Seminars in Thrombosis and Hemostasis

Publications in this journal

• Article: JAK2 Mutation-Related Disease and Thrombosis.

  Alessandro M Vannucchi, Paola Guglielmelli
  [show abstract] [hide abstract]
  ABSTRACT: A recurrent JAK2V617F mutation is typically associated with chronic myeloproliferative neoplasms (MPNs) that include polycythemia vera (PV), essential thrombocythemia (ET), and primary myelofibrosis. This mutation results in a gain of function that is credited to underlie most of the pathogenesis and phenotypic characteristics of these disorders; it serves as a key diagnostic marker and represents a suitable target for JAK2 inhibitors. Because cardiovascular events represent the main cause of morbidity and mortality in PV and ET, current patients' risk stratification is based on variables predicting individual thrombotic risk (age and previous thrombotic history). However, evidence is accumulating that supports a role of JAK2V617F mutation as a novel risk factor for thrombosis, although prospective validation has not been provided yet. In this review, we discuss about potential mechanisms that link mutated JAK2 with the thrombotic propensity of MPN and the clinical correlates; hopefully, novel information could result in better patient management.
  Seminars in Thrombosis and Hemostasis 04/2013;
• Article: Pregnancy and Venous Thromboembolism.

  Stefano Barco, Mathilde Nijkeuter, Saskia Middeldorp
  [show abstract] [hide abstract]
  ABSTRACT: Pregnancy and the postpartum period are associated with an increased risk of venous thromboembolism (VTE), which complicates 1 to 2 of 1,000 pregnancies and represents a leading cause of mortality during pregnancy in developed countries. Strong evidence for the management of pregnancy-related VTE is missing, mostly because pregnant women have been excluded from all major trials investigating different diagnostic tools and treatment regimens. Nevertheless, proper evaluation of the involved risk factors is mandatory to reduce the incidence of pregnancy-related VTE and improve outcomes. Low-molecular-weight heparins are considered as a first-line option in the management of pregnancy-related VTE. With regard to future research, there is a need for methodologically strong studies in pregnant women, especially with respect to risk stratification, optimal heparin doses, usefulness of anti-FXa levels and their correlation with clinical outcomes, and correct management of anticoagulation during delivery.
  Seminars in Thrombosis and Hemostasis 04/2013;
• Article: Arterial and Venous Thrombosis in Endocrine Diseases.

  Bregje van Zaane, Danka J F Stuijver, Alessandro Squizzato, Victor E A Gerdes
  [show abstract] [hide abstract]
  ABSTRACT: Endocrine diseases have been associated with cardiovascular events. Both altered coagulation and fibrinolysis markers and thrombotic disorders have been described in several endocrine diseases. This review summarizes the evidence on the influence of thyroid diseases, cortisol excess and deficiency, pheochromocytoma, hyperparathyroidism, hyperaldosteronism, hyperprolactinemia, and growth hormone excess and deficiency; on parameters of hemostasis; and on arterial and venous thrombotic events. All these endocrine diseases do have, or may have, influence either on hemostasis or on the risk of thrombotic events. Future studies are needed to establish the clinical relevance of these associations.
  Seminars in Thrombosis and Hemostasis 04/2013;
• Article: Prothrombotic Changes in Diabetes Mellitus.

  Olivier Morel, Laurence Jesel, Malak Abbas, Nicolas Morel
  [show abstract] [hide abstract]
  ABSTRACT: Although our understanding of vascular pathology has greatly improved in recent years, the cellular and molecular mechanisms underlying the enhanced thrombotic propensity in type 2 diabetes mellitus (T2DM) remain incompletely characterized. Detrimental interactions between activated vascular cells (i.e., platelets, leukocytes, endothelial cells) and the vulnerable atheromatous plaque are a major determinant of the increased atherothrombotic burden in T2DM patients. Endothelial damage and accelerated senescence, impairment of the endothelial progenitor cell repair system, plaque neovascularization and inflammation, decreased clearance of detrimental molecules within the plaque, and increased expression of matrix metalloproteinases may collectively contribute to intraplaque hemorrhage and subsequent rupture. Notably, recent data demonstrates the central importance of the tissue factor-microparticle-mediated pathway in diabetic thrombophilia and cardiovascular complications. Acting as detrimental amplifiers of various biological responses (including thrombogenicity and plaque remodeling), microparticles have also emerged as a key marker of global vascular damage in T2DM patients. Available evidence suggests that targeting the tissue factor-microparticle pathway may be a promising approach for reducing the burden of the atherosclerotic complications of diabetes.
  Seminars in Thrombosis and Hemostasis 04/2013;
• Article: Venous Thromboembolism after Traumatic Brain Injury.

