesis inhibitors and vascular disrupting agents have been developed that have significant activity against neoplasms. Potentially life-threatening side effects of hemorrhage and thrombosis have been observed with many of these new agents. As new treatments that disrupt angiogenesis or existing tumor vasculature are developed, attention should be given to these toxicities in clinical practice and clinical trials.     

Tissue factor: A key molecule in hemostatic and nonhemostatic systems

Tissue factor (also known as tissue thromboplastin or CD142) is the protein that activates the blood clotting system by binding to, and activating, the plasma serine protease, factor VIIa, following vascular injury. Because of its essential role in hemostasis, tissue factor plays a role in pathology associated with hemostasis, triggering the coagulation system in many thrombotic diseases and the coagulopathies associated with sepsis and other forms of disseminated intravascular coagulation. Recent research has also implicated tissue factor in a variety of nonhemostatic roles, including cell signaling, inflammation, vasculogenesis, and tumor growth and metastasis. This review focuses on both the well-known roles of tissue factor in hemostasis and thrombosis and the newer concepts of tissue-factor biology including how it functions as a signaling receptor and the possible role of blood-borne tissue factor in thrombosis.     

Thrombin: Structure, Biochemistry, Measurement, and Status in Clinical Medicine

Thrombin remains a molecule of great interest to scientists and clinicians alike because of its important role in hemostasis, thrombosis, inflammation and vascular remodeling. Yet one of the great challenges has been the inhibition of thrombin generation to a degree that minimizes intravascular thrombosis while preserving physiologic hemostasis. It has become increasingly clear that high levels of anticoagulation with either direct or indirect thrombin antagonists are not beneficial and, in fact, are quite detrimental. Despite the overwhelming shift of interest toward the platelet in clinical trials of acute coronary syndromes, much can be gained through further investigation of coagulation processes responsible for thrombin generation and activity.     

Coagulation abnormalities in malignancy: a review.

As outlined in this review, patients with cancer may harbor many alterations of hemostasis. These are multifaceted and must be taken into account when trying to control hemorrhage or thrombosis in cancer patients. Often, hemorrhage or thrombosis is the final fatal event in many patients with metastatic solid tumor or hematologic malignancies. Patients with malignancy present a major clinical challenge in this new era of oncologic awareness and more aggressive care, which has led to prolonged survival for patients and a longer time frame during which these complications may develop. Therefore, these complications are occurring more commonly. It is important to realize that these alterations of hemostasis exist and must be approached in a sequential and logical manner with respect to diagnosis; only in this way can responsible, efficacious, and rational therapy be delivered to patients. By far the most common alteration of hemostasis in malignancy is that of hemorrhage associated with thrombocytopenia, either drug-induced, radiation-induced, or from bone marrow invasion. However, hemorrhage resulting from DIC is also quite common and may present as hemorrhage, thrombosis, thromboembolus, or any combination thereof. Many antineoplastic drugs and radiation therapy may lead to or significantly enhance hemorrhage in patients with malignancy. Thrombosis, also commonly seen in patients with malignancy, is often a manifestation of low-grade DIC, conspicuous as an intravascular thrombotic or thromboembolic event instead of an intravascular proteolytic (hemorrhagic) event. When suspecting this, confirmatory laboratory evidence must be sought and the patient treated appropriately. When approaching the patient with malignancy and either hemorrhage or thrombosis, all the potential defects in hemostasis must be taken into account, defined from the laboratory standpoint, and treated in as precise and logical manner as possible.     

Vascular functions of the plasminogen activation system

The plasminogen activator (PA) system, which controls the formation and activity of plasmin, plays a key role in modulating hemostasis, thrombosis, and several other biological processes. While a great deal is known about the function of the PA system, it remains a focus of intensive investigation, and the list of biological pathways and human diseases that are modulated by normal and pathologic function of its components continues to lengthen. Because of remarkable advances in molecular genetics, the laboratory mouse has become the most useful animal system to study the normal and pathologic functions of the PA system. The purpose of this review is to summarize studies that have used genetically modified mice to examine the functions of the PA system in hemostasis and thrombosis, intimal hyperplasia after vascular injury, and atherosclerosis. Particular emphasis is placed on the vascular functions of PA inhibitor-1, a key regulator of the PA system, and the multiple variables that appear to account for the complex role of PA inhibitor-1 in regulating vascular remodeling. Lastly, the strengths and limitations of using mice to model human vascular disease processes are discussed.     

