|Year : 2015 | Volume
| Issue : 2 | Page : 282-288
Clinical aspects of the haemostasis-inflammation interface
Ali Z Galal, Sabry A Shoeib, Hany S El Barbary, Wael R Abu-Sabala
Department of Internal medicine, Al-Mahallah al-Kubra Hospital, Menoufia University, Menoufia Governorate, Egypt
|Date of Submission||09-Oct-2013|
|Date of Acceptance||19-Jan-2014|
|Date of Web Publication||31-Aug-2015|
Wael R Abu-Sabala
Al-Mahallah al-Kubra, Bolkina 31951
Source of Support: None, Conflict of Interest: None
The aim of the study was to evaluate the clinical aspects of the haemostasis and inflammation interface.
Data sources were medical text books, medical journals and medical websites that have updated research with keywords (haemostasis and inflammation) in the title of the paper.
Systematic reviews that addressed haemostasis and inflammation and the role of haemostasis and inflammation in clinical studies were included.
A special search was performed in MEDLINE with keywords (haemostasis and inflammation) in the title of the papers; extraction was performed, including assessment of the quality and validity of the papers that met the prior criteria that describe haemostasis and inflammation and their role in clinical studies.
It included the main result of the review. Each study was reviewed independently; the obtained data were rebuilt in a new language according to the need of the researcher and arranged in topics through the article.
Improved understanding of the molecular mechanisms that play a role in the bidirectional relationship between inflammation and haemostasis could help in the clinical management of patients by identifying new potential therapeutic targets that can modify excessive and inappropriate activation or deregulation of both systems. On the basis of experimental and clinical studies, it is likely that simultaneous modulation of both inflammatory and haemostatic activities, rather than specific therapy aimed at only one component, could be more successful in the treatment of clinical states and diseases in which a close link between inflammation and haemostasis considerably contributes to the pathogenesis or progression of the disease.
Keywords: atherosclerosis chronic kidney disease; diabetes mellitus; fibrinolytic system; haemostasis; inflammation mediators
|How to cite this article:|
Galal AZ, Shoeib SA, El Barbary HS, Abu-Sabala WR. Clinical aspects of the haemostasis-inflammation interface. Menoufia Med J 2015;28:282-8
|How to cite this URL:|
Galal AZ, Shoeib SA, El Barbary HS, Abu-Sabala WR. Clinical aspects of the haemostasis-inflammation interface. Menoufia Med J [serial online] 2015 [cited 2020 Sep 20];28:282-8. Available from: http://www.mmj.eg.net/text.asp?2015/28/2/282/163865
| Introduction|| |
Inflammation and haemostasis are closely interrelated pathophysiologic processes that considerably affect each other. In this bidirectional relationship, inflammation leads to activation of the haemostatic system, which in turn also considerably influences inflammatory activity  .
The two examples of clinical conditions in which the tightly interdependent relationship between inflammation and haemostasis considerably contributes to the pathogenesis and/or progression of disease are systemic inflammatory response to infection or sepsis and acute arterial thrombosis as a consequence of a ruptured atherosclerotic plaque; the close link between inflammation and haemostasis helps explain the prothrombotic tendency in these two clinical conditions.
| Materials and methods|| |
The guidance published by the Centre for Reviews and Dissemination was used to assess the methodology and outcomes of the studies. This review was reported in accordance with the Preferred Reporting Items for Systematic reviews and Meta-Analyses statement. An institutional review board and ethics committee approved this study.
A systematic search was performed of several bibliographical databases to identify relevant reports in any language. These included MEDLINE, Cochrane Database of Systematic Reviews, Cochrane Central Register of Controlled Trials, TRIP database, Clinical Trials Registry, ISI Web of Knowledge and Web of Science. Articles electronically published ahead of print were included. The search was performed in the electronic databases from the initiation date of the database until 2012.
All studies were independently assessed for inclusion. They were included if they fulfilled the following criteria:
Patients with atherosclerosis, sepsis, diabetes mellitus or systemic lupus erythematosus were included.
Interventions included therapeutic modalities of treating atherosclerosis, sepsis, diabetes mellitus and systemic lupus erythematosus (SLE).
The outcome was decreased atherosclerosis.
If the studies did not fulfil the above criteria, they were excluded. Articles in non-English languages were translated. The article title and abstracts were initially screened, and then the selected articles were read in full and further assessed for eligibility. All references from the eligible articles were reviewed to identify additional studies.