  Herb A Phelan
  [show abstract] [hide abstract]
  ABSTRACT: No standard exists for venous thromboembolism (VTE) prophylaxis after traumatic brain injury (TBI). Caregivers agree that there is an early time point after injury in which the chances of spontaneous injury progression are high and the risks of prophylactic anticoagulation are excessive, and that these injuries eventually stabilize to the point that anticoagulation may be safely started. Translating this consensus into an application that can inform bedside decision making has not occurred. National groups have promulgated guidelines in the United States suggesting that anticoagulants be used when the risk of renewed intracranial hemorrhage has ceased with no guidance beyond this vague recommendation. This is largely due to the relative paucity of literature about pharmacologic prophylaxis, which has in turn been due to fears of propagation of intracranial hemorrhage. Although interest in this field has increased of late, many studies are limited by the simple dichotomization of TBI patients as having the presence or absence of intracranial blood. Although methodologically easier, this approach does not account for the heterogeneity of TBI and, consequently, the spectrum of time to stabilization. To address this, our group has created an algorithm which stratifies patients by risk for spontaneous progression and tailors a unique VTE prophylaxis regimen to each arm.
  Seminars in Thrombosis and Hemostasis 04/2013;
• Article: Cancer and Venous Thrombosis: Current Comprehensions and Future Perspectives.

  Mandy N Lauw, Frederiek F van Doormaal, Saskia Middeldorp, Harry R Buller
  [show abstract] [hide abstract]
  ABSTRACT: Venous thromboembolism (VTE) is a common complication in all types of cancer and adversely impacts cancer prognosis. Randomized controlled trials with primary thromboprophylaxis in cancer patients generally show effective VTE relative risk reductions of up to 60%. However, absolute risks of VTE were fairly low. Thromboprophylaxis should therefore only be recommended to cancer patients at highest risk of VTE, who may benefit most from prophylaxis. Predictive risk models to identify patients at a high risk of VTE are promising, however additional validation is required. An increasing proportion of cancer-associated VTE is formed by incidental VTE, with similar risk factors and clinical consequences. Randomized trials are not yet available, but it seems reasonable to treat incidental VTE similarly to symptomatic VTE. In a substantial proportion of patients with unprovoked VTE without known cancer at the time of VTE diagnosis, concomitant or occult cancer is identified. Studies have investigated the value of extensive screening over routine examinations alone for occult cancer. Although extensive screening may be able to identify more occult cancers, its clinical benefit over routine screening has not been demonstrated.
  Seminars in Thrombosis and Hemostasis 04/2013;
• Article: Risk of Venous Thromboembolism in Patients with Inflammatory Bowel Disease.

  Efstratios I Koutroumpakis, Georgia Tsiolakidou, Ioannis E Koutroubakis
  [show abstract] [hide abstract]
  ABSTRACT: There is ample evidence of an increased risk of venous thromboembolism (VTE) in inflammatory bowel disease (IBD). Recent large studies have quantified this risk showing that IBD patients run a 1.5 to 3.6 higher risk of developing VTE than healthy controls. The development of VTE in IBD seems to be multifactorial, resulting from multiple interactions between acquired and inherited risk factors. The most important independent acquired risk factors include disease activity, hospitalization, colonic localization, and recent surgery. The main genetic defects that have been established as risk factors for VTE in the general population are rather uncommon in IBD, but when present, they increase the risk of VTE. IBD has been demonstrated to represent an independent risk factor for the recurrence of VTE. An increased risk of VTE-related mortality when compared with non-IBD patients has been reported. The guidelines for diagnosis and treatment of IBD patients with VTE are similar to that of thrombotic non-IBD patients. There is a consensus on the use of thromboprophylaxis mainly in hospitalized IBD patients with acute flares, but the prevention strategies need further evaluation in future studies.
  Seminars in Thrombosis and Hemostasis 04/2013;
• Article: Venous Thrombosis Associated with HMG-CoA Reductase Inhibitors.

