Showing papers in "Seminars in Thrombosis and Hemostasis in 2015"

Clinical Utility of Viscoelastic Tests of Coagulation (TEG/ROTEM) in Patients with Liver Disease and during Liver Transplantation.

Abstract: The concept that patients with stable liver disease are at an increased risk of bleeding, based solely on abnormalities of conventional coagulation tests such as prothrombin time (PT) and international normalized ratio (INR), is now recognized to be an overly simplistic interpretation of an extremely complex situation. These tests are in fact very poor predictors of bleeding in patients with liver disease who undergo invasive or surgical procedures. Commercially available whole blood viscoelastic tests (thromboelastography [TEG] and thromboelastometry [ROTEM]) evaluate the kinetics of coagulation from initial clot formation to final clot strength. These dynamic tests provide a composite picture reflecting the interaction of plasma, blood cells, and platelets, and more closely reflect the situation in vivo than do PT/INR, which are performed on plasma samples and measure isolated end points. Despite prolonged PT/INR and low platelet counts, viscoelastic tests are within normal range in many patients with both acute and chronic liver disease, commensurate with the concept of rebalanced hemostasis, and in keeping with the fact that an increasing number of these patients undergo liver transplantation without the need for blood or blood products. In addition, these tests reveal important additional information, such as the presence of hypercoagulability and a prothrombotic state, and also information about the presence of endogenous heparinoids associated with vascular endothelial damage, due to sepsis or acute inflammation. This review provides an overview of the current literature on the potential clinical utility of viscoelastic tests of coagulation in patients with liver disease.

Coagulation in Patients with Severe Sepsis

Abstract: In the majority of patients with severe sepsis, systemic activation of coagulation is present. Increasing evidence points to an extensive cross-talk between coagulation and inflammation that may play an important role in the pathogenesis of sepsis. Inflammation not only leads to activation of coagulation, but coagulation also considerably affects inflammatory activity. Molecular pathways that contribute to inflammation-induced activation of coagulation have been precisely identified. Proinflammatory cytokines and other mediators are capable of activating the coagulation system and downregulating important physiological anticoagulant pathways. Activation of the coagulation system and ensuing thrombin generation is dependent on expression of tissue factor on activated mononuclear cells and endothelial cells, and is insufficiently counteracted by TFPI. Simultaneously, endothelial-bound anticoagulant mechanism, in particular the protein C system, is shutoff by proinflammatory cytokines. In addition, fibrin removal is severely inhibited, because of inactivation of the fibrinolytic system, caused by an upregulation of its main inhibitor, plasminogen activator inhibitor type 1 (PAI-1). Increased fibrin formation and impaired removal lead to (micro)vascular thrombosis, which may result in tissue ischemia and subsequent organ damage. The cornerstone of the management of coagulation in sepsis is the specific and vigorous treatment of the underlying disorder. Strategies aimed at the inhibition of coagulation activation may theoretically be justified and have been found beneficial in experimental and initial clinical studies. Heparin may be an effective anticoagulant approach and alternative strategies comprise restoration of physiological anticoagulant pathways.

Heparin-Induced Thrombocytopenia in Critically Ill Patients

Abstract: Many critically ill patients receive heparin, either before intensive care unit (ICU) admission (e.g., postcardiac surgery), for prophylaxis/treatment of thrombosis, for hemodialysis/filtration, or even incidentally (e.g., flushing of intravascular catheters), and are therefore at risk for developing immune heparin-induced thrombocytopenia (HIT), a prothrombotic drug reaction caused by platelet-activating antiplatelet factor 4 (PF4)/heparin antibodies. However, HIT explains at most 1 in 100 thrombocytopenic ICU patients (HIT frequency 0.3–0.5% vs. 30–50% background frequency of ICU-associated thrombocytopenia), and most patients who form anti-PF4/heparin antibodies do not develop HIT; hence, HIT overdiagnosis often occurs. This review discusses HIT-related issues relevant to ICU patients, including how to (1) distinguish HIT both clinically and serologically from non-HIT–related thrombocytopenia; (2) recognize HIT-mimicking disorders, such as the acute disseminated intravascular coagulation (DIC)/liver necrosis-limb necrosis syndrome; (3) prevent HIT in the ICU through use of low-molecular-weight heparin; and (4) treat HIT, including awareness of “PTT confounding” when anticoagulating patients with DIC.

