Adverse effects of glucocorticoids: coagulopathy

in European Journal of Endocrinology

Hypercortisolism is associated with various systemic manifestations, including central obesity, arterial hypertension, glucose intolerance/diabetes mellitus, dyslipidemia, nephrolithiasis, osteoporosis, gonadal dysfunction, susceptibility to infections, psychiatric disorders, and hypercoagulability. The activation of the hemostatic system contributes to the development of atherosclerosis and subsequent cardiovascular morbidity and mortality. Previous studies have identified an increased risk of both unprovoked and postoperative thromboembolic events in patients with endogenous and exogenous Cushing's syndrome (CS). The risk for postoperative venous thromboembolism in endogenous CS is comparable to the risk after total hip or knee replacement under short-term prophylaxis. The mechanisms that are involved in the thromboembolic complications in hypercortisolism include endothelial dysfunction, hypercoagulability, and stasis (Virchow's triad). It seems that at least two factors from Virchow's triad must be present for the occurrence of a thrombotic event in these patients. Most studies have demonstrated that this hypercoagulable state is explained by increased levels of procoagulant factors, mainly factors VIII, IX, and von Willebrand factor, and also by an impaired fibrinolytic capacity, which mainly results from an elevation in plasminogen activator inhibitor 1. Consequently, there is a shortening of activated partial thromboplastin time and increased thrombin generation. For these reasons, anticoagulant prophylaxis might be considered in patients with CS whenever they have concomitant prothrombotic risk factors. However, multicenter studies are needed to determine which patients will benefit from anticoagulant therapy and the dose and time of anticoagulation.

Abstract

Hypercortisolism is associated with various systemic manifestations, including central obesity, arterial hypertension, glucose intolerance/diabetes mellitus, dyslipidemia, nephrolithiasis, osteoporosis, gonadal dysfunction, susceptibility to infections, psychiatric disorders, and hypercoagulability. The activation of the hemostatic system contributes to the development of atherosclerosis and subsequent cardiovascular morbidity and mortality. Previous studies have identified an increased risk of both unprovoked and postoperative thromboembolic events in patients with endogenous and exogenous Cushing's syndrome (CS). The risk for postoperative venous thromboembolism in endogenous CS is comparable to the risk after total hip or knee replacement under short-term prophylaxis. The mechanisms that are involved in the thromboembolic complications in hypercortisolism include endothelial dysfunction, hypercoagulability, and stasis (Virchow's triad). It seems that at least two factors from Virchow's triad must be present for the occurrence of a thrombotic event in these patients. Most studies have demonstrated that this hypercoagulable state is explained by increased levels of procoagulant factors, mainly factors VIII, IX, and von Willebrand factor, and also by an impaired fibrinolytic capacity, which mainly results from an elevation in plasminogen activator inhibitor 1. Consequently, there is a shortening of activated partial thromboplastin time and increased thrombin generation. For these reasons, anticoagulant prophylaxis might be considered in patients with CS whenever they have concomitant prothrombotic risk factors. However, multicenter studies are needed to determine which patients will benefit from anticoagulant therapy and the dose and time of anticoagulation.

Invited Author's profile

Mônica Gadelha MD, PhD, is Professor of Endocrinology at the Medical School, the Universidade Federal do Rio de Janeiro (UFRJ), and she directs the Neuroendocrine Research Center at the Hospital Universitário Clementino Fraga Filho, UFRJ. Dr Gadelha also heads the Neuroendocrine Section at the Instituto Estadual do Cérebro Paulo Niemeyer. She is a board member of the Department of Neuroendocrinology, Brazilian Society of Endocrinology and Metabolism, as well as a researcher at Brazil's Conselho Nacional de Desenvolvimento Cientifico e Tecnológico. Her major research interests include the molecular pathogenesis, diagnosis, and treatment of pituitary tumors.

Introduction

Patients with chronic hypercortisolism present a variety of systemic manifestations that are associated with increased cardiovascular risk, such as abdominal adiposity, arterial hypertension, insulin resistance/impaired glucose tolerance/diabetes mellitus (DM), dyslipidemia, and hypercoagulability (1, 2, 3).

The mortality rates in Cushing's syndrome (CS) are about two times higher than those in the general population, whereas the mortality from cardiovascular diseases (CVDs) is even higher (3). Myocardial infarction, cerebrovascular disease, congestive heart failure, and venous thromboembolism (VTE) appear to be the main causes of mortality (4).

Recent clinical studies have indicated various abnormalities in coagulation and fibrinolysis parameters in patients with endogenous (5, 6, 7) and exogenous hypercortisolism (8, 9, 10) that contribute to the development of thromboembolic events, atherosclerosis (11), and subsequent cardiovascular morbidity and mortality (12, 13, 14).

A literature review was undertaken from July 2013 to December 2014, and it comprised of studies that evaluated the abnormalities of coagulation and fibrinolysis parameters in patients with CS. Several studies have assessed hemostatic parameters in CS since the early 1950s (15). Nevertheless, only articles that were written in English, original studies, review articles, and current guidelines were included. Case reports, in vitro studies, and animal model experiments were excluded.

Clinical data on the association between exogenous glucocorticoids (GC) and VTE are sparse, and these studies have focused on specific populations. Although patients that receive GC therapy usually suffer from a primary disease that may have a negative influence on coagulation, endogenous CS is not associated with an underlying primary condition that is known to directly affect the risk of thrombosis. Moreover, in studies on GC use and VTE risk in the general population, no data on patient compliance regarding prescribed GC are available. Thus, endogenous CS is a suitable clinical model for investigating the pure effects of cortisol excess on hemostasis, attenuating other confounding factors. The vast majority of the studies that were included in the present review describe the association between endogenous hypercortisolism and hypercoagulability.

The aim of the present review is to report the alterations in the coagulation system in patients with endogenous and exogenous CS, to outline their potential clinical consequences, and to discuss anticoagulant prophylaxis.