Critical role for Syk in responses to vascular injury

Although current antiplatelet therapies provide potent antithrombotic effects, their efficacy is limited by a heightened risk of bleeding and failure to affect vascular remodeling after injury. New lines of research suggest that thrombosis and hemorrhage may be uncoupled at the interface of pathways controlling thrombosis and inflammation. Here, as one remarkable example, studies using a novel and highly selective pharmacologic inhibitor of the spleen tyrosine kinase Syk [PRT060318; 2-((1R,2S)-2-aminocyclohexylamino)-4-(m-tolylamino)pyrimidine-5-carboxamide] coupled with genetic experiments, demonstrate that Syk inhibition ameliorates both the acute and chronic responses to vascular injury without affecting hemostasis. Specifically, lack of Syk (murine radiation chimeras) attenuated shear-induced thrombus formation ex vivo, and PRT060318 strongly inhibited arterial thrombosis in vivo in multiple animal species while having minimal impact on bleeding. Furthermore, leukocyte-platelet-dependent responses to vascular injury, including inflammatory cell recruitment and neointima formation, were markedly inhibited by PRT060318. Thus, Syk controls acute and long-term responses to arterial vascular injury. The therapeutic potential of Syk may be exemplary of a new class of antiatherothrombotic agents that target the interface between thrombosis and inflammation.     

Vascular disorders associated with thrombohemorrhagic phenomena.

This paper has attempted to summarize the more common disease entities which may be accompanied by or may lead to a disorder of hemostasis and/or thrombosis. It is to be emphasized that the vascular component of hemostasis is often overlooked by clinicians caring for individuals with disorders in hemostasis and thrombosis. It is hoped that this brief summary will alert clinicians that the vasculature is equal in importance to the coagulation protein system and to platelets in leading to a hemorrhagic or thrombotic diathesis.     

The Hemostatic Defect of Cardiopulmonary Bypass

Cardiac surgery involving cardiopulmonary bypass is a common yet complex procedure that results in considerable disruption of hemostasis during and following surgery. Despite the relatively common and widespread use of this procedure, there remains a significant peri-operative risk of both thrombosis and hemorrhage in some patients. This is known as the hemostatic defect of cardiopulmonary bypass.Strategies including the use of pharmacological agents, hemodilution, autologous blood transfusion, rapid in-theatre monitoring of hemostatic potential with fine-tuning of the degree of heparinization, minimally invasive surgery and the use of biologically coated cardiopulmonary bypass equipment have been employed to ameliorate the effects of cardiopulmonary bypass on hemostasis. However there exists a fine line between preventing hemorrhage and promoting thrombosis. Likewise attempts to prevent thrombosis may result in increased hemorrhage. Research into many strategies for minimizing the hemostatic defect of cardiopulmonary bypass is incomplete, with safety and efficacy the subjects of intensive investigation.     

The diagnosis of cytomegalovirus retinitis

Immunosuppressed patients are at risk for developing cytomegalovirus retinitis. This disorder is the most common cause of vision loss in patients with the acquired immunodeficiency syndrome (AIDS). Cytomegalovirus retinitis is probably the result of hematogenous spread of the virus to the retina after systemic reactivation of a latent cytomegalovirus infection. Although the ophthalmic infection may initially be asymptomatic, the retinal necrosis it produces may result in both loss of visual field and decreased visual acuity. Routine screening of these patients is required for early diagnosis. The retinitis is detected with ophthalmoscopy as either a perivascular yellow-white retinal lesion frequently associated with retinal hemorrhage or as a focal white granular infiltrate, often without hemorrhage. Both lesions enlarge in a progressively expanding "brushfire" pattern. The diagnosis of cytomegalovirus retinitis, as well as the evaluation of its response to therapy, is determined primarily by clinical criteria. Serial retinal photography is an objective method to assess the changing appearance of these lesions. Ganciclovir and foscarnet are investigational antiviral drugs that appear to be effective in treating cytomegalovirus retinitis. However, maintenance therapy with these medications is required after initial treatment because the disease often relapses. The combined expertise of the internist and the ophthalmologist is needed to diagnose and treat these patients.     

