A M Isidori, A B Grossman in haemostasis 173:3 R101–R113 Review and others

MECHANISMS IN ENDOCRINOLOGY The spectrum of haemostatic abnormalities in excess and defect

Andrea M Isidori1,*, Marianna Minnetti1,2, Emilia Sbardella1, Chiara Graziadio1 and Ashley B Grossman2,* Correspondence should be addressed 1Department of Experimental Medicine, Sapienza University of Rome, Viale del Policlinico 155, Rome 00161, Italy to A M Isidori or A B Grossman and 2Oxford Centre for Diabetes, Endocrinology and Metabolism, Churchill Hospital, University of Oxford, Emails Headington, Oxford OX3 7LE, UK [email protected] or *(A M Isidori and A B Grossman contributed equally to this work) ashley.grossman@ ocdem.ox.ac.uk

Abstract

Glucocorticoids (GCs) target several components of the integrated system that preserves vascular integrity and free blood flow. Cohort studies on Cushing’s syndrome (CS) have revealed increased thromboembolism, but the pathogenesis remains unclear. Lessons from epidemiological data and post-treatment normalisation time suggest a bimodal action with a rapid and reversible effect on coagulation factors and an indirect sustained effect on the vessel wall. The redundancy of the steps that are potentially involved requires a systematic comparison of data from patients with endogenous or exogenous hypercortisolism in the context of either inflammatory or non-inflammatory disorders. A predominant alteration in the intrinsic pathway that includes a remarkable rise in factor VIII and von Willebrand factor (vWF) levels and a reduction in activated partial thromboplastin time appears in the majority of studies on endogenous CS. There may also be a rise in , thromboxane B2, thrombin–antithrombin complexes and fibrinogen (FBG) levels and, above all, impaired fibrinolytic capacity. The increased activation of coagulation inhibitors seems to be compensatory in order to counteract disseminated coagulation, but there remains a net change towards an increased risk of venous thromboembolism (VTE). European Journal of Endocrinology Conversely, GC administered in the presence of inflammation lowers vWF and FBG, but fibrinolytic activity is also reduced. As a result, the overall risk of VTE is increased in long-term users. Finally, no studies have assessed haemostatic abnormalities in patients with Addison’s disease, although these may present as a consequence of bilateral adrenal haemorrhage, especially in the presence of antiphospholipid antibodies or treatments. The present review aimed to provide a comprehensive overview of the complex alterations produced by GCs in order to develop better screening and prevention strategies against and thrombosis.

European Journal of Endocrinology (2015) 173, R101–R113

Introduction

The haemostatic–coagulation system is the first line of abnormalities (2) and unbalanced coagulation–fibrinolysis defence against trauma, and it is finely tuned to prevent (3). Glucocorticoids (GCs) have potent anti-inflammatory excessive bleeding or thrombosis (1). It is a complex but effects and play an important role in haemostasis (4, 5). highly regulated system designed to stabilise the free flow Endogenous hypercortisolism is well known to increase of blood and blood constituents while also preserving the cardiovascular mortality (6, 7), but although hypercorti- integrity of the vasculature. A broad variety of endocrine solism was initially thought to be purely a consequence of disorders have been associated with hematologic high blood pressure, diabetes and hyperlipidaemia, it has

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more recently been linked to an increased risk of By contrast, in 2014, Karamouzis et al. (21) described thrombosis. In addition, several studies have also found enhanced aggregation in patients with CS: that patients on corticosteroid replacement therapy show thromboxane A2 (TXA2) has been shown to cause platelet increased mortality, and the authors have tentatively release, activation and accumulation and to exert potent attributed this increased mortality to supraphysiological vasoconstrictive effects (22); TXB2, which represents a GC replacement therapy (8, 9, 10). Thus, now seems to be reliable indicator of TXA2 biosynthesis, was significantly an appropriate time to review and summarise the available higher (P!0.01) in patients affected by CS (21). data on the influence of endogenous and exogenous It therefore seems likely that there is a minor, albeit GCs on the haemostatic–coagulation system and to significant, increase in platelet functionality in CS. consider the relevance of that system to clinical disorders and their therapy. von Willebrand factor

