sarcoidosis is a systemic disease of unknown etiology with systemic inflammation leading to formation of granulomas .
macrophages and activated lymphocytes , an immunological hallmark of sarcoidosis , are also involved in the process of thrombin activation and fibrin formation [ 2 , 3 ] .
the association between sarcoidosis and venous thromboembolism ( vte ) has been reported recently [ 4 , 5 ] , nevertheless it is still not clear if sarcoidosis is a risk factor for vte .
thus , the aim of the present study was to describe possible mechanisms that could be responsible for the increased occurrence of vte in sarcoidosis .
a higher risk of pulmonary embolism ( pe ) in sarcoidosis patients has been reported recently , according to data from the uk , with a risk ratio of 2.0 ( 95% ci : 1.1 - 3.4 ) , in patients under 65 years of age , comparing to a reference cohort .
swigris et al . found pe in 2.5% of us decedents with sarcoidosis , regardless of gender , race or age . in the retrospective analysis of clinical outcome and comorbidities among 798 sarcoidosis patients who have been hospitalized in the 2 pulmonary department of our institution between 2004 and 2014
the mechanisms that could predispose sarcoidosis patients to the development of vte may be related to several factors : activity of inflammation , clinical picture of sarcoidosis or comorbidities .
a close anatomic relation between the site of active sarcoidosis and thrombus formation was described in the literature : mural thrombus in myocardial sarcoidosis , cerebral vein thrombosis in neurosarcoidosis [ 79 ] , thoracic vein thrombosis in mediastinal sarcoidosis [ 1012 ] , portal vein hypertension in hepatic sarcoidosis , suggesting the local hypercoagulability status as the cause of thrombosis .
local hypercoagulability might have been the consequence of active granulomatous inflammation with an increased concentration of inflammatory markers [ 1419 ] .
we have found recently features of disease activity : elevated crp , esr , and ace , monocytosis and hypergammaglobulinemia in our patients with sarcoidosis who developed vte ( unpublished data ) .
nonspecific hypergammaglobulinemia reflecting the b cell activation , which is observed in the active disease may indicate a more generalized inflammatory process , although the definitive role for humoral immunity in the pathogenesis of sarcoidosis is not established . the regulatory influence of cytokines produced by local mononuclear phagocytes results in granulomatous inflammation in sarcoidosis patients [ 3 , 21 , 22 ] .
demonstrated that peripheral blood monocytes incubated with highly purified ( > 90% ) human crp for 6 hours present a significant increase in the tissue factor ( tf ) expression and acquire a significant pro - coagulant activity .
the same phenomenon might be responsible for the increased pro - coagulant ability of granulomatous inflammation in sarcoidosis . in sarcoidosis patients ,
as compared to normal control subjects , an enhanced activity of bal fluid tf and plasma factor vii were found .
only patients with stage ii or stage iii disease had a consistently elevated procoagulant activity that corresponded to the site most involved radiographically .
found that dd plasma levels correlate with activation of the proinflammatory cytokine cascade [ interleukin ( il)-6 , il-8 , tumor necrosis factor  ( tnf- ) but not with il-10 .
tumor necrosis factor  ( tnf- ) is a key cytokine in the pathogenesis of sarcoidosis and may indicate the activity of the disease [ 26 , 27 ] .
elevated tnf- concentration in active sarcoidosis might be responsible for the increased risk of vte .
locally derived il-6 and il-8 were increased in sarcoidosis and correlated with activity of this granulomatous lung disease .
interleukin 10 , an anti - inflammatory cytokine , expresses protective potential against venous thrombosis [ 14 , 28 ] .
a down - modulating mechanism resulting in the spontaneous resolution of sarcoid alveolitis is partially controlled by an increased local secretion of il-10 .
the question whether an increased il-10 concentration is combined with the protection against vte in sarcoidosis , needs further investigations .
the risk factor for the development of vte in sarcoidosis might be related to clinical characteristics such as : compression of pulmonary arteries by the enlarged mediastinal lymph nodes . nevertheless , according to the literature
, mediastinal lymphadenopathy was combined rather with thoracic vein thrombosis than pulmonary artery thrombosis [ 1012 ] .