Laboratory testing in the era of direct or non-vitamin K antagonist oral anticoagulants: a practical guide to measuring their activity and avoiding diagnostic errors

Abstract: A new generation of antithrombotic agents has recently emerged. These provide direct inhibition of either thrombin (factor IIa [FIIa]) or FXa, and are increasingly replacing the classical anticoagulants (heparin and coumarins such as warfarin) in clinical practice for a variety of conditions. These agents have been designated several acronyms, including NOACs, DOACs, and TSOACs, respectively, referring to n ew ( n ovel; n on–vitamin K antagonist) o ral a nti c oagulant s , d irect o ral a nti c oagulant s , and t arget- s pecific o ral a nti c oagulant s , and currently include dabigatran (FIIa inhibitor), and rivaroxaban, apixaban, edoxaban, and betrixaban (FXa inhibitors). The pervading mantra that NOACs do not require laboratory monitoring is countered by ongoing recognition that laboratory testing for drug effects is needed in many situations. Moreover, since these agents “do not require” laboratory monitoring, some clinicians inappropriately take this to mean that they do not affect hemostasis tests. This review aims to briefly review the laboratory studies that have evaluated the NOACs against a wide range of laboratory assays to assess utility for qualitative or quantitative measurements of these drugs, as well as interferences that may cause misdiagnosis of hemostatic defects. Point of care testing, including use of alternate samples such as urine and serum, is also under development but is not covered extensively in this review. The main aims of this article are to provide practical guidance to general laboratory testing for NOACs, as well as to help avoid diagnostic errors associated with hemostasis testing performed on samples from treated patients, as these currently comprise major challenges to hemostasis laboratories in the era of the NOACs.

Coagulopathy of Acute Sepsis.

Abstract: Coagulopathy is common in acute sepsis and may range from subclinical activation of blood coagulation (hypercoagulability), which may contribute to venous thromboembolism, to acute disseminated intravascular coagulation, characterized by widespread microvascular thrombosis and consumption of platelets and coagulation proteins, eventually causing bleeding. The key event underlying this life-threatening complication is the overwhelming inflammatory host response to the pathogen leading to the overexpression of inflammatory mediators. The latter, along with the microorganism and its derivatives drive the major changes responsible for massive thrombin formation and fibrin deposition: (1) aberrant expression of tissue factor mainly by monocytes-macrophages, (2) impairment of anticoagulant pathways, orchestrated by dysfunctional endothelial cells (ECs), and (3) suppression of fibrinolysis because of the overproduction of plasminogen activator inhibitor-1 by ECs and thrombin-mediated activation of thrombin-activatable fibrinolysis inhibitor. Neutrophils and other cells, upon activation or death, release nuclear materials (neutrophil extracellular traps and/or their components such as histones, DNA, lysosomal enzymes, and High Mobility Group Box-1), which have toxic, proinflammatory and prothrombotic properties thus contributing to clotting dysregulation. The ensuing microvascular thrombosis-ischemia significantly contributes to tissue injury and multiple organ dysfunction syndromes. These insights into the pathogenesis of sepsis-associated coagulopathy may have implications for the development of new diagnostic and therapeutic tools.

The influence of herbal medicine on platelet function and coagulation: a narrative review.

Abstract: Cardiovascular disease (CVD) is the leading cause of death worldwide. Platelet activation and aggregation play a central role in hemostasis and thrombosis. Herbal medicines have been traditionally used in the management of CVD and can play a role in modifying CVD progression, particularly in platelet function, and have the potential of altering platelet function tests, as well as some coagulation parameters. Herbal medicines, such as feverfew, garlic, ginger, ginseng, motherwort, St John's wort, and willow bark, were found to reduce platelet aggregation. In vitro studies show promise in the reduction of platelet aggregation for Andrographis, feverfew, garlic, ginger, Ginkgo, ginseng, hawthorn, horse chestnut, and turmeric. In addition, cranberry, danshen, dong quai, Ginkgo, ginseng, green tea, and St John's wort were found to have potential interactions with warfarin. Furthermore, St John's wort interacted with clopidogrel and danshen with aspirin. Therefore, repeat testing of platelet function and coagulation studies, particularly for patients on warfarin therapy, may be required after exclusion of herbal medicines that could have possibly affected initial test results.

Rebalanced Hemostasis in Patients with Acute Liver Failure.

Abstract: Patients with acute liver failure (ALF) have substantial alterations in their hemostatic system. Since an international normalized ratio of ≥ 1.5 is part of the definition of the syndrome, it has long been believed that patients with ALF had a hemostasis-related bleeding tendency. Recent data, however, show that spontaneous bleeding in ALF is rare. In addition, thrombotic complications may be more common than spontaneous bleeding complications. Laboratory studies have suggested that patients with ALF may be in hemostatic balance as a result of a commensurate decline in pro- and anti-hemostatic factors. The unstable nature of the hemostatic balance in ALF may explain the occurrence of both bleeding and thrombotic complications. The hemostatic profile of patients with ALF includes hypercoagulable features, including von Willebrand factor/a disintegrin and metalloproteinase with a thrombospondin type 1 motif, member 13 unbalance, elevated levels of highly procoagulant, platelet-derived microparticles, and a profound hypofibrinolytic status. These hypercoagulable features may contribute to systemic thrombotic complications, but may also drive intrahepatic clot formation. Studies in experimental animal models of ALF have demonstrated that intrahepatic clot formation contributes to disease progression. The clinical consequences of these new insights in the hemostatic system of patients with ALF will be discussed in this review.