  Giuseppe Lippi, Emmanuel J Favaloro, Fabian Sanchis-Gomar
  [show abstract] [hide abstract]
  ABSTRACT: Among the various hypolipidemic drugs, 3-hydroxy-3-methyl-glutaryl-coenzyme A (HMG-CoA) reductase inhibitors (also known as "statins") belong to a heterogeneous class of compounds, sharing an identical hypocholesterolemic effect that develops through direct inhibition of a rate-limiting step in endogenous cholesterol synthesis. Their mechanism of action entails competitive inhibition of HMG-CoA reductase. Several lines of evidence suggest that the pleiotropic effects of statins may also play a role in prevention of venous thrombosis, wherein hypercholesterolemic patients are characterized by enhanced thrombin generation, increased susceptibility to endothelial dysfunction and platelet hyperreactivity, so that limiting or counteracting the burden of one or more of these mechanisms would provide an effective means of prophylaxis. Plausible biological links can also be found between statin therapy and reduction of thrombotic risk, mainly targeting immune system, blood coagulation, endothelium, lipid metabolism, and inflammation. The earlier JUPITER (Justification for the Use of Statins in Primary Prevention) trial provided appealing evidence that the risk of venous thrombosis may be lowered by statins. The results of the following studies and those of recent meta-analyses have, however, questioned this assumption. Currently, it seems thereby cautious to conclude that the use of statins as part of the approach used for preventing venous thromboembolism appears unwarranted. This is due to the existence of controversial clinical evidence, to the large number of patients who would need to be treated to prevent one case of venous thrombosis, as well as to the tangible risk of side effects. More randomized and the larger studies are needed before definitive conclusions can be drawn.
  Seminars in Thrombosis and Hemostasis 04/2013;
• Article: Sepsis and Thrombosis.

  Marcel Levi, Marcus Schultz, Tom van der Poll
  [show abstract] [hide abstract]
  ABSTRACT: Activation of coagulation frequently occurs in severe infection and sepsis and may contribute to the development of thrombosis. Coagulation abnormalities in sepsis range from a small decrease in platelet count and subclinical prolongation of global clotting times to fulminant disseminated intravascular coagulation (DIC), characterized by simultaneous widespread microvascular thrombosis and profuse bleeding from various sites. Septic patients with severe forms of DIC may present with manifest thromboembolic disease or clinically less apparent microvascular fibrin deposition, which predominantly presents as multiple organ dysfunction. Thrombophilia is associated with a prohemostatic state and consequently with an increased tendency to develop thrombosis. Hypothetically, patients with thrombophilia may suffer from more severe coagulopathy in case of severe infection or sepsis, which may result in a more serious clinical course and an unfavorable outcome. On the basis of the knowledge of the pathogenesis of thrombosis in severe inflammation and sepsis, strategies aimed at the inhibition of coagulation activation have been developed and have been found favorable in experimental and clinical studies.
  Seminars in Thrombosis and Hemostasis 04/2013;
• Article: Thrombosis in Nephrotic Syndrome.