patients with chronic disabling sarcoidosis on steroid therapy ( resulting in immobilization because of pulmonary fibrosis , pulmonary hypertension , osteoporosis with fractures , obesity etc . ) should be at the highest risk of vte .
nevertheless , our own experience indicates that sarcoidosis patients in whom vte was recognized , recruited from a group with active stage ii sarcoidosis , receiving no treatment at the time of this complication , and not disabled otherwise .
in recently recognized three cases of pe in the course of sarcoidosis we have found some similarities .
all of them concerned middle - aged , non - smoking males with active sarcoidosis according to international consensus .
none of them had severe disabling sarcoidosis with respiratory insufficiency at the time of pe development .
none of our patients suffered from pulmonary hypertension prior to pe diagnosis and no - one was on immunosuppressive treatment .
no clinically significant organ involvement was seen although in one case splenomegaly and peripheral lymph nodes sarcoidosis were diagnosed .
extrinsic arterial compression at a mediastinal or hilar level was not diagnosed in pulmonary angiography . as the histopathological diagnosis
was based on fine needle biopsy , it was impossible to conclude about the presence of vascular granulomata as a risk factor for local thrombosis [ 13 , 32 ] . in all our cases ,
the vte had favorable course with no serious late complications . in all cases we observed favorable course of pulmonary sarcoidosis with no impact on pft and exercise ability . regarding some similarities in the clinical picture of sarcoidosis in our set of patients
, we hypothesized that there might exist a prothrombotic phenotype of sarcoidosis , probably related rather to the inflammatory process than to clinical characteristics of patients .
nevertheless , swigris et al . found that sarcoidosis decedents with pe were even less likely than those without pe to have certain other conditions predisposing to pe , including myocardial infarction or ischemia , congestive heart failure , cardiomyopathy , cardiac dysrhythmia , sudden cardiac death , pneumonia or stroke contributing to death .
 one of the diagnostic criteria for antiphospholipid syndrome ( aps )  which by definition are characterized by recurrent thromboembolic events , were detected in 38% of sarcoidosis patients .
the presence of antiphospholipid antibodies was associated with extra - thoracic lesions and persistence of abnormal radiological findings in sarcoidosis , and were judged by the authors to be a useful marker for prolonged disease .
the authors did not search for vte occurrence in that group of sarcoidosis patients , although they should be considered at a high risk of such events .
on the other hand , in numerous case reports concerning sarcoidosis complicated by vte , the level of antiphospholipid antibodies was not examined [ 610 , 13 ] .
thus , so far it has been impossible to conclude based on the literature whether the increased risk of vte in sarcoidosis is combined with the presence of aps . in our group of patients with sarcoidosis complicated by vte
nevertheless , at least 50% of thrombotic episodes in individuals with factor v leiden mutation are provoked by additional predisposing factors . to the best of our knowledge ,
only one case of sarcoidosis with factor v leiden mutation , presenting with cerebral venous thrombosis was described in the literature .
authors concluded that since most factor v leiden gene heterozygous individuals do not develop clinical thrombosis , the venous thrombosis of their patient suggested convergence of an inherited predisposition ( heterozygous factor v leiden mutation ) with an acquired thrombogenic stimulus ( sarcoidosis ) .
we have recently described a case of sarcoidosis complicated by pe in a sarcoidosis patient , in whom subsequently congenital factor v leiden mutation was found ( data not published ) .
we observed the favorable course of pulmonary sarcoidosis ( total resolution of chest lymphadenopathy ) with no impact on pft and exercise ability during anticoagulation therapy in our patient with pe .
a persistent disappearance of the pulmonary infiltrates in the patient with sarcoidosis during anticoagulant treatment for venous thrombosis has already been observed .
unfractionated heparin ( ufh ) and lmwh proved to have the anti - inflammatory properties .