Physiology of coagulation and fibrinolysis

Primary hemostasis: platelet activation

When the endothelium is damaged, the underlying collagen is exposed to circulating platelets that bind directly to collagen through collagen-specific glycoprotein (GP) Ia/IIa surface receptors. This adhesion is further strengthened by von Willebrand factor (vWF), which is released from the endothelium and from the platelets. The vWF forms additional links between the platelets, GP Ib, and collagen fibrils. These interactions also activate the platelets. Activated platelets release into the plasma ADP, serotonin, platelet activation factor (PAF), vWF, platelet factor 4, and thromboxane A2 (TXA2). These factors in turn activate additional platelets. The activated platelets change shape from spherical to stellatem and the fibrinogen cross-links with GP IIb/IIIa, which aids in the aggregation of adjacent platelets (Fig. 1) (16).

Figure 1
Figure 1

Platelet adhesion and aggregation. After endothelium damage, platelets adhere to subendothelial collagen through the glycoprotein Ia/IIa with the aid of vWF, which binds to the glycoprotein Ib and leads to platelet activation. Once activated, platelets clump together via GPIIb/IIIa, forming bridges with the fibrinogen. vWF, von Willebrand factor; GPIb, glycoprotein Ib; GPIIb/IIIa, glycoprotein IIb/IIIa; GPIa/IIa, glycoprotein Ia/IIa. Blue, platelet; orange, GPIa/IIa; green, vWF; dashed gray lines, GPIb; yellow, GPIIb/IIIa; blue line with black ball in middle, fibrinogen.

Citation: European Journal of Endocrinology 173, 4; 10.1530/EJE-15-0198

Secondary hemostasis: the coagulation cascade

Coagulation is the process by which blood forms fibrin clots. There are two important pathways that lead to fibrin formation: the extrinsic pathway and the intrinsic pathway. The extrinsic pathway is initiated after tissue factor (TF) expression, a process that occurs after vascular injury. The TF binds to factor VII in the presence of ionized calcium, which results in the activation of factor VII (VIIa). The TF–factor VIIa complex activates factor IX to factor IXa and factor X to factor Xa. Furthermore, this complex activates additional factor VII (Fig. 2) (17).

Figure 2
Figure 2

Extrinsic pathway. Factor VII, after tissue injury, binds to TF in the presence of ionized calcium, which results in the formation of activated factor VII (VIIa). The FT–VIIa complex activates factors IX and X, which results in the activation of more factor VII. FVII, factor VII; FVIIa, activated factor VII; TF, tissue factor; FIX, factor IX; FX, factor X; FIXa, activated factor IX; FXa, activated factor X. The activated factors FVIIa, FIXa, and FXa are represented by the colors gray green, and purple respectively.

Citation: European Journal of Endocrinology 173, 4; 10.1530/EJE-15-0198

In the intrinsic pathway, contact activation stimulates the formation of factor XIIa from factor XII in the presence of high-molecular-weight kininogen and kallicrein. Factor XIIa converts factor XI into factor XIa, which activates factor IX. Factor IXa, in the presence of its cofactor VIIIa and ionized calcium, activates factor X (Fig. 3) (18).

Figure 3
Figure 3

Intrinsic pathway. Collagen expresses HMWK, which contributes to the activation of factor XII into factor XIIa. FXIIa activates factor XI, which activates factor IX. FIXa activates FX in the presence of calcium and factor VIIIa. HMWK, high-molecular-weight kininogen; FXII, factor XII; FXIIa, activated factor XII; PK, kallicrein; Ka, kallicrein activated; FXI, factor XI; FXIa, activated factor XI; FIX, factor IX; FIXa, activated factor IX; FX, factor X; FXa, activated factor X. The activated factors FXIIa, FXIa, FIXa, and FXa are represented by the colors yellow, blue, green, and purple respectively.

Citation: European Journal of Endocrinology 173, 4; 10.1530/EJE-15-0198

The final common pathway initiates when the factor Xa–factor Va complex, in the presence of ionized calcium, activates factor II (prothrombin) to factor IIa (thrombin), whose primary role is the conversion of fibrinogen (factor I) to fibrin. The fibrin monomers group to form the clot, which is stabilized by factor XIIIa (Fig. 4). Thrombin is responsible for the activation of factors V, VIII, and XIII.

Figure 4
Figure 4

The factor Xa converts prothrombin (factor II) into thrombin (factor IIa) in the presence of ionized calcium and factor Va. Thrombin converts fibrinogen to fibrin, which when stabilized by factor XIII forms the clot. FXa, activated factor X; FII, factor II; FVa, activated factor V; FIIa, activated factor II; FXIII, factor XIII. The FXa, FIIa, and fibrin connections are represented by the colors purple, green, and yellow respectively.

Citation: European Journal of Endocrinology 173, 4; 10.1530/EJE-15-0198

Factors that inhibit fibrin formation include antithrombin (AT), TF pathway inhibitor (TFPI), protein C (PC), and protein S (PS). AT is a protease inhibitor that degrades thrombin, factors IXa, Xa, and Xia, and TF-bound factor VIIa. TFPI is a protein that is produced by endothelial cells that inhibit the TF–factor VIIa complex and factors IXa and Xa. PS is a cofactor to PC, which degrades factors Va and VIIIa (Fig. 5) (19).

Figure 5
Figure 5

The endogenous anticoagulants are TFPI, AT, and PC. AT inhibits thrombin, TF–VIIa, IXa, Xa, and XIa. TFPI inhibits all of the coagulation factors that are inhibited by thrombin, except for factor XIa. Protein C inhibits factors Va and VIIIa. TFPI, tissue factor pathway inhibitor; PC, protein C; AT, antithrombin; FXII, factor XII; FXIIa, activated factor XII; FXI, factor XI; FXIa, activated factor XI; FIX, factor IX; FIXa, activated factor IX; FVIIIa, activated factor VIII; FXa, activated factor X; FVIIa, activated factor VII; TF, tissue factor; FVa, activated factor V; FII, factor II; FIIa, activated factor II.