Study quality assessments included determining whether ethical approval was gained, whether the study had a prospective design, whether the eligibility criteria were specified, whether appropriate controls were used, whether adequate follow-up was conducted and whether outcome measures such as regression of atherosclerosis and the role of platelets were defined.
The quality of all the studies was assessed. Important factors included a prospective study design, attainment of ethical approval, evidence of a power calculation, specified eligibility criteria, appropriate controls, specified outcome measures and adequate follow-up. It was expected that confounding factors would have been reported and controlled for and appropriate data analysis would have been carried out, in addition to providing an explanation for missing data.
Because of the reported heterogeneity in postoperative follow-up periods and outcome measures, it was not possible to pool the data and carry out a meta-analysis. Comparisons were made through a structured review.
| Results|| |
Inflammation initiates clotting, decreases the activity of natural anticoagulants and impairs the fibrinolytic system. Inflammatory cytokines are the major mediators involved in the activation of coagulation. Natural anticoagulants dampen elevations in cytokine levels. Further, components of the natural anticoagulant cascades, such as thrombomodulin, minimize endothelial cell dysfunction by rendering the cells less responsive to inflammatory mediators, facilitate the neutralization of some inflammatory mediators and decrease loss of endothelial barrier function. Hence, downregulation of anticoagulant pathways not only promotes thrombosis but also amplifies the inflammatory process. When the inflammation-coagulation interactions overwhelm the natural defence systems, catastrophic events occur.
| Discussion|| |
The historical and modern views on haemostasis
In the 1960s, two groups proposed the waterfall or cascade model of coagulation composed of a sequential series of steps in which activation of one clotting factor led to the activation of another, finally leading to a burst of thrombin generation. Each clotting factor was believed to exist as a proenzyme that could be converted to an active enzyme  .
The original cascade models were subsequently modified to include the observation that some procoagulants are cofactors and do not possess enzymatic activity. The coagulation process is now often outlined in a Y-shaped scheme, with distinct intrinsic and extrinsic pathways initiated by factor XIIFXII and FVIIa/tissue factor (TF), respectively. The pathways converge in a common pathway at the level of the FXa/FVa (prothrombinase) complex. The coagulation complexes are generally observed to require phospholipids and calcium for their activity  .
Natural anticoagulant mechanisms
There are three major anticoagulant mechanisms that control the blood clotting process: tissue factor pathway inhibitor (TFPI), the heparin-antithrombin (AT) pathway and the protein C (PC) anticoagulant pathway. Deficiencies in the heparin-AT or the PC pathway in humans lead to an increased risk for thrombosis, whereas the impact of deficiencies in the TF pathway in humans is less clear , . The physiological significance of these pathways is demonstrated further through gene disruption experiments in mice, which result in embryonic or neonatal lethality when any single pathway is disrupted  .
In the inflammatory state, the function of AT can be impaired as a result of increased consumption (due to activation of the coagulation cascade), decreased synthesis (as a result of a negative acute phase response) and increased degradation by proteolytic enzymes (elastase from activated neutrophils). In addition, proinflammatory cytokines can cause reduced synthesis of glycosaminoglycans (GAGs), such as heparan sulphate, on the endothelial surface, which may also contribute to the impairment in AT function as endogenous GAGs act as physiologic heparin-like cofactors, thus promoting the anticoagulant activity of AT  .
Protein C system
Among the three key natural anticoagulant mechanisms, the PC system appears to be the most important in regulating inflammatory response and also the most negatively influenced by inflammatory states. Under physiological conditions, PC is activated by thrombin bound to the endothelial cell membrane-associated protein thrombomodulin. Activated PC with its cofactor protein S inactivates FVa and FVIIIa. There is increasing evidence that the PC system also has important functions in modulating inflammatory response through its anti-inflammatory and profibrinolytic activities  . Anti-inflammatory activities of activated PC include inhibition of cytokine [tumour necrosis factor-α, interleukin (IL)-1, IL-6] production by monocytes/macrophages, inhibition of chemotaxis and adhesion of leucocytes to the endothelium and suppression of NF-kB transcription  .