Profound endothelial damage predicts impending organ failure and death in sepsis.

Abstract: Endothelial damage contributes to organ failure and mortality in sepsis, but the extent of the contribution remains poorly quantified. Here, we examine the association between biomarkers of superficial and profound endothelial damage (syndecan-1 and soluble thrombomodulin [sTM], respectively), organ failure, and death in sepsis. The data from a clinical trial, including critically ill patients predominantly suffering sepsis (Clinicaltrials.gov: NCT00271752) were studied. Syndecan-1 and sTM levels at the time of study enrollment were determined. The predictive ability of biomarker levels on death and organ failures during follow-up were assessed in Cox models adjusted for potential confounders including key organ dysfunction measures assessed at enrollment. Of the 1,103 included patients, 418 died. sTM levels at the time of enrollment independently predicted risk of death in adjusted models (hazard ratio [HR] [highest quartile > 14 ng/mL vs. lowest quartile 240 vs. 14 ng/mL vs.

Cancer Tissue Procoagulant Mechanisms and the Hypercoagulable State of Patients with Cancer.

Abstract: Thrombosis is a major cause of morbidity and mortality in cancer patients. Many clinical factors contribute to the high thrombotic risk of this condition, including the type of malignancy, its disease stage, anticancer therapies, and comorbidities. However, the cancer cell-specific prothrombotic properties together with the host cell inflammatory response are important players in the pathogenesis of the cancer-associated hypercoagulability. Tissue factor (TF) is the most important procoagulant protein expressed by cancer cells, and with other cancer tissue procoagulant properties highly contributes to the procoagulant phenotype of malignant cells. Recent discoveries indicate that oncogenes determine the procoagulant protein expression, including TF, in cancer tissues. In addition, in malignancy, TF is also overexpressed by host normal blood cells triggered by cancer-derived inflammatory stimuli. As a consequence, a subclinical activation of blood coagulation is typically present in cancer patients, as demonstrated by abnormalities of circulating thrombotic biomarkers. The relevance of measuring these biomarkers to determine the patient thrombotic risk level is under active investigation. The goal is to identify the high-risk subgroups to establish more accurate and targeted anticoagulation strategies to prevent thrombosis in cancer patients. Ultimately, the clarification of specific molecular mechanisms triggering blood coagulation in specific cancer types may also indicate alternative ways to inhibit clotting activation in these conditions.

Pathophysiology of Trauma-Induced Coagulopathy and Management of Critical Bleeding Requiring Massive Transfusion.

Abstract: Trauma-induced coagulopathy is caused by multiple factors, such as anemia, hemodilution, hypothermia, acidosis, shock, and serious trauma itself, which affects patient outcomes due to critical bleeding requiring massive transfusion. Disseminated intravascular coagulation (DIC) with the fibrinolytic phenotype directly caused by trauma and/or traumatic shock has been considered to be the primary pathophysiology of trauma-induced coagulopathy. The key to controlling DIC is vigorous treatment of the underlying disorder, that is, trauma itself and hemorrhagic shock. Damage control resuscitation, consisting of damage control surgery, permissive hypotension, and hemostatic resuscitation, aims to control severe trauma and critical bleeding, which is equivalent to managing the underlying disorder of DIC. At present, however, evidence-based practices for damage control resuscitation are lacking. A robust prospective outcome study for damage control resuscitation that considers DIC with the fibrinolytic phenotype as the main pathological condition of trauma-induced coagulopathy affecting patient outcome is essential for improving therapeutic strategies.