a close anatomic relation between the site of active sarcoidosis and thrombus formation was described in the literature : mural thrombus in myocardial sarcoidosis , cerebral vein thrombosis in neurosarcoidosis [ 79 ] , thoracic vein thrombosis in mediastinal sarcoidosis [ 1012 ] , portal vein hypertension in hepatic sarcoidosis , suggesting the local hypercoagulability status as the cause of thrombosis .
local hypercoagulability might have been the consequence of active granulomatous inflammation with an increased concentration of inflammatory markers [ 1419 ] .
we have found recently features of disease activity : elevated crp , esr , and ace , monocytosis and hypergammaglobulinemia in our patients with sarcoidosis who developed vte ( unpublished data ) .
nonspecific hypergammaglobulinemia reflecting the b cell activation , which is observed in the active disease may indicate a more generalized inflammatory process , although the definitive role for humoral immunity in the pathogenesis of sarcoidosis is not established . the regulatory influence of cytokines produced by local mononuclear phagocytes results in granulomatous inflammation in sarcoidosis patients [ 3 , 21 , 22 ] .
demonstrated that peripheral blood monocytes incubated with highly purified ( > 90% ) human crp for 6 hours present a significant increase in the tissue factor ( tf ) expression and acquire a significant pro - coagulant activity .
the same phenomenon might be responsible for the increased pro - coagulant ability of granulomatous inflammation in sarcoidosis . in sarcoidosis patients ,
as compared to normal control subjects , an enhanced activity of bal fluid tf and plasma factor vii were found .
only patients with stage ii or stage iii disease had a consistently elevated procoagulant activity that corresponded to the site most involved radiographically .
found that dd plasma levels correlate with activation of the proinflammatory cytokine cascade [ interleukin ( il)-6 , il-8 , tumor necrosis factor  ( tnf- ) but not with il-10 .
tumor necrosis factor  ( tnf- ) is a key cytokine in the pathogenesis of sarcoidosis and may indicate the activity of the disease [ 26 , 27 ] .
elevated tnf- concentration in active sarcoidosis might be responsible for the increased risk of vte .
locally derived il-6 and il-8 were increased in sarcoidosis and correlated with activity of this granulomatous lung disease .
interleukin 10 , an anti - inflammatory cytokine , expresses protective potential against venous thrombosis [ 14 , 28 ] .
a down - modulating mechanism resulting in the spontaneous resolution of sarcoid alveolitis is partially controlled by an increased local secretion of il-10 .
the question whether an increased il-10 concentration is combined with the protection against vte in sarcoidosis , needs further investigations .
the risk factor for the development of vte in sarcoidosis might be related to clinical characteristics such as : compression of pulmonary arteries by the enlarged mediastinal lymph nodes . nevertheless ,
according to the literature , mediastinal lymphadenopathy was combined rather with thoracic vein thrombosis than pulmonary artery thrombosis [ 1012 ] .
patients with chronic disabling sarcoidosis on steroid therapy ( resulting in immobilization because of pulmonary fibrosis , pulmonary hypertension , osteoporosis with fractures , obesity etc . ) should be at the highest risk of vte .
nevertheless , our own experience indicates that sarcoidosis patients in whom vte was recognized , recruited from a group with active stage ii sarcoidosis , receiving no treatment at the time of this complication , and not disabled otherwise . in recently recognized three cases of pe in the course of sarcoidosis we have found some similarities .
all of them concerned middle - aged , non - smoking males with active sarcoidosis according to international consensus .
none of them had severe disabling sarcoidosis with respiratory insufficiency at the time of pe development .
none of our patients suffered from pulmonary hypertension prior to pe diagnosis and no - one was on immunosuppressive treatment .
no clinically significant organ involvement was seen although in one case splenomegaly and peripheral lymph nodes sarcoidosis were diagnosed .