Tissue factor pathway inhibitor
The third physiological anticoagulant mechanism is TFPI, a serine protease inhibitor attached to the endothelium through GAGs and secreted through endothelial cells (ECs). As in the case of AT, proinflammatory cytokines can cause reduced synthesis of GAGs on the endothelial surface, which may affect the function of TFPI. However, relatively little is known about the impact of inflammation on TFPI function. Its role in the regulation of inflammation-induced activation of haemostasis is not completely clear, mostly because the majority of TFPIs are associated with the vessel endothelium and direct assays of endogenous TFPI activity in vivo are not routinely available  .
| Fibrinolysis|| |
During the process of fibrin clot formation in the body, the fibrinolytic system is initiated to disrupt it. The final effector of the fibrinolytic system is plasmin, which cleaves fibrin into soluble degradation products. Plasmin is produced from the inactive precursor plasminogen by the action of two plasminogen activators (PAs), urokinase-type PA and tissue-type PA (tPA). The PAs are in turn regulated by PA inhibitors (PAIs). Plasminogen is found at a much higher plasma concentration than PAs. The availability of the two PAs in plasma therefore generally determines the extent of plasmin formation. Release of tPA from ECs is provoked by thrombin and venous occlusion; tPA and plasminogen both bind to the evolving fibrin polymer  .
Mechanisms by which inflammation induces disturbance of the haemostatic system
The extensive cross-talk between the immune and haemostatic systems occurs at the level of all components of the haemostatic system, including vascular ECs, platelets, the plasma coagulation cascade, physiologic anticoagulant pathways and fibrinolytic activity. During an inflammatory response, inflammatory mediators, in particular proinflammatory cytokines, play a central role in the effects on the haemostatic system  .
The main mediators of inflammation-induced activation of the haemostatic system are proinflammatory cytokines such as tumour necrosis factor-α (TNF-α), IL-1 and IL-6. Inflammatory mediators trigger disturbance of the haemostatic system through a number of mechanisms including endothelial cell dysfunction, increased platelet activation, TF-mediated activation of the plasma coagulation cascade, impairment of the function of physiologic anticoagulant pathways and suppression of fibrinolytic activity  .
Platelet activation induced by inflammation
Besides the important role in haemostasis, platelets also play a relevant role in inflammation, acting as proinflammatory cells; under physiological conditions, platelets circulate in a resting state, protected from activation by inhibitory mediators, such as nitric oxide (NO) and prostacyclin (PGI2), released from intact ECs. Numerous factors promote platelet activation during an inflammatory response  .
Activation of the plasma coagulation cascade in inflammation
The main mechanism of plasma coagulation cascade activation in inflammation is mediated by TF. It is a transmembrane protein constitutively expressed by a variety of cell types, including circulatory blood cells and ECs  .
Physiologic anticoagulants in inflammation
Normal level and function of physiologic anticoagulants appear to be important in the defence against haemostatic abnormalities in inflammatory states. There is increasing evidence that physiologic inhibitors of coagulation, besides their anticoagulant actions, also have important anti-inflammatory functions. However, the function of all three pathways can be impaired during inflammation-induced disturbance of the haemostatic system. This represents an important mechanism for the procoagulant state in inflammation  .
Haemostasis is further controlled by the fibrinolytic system, in which the key enzyme plasmin degrades a fibrin clot. Plasmin is generated from plasminogen by activators such as tPA and urokinase-type PA. The main inhibitor of these PAs is PAI-1. Binding to PAs, PAI-1 causes their inactivation, thus suppressing their fibrinolytic activity; inhibition of the fibrinolytic system is another important component in haemostatic disorder during inflammatory states. The initial acute fibrinolytic response in inflammatory states is a transient increase in fibrinolytic activation mediated by the immediate release of tPA from vascular ECs. However, this increase in plasminogen activation is followed by a delayed but sustained increase in the main fibrinolytic inhibitor PAI-1, which results in significant suppression of fibrinolytic activity and subsequent inadequate fibrin removal  .
Mechanisms by which the activated haemostatic system influences inflammatory response
The communication between inflammation and haemostasis is a bidirectional process; hence, the activated haemostatic system also considerably modulates inflammatory activity. Individual components of the activated haemostatic system, such as activated coagulation factors thrombin, FXa and the TF-FVIIa complex, can directly stimulate cells involved in inflammatory response (platelets, leucocytes and ECs), with consequent increases in the production of proinflammatory mediators by these cells. The key mechanism by which activated coagulation factors augment an inflammatory response is by binding to platelet activating receptor (PARs). The PAR family of receptors consists of four members, PAR-1-PAR-4, which are localized on different cell types such as ECs, leucocytes, platelets, fibroblasts and smooth muscle cells (Schouten et al., 2008).
The vicious cycle of inflammation and coagulation
As increased inflammation can increase coagulation, which in turn can enhance inflammation, the failure of natural anticoagulant mechanisms in controlling the clotting process would naturally increase the inflammatory process  .