The Impact of Residual Thrombosis on the Long-Term Outcome of Patients with Deep Venous Thrombosis Treated with Conventional Anticoagulation

Abstract: The impact of residual vein thrombosis (RVT) on the long-term outcome of patients with deep vein thrombosis (DVT) is unknown. We assessed the incidence of recurrent venous thromboembolism (VTE), postthrombotic syndrome (PTS), arterial thrombotic events, and cancer in patients with DVT with and without RVT. For this purpose, we evaluated up to 3 years 869 consecutive patients with acute proximal DVT who had conventional anticoagulation. RVT, defined as ultrasound incompressibility of at least 4 mm in the common femoral and/or the popliteal vein after 3 months, was detected in 429 (49.4%) patients, and was more likely in males (adjusted odds ratio [OR], 1.82; 95% confidence interval [CI], 1.37-2.04), in patients with previous VTE (OR, 1.64; 95% CI, 1.06-2.54), and in those with extensive thrombosis (OR, 3.58; 95% CI, 2.19-5.86). During the 3-year follow-up, recurrent VTE developed in 84 (19.6%) patients with RVT and 43 (9.8%) patients without RVT (adjusted hazard ratio [HR], 2.03; 95% CI, 1.40-2.94); PTS in 225 (52.4%) and 118 (26.8%), respectively (HR, 2.34; 95% CI, 1.87-2.93); arterial thrombosis in 29 (6.7%) and 14 (3.2%), respectively (HR, 2.05; 95% CI, 1.08-3.88); and cancer in 21 (4.9%) and 8 (1.8%), respectively (HR, 3.09; 95% CI, 1.31-7.28). In conclusion, in patients treated with vitamin K antagonists for prevention of recurrent VTE, RVT doubles the risk of recurrent VTE, PTS, arterial thrombosis, and cancer. Males, patients with previous VTE, and those with extensive thrombosis are independent risk factors of RVT development. Studies addressing the impact of the novel direct anticoagulants on the development of RVT as well as the long-term complications of DVT are needed.

Venous thromboembolism prophylaxis in critically ill patients.

Abstract: Venous thromboembolism (VTE), including deep vein thrombosis (DVT) and pulmonary embolism (PE), is recognized as a common complication in critically ill patients. Risk factors including critical illness, mechanical ventilation, sedative medications, and central venous catheter insertion are major contributing factors to the high risk of VTE. Because of their impaired cardiopulmonary reserve, PE arising from thrombosis in the deep veins of the calf that propagates proximally is poorly tolerated by critically ill patients. Pharmacologic prophylaxis with unfractionated heparin (UFH) or low-molecular-weight heparin (LMWH) has been shown to decrease the incidence of VTE in medical, surgical, and critically ill patients. As a result, over the past decades, VTE prophylaxis had become a standard of preventive measure in the intensive care unit (ICU). In clinical practice, the rate of VTE prophylaxis varies and may be inadequate in some centers. A perception of a high bleeding risk in critically ill patients is a major concern for most physicians that may lead to inadequate prophylaxis.

Fibrinogen level deteriorates before other routine coagulation parameters and massive transfusion in the early phase of severe trauma: a retrospective observational study.

Abstract: In trauma, hemostatic functions should be maintained appropriately to prevent massive bleeding This study elucidated the time-dependent changes in platelet count and coagulation variables, and the effects of disseminated intravascular coagulation (DIC) on these changes during the early phase of trauma Trauma patients with an injury severity score ≥16 were enrolled The critical levels of platelet count and coagulation variables were defined according to recent trauma guidelines Massive transfusion was defined as >10 units red cell concentrate The time from arrival at the emergency department to reaching the critical levels and meeting the criteria for massive transfusion were evaluated Eighty trauma patients were enrolled; 35 were diagnosed with DIC on arrival Among all patients, fibrinogen levels reached the critical level earliest among routine coagulation parameters; other routine coagulation parameters deteriorated after the patients met the criteria for massive transfusion Routine coagulation parameters reached their critical levels earlier in DIC patients than patients without DIC Massive transfusion was performed more frequently in DIC patients, who met the criteria earlier During the early phase of trauma, fibrinogen levels deteriorate earlier than other routine coagulation parameters, especially in DIC patients

Can immune thrombocytopenia be cured with medical therapy

Abstract: Primary immune thrombocytopenia (ITP) in adults often assumes a chronic course that requires persistent monitoring and treatment. Medical therapy has traditionally been viewed as a means of temporarily raising the platelet count with little or no potential to induce long-term platelet responses off treatment. However, several recent studies have tested the hypothesis that intensive medical therapy administered early in the disease course may ameliorate or even cure ITP. In this review, we propose a biological rationale for medical intervention that simultaneously targets the innate and adaptive immune responses administered early in the course of disease. We also critically examine data on long-term outcomes after single-agent and multi-agent medical therapy. Intensive regimens that target inflammation and adaptive immunity (e.g., combination high-dose dexamethasone and rituximab) appear to improve response rates at 6 to 12 months compared with standard first-line therapy (e.g., prednisone, high-dose dexamethasone alone) in newly diagnosed patients. Controlled trials with extended follow-up are needed to determine whether these intensive regimens induce more cures compared with standard treatment or merely delay relapse at the expense of potentially greater toxicity.