Citation: European Journal of Endocrinology 173, 4; 10.1530/EJE-15-0198

Fibrinolysis

During fibrinolysis, a fibrin clot, the product of coagulation, is broken down, and the enzyme that is responsible for this process is plasmin. Fibrinolysis is initiated when tissue plasminogen activator (tPA) and urokinase-type plasminogen activator convert plasminogen to plasmin. Plasmin, in turn, dissolves the fibrin complex. When this dissolution occurs, a number of soluble parts of fibrin are produced. These parts are called fibrin degradation products (FDP); one of these parts is called D-dimers. The FDP compete with thrombin and thus slow down clot formation by preventing the conversion of fibrinogen to fibrin.

Factors that inhibit fibrinolysis include plasminogen activator inhibitor 1 (PAI1), thrombin activatable fibrinolysis inhibitor (TAFI) and α2-antiplasmin. PAI1 inhibits tPA, α2-antiplasmin inactivates plasmin, and TAFI modifies fibrin to make it more resistant to the tPA-mediated plasminogen action (Fig. 6) (20).

Figure 6
Figure 6

Fibrinolysis. Once the clot is formed, the endothelium releases tPA, which converts plasminogen into plasmin. Plasmin degrades the fibrin into smaller fragments called FDP, which are cleared by macrophages. At the end of the process, plasmin is destroyed by α2-antiplasmin and tPa is destroyed by PAI1. The TAFI is able to make the fibrin resistant to clot lysis. PAI1, plasminogen activator inhibitor 1; tPA, tissue plasminogen activator; FXIII, factor XIII; TAFI, thrombin-activatable fibrinolysis inhibitor; FDP, fibrin degradation products. The fibrin connection, plasmin, FDP and macrophage are represented by the colors yellow, lilac, green, and red respectively.

Citation: European Journal of Endocrinology 173, 4; 10.1530/EJE-15-0198

Thromboembolic complications in CS: mechanisms

Thrombosis is frequently a multifactorial disease, and all three components of the Virchow triad (vascular abnormalities and endothelial dysfunction, hypercoagulability, and stasis) may play a role in the pathogenesis of the prothrombotic state in patients with CS (21).

Endothelial dysfunction

CS is associated with endothelial dysfunction, which significantly predisposes to an increased risk for CVD (21). Previous studies have observed decreased availability of nitric acid in patients with obesity (22), DM (23), hypertension (24), dyslipidemia (25), and insulin resistance (26), all of which are complications that are frequently associated with CS. Insulin regulates the balance between the levels of nitric acid and endothelin 1 by phosphatidylinositol 3-kinase (PI3K) and MAPK respectively. An impairment in these pathways takes place in individuals with insulin resistance, which leads to endothelial dysfunction through a lower production of nitric oxide and increased endothelin (26).

Prázny et al. (27) reported that patients with hypercortisolism have increased levels of intercellular adhesion molecule 1 and serum N-acetyl-β-glucosaminidase activity, which are markers of endothelial dysfunction. Furthermore, impaired microvascular reactivity is observed in these patients (27). Anagnostis et al. (28) reported that brachial artery flow-mediated dilatation is lower in CS patients than it is in healthy controls (29).

Hypercoagulability

Thromboembolic complications are observed in CS with elevations in the plasma levels of the procoagulant factors that apparently contribute to thrombosis (14, 30). Cortisol induces an increase in vWF; however, this increase depends on genetic characteristics present in the vWF gene promoter. Haplotype 1 (-3268G/-2709C/-2661A/2527G) mainly cosegregates with short GT repeats (15–19, GTs) and confers a greater risk of vWF up-regulation by cortisol than does haplotype 2 (-3268C/-2709T/-2661G/-2527A), which cosegregates with long repeats (GT ≥20, GTL). Therefore, in CS, the presence of haplotype 1 is associated with an increased risk of developing high vWF levels and a consequent hypercoagulable condition, whereas haplotype 2 correlates more frequently with normal vWF levels and thus protects against thrombotic complications (31).

Casonato et al. (5) reported that patients with CS not only had higher plasma levels of vWF, but they also exhibit unusually large vWF multimers, which may be evidence of endothelial dysfunction. The authors found an increase in the plasma levels of large vWF multimers in the immediate postoperative period, and the persistence of this increase was sporadically observed in cured patients (5).

Most of the studies that have evaluated the procoagulant factors in patients with hypercortisolism have found a decrease in PTT values (5, 6, 7, 14, 32, 33, 34, 35, 36, 37, 38) and an increase in the plasma levels of factors II (14, 34, 39), V (14, 34, 39), VIII (5, 7, 14, 30, 32, 34, 36, 37, 38, 39, 40), and IX (7, 14, 34, 39) (Table 1). The PTT is shortened, probably because of an increase in FVIII.The levels of FVIII may be influenced by the high levels of vWF, because the latter reduces the degradation of FVIII (41). In one systematic review, the authors observed that even after remission of hypercortisolism, vWF, VIII, and IX factors remained high (42).

Table 1

Alterations in coagulation and fibrinolysis in Cushing's syndrome.