  Biagio Barbano, Antonietta Gigante, Antonio Amoroso, Rosario Cianci
  [show abstract] [hide abstract]
  ABSTRACT: Nephrotic syndrome (NS) is characterized by heavy proteinuria, edema, hypoalbuminemia, and hyperlipidemia and the most frequent causes are glomerular diseases. An uncommon presentation is iatrogenic NS, an adverse effect of some drugs administration. In the clinical course of NS, a typical feature is dysregulated coagulation state, promoted by the breakdown of permselectivity barrier of the glomerular capillary wall, resulting in the leakage of high-molecular-mass proteins, at least the size of albumin. This hypercoagulable condition is supported by several factors, such as abnormalities in platelet activation and an imbalance between anticoagulation/antithrombosis and procoagulant/prothrombotic mechanisms. Thus, NS and the risk of developing thromboses are strictly related. Thrombotic events affect the venous system rather than arterial vessels with different features and frequencies. Deep venous system of the lower extremities and renal veins are the most frequent source of pulmonary embolism, the most dangerous NS complication. Prophylactic anticoagulation and thrombosis treatment are not clearly established because large randomized trials and guidelines are lacking. The management of NS and the decision of when and how to anticoagulate the patient represent a teamwork challenge for physicians.
  Seminars in Thrombosis and Hemostasis 04/2013;
• Article: Role of Obesity in the Etiology of Deep Vein Thrombosis and Pulmonary Embolism: Current Epidemiological Insights.

  Sigrid K Braekkan, Bob Siegerink, Willem M Lijfering, John-Bjarne Hansen, Suzanne C Cannegieter, Frits R Rosendaal
  [show abstract] [hide abstract]
  ABSTRACT: The number of overweight and obese individuals in the population has increased dramatically in the past few decades, and the rising prevalence of obesity is a major public health concern. Growing evidence has accrued for obesity as a risk factor for venous thrombosis. The risk of venous thrombosis increases in a dose-dependent manner with increasing body mass index and is also associated with the majority of other anthropometric measures of overweight and obesity, such as waist circumference, hip circumference, and waist-to-hip ratio. An increased relative risk of both unprovoked and provoked venous thrombosis has been shown in obese compared with normal-weight subjects. However, encountering obesity as a causal factor for venous thrombosis is problematic due to the ill-defined concept of obesity. In this review, we will examine the current epidemiological evidence for an association between obesity and venous thrombosis. We will comment on the problem of causal interpretation of obesity per se and discuss how individual components that define obesity can serve as potential biological mechanisms for the observed association between obesity and venous thrombosis.
  Seminars in Thrombosis and Hemostasis 04/2013;
• Article: Quality in Hemostasis and Thrombosis, Part II.

  Giuseppe Lippi, Mario Plebani, Emmanuel J Favaloro
  Seminars in Thrombosis and Hemostasis 04/2013; 39(3):229-32.
• Article: Plasminogen Activators and Ischemic Stroke: Conditions for Acute Delivery.

  Gregory J Del Zoppo
  [show abstract] [hide abstract]
  ABSTRACT: Appropriate acute treatment with plasminogen activators (PAs) can significantly increase the probability of minimal or no disability in selected ischemic stroke patients. There is a great deal of evidence showing that intravenous recombinant tissue PAs (rt-PA) infusion accomplishes this goal, recanalization with other PAs has also been demonstrated in the development of this treatment. Recanalization of symptomatic, documented carotid or vertebrobasilar arterial territory occlusions have also been achieved by local intra-arterial PA delivery, although only a single prospective double-blinded randomized placebo-controlled study has been reported. The increase in intracerebral hemorrhage with these agents by either delivery approach underscores the need for careful patient selection, dose-appropriate safety and efficacy, proper clinical trial design, and an understanding of the evolution of cerebral tissue injury due to focal ischemia. Principles underlying the evolution of focal ischemia have been expanded by experience with acute PA intervention. Several questions remain open that concern the manner in which PAs can be applied acutely in ischemic stroke and how injury development can be limited.
  Seminars in Thrombosis and Hemostasis 03/2013;
• Article: Plasminogen Receptors: The First Quarter Century.