Factor XIII deficiency in Iran: A comprehensive review of the literature

Abstract: Factor XIII deficiency (FXIIID) is a rare bleeding disorder with an estimated prevalence of 1 in 2-million population worldwide. In Iran, a Middle Eastern country with a high rate of consanguineous marriages, there are approximately 473 patients afflicted with FXIIID. An approximately 12-fold higher prevalence of FXIIID is estimated in Iran in comparison with overall worldwide frequency. In this study, we have undertaken a comprehensive review on different aspects of FXIIID in the Iranian population. The distribution of this disease in different regions of Iran reveals that Sistan and Baluchestan Province has not only the highest number of patients with FXIIID in Iran but the highest global incidence of this condition. Among Iranian patients, umbilical cord bleeding, hematoma, and prolonged wound bleeding are the most frequent clinical manifestations. There are several disease causing mutations in Iranian patients with FXIIID, with Trp187Arg being the most common mutation in FXIIID in Iran. Traditionally, the management of FXIIID in Iran was only based on administration of fresh frozen plasma or cryoprecipitate, until 2009 when FXIII concentrate became available for patient management. Various studies have evaluated the efficacy and safety of prophylactic regimens in different situations with valuable findings. Although the focus of this study is on Iran, it offers considerable insight into FXIIID, which can be applied more extensively to improve the management and quality of life in all affected patients.

Classical Notions of Coagulation Revisited in Relation with Blood Losses, Transfusion Rate for 700 Consecutive Liver Transplantations.

Abstract: During the last decade, improved surgical and anesthetic management, such as better understanding of coagulation defects and the use of the phlebotomy, has reduced intraoperative blood product transfusions during orthotopic liver transplantation (OLT). The goal of this study was to look at the impact of initial conventional coagulation tests on blood loss and blood product requirement and to evaluate the role of the phlebotomy during liver transplantations. A total of 700 consecutive OLTs were studied. The group of patients was split into two according to the median of starting international normalized ratio to study blood losses and transfusion rate. Logistic regression was used to determine the main predictors of blood loss, intraoperative blood transfusion, and survival. There was no intergroup difference for demographic characteristics. The mean blood loss was 1,184 mL with a median of 920 mL. Overall, 77.4% of the patients did not receive any blood product and the mean transfusion rate of red blood cells (RBCs) was 0.5 ± 1.4 units per patient. Severity of recipients' disease did not correlate with blood loss or transfusion rate. Starting hemoglobin value was the only biochemical variable linked to RBC transfusions. Phlebotomy was linked to decrease in blood loss, RBC transfusions, and increased survival rate. It is concluded that bleeding did not correlate with traditional coagulation defects or the severity of recipient's disease. Preemptive phlebotomy was linked to a decreased blood loss, a decreased transfusion rate, and an increased 1-year survival rate.

Hemostatic and thrombotic issues in cardiac surgery.

Abstract: Cardiac surgery with cardiopulmonary bypass determines a serious imbalance of the hemostatic system. The clinical pattern is multifactorial, involving patient-related, drug-related, and surgery-related factors. As a result, the patient is prone to both hemorrhagic and thrombotic complications. To address the clinical management of a bleeding patient after cardiac surgery, avoiding empirical administration of drugs and blood derivates, it is mandatory to correctly identify the factor(s) responsible for bleeding. Bleeding after cardiac operations can be ascribed to seven basic mechanisms: residual heparin effect; reduced thrombin generation; fibrinogen deficiency; thrombocytopenia; platelet dysfunction; hyperfibrinolysis; and surgical sources. These factors may interact together, creating a complex coagulopathy. Point-of-care coagulation tests are useful to orienteer the clinician in this complex scenario. Viscoelastic coagulation tests find their greater usefulness in the diagnosis of the bleeding mechanism(s), whereas platelet function tests appear more useful for the preoperative assessment of patients under the effects of antiplatelet agents. Thromboembolic complications are the other side of the coin, and their prevention is still a matter of debate. Consumption of natural anticoagulants and endothelial disturbance are important mechanisms underlying this condition. Strategies to limit antithrombin (AT) consumption or to correct low postoperative levels of AT are still a matter of discussion.

The Fibrinolytic Status in Liver Diseases.