Hemostatic parametersDal Bo Zanon et al.(39)Ikkala et al.(30)Patrassi et al.(7)Patrassi et al.(6)Casonato et al.(5)Fatti et al.(44)Boscaro et al.(32)Terzolo(33)Kastelan et al.(14)Erem et al.(35)Van der Pas et al.(36)Kastelan et al.(34)Koutroumpi et al.(40)Coelho et al.(37)Barbot et al.(38)
198219851985199219992000200220042009200920122013201320142014
n=15n=20n=9n=30n=20n=17n=313n=57n=33n=24n=17n=18n=58n=30n=78
aPTT
PTNS
PlateletNS
vWFNS
FII
FV
FVIINSNS
FVIII
FIX
FX
FXINS
FXIINS
FibrinogenNSNSNSNS
PCNS
PS
ATNS
TFPI
PlasminogenNSNS
tPA
α2-antiplasmin
PAI1NS
TAFINS

aPTT, activated partial thromboplastin time; PT, prothrombin time; vWF, von Willebrand factor; FII, factor II; FV, factor V; FVII, factor VII; FVIII, factor VIII; FIX, factor IX; FX, factor X; FXI, factor XI; FXII, factor XII; PC, protein C; PS, protein S; AT, antithrombin; TFPI, tissue factor pathway inhibitor; tPA, tissue plasminogen activator; PAI1, plasminogen activator inhibitor 1; TAFI, thrombin activatable fibrinolysis inhibitor; n, number of patients; NS, not significant. Blank means not evaluated.

With respect to endogenous anticoagulants, two studies found an increase in PS, PC, and AT plasma levels (14, 38). Moreover, an increase in the elements involved in the fibrinolytic pathway, such as plasminogen and tPA, was described (6, 7). This elevation in endogenous anticoagulants is probably secondary to the high levels of procoagulant factors, which represent a protective mechanism against hypercoagulability in these patients. However, an increase in factors that inhibit fibrinolysis, such as PAI1 (6, 14, 32, 34, 35, 36, 38), TAFI (36) and α2-antiplasmin (36, 43), was also reported, which demonstrates that the fibrinolytic pathway is also impaired in hypercortisolism.

The majority of the studies included in the present review were cross-sectional analyses of coagulation parameters in patients with CS vs healthy subjects, and they did not evaluate the presence of common comorbidities associated with CS, like arterial hypertension, DM, and smoking, which could lead to a hypercoagulable state (7, 30, 39, 44). It is also known that individuals with blood type O have lower values of vWF as compared to individuals with the blood types that are not O (45). However, only two studies matched the patients with CS and controls for ABO blood type (36, 37).

Recently, our group studied hemostatic and thromboelastometric parameters in 30 patients with active CS and in 30 control subjects matched for age, sex, BMI, DM, arterial hypertension, ABO blood group, and smoking (37). Rotation thromboelastometry was used to evaluate the intrinsic, extrinsic, and fibrinogen pathways. We demonstrated that only the beginning of clot formation (the intrinsic pathway) is altered, and we found increased plasma levels of FVIII, vWF, and D-dimer and decreased activated partial thromboplastin time in patients with active CS. In addition, we observed an increased clot formation speed and higher clot strength in obese CS patients as compared to non-obese CS patients (37).

Stasis

Venous thrombi frequently occur at regions of slow blood flow, such as large venous sinuses in the calf, the valve cusp pockets of the deep veins of the calf or thigh, or the parts of the veins that are exposed to external compression. The concentration of endogenous anticoagulants varies among vascular beds, and the major difference is determined by the ratio of the endothelial cell surface to the blood volume. The efficacy of natural anticoagulants is increased inside the microcirculation as compared to larger vessels. During stasis, blood increases its residence time in the large vessels, which increases the propensity for developing clots (46). Moreover, in CS patients, previous studies found increased hematocrit, and this alteration can lead to hyperviscosity, which results in reduced blood flow and predisposes to thromboembolic complications (21).

Clinical events that are related to the disturbance of coagulation and fibrinolysis in CS

We reviewed the occurrence of clinical events related to hypercoagulability in endogenous hypercortisolism in a total of 13 studies with 1356 patients with CS (1080 cases of Cushing's disease (CD), 234 cases of adrenal adenoma or hyperplasia, 21 cases of adrenal carcinoma, and 21 cases of ectopic CS). Of these patients, 8.9% had VTE, and 53% of the thromboembolic events were related to surgery, whereas VTE unrelated to surgery was reported in 44% of the patients with CS (9, 14, 15, 32, 36, 38, 39, 40, 47, 48, 49, 50, 51). VTE was reported as the cause of death in 11% (13/121) of the patients with CS. Only one retrospective study documented the occurrence of arterial thrombosis in four CS patients who were heavy smokers (15).

It is well known that patients with ectopic CS and adrenal carcinoma carry an additional risk of VTE related to malignancy, and they should therefore probably be discussed separately. The majority of the studies included patients with different etiologies of CS. It is recognized that the use of preoperative cortisol-lowering medications might prevent the occurrence of postoperative VTE by reducing the cortisol withdrawal syndrome that can trigger an inflammatory state, which results in an increase in acute-phase proteins like FVIII and fibrinogen (38). Of the 13 studies included, only four evaluated the use of ketoconazole before surgery (32, 36, 38, 51). Furthermore, as stated earlier in the present review, hypercoagulability in CS may be related to arterial hypertension, DM, obesity, and smoking. Only two studies that evaluated clinical outcomes of thrombosis compared groups matched for all of these risk factors (14, 40). In addition, most of the authors did not mention the time of deambulation after surgery or whether a replacement regimen was used until the assessment of the outcome of the surgical procedure; these factors may influence the risk of thrombosis.

Considering the studies that documented VTE related to surgery, few of them assessed inherited risk factors for thrombophilia (36, 40). Koutroumpi et al. (40) observed that most of the patients with VTE unrelated to surgery had at least four acquired risk factors among DM, hypertension, obesity, dyslipidemia, and infection and at least one inherited risk factor (such as factor V Leiden, prothrombin gene 20210A variants, or the genotype GCAG/GCAG of the vWF gene promoter region). These authors believed that high levels of vWF, inherited prothrombotic genetic characteristics, and acquired prothrombotic risk factors may act synergistically to trigger the VTE in patients with CS.