  Lindsey A Miles, Robert J Parmer
  [show abstract] [hide abstract]
  ABSTRACT: The interaction of plasminogen with cell surfaces results in promotion of plasmin formation and retention on the cell surface. This results in arming cell surfaces with the broad-spectrum proteolytic activity of plasmin. Over the past quarter century, key functional consequences of the association of plasmin with the cell surface have been elucidated. Physiologic and pathophysiologic processes with plasmin-dependent cell migration as a central feature include inflammation, wound healing, oncogenesis, metastasis, myogenesis, and muscle regeneration. Cell surface plasmin also participates in neurite outgrowth and prohormone processing. Furthermore, plasmin-induced cell signaling also affects the functions of inflammatory cells, via production of cytokines, reactive oxygen species, and other mediators. Finally, plasminogen receptors regulate fibrinolysis. In this review, we highlight emerging data that shed light on longstanding controversies and raise new issues in the field. We focus on (1) the impact of the recent X-ray crystal structures of plasminogen and the development of antibodies that recognize cell-induced conformational changes in plasminogen on our understanding of the interaction of plasminogen with cells; (2) the relationship between apoptosis and plasminogen binding to cells; (3) the current status of our understanding of the molecular identity of plasminogen receptors and the discovery of a structurally unique novel plasminogen receptor, Plg-RKT; (4) the determinants of the interplay between distinct plasminogen receptors and cellular functions; and (5) new insights into the role of colocalization of plasminogen and plasminogen activator receptors on the cell surface.
  Seminars in Thrombosis and Hemostasis 03/2013;
• Article: The Apparent uPA/PAI-1 Paradox in Cancer: More than Meets the Eye.

  Hau C Kwaan, Andrew P Mazar, Brandon J McMahon
  [show abstract] [hide abstract]
  ABSTRACT: The expression of several components of the plasminogen-plasmin (P-P) system in tumor tissues has been shown to have prognostic significance in many human cancers, including those of the breast, prostate, lung, brain, ovary, stomach, colon, rectum, oral cavity, kidney, and bone. Mechanisms of action of the individual components have been extensively studied in tumor cells in vitro and in animal models. By interrupting various putative pathways involved in tumor progression in several experimental tumor models in animals, varying degrees of tumor control have been achieved. However, these efforts have thus far not been able to exert any impact in oncologic clinical practice. A possible explanation is our incomplete understanding of the complex involvement of the P-P system and its interactions with other tumorigenic factors. In this article, the role of various members of the P-P system in cancer is reviewed. Proteolysis via the urokinase-type plasminogen activator-plasminogen activation pathway tends to enhance tumor growth and invasion, and its natural inhibitor plasminogen activator inhibitor type 1 may also enhance tumor growth through the inhibition of apoptosis, enhancing cell proliferation and the promotion of angiogenesis. Meaningful drug designs for therapeutic intervention require a thorough understanding of the role of all of the components involved in this complex mechanism of tumor progression.
  Seminars in Thrombosis and Hemostasis 03/2013;
• Article: Urokinase Plasminogen Activator Receptor: A Functional Integrator of Extracellular Proteolysis, Cell Adhesion, and Signal Transduction.

  Gian Maria Sarra Ferraris, Nicolai Sidenius
  [show abstract] [hide abstract]
  ABSTRACT: The urokinase plasminogen activator receptor (uPAR) is a cell surface receptor involved in a multitude of physiologic and pathologic processes. uPAR regulates simultaneously a branch of the plasminogen activator system and modulates cell adhesion and intracellular signaling by interacting with extracellular matrix components and signaling receptors. The multiple uPAR functions are deeply interconnected, and their integration determines the effects that uPAR expression triggers in different contexts. The proteolytic function of uPAR affects both the signaling and the adhesive functions of the receptor, whereas these latter two are closely interconnected. This review focuses on the molecular mechanisms that connect and mutually regulate the different uPAR functions.
  Seminars in Thrombosis and Hemostasis 03/2013;
• Article: Plasminogen-Plasmin System in the Pathogenesis and Treatment of Lung and Pleural Injury.