The twin observations that inflammation downregulates the natural anticoagulant mechanisms and that these mechanisms have anti-inflammatory activity above and beyond their antithrombotic functions further exacerbate the situation. This suggests that in acute inflammatory diseases, such as sepsis, natural anticoagulants might provide an effective treatment  .
Clinical significance of haemostasis and inflammation overlap
Atherosclerosis is a chronic inflammatory process  in which thrombus formation on a ruptured atherosclerotic plaque is the pathological basis of an acute arterial thrombotic event such as myocardial infarction  . Inflammation plays an important role in the atherosclerotic process, including fatty streak formation, plaque destabilization and subsequent thrombosis  .
Another example of the close interaction between the immune and haemostatic systems is sepsis. Sepsis is a clinical syndrome characterized by an excessive systemic host response to infection, resulting in uncontrolled activation of the inflammatory response. As the immune and haemostatic systems are tightly linked, an excessive inflammatory response can also lead to systemic activation of the haemostatic system. In fact, local activation of coagulation in septic patients is an integral component of the host defence in an attempt to eradicate the invading microorganism. However, an exaggerated response to infection can lead to a situation in which systemic activation of the haemostatic system itself contributes to disease severity, causing a syndrome known as disseminated intravascular coagulation (Schouten et al., 2008).
Chronic kidney disease
Chronic kidney disease (CKD) is a growing global health problem, and although end-stage renal disease is a prominent and much feared complication of the disease, the high mortality rate associated with CKD is mainly due to the increased incidence of cardiovascular disease  . This is not surprising because CKD patients have a greater prevalence of traditional cardiovascular risk factors such as older age, smoking, hypertension, type 2 diabetes and obesity (all considered prothrombotic conditions) compared with the general population  . Several haemostatic abnormalities have been described even in patients with mild CKD in addition to platelet hyperactivity. One report documented impaired release of tPA from the endothelium in patients with CKD, despite intact endothelium-dependent vasodilatation  .
In diabetes, platelet hyperactivation and hyperaggregation play crucial roles in thrombotic complications. In general, platelets are reported to respond more frequently to subthreshold stimuli, thus being consumed more rapidly, which results in an accelerated thrombopoiesis of fresh and hyper-reactive platelets in diabetic patients  .
Endothelial dysfunction plays a crucial role in the development of atherothrombosis. ECs produce mediators of vasodilatation (i.e. NO and prostacyclin) and vasoconstriction (i.e. angiotensin II and tranexamic acid (TXA)) to regulate vascular tone and thrombotic processes. In diabetes, vasoconstrictive, prothrombotic effects dominate, and hyperglycaemia and insulin resistance play a crucial role by inhibiting NO production and increasing reactive oxygen species production, leading to increased expression of proinflammatory cytokines and platelet adhesion molecules. Apart from affecting platelet function, these alterations may also alter coagulation and fibrinolysis, further contributing to an enhanced thrombotic milieu in diabetes  .
Systemic lupus erythematosus
Patients with SLE have an increased risk for thrombosis. Arterial and/or venous thrombosis is a well-known clinical entity in SLE, with prevalence greater than 10%. This prevalence may even exceed 50% in high-risk patients  . The incidence of thrombosis in SLE patients according to two inception cohorts was 26.8 and up to 51.9/1000 patient-years, on the basis of disease duration  ; another study reported an incidence of thrombosis of 36.3/1000 patient-years  .
In 10-year prospective cohort study on patients with SLE, the most frequent causes of death were active SLE (26.5%), thrombosis (26.5%) and infection (25%)  . The age at onset of thrombosis in SLE patient is lower than that in the general population, which is a major concern. The incidence of thrombosis increased in the first year. The possible reasons for this early higher incidence of thrombosis could be the high levels of disease activity and circulating immune complexes, the presence of cytotoxic antibodies or a higher inflammatory state  .
Inflammation and coagulation are two crucial systems in mammals. They constantly influence each other and are constantly in balance. In particular, inflammatory processes can promote coagulation, which in turn can also sustain inflammation. The interdependence of the two processes is confirmed in clinical settings in which inherited or acquired deficiency of natural anticoagulants is associated with an increase in inflammatory processes  .
This observation is particularly relevant in acute inflammatory diseases, such as sepsis  , but it also seems to be very important in chronic inflammatory conditions, such as inflammatory bowel disease (IBD). Patients with Crohn's disease and ulcerative colitis have an increased risk for thromboembolic events (Shen et al., 2007), which appear to be more frequent when IBD is in an active phase and is affecting the entire colon. However, it is worth noting that, in a large study, one-third of thromboembolic complications occurred during disease quiescence, supporting the hypothesis of a greater prothrombotic tendency in IBD, independent of disease activity  .