In a recent study, the increased risk for VTE (hazard ratio (HR) 2.6, 95% CI 1.5–4.7) in patients with CS was already present 3 years before the diagnosis (HR 8.4, 95% CI 3.0–23.4), highest 1 year after the diagnosis (HR 20.6, 95% CI 7.8–53.9), and still remained elevated 1–30 years after the diagnosis (HR 1.6, 95% CI 0.8–3.4) (3). Most of the cases occurred during persistent hypercortisolism or relapse (3). Table 2 summarizes the thromboembolic events in endogenous CS.

Table 2

Thromboembolic events in Cushing's syndrome.

AuthorPatients (n)Hemostatic parametersEvents (n)Time
DVTPEATDVT+PEUnrelated to surgeryRelated to surgery
Zanon et al. 1982 (39)15↑ FII, FV, FVIII, FIX, D-dimer22
Small et al. 1983 (15)5333a4a45
Fahlbusch et al. 1986 (47)1014b4b4
Semple & Laws 1999 (9)10544
Boscaro et al. 2002 (32)307↑ PT, FVIII, vWF, PAI1, fibrinogen ↓ aPTT18291118
Rees et al. 2002 (48)54123
Sudhakar et al. 2004 (49)2211
Kastelan et al. 2009 (14)33↑ FII, FV, FVIII, FIX, FXI, FXII, PC, PS, PAI1, plasminogen, AT ↓ aPTT123
Manetti et al. 2010 (50)40↑ FIX, PAI1, fibrinogen, AT, D-dimer, vWF, α-2antiplasmin ↓ aPTT2112
Stuijver et al. 2011 (51)473161562512
Van der Pas et al. 2012 (36)17↑ FVIII, fibrinogen, PS, α-2antiplasmin, PAI1, TAF1123
Koutroumpi et al. 2013 (40)58↑ vWF, FVIII8b8b53
Barbot et al. 2014 (38)78↑ PT, FVIII, vWF, AT, PC, PS, PAI1 ↓ aPTT1113
Total135665 (49%)49 (36%)4 (3%)16 (12%)53 (44%)68 (56%)

aPTT, activated partial thromboplastin time; PT, prothrombin time; vWF, von Willebrand factor; FII, factor II; FV, factor V; FVIII, factor VIII; FIX, factor IX; FXI, factor XI; FXII, factor XII; PC, protein C; PS, protein S; AT, antithrombin; PAI1, plasminogen activator inhibitor 1; TAFI, thrombin activatable fibrinolysis inhibitor; PE, pulmonary embolism; DVT, deep vein thrombosis; AT, arterial thrombosis; n, number of patients.

One patient: PE+AT.

VTE, venous thromboembolism.

Few studies have reported an association between exogenous GC and VTE. A recent case–control study (52) was performed with 38 765 VTE patients (53.7% women; median age 67 years) and 387 650 control individuals from the general population to evaluate the risk of VTE among GC users. They found 6696 cases of VTE (17%) related to GC in patients with risk factors for thrombosis, such as surgery, major trauma or fracture, and cancer, and 3177 cases (8.1%) in patients without risk factors. The authors considered different routes of administration of GC and subdivided the subjects into three groups according to when the patients had filled their most recent GC prescription: 90 days or less, 91–365 days, and more than 365 days before the date when VTE was diagnosed. Among the VTE cases, 61.2% had deep vein thrombosis, 38.8% had pulmonary embolism (PE), and 57.7% had unprovoked VTE. Patients who used oral GC showed a greater risk as compared to individuals who used the injectable form, and the risk was greater for prednisolone-equivalent cumulative doses from 1000 to 2000 mg. For systemic GC, the risk of VTE was higher among individuals who had a GC prescription for 90 days or less as compared to those who used GC 91–365 days before the date when VTE had been diagnosed. An association with VTE was not observed in patients who used GC for more than 365 days before the thrombosis. For inhaled GC, only individuals with first-ever prescription redemption within 90 days before VTE were associated with an increased VTE risk. Another study in 3550 VTE cases showed that the relative risk for VTE was 4.7 for 0–30 days of use of GC, but the risk decreased to 2.0 for more than 1 year of use (53).

Prophylaxis for thromboembolism in patients with CS

Of the 22 studies (5, 6, 7, 9, 14, 15, 30, 32, 33, 34, 35, 36, 37, 38, 39, 40, 44, 47, 48, 49, 50, 51) that evaluated hypercoagulability in CS, few of them assessed the risk of thromboembolism in patients who received thromboprophylaxis (32, 38, 51). Prophylactic treatment appeared to besafe, seeing as no case of bleeding was reported in patients during anticoagulant treatment (54).

Boscaro et al. (32) examined 307 patients with CS (203 patients with CD) and divided them into two groups: 75 patients who did not receive thromboprophylaxis after surgery and 232 patients who received unfractionated heparin (doses of 15 000–22 500 U/day for at least 2 weeks) and warfarin for at least 4 months. During follow-up, 15 patients (20%) in the first group and 14 (6%) in the second group showed thromboembolic complications, and most of these complications occurred within 3 months after the surgical procedure. Of these patients, eight patients from group 1 (10.7%) and one patient from group 2 (0.4%) died. The authors concluded that after the introduction of postoperative antithrombotic prophylaxis (group 2), the morbidity and mortality resulting from thromboembolic events dropped to 6% and 0.4% respectively.

Stuijver et al. (51) studied 473 patients with CS (353 patients with CD) and compared them to patients who were surgically treated for nonfunctioning pituitary adenoma, which allowed them to distinguish between the risk of VTE associated with cortisol overexposure and the risk resulting from the surgical procedure itself. The patients who had undergone surgery received thromboprophylaxis based on the recommendations that were used for surgical procedures at a low risk of VTE: dalteparin 2500 U/day or nadroparin 2850 U/day from the day of surgery or 1 day before surgery until mobilization or discharge (calparin or i.v. unfractionated heparin was used in 12 surgeries). Nineteen VTE events occurred before treatment, 12 occurred after surgery, and five occurred during cortisol-lowering treatment. None of the VTE events were fatal. In four out of 12 patients with postoperative VTE, the event occurred while they patient was receiving thromboprophylaxis, and most of the events occurred between 1 week and 2 months after surgery. The risk for postoperative VTE in patients with CS was 3.4% as compared to 0% for controls, and the risk was comparable with the risk after total hip or knee replacement under short-term prophylaxis (7–10 days). Based on these results, the authors recommended that thromboprophylaxis should be considered before starting treatment and mainly when additional risk factors for VTE are present. In patients with adrenocorticotrophin-dependent CS who undergo pituitary surgery, thromboprophylaxis should be extended to 10–35 days after surgery, which is comparable to surgical procedures for patients at a high risk for VTE.