von Willebrand factor (vWF) is a multimeric glycoprotein Endogenous hypercortisolism that mediates platelet adhesion at the site of vascular Numerous alterations of coagulation and fibrinolysis damage and that stabilises factor VIII (FVIII) (23). Plasma parameters have been described in patients with endogen- levels of vWF were found to be markedly increased in ous Cushing’s syndrome (CS; Fig. 1) independently of its several studies (16, 24, 25, 26, 27). Chopra et al. (28) found cause (11, 12, 13). However, many studies have failed to that vWF was elevated in 40.9% of endogenous CS as discriminate between the effects of GCs per se and the compared to healthy volunteers. Considering that vWF secondary effects of obesity and other manifestations of CS concentration is related to AB0 blood grouping, Manetti (14, 15). Furthermore, when CS is cured, cortisol levels et al. (16) found that both untreated CS patients with normalise, but hypercoagulability may not completely blood group 0 (PZ0.007) and blood group non-0 disappear (5). However, patients with active disease after (P!0.0001) had higher values of vWF. CS is also surgery clearly maintain a higher thrombotic risk than do characterised by the presence of unusually large vWF those who are cured (16). It is therefore likely that an acute multimers, which are recognised to have the greatest direct role of GCs may give rise to a more general, indirect haemostatic capacity (24). The high prevalence of specific chronic effect on endothelial function and atherosclerosis. polymorphisms in the VWF gene (promoter haplotypes) was found to be associated with higher vWF levels in patients with CS as compared to controls (29). Casonato Platelet count European Journal of Endocrinology et al. (24) studied the clotting profile in patients with CS Platelets have been recognised to play a crucial role in the before and after surgical treatment and found that plasma interface between coagulation and iny˜¨ ammation, and levels of vWF decreased after surgery and normalised platelet adherence at the site of vascular is an within 12 months. important step in the early phase of thrombogenesis (17). In 1983, Sato et al. were the first to describe a significant Coagulation cascade increase in the number of platelets in patients with CS as compared to control obese patients (18) or age-matched Prothrombin time (PT) assesses the integrity of the healthy controls (19). extrinsic clotting cascade, and it is mostly maintained in patients with CS (27, 30, 31), although increased PT values as compared to healthy control subjects were recently Platelet activation noted in two studies (19, 32). However, a reduction in The serum/glucocorticoid regulated kinase 1 (SGK1) is a activated partial thromboplastin time (aPTT), a marker of powerful regulator of ORAI1 protein in platelets, and the intrinsic system, in CS has been repeatedly described C ORAI1 is the key mediator of the store-operated Ca2 (16, 19, 24, 25, 26, 33, 34, 35). Recently, Gadelha et al. entry that is required for platelet activity. A recent study – using the rotation thromboelastometry (ROTEM) meth- showed that SGK1 expression is stimulated by a wide odology – showed that the beginning of the clot formation variety of hormones, including GCs and mineralocorti- is the altered step in the intrinsic pathway of CS patients coids (20). A previous systematic review failed to show (35). The most remarkable change in the intrinsic pathway significantly altered platelet aggregation in patients with is the significant increase in FVIII levels (24, 25, 26, 33, 34, CS, although the studies reviewed were of low quality (21). 35, 36). Several coagulation markers have been found to be

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Extrinsic Tissue factor FXIIa FXII Intrinsic Injury to pathway (PT) released by pathway (aPTT) injured cells blood vessel Coagulation cascade FXIa FXI

FVlI FVlIa FIXa FIX FVlII vWF TXA2

Increase in endogenous FXa Protein C and hypercortisolism FX FX protein S Platelets Decrease in endogenous hypercortisolism FVa FV Activation of the next step Activated platelets Regulators Inhibitory action

Proteolytic cleavage Prothrombin Thrombin

Antithrombin Fibrinogen

α2 Fibrin Activated Fibrin platelets Antiplasmin Plasmin Fibrin degradation TAFI products PAI1 tPA