  Torry Tucker, Steven Idell
  [show abstract] [hide abstract]
  ABSTRACT: Lung and pleural injuries are characterized by inflammation, fibrinous transitional matrix deposition, and ultimate scarification. The accumulation of extravascular fibrin is due to concurrently increased local coagulation and decreased fibrinolysis, the latter mainly as a result of increased plasminogen activator inhibitor-1 (PAI-1) expression. Therapeutic targeting of disordered fibrin turnover has long been used for the treatment of pleural disease. Intrapleural fibrinolytic therapy has been found to be variably effective in clinical trials, which likely reflects empiric dosing that does not account for the wide variation in pleural fluid PAI-1 levels in individual patients. The incidence of empyema is increasing, providing a strong rationale to identify more effective, nonsurgical treatment to improve pleural drainage and patient outcomes. Therapeutics designed to resist inhibition by PAI-1 are in development for the treatment of pleural loculation and impaired drainage. The efficacy and safety of these strategies remains to be proven in clinical trial testing. Fibrinolytic therapy administered via the airway has also been proposed for the treatment of acute lung injury, but this approach has not been rigorously validated and is not part of routine clinical management at this time. Challenges to airway delivery of fibrinolysins relate to bioavailability, distribution, and dosing of the interventional agents.
  Seminars in Thrombosis and Hemostasis 03/2013;
• Article: Thrombosis in Systemic Lupus Erythematosus: Role of Impaired Fibrinolysis.

  Parvinderjit K Dhillon, Murray J Adams
  [show abstract] [hide abstract]
  ABSTRACT: Systemic lupus erythematosus (SLE) is a chronic inflammatory autoimmune disease that can affect any part of the body, including the skin, liver, kidneys, and blood. Thrombosis is a frequent manifestation in SLE, contributing significantly to patient morbidity and mortality, although the precise mechanism(s) of how this occurs remains unclear. Fibrinolysis is the physiologic process of thrombus digestion and provides an important balance to hemostasis. This process is triggered upon vessel injury with the release of tissue-type plasminogen activator (t-PA) from endothelial cells. The central component of the fibrinolytic pathway is plasminogen, a zymogen that is converted to plasmin by t-PA. Plasminogen/plasmin is absorbed into the developing thrombus and digests fibrinogen and fibrin within the hemostatic plug to prevent excessive clot formation. Abnormalities of the fibrinolytic pathway are associated either with the development of thrombosis (impaired fibrinolysis) or, to a lesser extent, bleeding (excessive fibrinolysis). Indeed, impaired fibrinolysis has been reported in patients with SLE and may contribute to both the development of hypercoagulability and an increased risk of thrombosis. Here we discuss the role of impaired fibrinolysis and its contribution to hypercoagulability and thrombosis in SLE.
  Seminars in Thrombosis and Hemostasis 03/2013;
• Article: Clotting Activation and Hyperfibrinolysis in Cirrhosis: Implication for Bleeding and Thrombosis.

  Francesco Violi, Domenico Ferro
  [show abstract] [hide abstract]
  ABSTRACT: Hyperfibrinolysis may be detected in patients with cirrhosis, particularly in case of severe liver failure. Hyperfibrinolysis is usually associated with prolonged global tests of clotting activation, which are then dependent on impaired synthesis of clotting factors by liver cells. The term "coagulopathy" has therefore been coined to indicate the existence of hyperfibrinolysis and blood hypocoagulation in cirrhosis, and, for a long time, these changes have been believed to facilitate bleeding. However, apart from gastrointestinal bleeding, which is related prevalently to hemodynamic factors in the portal circulation, spontaneous bleeding is less frequent than would be expected by the abnormality of laboratory tests. This apparent paradox may be explained by studies questioning the term "coagulopathy," instead documenting a hypercoagulation state in portal as well as in peripheral circulation of cirrhotic patients. The support of these findings by more recent data allows a redefinition of the overall clotting picture, in particular hyperfibrinolysis, in cirrhosis. Thus, this review analyzes prevalence and clinical impact of hyperfibrinolysis in cirrhosis, focusing in particular on whether it is primary or secondary to clotting activation. Furthermore, we focused such changes in the context of more recent data showing an association between cirrhosis and thrombosis.
  Seminars in Thrombosis and Hemostasis 03/2013;