Recently, Barbot et al. (38) studied 78 patients with CD who underwent pituitary transsphenoidal surgery, and they divided the patients into two groups: group A (34 patients) received fractionated heparin (nadroparin 3800 U/day or enoxaparin 4000 U/day) from the day after surgery until discharge or for a maximum of 14 days after surgery plus GC replacement therapy, and group B (44 patients) was treated with fractionated heparin (enoxaparin 4000–8000 U/day) for 30 days, starting 24 h after the surgical procedure, plus graduated elastic compression stockings, early ambulation, and no early GC replacement. Three cases of VTE were recorded in group A (all occurring within 30 days after surgery), and none were observed in group B. The authors concluded that the prevention of postoperative VTE with low-molecular-weight heparins for long-term, early mobilization and the use of graduated compression stockings are the best management practices in patients with CD, seeing as fatal PE can occur without warning signs. Furthermore, the occurrence of more cases of VTE in groups who received GC replacement before the assessment of the success of the surgical procedure raises the question of whether patients with persistent disease who receive GC unnecessarily may be at an even greater risk of VTE.

In conclusion, in order for thrombotic events in patients with CS to occur, the presence of at least two components from Virchow's triad (vascular abnormalities and endothelial dysfunction, hypercoagulability, and stasis) seems to be necessary. Studies recommend that thromboprophylaxis with low-molecular-weight heparin or low-dose unfractionated heparin should be used routinely in patients with CS who undergo transsphenoidal or adrenal surgery (open or laparoscopic) (42, 50). However, there is no consensus about the dose or duration of use of prophylactic anticoagulant therapy. Moreover, it is not clear whether thromboprophylaxis should be undertaken in patients with CS, either postoperatively or throughout the active disease. Multicenter prospective studies are needed to answer these important questions and to thereby reduce the morbidity and mortality associated with this disease.

Declaration of interest

The authors declare that there is no conflict of interest that could be perceived as prejudicing the impartiality of the review.

Funding

This research did not receive any specific grant from any funding agency in the public, commercial or not-for-profit sector.

Acknowledgements

This paper forms part of a special issue of European Journal of Endocrinology on Cushing's syndrome. This article is adapted from work presented at the IMPROCUSH-1: Improving Outcome of Cushing's Syndrome symposium, 12–14 October 2014. The meeting was supported by the European Science Foundation, Deutsche Forschungsgemeinschaft, Carl Friedrich von Siemens Stiftung, European Neuroendocrine Association and the Deutsche Gesellschaft fur Endokrinologie. The opinions or views expressed in this special issue are those of the authors, and do not necessarily reflect the opinions or recommendations of the European Science Foundation, Deutsche Forschungsgemeinschaft, Carl Friedrich von Siemens Stiftung, European Neuroendocrine Association and the Deutsche Gesellschaft fur Endokrinologie.

References

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  • 2

    FalloFSoninoN. Should we evaluate for cardiovascular disease in patients with Cushing's syndrome?Clinical Endocrinology200971768771. (doi:10.1111/j.1365-2265.2009.03610.x).

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    DekkersOMHorvath-PuhoEJorgensenJOCannegieterSCEhrensteinVVandenbrouckeJPPereiraAMSorensenHT. Multisystem morbidity and mortality in Cushing's syndrome: a cohort study. Journal of Clinical Endocrinology and Metabolism20139822772284. (doi:10.1210/jc.2012-3582).

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    ClaytonRNRaskauskieneDReulenRCJonesPW. Mortality and morbidity in Cushing's disease over 50 years in Stoke-on-Trent, UK: audit and meta-analysis of literature. Journal of Clinical Endocrinology and Metabolism201196632642. (doi:10.1210/jc.2010-1942).

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    • Export Citation
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    ManciniTKolaBManteroFBoscaroMArnaldiG. High cardiovascular risk in patients with Cushing's syndrome according to 1999 WHO/ISH guidelines. Clinical Endocrinology200461768777. (doi:10.1111/j.1365-2265.2004.02168.x).

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    • Export Citation
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    • Export Citation
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    SavageBShattilSJRuggeriZM. Modulation of platelet function through adhesion receptors. A dual role for glycoprotein IIb-IIIa (integrin α IIb β 3) mediated by fibrinogen and glycoprotein Ib-von Willebrand factor. Journal of Biological Chemistry19922671130011306.

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    • Export Citation
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    CollenD. The plasminogen (fibrinolytic) system. Thrombosis and Haemostasis199982259270.

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    MiljicPMiljicDCainJWKorbonitsMPopovicV. Pathogenesis of vascular complications in Cushing's syndrome. Hormones2012112130.

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    KimJAMontagnaniMChandrasekranSQuonMJ. Role of lipotoxicity in endothelial dysfunction. Heart Failure Clinics20128589607. (doi:10.1016/j.hfc.2012.06.012).

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    PraznyMJezkovaJHorovaELazarovaVHanaVKvasnickaJPecenLMarekJSkrhaJKrsekM. Impaired microvascular reactivity and endothelial function in patients with Cushing's syndrome: influence of arterial hypertension. Physiological Research2008571322.