Plasminogen Fibrinolysis Blood clot

Figure 1

European Journal of Endocrinology Effects of endogenous hypercortisolism (blue circles with white activator Inhibitor-1; PT, Prothrombin time; TAFI, Thrombin- arrows) on coagulation cascade, platelets, regulators and activatable fibrinolysis inhibitor; TXA2, Thromboxane A2; fibrinolysis. aPTT, Activated partial thromboplastin time; tPA, Tissue Plasminogen Activator; vWF, Von Willebrand factor. FVIII, Factor VIII; FVIIIa, Activated factor VIII; PAI1, Plasminogen

marginally increased in CS (e.g. factor II, factor V, factor 31, 34, 41), but not all (25), studies on CS. Patients with IX, factor XI and factor XII) (33), but only the increase in untreated CS had higher values of D-dimer (35), although FVIII is consistently and markedly elevated (37). Elevated D-dimer concentrations were not significantly different FVIII levels expose to clinically relevant thrombophilia, between patients before and after surgery (16). and it has been demonstrated that high FVIII is a dose- dependent risk factor for venous thromboembolism (VTE) Coagulation regulators: protein C, protein S and ATIII (38). FVIII decreases slowly after the normalisation of elevated GC levels and becomes normal 3–4 months later Uncontrolled blood coagulation is potentially dangerous, (39). One of the most commonly used markers of and redundant regulatory mechanisms are present at each thrombin (factor II) generation is the presence of level of the pathway. The protein C anticoagulant inhibits thrombin–antithrombin (TAT) complexes; increased the procoagulant agents FVIIIa and factor V, whereas TATs have been described in patients with CS in two protein S supports the anticoagulant activity of activated studies (16, 27). Fibrinogen (FBG, factor I) is an inflam- protein C in the degradation of factor Va and FVIIIa (42). matory marker that contributes to thrombotic risk (40). Unexpectedly, Kastelan et al. (33) showed that both Increased FBG levels have been found in most (16, 19, 26, protein C and protein S were significantly higher in CS.

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Koutroumpi et al. (32) compared 33 patients with CS to a developed post-operative bleeding. This finding was group of 28 patients that were matched for the features of concordant with the incidence of bleeding in patients the metabolic syndrome and to 31 healthy volunteers, and that underwent laparoscopic adrenalectomy for causes they found that protein C and protein S were both other than adrenal CS (47). Pituitary tumour apoplexy is a significantly higher in CS as compared to either groups. rare clinical syndrome that often occurs spontaneously as Even in patients with subclinical CS, higher levels of a result of haemorrhage and/or infarction into a pituitary protein C activity and free protein S have been described macroadenoma; CD arises in most cases within a (43). However, not all studies have confirmed differences microadenoma, and it is thus not unexpected that in the activity of protein C and protein S (16, 19), which pituitary apoplexy in CD is rare (48). suggests that alternative mechanisms could be involved. AT is a serine protease inhibitor (serpin) that plays an Venous thromboembolism important role in the regulation of coagulation as the major inhibitor of thrombin (factor IIa) and factor Xa (44). In general, chronic GC excess can influences all three Many authors have described increased AT levels in CS factors of the Virchow triad: endothelial dysfunction, patients (16, 19, 32, 33). These changes in anticoagulant haemodynamic changes and hypercoagulability (12).Ina factors are difficult to explain in terms of the generalised systematic review, Van Zaane et al. showed that VTE alteration in procoagulant activity just noted, but they events were the cause of death in 0–1.9% of patients with may in part constitute a compensatory response to the CS. There was a 1.9–2.5% risk not provoked by surgery, prothrombotic processes (32, 33, 38, 43). This should be whereas the risk of post-operative VTE varied between 0 taken into account in the treatment strategy. and 5.6% (30). The risk of VTE in patients with CD is comparable to the risk that follows major orthopaedic surgery (5). Fibrinolysis