Thrombophilia in ischemic stroke subtypes: Implications for treatment

Opinion statement The current understanding of thrombogenesis is modeled on Virchow’s triad: stasis, hypercoagulability, and vessel wall injury. There is a dynamic (always changing) nonlinear interaction between the vascular wall, blood components, and flow, which at times defined “pathologic” leads to thrombosis or hemorrhage, at other times called “healthy” to normal hemostasis. The triad named after Virchow was not designated as such in Virchow’s work. Instead, Virchow showed that thrombosis itself leads to endothelial damage, hypercoagulability, and stasis. Thus, cause and effect regarding the elements of Virchow’s triad and thrombosis become indistinguishable if linearity is considered mandatory. Considering a nonlinear relation solves this problem. In the real patient, each element is present to a degree. At every moment in time, the direction of coagulation (toward hemostasis, thrombosis, or hemorrhage) and the dynamic of interaction of the elements of the triad change. The complexity and nonlinearity of the thrombotic context is evident. These facts suggest a new venue for diagnostic classification of stroke (ischemic and hemorrhagic) by causation and have implications for its prevention and treatment. Clinical and laboratory evidence can be gathered for the elements of Virchow’s triad as well as for fibrinolysis and thrombosis. Mathematical methods other than probability-based statistics can represent the measured presence of these elements to a degree and their nonlinear relationship. These include, but may not be limited to, Riemannian geometry, fuzzy logic, cellular automata, and infinitesimals, all proscribed by evidence-based medicine. However, by using these methods, diagnosis and treatment measures for stroke can be built on a causal rather than risk methodology, individualizing medical decisions to the patient. All current clinical guidelines are based on linear methods of probability-based statistics and group-based data. The therapeutic choice of antithrombotic therapy in the individual patient for whom measured elements of thrombogenesis are available rests on the knowledge and expertise of the treating physician.     

Zebrafish: a tool to study hemostasis and thrombosis

PURPOSE OF REVIEW: In the past eight years our laboratory has developed the zebrafish model to study hemostasis and thrombosis. The purpose of this review is to explore current developments involving the zebrafish model in the study of hemostasis and thrombosis because the time is now ripe to apply this model to identify novel players that participate in hemostasis and thrombosis. RECENT FINDINGS: In the past twelve months, three papers appeared in the hemostasis and thrombosis area using the zebrafish model. The first one is a review article that summarizes establishment of the zebrafish model to study hemostasis and thrombosis. The second study is a methodological paper describing assays for measuring hemostasis and thrombosis by inducing vascular occlusion in zebrafish larvae. The third paper describes a knockdown of prothrombin in zebrafish, which recapitulates knockout studies in mouse, and marks the beginning of studies in the hemostasis and thrombosis area by this new knockdown technology. In addition to the above papers, there is one abstract that describes kinetics of thrombocyte and thrombocyte-microparticle recruitment in laser-induced arterial thrombus formation in zebrafish. SUMMARY: With the above advances, the zebrafish model has now matured to the point that it can address more important questions in the hemostasis and thrombosis area using genetic approaches. This review therefore summarizes the issues described in the above papers along with thoughts about future progress of the zebrafish model as a tool to study hemostasis and thrombosis.     

Acute cytomegalovirus infection complicated by vascular thrombosis: a case report.

We present a case report of a previously healthy adult with cytomegalovirus infection that was complicated by extensive mesenteric arterial and venous thrombosis. To our knowledge, this is the first reported case of this syndrome in an immunocompetent individual who had no predisposing risk factors for thrombosis, and it demonstrates the propensity for cytomegalovirus to be involved in vascular disease.     

Mouse laser injury models: variations on a theme

Abstract

A confluence of technological advances in genetic manipulation and molecular-based fluorescence imaging has led to the widespread adoption of laser injury models to study hemostasis and thrombosis in mice. In all animal models of hemostasis and thrombosis, detailing the nature of experimentally induced vascular injury is paramount in enabling appropriate interpretation of experimental results. A careful appraisal of the literature shows that direct laser-induced injury can result in variable degrees of vascular damage. This review will compare and contrast models of laser injury utilized in the field, with an emphasis on the mechanism and extent of injury, the use of laser injury in different vascular beds and the molecular mechanisms regulating the response to injury. All of these topics will be discussed in the context of how distinct applications of laser injury models may be viewed as representing thrombosis and/or hemostasis.     