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This article is adapted from work presented at IMPROCUSH-1, 12–14 October 2014. The meeting was supported by the European Science Foundation, Deutsche Forschungsgemeinschaft, Carl Friedrich von Siemens Stiftung, European Neuroendocrine Association and the Deutsche Gesellschaft für Endokrinologie. The opinions or views expressed in this article are those of the authors, and do not necessarily reflect the opinions or recommendations of the supporters of the symposium.

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  • View in gallery

    Platelet adhesion and aggregation. After endothelium damage, platelets adhere to subendothelial collagen through the glycoprotein Ia/IIa with the aid of vWF, which binds to the glycoprotein Ib and leads to platelet activation. Once activated, platelets clump together via GPIIb/IIIa, forming bridges with the fibrinogen. vWF, von Willebrand factor; GPIb, glycoprotein Ib; GPIIb/IIIa, glycoprotein IIb/IIIa; GPIa/IIa, glycoprotein Ia/IIa. Blue, platelet; orange, GPIa/IIa; green, vWF; dashed gray lines, GPIb; yellow, GPIIb/IIIa; blue line with black ball in middle, fibrinogen.

  • View in gallery

    Extrinsic pathway. Factor VII, after tissue injury, binds to TF in the presence of ionized calcium, which results in the formation of activated factor VII (VIIa). The FT–VIIa complex activates factors IX and X, which results in the activation of more factor VII. FVII, factor VII; FVIIa, activated factor VII; TF, tissue factor; FIX, factor IX; FX, factor X; FIXa, activated factor IX; FXa, activated factor X. The activated factors FVIIa, FIXa, and FXa are represented by the colors gray green, and purple respectively.

  • View in gallery

    Intrinsic pathway. Collagen expresses HMWK, which contributes to the activation of factor XII into factor XIIa. FXIIa activates factor XI, which activates factor IX. FIXa activates FX in the presence of calcium and factor VIIIa. HMWK, high-molecular-weight kininogen; FXII, factor XII; FXIIa, activated factor XII; PK, kallicrein; Ka, kallicrein activated; FXI, factor XI; FXIa, activated factor XI; FIX, factor IX; FIXa, activated factor IX; FX, factor X; FXa, activated factor X. The activated factors FXIIa, FXIa, FIXa, and FXa are represented by the colors yellow, blue, green, and purple respectively.

  • View in gallery

    The factor Xa converts prothrombin (factor II) into thrombin (factor IIa) in the presence of ionized calcium and factor Va. Thrombin converts fibrinogen to fibrin, which when stabilized by factor XIII forms the clot. FXa, activated factor X; FII, factor II; FVa, activated factor V; FIIa, activated factor II; FXIII, factor XIII. The FXa, FIIa, and fibrin connections are represented by the colors purple, green, and yellow respectively.

  • View in gallery

    The endogenous anticoagulants are TFPI, AT, and PC. AT inhibits thrombin, TF–VIIa, IXa, Xa, and XIa. TFPI inhibits all of the coagulation factors that are inhibited by thrombin, except for factor XIa. Protein C inhibits factors Va and VIIIa. TFPI, tissue factor pathway inhibitor; PC, protein C; AT, antithrombin; FXII, factor XII; FXIIa, activated factor XII; FXI, factor XI; FXIa, activated factor XI; FIX, factor IX; FIXa, activated factor IX; FVIIIa, activated factor VIII; FXa, activated factor X; FVIIa, activated factor VII; TF, tissue factor; FVa, activated factor V; FII, factor II; FIIa, activated factor II.

  • View in gallery

    Fibrinolysis. Once the clot is formed, the endothelium releases tPA, which converts plasminogen into plasmin. Plasmin degrades the fibrin into smaller fragments called FDP, which are cleared by macrophages. At the end of the process, plasmin is destroyed by α2-antiplasmin and tPa is destroyed by PAI1. The TAFI is able to make the fibrin resistant to clot lysis. PAI1, plasminogen activator inhibitor 1; tPA, tissue plasminogen activator; FXIII, factor XIII; TAFI, thrombin-activatable fibrinolysis inhibitor; FDP, fibrin degradation products. The fibrin connection, plasmin, FDP and macrophage are represented by the colors yellow, lilac, green, and red respectively.

  • 1

    ArnaldiGAngeliAAtkinsonABBertagnaXCavagniniFChrousosGPFavaGAFindlingJWGaillardRCGrossmanAB. Diagnosis and complications of Cushing's syndrome: a consensus statement. Journal of Clinical Endocrinology and Metabolism20038855935602. (doi:10.1210/jc.2003-030871).

    • Search Google Scholar
    • Export Citation
  • 2

    FalloFSoninoN. Should we evaluate for cardiovascular disease in patients with Cushing's syndrome?Clinical Endocrinology200971768771. (doi:10.1111/j.1365-2265.2009.03610.x).

    • Search Google Scholar
    • Export Citation
  • 3

    DekkersOMHorvath-PuhoEJorgensenJOCannegieterSCEhrensteinVVandenbrouckeJPPereiraAMSorensenHT. Multisystem morbidity and mortality in Cushing's syndrome: a cohort study. Journal of Clinical Endocrinology and Metabolism20139822772284. (doi:10.1210/jc.2012-3582).

    • Search Google Scholar
    • Export Citation
  • 4

    ClaytonRNRaskauskieneDReulenRCJonesPW. Mortality and morbidity in Cushing's disease over 50 years in Stoke-on-Trent, UK: audit and meta-analysis of literature. Journal of Clinical Endocrinology and Metabolism201196632642. (doi:10.1210/jc.2010-1942).

    • Search Google Scholar
    • Export Citation
  • 5

    CasonatoAPontaraEBoscaroMSoninoNSartorelloFFerasinSGirolamiA. Abnormalities of von Willebrand factor are also part of the prothrombotic state of Cushing's syndrome. Blood Coagulation & Fibrinolysis199910145151. (doi:10.1097/00001721-199904000-00006).