Fibrinolysis is the process that prevents blood clots from Antithrombotic prophylaxis in CS growing, which thus limits the haemostatic process and aids in recovery from thrombosis (45). CS is correlated Boscaro et al. retrospectively analysed post-operative with increased levels of the natural fibrinolytic inhibitors thromboembolic events in patients with CS that were (plasminogen activator inhibitor type 1 (PAI1), thrombin- evaluated in the period from 1982 to 2000. Before activatable fibrinolysis inhibitor (TAFI) and a2-antiplas- anticoagulant prophylaxis was routinely used in their

European Journal of Endocrinology min) (34). This defective fibrinolytic potential could centre, they had a 10% mortality resulting from VTE contribute to the hypercoagulability of CS. PAI1 is the events and 10% vascular morbidity (26). They reported main inhibitor of the fibrinolytic system, and a significant that since post-operative antithrombotic prophylaxis increase in PAI1 activity has been described in many (unfractionated at doses of 15 000–22 500 U/day studies (16, 19, 25, 26, 33, 34). However, a systematic for at least 2 weeks and warfarin for at least 4 months) had review suggests that both inhibitors and stimulators of become their standard of care, morbidity and mortality fibrinolysis (i.e. plasminogen activity) were found to be resulting from VTE events fell to 6 and 0.4% respectively increased in patients with CS (30), and it is thus difficult (26). Furthermore, Trementino et al. (13) have suggested to differentiate between changes that are causal and those the routine use of antithrombotic prophylaxis even during that are compensatory. inferior petrosal sinus sampling as well as during the immediate post-operative period after transsphenoidal or adrenal surgery. Bleeding risk To date, there have been no prospective placebo- The ‘bleeding time’ is mostly unchanged in patients with controlled trials to evaluate the effects of thrombo- CS (30). Hypercortisolism is associated with bruising and prophylaxis in patients with CD. poor wound healing, although these manifestations are most probably a result of alterations in the synthesis of key Conclusions regarding endogenous hypercortisolism skin components rather than a specific coagulation disorder (46). Between 1994 and 2008, 114 patients with ThereisnowampleevidencethatCSleadstoa adrenal CS and subclinical CS were studied during and prothrombotic state mainly as a result of an increase in after laparoscopic adrenalectomy: only one single patient vWF and FVIII, along with a decrease in fibrinolytic factors

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and enhanced VTE. Accordingly, it is wise to screen all CS rheumatica after several years of prednisolone treatment patients for concomitant genetic defects in coagulation (56). Most physicians routinely use systematic corticos- factors that could precipitate catastrophic thrombosis. teroids, such as oral prednisone, for the treatment of Routine antithrombotic measures that are more intensive thrombotic thrombocytopenic purpura (TTP), and than those that are currently being undertaken should be around 60–80% of patients respond with an elevation in tested for surgical prophylaxis. Since platelet activation platelet count. Several mechanisms have been described has also been documented, a chronic anti-aggregation for the action of corticosteroids in TTP, including a therapy could be hypothesised, but further studies are reduction in autoantibody production, a stabilisation of needed to establish the risk benefits of such therapy in platelets and endothelial cell membranes and a suppres- view of the gastrointestinal side effects. sion of reticulo-endothelial phagocytic activity (57, 58, 59, 60, 61). However, this is clearly quite a different situation to that wherein patients with normal platelet Exogenous hypercortisolism numbers and function are subject to GT. Glucocorticoid therapy (GT) is frequently used for a wide range of autoimmune, inflammatory and neoplastic Platelet activation disorders, and oral GCs are used by w1% of the adult population in the UK (49). Prolonged or high-dose GT has Several studies have reported contradictory results con- multiple side effects (50), and the chronic administration cerning the effect of GC treatment on platelet function. of GCs may induce the development of an iatrogenic CS Most of the discrepancies between the studies can be (11). Patients that receive systemic GT and develop clinical attributed to the dose amount and the steroid used as well features of iatrogenic CS have also been shown to exhibit a as the experimental design. Ex vivo measured platelet greater incidence of cardiovascular events as compared to aggregation is dose-dependently inhibited by DEX treat- those who do not develop a Cushingoid appearance (51). ment (62). Van Giezen et al. (63) investigated the effect However, inflammation has been shown to modulate of oral DEX administration in rats and found that the thrombotic responses by up-regulating procoagulants, primary effect on haemostasis was an inhibition of arterial down-regulating and suppressing fibrino- thrombosis via lowered platelet aggregation; the latter lysis (52), and one might thus anticipate a lower number effect, however, was lost at higher doses of steroids because of such events. On the other hand, the thrombotic risks of decreased fibrinolytic activity. Conventional clinical in GT-treated patients may reflect the severity of the doses of prednisone (80 mg given orally for 2 days) and the