Abstract: The liver is the main site of synthesis and/or clearance of proteins involved in fibrinolysis. Therefore, chronic liver disease, including cirrhosis, leads to altered plasma levels of fibrinolytic proteins. Historical studies using in vitro clot lysis assays suggested that patients with chronic liver disease had accelerated fibrinolysis. Subsequent studies measured levels of individual pro- and antifibrinolytic proteins and showed that levels of tissue-type plasminogen activator are elevated. Plasma levels of plasminogen activator inhibitor-1 may also be altered, which leads to a shift in balance in the fibrinolytic system. Despite the fact that a more recent study using a plasma clot lysis assay challenged the existence of hyperfibrinolysis, other recent studies detected hyperfibrinolysis in a considerable number of patients with cirrhosis. Therefore, it is now recognized that hyperfibrinolysis may occur in 30 to 50% of patients with end-stage liver disease. A causal role of hyperfibrinolysis in bleeding is difficult to establish because also other concomitant changes in hemostasis occur. Treatment of hyperfibrinolysis consists of the use of fibrinolysis inhibitors, such as tranexamic acid. In this review we summarize current insights of the role of the liver in fibrinolysis, changes in fibrinolytic proteins, the potential clinical implications, and management of hyperfibrinolysis in liver disease.

International survey on D-dimer test reporting: a call for standardization.

Abstract: D-dimer is the biochemical gold standard for diagnosing a variety of thrombotic disorders, but result reporting is heterogeneous in clinical laboratories. A specific five-item questionnaire was developed to gain a clear picture of the current standardization of D-dimer test results. The questionnaire was opened online (December 24, 2014–February 10, 2015) on the platform “Google Drive (Google Inc., Mountain View; CA),” and widely disseminated worldwide by newsletters and alerts. A total of 409 responses were obtained during the period of data capture, the largest of which were from Italy (136; 33%), Australia (55; 22%), Croatia (29; 7%), Serbia (26; 6%), and the United States (21; 5%). Most respondents belonged to laboratories in general hospitals (208; 51%), followed by laboratories in university hospitals (104; 26%), and the private sector (94; 23%). The majority of respondents (i.e., 246; 60%) indicated the use of fibrinogen equivalent unit for expressing D-dimer results, with significant heterogeneities across countries and health care settings. The highest prevalence of laboratories indicated they were using “ng/mL” (139; 34%), followed by “mg/L” (136; 33%), and “µg/L” (73; 18%), with significant heterogeneity across countries but not among different health care settings. Expectedly, the vast majority of laboratories (379; 93%) declared to be using a fixed cutoff rather than an age-adjusted threshold, with no significant heterogeneity across countries and health care settings. The results of this survey attest that at least 28 different combinations of measurement units are currently used to report D-dimer results worldwide, and this evidence underscores the urgent need for more effective international joined efforts aimed to promote a worldwide standardization of D-dimer results reporting.

Antiphospholipid Syndrome–Not a Noninflammatory Disease

Abstract: The autoimmune disease antiphospholipid syndrome (APS) is characterized by thrombosis or pregnancy morbidity in patients with persistent antiphospholipid antibodies (aPLs). Although inflammation is not a key feature of the clinical presentation of the syndrome, there are indications that the inflammatory response plays an important role in APS. The major antigen of aPLs, the plasma protein β2-glycoprotein I, is involved in clearance of microparticles and in the innate immune response. In light of these physiological functions, the formation of antibodies against the protein is easily understood, as antibodies might augment the clearance reaction. In addition, inflammatory mediators are thought to play a role in the activation of leukocytes and the induction of endothelial dysfunction in APS. Moreover, evidence for a role of complement activation in the pathogenesis of the syndrome is accumulating. This review will provide an overview of current knowledge on the physiological function of β2-glycoprotein I, the formation of autoantibodies against β2-glycoprotein I and will explore the contribution of inflammation to the clinical manifestations of APS.

Platelets in Inflammatory Disorders: A Pathophysiological and Clinical Perspective.

Abstract: Platelets are well recognized as a key cell component of the hemostatic system. Recently, several additional functions have been discovered for these blood cells but most importantly in the process of inflammation. Numerous research groups have demonstrated crucial roles for platelets in the pathogenesis of varied clinical conditions where inflammation is important. Alterations in both platelet number and function have been observed with these different conditions. The relevance of these findings is their therapeutic implications through simple antiplatelet therapy to more complex, as yet clinically untrialed options, like interfering with platelet-leukocyte or platelet-endothelial interaction. This review focuses on how platelets are relevant in inflammatory conditions with an impetus on the clinical aspects.

Clinical Significance of Tissue Factor-Exposing Microparticles in Arterial and Venous Thrombosis.