Role of tissue factor in hemostasis, thrombosis, and vascular development

Tissue factor (TF) is best known as the primary cellular initiator of blood coagulation. After vessel injury, the TF:FVIIa complex activates the coagulation protease cascade, which leads to fibrin deposition and activation of platelets. TF deficiency causes embryonic lethality in the mouse and there have been no reports of TF deficiency in humans. These results indicate that TF is essential for life, most likely because of its central role in hemostasis. In addition, aberrant TF expression within the vasculature initiates life-threatening thrombosis in various diseases, such as sepsis, atherosclerosis, and cancer. Finally, recent studies have revealed a nonhemostatic role of TF in the generation of coagulation proteases and subsequent activation of protease activated receptors (PARs) on vascular cells. This TF-dependent signaling contributes to a variety of biological processes, including inflammation, angiogenesis, metastasis, and cell migration. This review focuses on the roles of TF in hemostasis, thrombosis, and vascular development.     

Functional Property of von Willebrand Factor Under Flowing Blood

von Willebrand factor (vWF) is produced in megakaryocytes and endothelial cells, is stored in the alpha-granule of platelets and in the Weibel-Palade body of endothelial cells, and is present in plasma and vascular subendothelium. This huge protein with a unique multimeric structure plays a pivotal role in both hemostasis and pathological intravascular thrombosis, in which vWF contributes to both platelet adhesion/aggregation and blood coagulation through its multiple adhesive functions for the platelet membrane receptors, glycoprotein Ib-IX-V complex, integrin alphaIIbbeta3, heparin, various types of collagen, and coagulation factor VIII. Among various functions, the most characteristic feature of vWF is its determinant role on platelet thrombus formation under high-shear-rate conditions. Indeed, at in vivo rheological situations where platelets are flowing with high speed in the bloodstream, the only reaction that can initiate mural thrombogenesis is the interaction of vWF with platelet glycoprotein Ibalpha. The recent x-ray analysis of the crystal structure of various functional domains and functional studies of this protein under experimental flow conditions have rapidly advanced and revised our knowledge of the structure-function relationships of vWF, a key protein for hemostasis and arterial thrombosis.     

Endoscopic treatment of upper gastrointestinal bleeding

Opinion statement Endoscopic therapy for nonvariceal bleeding should only be used if major stigmata of hemorrhage such as active bleeding and nonbleeding visible vessel are present. Treatment of peptic ulcers with adherent clots is currently controversial. Combination of epinephrine injection and coaptive coagulation is most effective in achieving endoscopic hemostasis. Hemoclips may be preferable for very deep ulcers and large visible blood vessels if coaptive coagulation is anticipated to have a high risk of perforation or bleeding. Adrenaline injection or hemoclip application should be used in bleeding Mallory-Weiss tears, as the safety of thermal methods is not well established. Argon plasma coagulation is the mainstay of endoscopic treatment for superficial lesions such as angiodysplasia and gastric antral vascular ectasia. Both sclerotherapy and band ligation are effective in acute hemostasis of bleeding esophageal varices. Variceal band ligation is preferred due to its superior safety profile and shorter procedure time. Due to the early recurrence of varices after banding ligation, there may be a role for metachronous combination therapy of ligation followed by sclerotherapy. Histoacryl glue is the preferred method of endoscopic hemostasis in gastric varices.     

抗血小板疗法在老年急性冠脉综合征的临床应用

虽然大多数抗血小板疗法治疗急性冠脉综合征（ACS）的临床试验证实有显著临床效益,但老年患者,特别是≥75岁患者,仅少数有效,多数疗效欠佳,而出血风险增加。本文对因老龄化导致的止血血栓与出血的病理生物学,血管修复与整合作用变化,以及ACS抗血小板疗法在近年来临床试验中老年患者的效益与风险进行讨论。     

Recurrent venous thrombosis

This report is concerned less with the clinical characteristics of recurrent venous thrombosis than with the current revolution in research into its etiology. Progress in knowledge of hemostasis has advanced the diagnosis of venous thrombosis from the risk factor epoch to that of molecular pathology. In this respect, venous thromboembolic disorder constitutes a particularly stimulating model for increasing understanding of vascular diseases.