European Journal of Endocrinology underlying diseases for which GT is prescribed (53). administration of DEX (15 mg for 4 days) do not appear Because of the widespread use of GT, an increased risk of to impair platelet function in healthy subjects (64, 65). thrombosis may carry profound clinical and socio- P-selectin is an adhesion molecule that is stored within economic implications. Features of exogenous hypercorti- platelet a-granules. P-selectin is important in the recruit- solism are depicted in Fig. 2 using a diagram that is similar ment and aggregation of platelets at injured sites, and to the one used for endogenous CS, which allows for a elevated baseline levels are associated with increased direct comparison. In addition, peculiar changes that cardiovascular risk (66). A double-blind, randomised, occurred when steroids were used in the context of placebo-controlled study showed that soluble P-selectin inflammatory disorders have been reported. rose 48 h after the infusion of a therapeutic dose of DEX (0.04 and 1.0 mg/kg b.i.d. on 2 days) in healthy men (PZ0.017) (55), whereas another study on healthy Platelet count subjects randomised to hydrocortisone (HCT) (daily dose The GC receptor has been described in human platelets 40 mg) or placebo on 7 consecutive days found no HCT- (50). Furthermore, megakaryocytes express steroid related changes in platelet activation or P-selectin (67). receptors, which may constitute an autocrine loop in the formation of proplatelets, the cytoplasmatic protru- von Willebrand factor sions within which nascent platelets are assembled (54). High-dose dexamethasone (DEX) has been shown to vWF levels were increased in in vitro studies when GCs increase platelet counts in healthy men by a maximum of were used in healthy volunteers, whereas a decrease in 18% above baseline (55). According to one study, platelet vWF levels has been described when GCs are used in the count was decreased in patients with polymialgya context of inflammation (Fig. 2). Two in vitro studies

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Tissue factor FXIIa FXII Intrinsic Extrinsic Injury to released by pathway (aPTT) pathway (PT) injured cells blood vessel Coagulation cascade FXIa FXI

FVlI FVlIa FIXa FlX FVlII vWF TXA2

Exogenous hypercortisolism FX FXa FX Protein C and in the context of inflammation protein S Platelets Exogenous hypercortisolism in healthy patients FVa FV Activation of the next step Activated platelets Regulators Inhibitory action

Proteolytic cleavage Prothrombin Thrombin

Antithrombin Fibrinogen

α2 Fibrin Activated Fibrin platelets Antiplasmin Plasmin Fibrin degradation TAFI products PAI1 tPA

Plasminogen Fibrinolysis Blood clot

Figure 2

European Journal of Endocrinology Effects of exogenous hypercortisolism on coagulation cascade, VIII; PAI1, Plasminogen activator Inhibitor-1; PT, Prothrombin platelets, regulators and fibrinolysis in the presence (orange time; TAFI, Thrombin-activatable fibrinolysis inhibitor; arrows) or absence (green circles with white arrows) of TXA2, Thromboxane A2; tPA, Tissue Plasminogen Activator; concomitant inflammatory disorders. aPTT, Activated partial vWF, Von Willebrand factor. thromboplastin time; FVIII, Factor VIII; FVIIIa, Activated factor