extrinsic arterial compression at a mediastinal or hilar level was not diagnosed in pulmonary angiography . as the histopathological diagnosis was based on fine needle biopsy , it was impossible to conclude about the presence of vascular granulomata as a risk factor for local thrombosis [ 13 , 32 ] . in all our cases ,
the vte had favorable course with no serious late complications . in all cases we observed favorable course of pulmonary sarcoidosis with no impact on pft and exercise ability . regarding some similarities in the clinical picture of sarcoidosis in our set of patients
, we hypothesized that there might exist a prothrombotic phenotype of sarcoidosis , probably related rather to the inflammatory process than to clinical characteristics of patients .
nevertheless , swigris et al . found that sarcoidosis decedents with pe were even less likely than those without pe to have certain other conditions predisposing to pe , including myocardial infarction or ischemia , congestive heart failure , cardiomyopathy , cardiac dysrhythmia , sudden cardiac death , pneumonia or stroke contributing to death .
 one of the diagnostic criteria for antiphospholipid syndrome ( aps )  which by definition are characterized by recurrent thromboembolic events , were detected in 38% of sarcoidosis patients .
the presence of antiphospholipid antibodies was associated with extra - thoracic lesions and persistence of abnormal radiological findings in sarcoidosis , and were judged by the authors to be a useful marker for prolonged disease .
the authors did not search for vte occurrence in that group of sarcoidosis patients , although they should be considered at a high risk of such events .
on the other hand , in numerous case reports concerning sarcoidosis complicated by vte , the level of antiphospholipid antibodies was not examined [ 610 , 13 ] .
thus , so far it has been impossible to conclude based on the literature whether the increased risk of vte in sarcoidosis is combined with the presence of aps . in our group of patients with sarcoidosis complicated by vte
nevertheless , at least 50% of thrombotic episodes in individuals with factor v leiden mutation are provoked by additional predisposing factors . to the best of our knowledge ,
only one case of sarcoidosis with factor v leiden mutation , presenting with cerebral venous thrombosis was described in the literature .
authors concluded that since most factor v leiden gene heterozygous individuals do not develop clinical thrombosis , the venous thrombosis of their patient suggested convergence of an inherited predisposition ( heterozygous factor v leiden mutation ) with an acquired thrombogenic stimulus ( sarcoidosis ) .
we have recently described a case of sarcoidosis complicated by pe in a sarcoidosis patient , in whom subsequently congenital factor v leiden mutation was found ( data not published ) .
we observed the favorable course of pulmonary sarcoidosis ( total resolution of chest lymphadenopathy ) with no impact on pft and exercise ability during anticoagulation therapy in our patient with pe . a persistent disappearance of the pulmonary infiltrates in the patient with sarcoidosis during anticoagulant treatment for venous thrombosis has already been observed .
unfractionated heparin ( ufh ) and lmwh proved to have the anti - inflammatory properties .
pulmonary embolism should be considered in all patients with sarcoidosis and worsening respiratory symptoms in presence of a high plasma dd level although elevated plasma dd should be interpreted in the context of an active inflammatory process . in our opinion ,
an increased risk of vte in sarcoidosis patients may depend mostly on a procoagulative phenotype related to the activity of inflammation .
 the association between venous thromboembolism ( vte ) and sarcoidosis has been reported recently , nevertheless the true incidence of co - incident sarcoidosis and vte is unknown . 
 sarcoidosis as a chronic disease of immune dysregulation might be associated with an increased risk of vte . 
 the mechanisms responsible for vte development are not clear and may be influenced by several factors : activity of inflammation , clinical characteristics of sarcoidosis and comorbidities . 
 pulmonary embolism ( pe ) as a potentially fatal condition should be considered in all of the patients with sarcoidosis in whom worsening of the respiratory status is diagnosed . 
 a high plasma d - dimers ( dd ) level may be suggestive of vte , nevertheless elevated plasma dd should be interpreted with caution , in the context of the active inflammatory process . 
 if sarcoidosis appears to be one of risk factors for vte development , further investigations are needed to define the pro - thrombotic phenotype of this disease . 
Introduction
Epidemiology
Possible mechanisms involved
Inflammatory profile
Clinical characteristics
Comorbidities
Conclusions
None