    • Search Google Scholar
    • Export Citation
  • 6

    PatrassiGMSartoriMTVieroMLScaranoLBoscaroMGirolamiA. The fibrinolytic potential in patients with Cushing's disease: a clue to their hypercoagulable state. Blood Coagulation & Fibrinolysis19923789793. (doi:10.1097/00001721-199212000-00013).

    • Search Google Scholar
    • Export Citation
  • 7

    PatrassiGMDal Bo ZanonRBoscaroMMartinelliSGirolamiA. Further studies on the hypercoagulable state of patients with Cushing's syndrome. Thrombosis and Haemostasis198554518520.

    • Search Google Scholar
    • Export Citation
  • 8

    ObuobieKDaviesJSOgunkoAScanlonMF. Venous thrombo-embolism following inferior petrosal sinus sampling in Cushing's disease. Journal of Endocrinological Investigation200023542544. (doi:10.1007/BF03343772).

    • Search Google Scholar
    • Export Citation
  • 9

    SemplePLLawsERJr. Complications in a contemporary series of patients who underwent transsphenoidal surgery for Cushing's disease. Journal of Neurosurgery199991175179. (doi:10.3171/jns.1999.91.2.0175).

    • Search Google Scholar
    • Export Citation
  • 10

    La BroccaATerzoloMPiaAPaccottiPDe GiuliPAngeliA. Recurrent thromboembolism as a hallmark of Cushing's syndrome. Journal of Endocrinological Investigation199720211214. (doi:10.1007/BF03346905).

    • Search Google Scholar
    • Export Citation
  • 11

    SkrhaJ. Pathogenesis of angiopathy in diabetes. Acta Diabetologica200340 (Suppl 2) S324S329. (doi:10.1007/s00592-003-0113-z).

  • 12

    EtxabeJVazquezJA. Morbidity and mortality in Cushing's disease: an epidemiological approach. Clinical Endocrinology199440479484. (doi:10.1111/j.1365-2265.1994.tb02486.x).

    • Search Google Scholar
    • Export Citation
  • 13

    ManciniTKolaBManteroFBoscaroMArnaldiG. High cardiovascular risk in patients with Cushing's syndrome according to 1999 WHO/ISH guidelines. Clinical Endocrinology200461768777. (doi:10.1111/j.1365-2265.2004.02168.x).

    • Search Google Scholar
    • Export Citation
  • 14

    KastelanDDusekTKraljevicIPolasekOGiljevicZSolakMSalekSZJelcicJAganovicIKorsicM. Hypercoagulability in Cushing's syndrome: the role of specific haemostatic and fibrinolytic markers. Endocrine2009367074. (doi:10.1007/s12020-009-9186-y).

    • Search Google Scholar
    • Export Citation
  • 15

    SmallMLoweGDForbesCDThomsonJA. Thromboembolic complications in Cushing's syndrome. Clinical Endocrinology198319503511. (doi:10.1111/j.1365-2265.1983.tb00025.x).

    • Search Google Scholar
    • Export Citation
  • 16

    SavageBShattilSJRuggeriZM. Modulation of platelet function through adhesion receptors. A dual role for glycoprotein IIb-IIIa (integrin α IIb β 3) mediated by fibrinogen and glycoprotein Ib-von Willebrand factor. Journal of Biological Chemistry19922671130011306.

    • Search Google Scholar
    • Export Citation
  • 17

    MorrisonSAJestyJ. Tissue factor-dependent activation of tritium-labeled factor IX and factor X in human plasma. Blood19846313381347.

  • 18

    GailaniDBrozeGJJrFactorXI. activation in a revised model of blood coagulation. Science1991253909912. (doi:10.1126/science.1652157).

  • 19

    von dem BornePAMeijersJCBoumaBN. Feedback activation of factor XI by thrombin in plasma results in additional formation of thrombin that protects fibrin clots from fibrinolysis. Blood19958630353042.

    • Search Google Scholar
    • Export Citation
  • 20

    CollenD. The plasminogen (fibrinolytic) system. Thrombosis and Haemostasis199982259270.

  • 21

    MiljicPMiljicDCainJWKorbonitsMPopovicV. Pathogenesis of vascular complications in Cushing's syndrome. Hormones2012112130.

  • 22

    BartonMBaretellaOMeyerMR. Obesity and risk of vascular disease: importance of endothelium-dependent vasoconstriction. British Journal of Pharmacology2012165591602. (doi:10.1111/j.1476-5381.2011.01472.x).

    • Search Google Scholar
    • Export Citation
  • 23

    ErikssonLNystromT. Activation of AMP-activated protein kinase by metformin protects human coronary artery endothelial cells against diabetic lipoapoptosis. Cardiovascular Diabetology201413152. (doi:10.1186/s12933-014-0152-5).

    • Search Google Scholar
    • Export Citation
  • 24

    KangKT. Endothelium-derived relaxing factors of small resistance arteries in hypertension. Toxicological Research201430141148. (doi:10.5487/TR.2014.30.3.141).

    • Search Google Scholar
    • Export Citation
  • 25

    KimJAMontagnaniMChandrasekranSQuonMJ. Role of lipotoxicity in endothelial dysfunction. Heart Failure Clinics20128589607. (doi:10.1016/j.hfc.2012.06.012).

    • Search Google Scholar
    • Export Citation
  • 26

    MuniyappaRSowersJR. Role of insulin resistance in endothelial dysfunction. Reviews in Endocrine & Metabolic Disorders201314512. (doi:10.1007/s11154-012-9229-1).

    • Search Google Scholar
    • Export Citation
  • 27

    PraznyMJezkovaJHorovaELazarovaVHanaVKvasnickaJPecenLMarekJSkrhaJKrsekM. Impaired microvascular reactivity and endothelial function in patients with Cushing's syndrome: influence of arterial hypertension. Physiological Research2008571322.

    • Search Google Scholar
    • Export Citation
  • 28

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