showed that GCs may increase the release of VWF and and found no differences in vWF levels (76, 77). On the mRNA expression of VWF from cultured human umbilical contrary, therapeutic doses of DEX (0.04 or 1.0 mg/kg for vein endothelial cells (68, 69). A positive correlation was 2 days) given parenterally to healthy men were shown to found between plasma cortisol and vWF levels, with a increase levels of vWF after 24 and 48 h (PZ0.011) (55). 1 mg/ml rise in plasma cortisol causing a 2.52 IU/dl increase in vWF (28). In contrast, a recent systematic Coagulation cascade review found that in patients with inflammatory disease (e.g. giant cell arteritis), GCs lowered vWF levels (70, 71, A recent study demonstrated that DEX prophylaxis in 72, 73). An acute high-dose of GC has been associated paediatric patients that underwent cardiopulmonary with a rapid activation of endothelial nitric oxide (NO) bypass for heart surgery was associated with decreased synthase via a direct non-genomic effect, which in turn aPTT (PZ0.025) (78). A rise in several coagulation factors enhances NO release (74). NO exerts a negative feedback was shown in a trial that randomised 24 healthy on vWF secretion (75). Two studies investigated the effect volunteers to receive either 3 mg DEX twice daily or of 1–3 mg DEX twice daily for 5–6 days in healthy males placebo for 5 days. The authors found increased levels of

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factor VII, FVIII, factor XI and FBG (77). Rat liver cells 3 mg DEX vs placebo for 5 days or with 1 mg DEX vs in vitro have been shown to respond to DEX by increasing placebo for 6 days (76, 77). the synthesis of FBG mRNA, whereas no induction of the FBG-polypeptide mRNA was observed in vivo at various Bleeding risk times after the injection of different doses of GCs into the Some studies have suggested a possible association livers of rats (79). When GCs are used in the setting of between DEX and an increased risk of post-operative increased inflammatory activity, they significantly haemorrhage; however, a meta-analysis excluded an decreased FBG (56, 71, 78, 80). This biphasic response is explained by the dose-dependency of GC anti-inflamma- association between DEX administration and post-operat- tory effects on the acute phase response (including FBG) ive bleeding in children that underwent tonsillectomy (70) (Fig. 2). or adeno-tonsillectomy (89). In their systematic review, Sauerland et al. (90) found that a perioperative single shot of high-dose methylprednisolone was not associated with Coagulation regulators: protein C, protein S and ATIII increased gastrointestinal bleeding. All of the regulators have been described as being increased in patients with systemic lupus erythematosus VTE events under chronic prednisone treatment (81) and in patients Cosgriff et al. first suggested a state of hypercoagulability with other autoimmune diseases (82). A recent study in patients that were treated with cortisone (91, 92). proposed that GC modulation of ATIII could represent a Isolated cases of cerebral VTE after i.v. steroid pulse low-cost alternative to exogenous ATIII supplementation therapy have been reported in patients with multiple in several non-specific conditions when endogenous AT sclerosis (93). A large prospective cohort study in 6550 UK activity is decreased (e.g. in the early post-operative period patients with VTE using the General Practice Research following major surgery) (83). Database showed a threefold increased risk of VTE in current users of oral GCs as compared to non-users (94). Fibrinolysis A Danish population-based case–control study found that The use of GT in an inflammatory context has been shown systemic GC increased VTE risk among present (incidence to induce alterations in fibrinolysis, which causes a rate ratio (IRR)Z2.31), new (IRRZ3.06), continuing significant rise in PAI1, the main inhibitor of the (IRRZ2.02) and recent (IRRZ1.18) steroid users but not Z European Journal of Endocrinology fibrinolytic system, whereas this has not been described among former users (IRR 0.94). Oral GCs are associated in healthy volunteers using GCs. GC responsive elements with a higher risk of VTE than the injectable form is, have been found in the promoter regions of the Tafi and possibly because some injections are used for intra- Pai1 genes in rat hepatoma cells (84, 85). Moreover, DEX articular treatment, which has lower bioavailability (95). has been shown to enhance PAI1 expression in cultured Finally, an association between oral GCs and a fourfold human adipose tissue (86). Van Zaane et al. suggested that increased risk of pulmonary embolism, especially during when GCs are used in the context of inflammation, they the first month of exposure, was reported in a case–control inhibit fibrinolytic activity, mainly because of increased study using a Dutch population-based pharmacy registry PAI1 activity and levels. In addition, during inflammation, (96). Thus, there appears to be little doubt that patients GCs inhibit the surgery-induced increase in tPA (70). with exogenous hypercortisolism have a higher risk of Darmon et al. (87) showed that moderate hypercortisolism VTE, and that risk is as high as that for patients with equivalent to that observed in response to mild stress endogenous CS. induces an elevation in circulating PAI1 levels that is significantly greater in obese subjects than in lean Conclusions regarding exogenous hypercortisolism subjects. In a controlled clinical trial performed in healthy subjects that received oral metyrapone followed by i.v. Although there are variable changes in thrombotic factors saline plus low- or high-dose HCT, short-term variations in after the acute short-term administration of GCs, longer- plasma GC levels did not alter the systemic fibrinolytic term use is complicated by the effects on the underlying balance or endothelial function (88); this was confirmed disease process as well as by specific changes that result in two studies that showed no significant changes in the from the GCs. However, there appears to be solid PAI1, tPA or D-dimer levels of healthy men treated with agreement that long-term use is associated with a