Abstract: Microparticles (MP) are small extracellular vesicles (30-1,000 nm) that are released from activated cells or platelets. Exposure of negatively charged phospholipids and tissue factor (TF) renders MP procoagulant. Normal plasma levels of intravascular TF-exposing MP (TFMP) are low, but their number may rise in pathological conditions, including cancer and infectious disease. Emerging evidence indicates an important role for these circulating TFMP in the pathogenesis of thrombotic complications such as venous thromboembolism and disseminated intravascular coagulation, whereas their contribution to arterial thrombosis is less studied. Despite serious limitations of the currently available assays for measuring TFMP levels or the procoagulant activity associated with TFMP with respect to sensitivity and specificity, the scientific interest in TFMP is rapidly growing because their application as prognostic biomarkers for thrombotic complications is promising. Future advances in detection methods will likely provide more insight into TFMP and eventually improve their clinical utility.

The Role of Blood-Borne Microparticles in Inflammation and Hemostasis

Abstract: Inflammation has a pivotal role in cardiovascular disease because it contributes to the progression of atherosclerosis, a chronic inflammatory disease of the vessel wall. Microparticles (MPs) have recently emerged as both surrogate markers for different cardiovascular conditions (i.e., biomarkers of vascular inflammation and coagulation) and paracrine biological shuttle modules with influence in target cells. MPs are vesicles that bud off from cells, lack a nucleus, contain a membrane skeleton, and are defined by their size and expression on their surface of antigens specific of parental cells. Interestingly, not only inflammation is one of the main stimuli causing MP release but also MPs, in its turn, can induce, regulate, and even in specific cases reduce inflammation. The present review aims to summarize and update the role of circulating MPs in inflammation and hemostasis with special emphasis on their novel associations and functions. Besides their role as biomarkers of atherosclerotic inflammation, blood-borne MPs possess mechanisms to alter vascular cell milieu, to disseminate proinflammatory mediators, and to spread the inflammatory cascade reaction, causing a chronic inflammation of the vascular wall and aggravating the atherothrombotic process.

The effect of omega-3 polyunsaturated fatty acids on fibrin and thrombin generation in healthy subjects and subjects with cardiovascular disease.

Abstract: Hypercoagulability plays a key role in the progression of cardiovascular disease (CVD). Although omega-3 polyunsaturated fatty acid (PUFA) intake has been inversely related to the risk of cardiovascular events, the mechanisms are not fully understood. The aim of this study was to investigate the effects of omega-3 on novel markers of global coagulation. The generation of fibrin and thrombin, measured via overall hemostasis potential (OHP) assay and calibrated automated thrombography, respectively, was determined in 40 healthy subjects and 16 patients with CVD at baseline and after 4 weeks of 640 mg/day omega-3 PUFA. In healthy subjects, fibrin generation was significantly reduced, as measured by overall coagulation potential (p = 0.013), OHP (p

Liver Disease and Hemostatic (Dys)function.

Abstract: Cirrhosis presents with decreased procoagulant factors as a consequence of the impaired synthetic capacity of the liver. This was taken as evidence to explain the abnormalities of the coagulation tests prothrombin time (PT) and activated partial thromboplastin time (aPTT) and the bleeding events that occur in these patients. It was for long time (and probably is still) common practice to test patients with the PT and to treat those with predefined (but arbitrary) cutoff values with plasma or prohemostatic agents to prevent or stop bleeding. However, anticoagulant factors that contrast the procoagulants are also decreased in cirrhosis. It was therefore postulated that the coagulation balance (i.e., the net result between the action of pro- and anticoagulants) is somewhat rebalanced. Subsequent studies supported this view showing that plasma from cirrhotic patients generates normal amounts of thrombin. In addition, primary hemostasis (i.e., platelet–vessel wall interaction) is rebalanced notwithstanding cirrhosis present with thrombocytopenia. It was shown that increased levels of the adhesive protein von Willebrand factor (a typical feature of cirrhosis) compensate for the low number (function) of platelets. The earlier considerations have been instrumental to help dismantle the old paradigms of cirrhosis as the epitome of the acquired hemorrhagic coagulopathies and the traditional coagulation tests PT and aPTT as suitable predictors of bleeding risk. The demise of the old paradigms and the rise of the new one may have important practical implications for the management of patients with cirrhosis and will be discussed in this chapter.

Oral anticoagulant drugs and the risk of osteoporosis: new anticoagulants better than old?

Abstract: Several drugs have been associated with an increased risk of osteoporosis when used chronically. Coumarins (warfarin, acenocoumarol, phenprocoumon, and fluindione) are oral anticoagulants widely used for the prevention and treatment of arterial and venous thromboembolic diseases. These drugs are vitamin K antagonists that interfere with γ-carboxyglutamate formation, and consequently inhibit the carboxylation of glutamate residues of proteins that are synthesized in the bone. These effects on bone turnover and dietary restrictions in patients on anticoagulation are possible mechanisms inducing osteoporosis in coumarin users. However, conflicting evidence is available concerning the risk of osteoporosis and bone fractures in patients on treatment with these drugs. This risk is likely to be clinically relevant in long-term (more than 1 year) coumarin users. Novel direct oral anticoagulants, recently introduced in clinical practice, exert reduced interference on bone metabolism; however, limited in vitro and animal data are currently available, and their long-term effects will only become apparent in time.