Inflammation initiates clotting, decreases the activity of natural anticoagulants and impairs the fibrinolytic system. Inflammatory cytokines are the major mediators involved in the activation of coagulation.
Natural anticoagulants function to dampen the elevation in cytokine levels. Further, components of the natural anticoagulant cascades, such as thrombomodulin, minimize endothelial cell dysfunction by rendering the cells less responsive to inflammatory mediators, facilitate the neutralization of some inflammatory mediators and decrease the loss of endothelial barrier function.
Hence, downregulation of anticoagulant pathways not only promotes thrombosis but also amplifies the inflammatory process. When inflammation-coagulation interactions overwhelm the natural defence systems, catastrophic events occur, such as those manifested in severe sepsis or IBD.
Haemostasis is a defence mechanism to stop bleeding. Activated by vessel wall injury, it involves intertwined activation of platelets and the coagulation cascade, tightly controlled by natural anticoagulants and the fibrinolytic system. Inflammation aims at restoring the integrity of the damaged or threatened tissues, most frequently due to injury or infectious pathogens.
The coagulation system and the innate inflammatory response share a common ancestry and are coupled by common activation pathways and feedback regulation systems. Primitive organisms such as the horseshoe crab have integrated coagulation and innate immune systems. More evolved species have more complex and specialized systems, but a two-way relationship between both has persisted throughout evolution; coagulation triggers inflammatory reactions and inflammation triggers the activation of the coagulation system. The extensive cross-talk between inflammation and coagulation involves cell receptor-mediated signalling, cellular interactions and the production of cell-derived microvesicles by ECs, leucocytes and platelets.
The role of platelets in (vascular) inflammation is illustrative of this two-way relationship. After adhering to an injured vessel wall, activated platelets release cytokines, growth factors and numerous proinflammatory mediators. In addition, leucocytes are recruited to the site of vascular damage by adhered platelet-leucocyte interactions, mediated by P-selectin expressed on the activated platelet surface and its counter-receptor on leucocytes - that is, P-selectin glycoprotein ligand-1 (PSGL-1). The same ligand recruits circulating microvesicles from leucocytes to the platelet surface, leading to rapid intravascular accumulation of microvesicular TF, which sustains the coagulation initially triggered by vascular TF. Platelets also facilitate leucocyte recruitment to the activated endothelium by forming P-selectin-PSGL-1-mediated conjugates with circulating leucocytes.
The many functions of TF and thrombin are also good illustrations of the extensive cross-talk between inflammation and coagulation. Inflammatory cytokines induce TF expression in leucocytes and ECs. Complex formation between TF and the coagulation factor FVIIa or FXa is instrumental in initiating coagulation on negatively charged cell membranes, whereas membrane-bound TF is also capable of signal transduction directly, mediating inflammatory reactions.
| Conclusion|| |
Improved understanding of the molecular mechanisms that play a role in the bidirectional relationship between inflammation and haemostasis could help in the clinical management of patients by identifying new potential therapeutic targets that can modify excessive and inappropriate activation or deregulation of both systems. On the basis of experimental and clinical studies, it is likely that simultaneous modulation of both inflammatory and haemostatic activities, rather than specific therapy aimed at only one component, could be more successful in the treatment of clinical states and diseases in which the close link between inflammation and haemostasis considerably contributes to the pathogenesis or progression of the disease. However, despite the impressive progress in understanding the molecular mechanisms linking inflammation and haemostasis in the recent years, many questions remain unanswered. Therefore, further study of the complex molecular mechanisms linking immune and haemostatic systems deserves attention from both medical experts and scientists.
| Acknowledgements|| |
Conflicts of interest
There are no conflicts of interest.
| References|| |
Verhamme P, Hoylaerts MF. Haemostasis and inflammation: two of a kind? Thromb J 2009; 7
Macfarlane RG. An enzyme cascade in the blood clotting mechanism, and its function as a biological amplifier. Nature 1964; 202
Davie EW, Ratnoff OD. Waterfall sequence for intrinsic blood clotting. Science 1964; 145
Lane DA, Mannucci PM, Bauer KA, et al.
Inherited thrombophilia: part 1. Thromb Haemost 1996; 76
Lane DA, Mannucci PM, Bauer KA, Bertina RM, Bochkov NP, Boulyjenkov V, et al
. Inherited thrombophilia: part 2. Thromb Haemost 1996; 6
Gu J-M, Crawley JTB, Ferrell G, et al.