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significant increase in VTE. Yet, dedicated guidelines for considered in a young female patient that presents with preventing VTE in long-term GC use are lacking. abdominal pain and haemodynamic instability (104) or in any patient with adrenocortical failure of unclear patho- genesis (105). Hypocortisolism Anticoagulant-associated adrenal haemorrhage is an Adrenal insufficiency (AI) is the clinical manifestation of infrequent complication of anticoagulant therapy, but it insufficient GC production or action. The cardinal can be successfully treated if it is recognised (106). HIT is symptoms of AI, as first described by Thomas Addison in characterised by the development of platelet-activating IgG 1855, include weakness, fatigue, abdominal pain, weight antibodies against the platelet factor 4–heparin complex, loss, anorexia, orthostatic hypotension and salt craving; which predisposes to VTE or arterial thromboembolism or characteristic hyperpigmentation of the skin occurs with heparin skin necrosis (107). HIT occurs in up to 1% of primary adrenal failure. Signs or symptoms related to patients that receive unfractionated heparin for post- coagulation disorders are not commonly described in AI operative antithrombotic prophylaxis (108). The mechan- (97), despite the fact that increased mortality from ism of HIT-induced adrenal haemorrhage begins with cardiovascular disorders has been reported. AI is not usually adrenal vein thrombosis triggered by platelet activation, complicated by thrombotic or bleeding episodes; however, endothelial injury and coagulation system activation (100). neither in vitro nor in vivo studies have been performed to Soran et al. reported a case of bilateral adrenal explore these aspects (98). To date, no studies that describe haemorrhage secondary to thrombosis in a patient who platelet count or function, vWF, coagulation cascade, was later found to have a heterozygous factor V Leiden regulators or fibrinolysis have been performed. What does defect. Anticoagulation may cause bilateral adrenal haem- seem clear is that various coagulation disorders may lead to orrhage, with subsequent permanent damage of both AI, and these will be the focus of the present section. adrenals that results in acute Addisonian crisis (109). Derex et al. (110) reported a case of spontaneous intracer- ebral haemorrhage that occurred in a young woman with Primary AI undiagnosed Addison’s disease; the authors concluded Primary AI results from disease that is intrinsic to the that primary AI should be considered as a rare potential . Not infrequently, primary AI is a conse- cause of non-hypertensive intracerebral haemorrhage. quence of bilateral adrenal haemorrhage that results from antiphospholipid antibody syndrome (APLS), anticoagu- Secondary AI European Journal of Endocrinology lant use, disseminated intravascular coagulation (97, 99) and immune-mediated heparin-induced thrombocytope- One of the possible causes of hypopituitarism is Sheehan’s nia (HIT) (100). syndrome, which is a result of ischaemic pituitary necrosis APLS, also variously known as Hughes syndrome, is a caused by severe postpartum haemorrhage. Several patients systemic, autoimmune, acquired disorder characterised with Sheehan’s syndrome have demonstrated acquired by the association of pregnancy morbidities and/or VTE FVIII and vWF deficiency, , shorter PT and/or arterial thrombosis with the detection of autoanti- and aPTT and higher FBG levels (111). The incidence of bodies to phospholipids (101). Addison’s disease has been hypopituitarism after aneurysmal subarachnoid haemor- reported in only 0.4% of patients with confirmed APLS; rhage is unclear because of conflicting reports in the conversely, APLS is diagnosed in !0.5% of all patients literature (112, 113). with Addison’s disease. (102). Furthermore, 10–26% of In 2002, Setian et al. (114) described a 9-year-old boy APLS patients can have adrenal failure in catastrophic with hypopituitarism and factor V, FVIII and vWF form. Adrenal vein thrombosis, adrenal haemorrhage and deficiency, but no other case reports have been described. autoimmune mechanisms have been proposed to be Peacey et al. (115) found that an increased dose of HCT for pathogenic factors for AI (103). The main hypothesis 2 weeks did not significantly affect PAI1, tPA or FBR levels suggests that the primary event is bilateral adrenal vein in patients with hypopituitarism. thrombosis, which results in bilateral haemorrhagic infarction of the adrenal glands. Another theory presumes Overall conclusions that bilateral spontaneous (without thrombosis) adrenal haemorrhage is the main event (103).PrimaryAPLS Several defects in the coagulation–fibrinolytic system have presenting as AI is very rare, but it should always be been described among patients affected by GC disorders.