Hypercoagulability and Platelet Abnormalities in Inflammatory Bowel Disease.

Abstract: Patients with inflammatory bowel disease (IBD) exhibit a threefold higher risk for development of systemic thrombosis than the general population. Although the underlying causes of the increased risk for thrombus development remain poorly understood, there is a large body of evidence suggesting that abnormalities in coagulation, fibrinolysis, and platelet function may contribute to this response. Changes in hemostatic biomarkers are consistent with subclinical activation of coagulation system, including tissue factor activation, impaired protein C pathway, enhanced thrombin generation, and diminished fibrinolytic capacity. There is also evidence for an increased production and reactivity of platelets, with an enhanced formation of platelet–platelet and platelet–leukocyte aggregates. The altered coagulation and platelet function, and the predisposition to thrombus formation have also been demonstrated in animal models of IBD. The animal studies have revealed a major role for inflammatory cytokines, including tumor necrosis factor-α, interleukin (IL)-1β, and IL-6, as mediators of the platelet abnormalities and enhanced thrombus development in experimental IBD. These findings in animal models raise hope for the development of novel therapeutic strategies to reduce thrombosis-related mortality in IBD patients.

Postsurgical Inflammation as a Causative Mechanism of Venous Thromboembolism

Abstract: Surgery is associated with an increased risk of venous thromboembolic events (VTE) including deep vein thrombosis and pulmonary embolism. Although the current treatment regiments such as mechanical manipulation and administration of pharmacological prophylaxis significantly reduced the incidence of postsurgical VTE, they remain a major cause of postoperative morbidity and mortality worldwide. The pathophysiology of venous thrombosis traditionally emphasizes the series of factors that constitute Virchow triad of factors. However, inflammation can also be a part of this by giving rise to a hypercoagulable state and endothelial damage. The inflammatory response after surgery, which is initiated by a cytokine "storm" and occurs within hours of surgery, creates a prothrombotic environment that is further accentuated by several cellular processes including neutrophil extracellular traps formation, platelet activation, and the generation of tissue factor-bearing microparticles. Although such inflammatory markers are elevated in undergoing surgery, the precise mechanism by which they give rise to venous thrombosis is poorly understood. Here, we discuss the potential mechanisms linking inflammation to thrombosis, and highlight strategies that may minimize surgical inflammation and reduce the incidence of postoperative VTE.

Homeostasis of Hemostasis: The Role of Endothelium.

Abstract: Forming an interface with virtually every other organ, endothelium has a strategic role in modulating vascular homeostasis. While its miscellany of functions includes regulation of vasomotor tone, promotion, and prevention of vascular growth, and modulation of inflammatory and hemostatic processes, it functions critically in maintaining the balance of hemostasis in health. Whereas endothelium has been recognized to influence all stages of hemostasis, new evidence suggests it to have a primary role for thrombin generation. Endothelial dysfunction is being increasingly appreciated in several pathological states and particularly, by virtue of its critical role in hemostasis, in causing thrombosis in a multitude of diseases.

Interplay of Inflammation and Endothelial Dysfunction in Bone Marrow Transplantation: Focus on Hepatic Veno-Occlusive Disease.

Abstract: Endothelial cells are unique multifunctional cells with basal and inducible metabolic and synthetic functions. Various stimuli can induce physiological or pathological changes in endothelial cell biology. Hematopoietic stem cell transplantation (HSCT) requires high-dose irradiation and/or chemotherapy and is associated with increased risk of bacterial infections and immune reactions. These factors can affect endothelial cells. This review provides an overview of the effects of HSCT on endothelial cells, based on findings observed in cultured cells as well as in patients. We first describe to what extent irradiation and chemotherapy constitute direct and indirect triggers for endothelial cell activation and injury. Then, we highlight the role of the endothelium in several complications of HSCT, including capillary leak syndrome, engraftment syndrome, transplant-associated microangiopathy, graft-versus-host disease, and diffuse alveolar hemorrhages. We also analyze in detail available data on sinusoidal obstruction syndrome, previously known as veno-occlusive disease of the liver, where liver sinusoidal endothelial cells are first injured and eventually lead to sinusoid occlusion and liver cell damage. Finally, we open the question of the possible contribution of endothelial damage to cardiovascular events occurring long after HSCT.