Disruption of the endothelial cell protein C receptor gene in mice causes placental thrombosis and early embryonic lethality. J Biol Chem 2002; 277
Bourin MC, Lindahl U. Glycosaminoglycans and the regulation of blood coagulation. Biochem J 1993; 289
Weiler H. Regulation of inflammation by the protein C system. Crit Care Med 2010; 38
Bernard GR, Vincent JL, Laterre PF, et al.
Recombinant human protein C worldwide evaluation in severe sepsis (PROWESS) study group. Efficacy and safety of recombinant human activated protein C for severe sepsis. N Engl J Med 2001; 344
Esmon CT. The impact of the inflammatory response on coagulation. Thromb Res 2004; 114
Szymanski LM, Pate RR, Durstine JL. Effects of maximal exercise and venous occlusion on fibrinolytic activity in physically active and inactive men. J Appl Physiol 1994; 77
Levi M, van der Poll T. Inflammation and coagulation. Crit Care Med 2010; 38
Wagner DD, Burger PC. Platelets in inflammation and thrombosis. Arterioscler Thromb Vasc Biol 2003; 23
Cimmino G, D´Amico C, Vaccaro V, et al.
The missing link between atherosclerosis, inflammation and thrombosis: Is it tissue factor? Expert Rev Cardiovasc Ther 2011; 9
Van der Poll T, de Jonge E, Levi M, et al.
Regulatory role of cytokines in disseminated intravascular coagulation. Semin Thromb Haemost 2004; 27
Abraham E, Reinhart K, Opal S, et al.
Efficacy and safety of tifacogin (recombinant tissue factor pathway inhibitor) in severe sepsis: a randomized controlled trial. J Am Med Assoc 2003; 290
Lusis AJ, Libby P, Aikawa M, et al.
Atherosclerosis. Stabilization of atherosclerotic plaque: new mechanisms and clinical targets. Nat Med 2002; 8
Bergmann K, Sypniewska G. Is there an association of allergy and cardiovascular disease? Biochem Med 2011; 21
Levey AS, Atkins R, Coresh J, et al.
Chronic kidney disease as a global public health problem: approaches and initiatives: a position statement from Kidney Disease Improving Global Outcomes. Kidney Int 2007; 72
Whaley-Connell AT, Sowers JR, Stevens LA, et al.
Kidney Early Evaluation Program Investigators. CKD in the United States: Kidney Early Evaluation Program (KEEP) and National Health and Nutrition Examination Survey (NHANES) 1999-2004. Am J Kidney Dis 2008; 51
Hrafnkelsdo´ ttir T, Ottosson P, Gudnason T, et al.
Impaired endothelial release of tissue-type plasminogen activator in patients with chronic kidney disease and hypertension. Hypertension 2004; 44
Watala C. Blood platelet reactivity and its pharmacological modulation in (people with) diabetes mellitus. Curr Pharm Des 2005; 11
De Vriese AS, Verbeuren TJ, Van de Voorde J, et al.
Endothelial dysfunction in diabetes. Br J Pharmacol 2000; 130
Afeltra A Vadacca M, Conti L et al.
Thrombosis in systemic lupus erythematosus: congenital and acquired risk factors. Arthritis Rheum 2005; 53
Sarabi EZ, Chang S, Bobba R, et al.
Incidence rates of arterial and venous thrombosis after diagnosis of systemic lupus erythematosus. Arthritis Rheum 2005; 53
Romero-D´ýaz J, Garc´ýa-Sosa I, ´Anchez-Guerrero JS. Thrombosis in systemic lupus erythematosus and other autoimmune diseases of recent onset. J Rheumatol 2009; 36
Cervera R, Khamashta MA, Font J, et al.
Morbidity and mortality in systemic lupus erythematosus during a 10-year period: a comparison of early and late manifestations in a cohort of 1000 patients. Medicine (Baltimore) 2003; 82
Manger K, Manger B, Repp R, et al.
Definition of risk factors for death, end stage renal disease, and thromboembolic events in a monocentric cohort of 338 patients with systemic lupus erythematosus. Ann Rheum Dis 2002; 61
Esmon CT. Is APC activation of endothelial cell PAR1 important in severe sepsis?: No J Thromb Haemost 2005; 3
Danese S, Papa A, Saibeni S. Inflammation and coagulation in inflammatory bowel disease: the clot thickens. Am J Gastroenterol 2007; 102