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A remarkable rise in FVIII and vWF levels and a reduction Supplementary data in aPTT have been confirmed in many studies as has a rise This is linked to the online version of the paper at http://dx.doi.org/10.1530/ in the number of platelets, TXB2 levels, TAT complex level EJE-15-0308. and FBG levels. In many studies, increased activity of the endogenous coagulation inhibitors has been described, probably as a compensating mechanism in the face of Declaration of interest increased haemostasis. Impaired fibrinolytic capacity, The authors declare that there is no conflict of interest that could be perceived as prejudicing the impartiality of the review. which is reflected especially by elevated plasma concen- tration of PAI1, has also been described (Supplementary Table 1, see section on supplementary data given at the Funding end of this article). The changes lead to a very significant This work was partially supported by a research grant from the MIUR Italian increase in VTE. Haemostatic abnormalities seem to persist Ministry of University (grant number RBFR10URHP to A M Isidori, 2012–2015). after treatment in CS patients, and this suggests that increased risk in thrombosis might be a result of the persistence of abdominal obesity, diabetes, hypertension References and dyslipidaemia. CS should be included in the checklist of VTE risk factors, and it is important to recognise that 1 Spronk HM, Govers-Riemslag JW & ten Cate H. The blood coagulation system as a molecular machine. BioEssays: News and Reviews in patients with CS are at high risk of VTE, especially Molecular, Cellular and Developmental Biology 2003 25 1220–1228. perioperatively. Based on these data, antithrombotic (doi:10.1002/bies.10360) prophylaxis in CS patients that undergo adrenal and 2 Orwoll ES & Orwoll RL. Hematologic abnormalities in patients with endocrine and metabolic disorders. Hematology/Oncology Clinics of transsphenoidal surgery is highly recommended. 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People treated with Hypercoagulability in Cushing’s syndrome: prevalence, pathogenesis and treatment. Clinical Endocrinology 2013 78 481–488. (doi:10.1111/ European Journal of Endocrinology GCs who develop iatrogenic CS should be targeted for cen.12094) early screening and management of thrombosis risk 6 Graversen D, Vestergaard P, Stochholm K, Gravholt CH & factors. In healthy men, in the absence of other Jorgensen JO. Mortality in Cushing’s syndrome: a systematic review and meta-analysis. European Journal of Internal Medicine 2012 23 influencing factors, the alterations in coagulation balance 278–282. (doi:10.1016/j.ejim.2011.10.013) depend on the dose and type of GCs administered 7 Dekkers OM, Horvath-Puho E, Jorgensen JO, Cannegieter SC, (Supplementary Table 1). Additional studies should Ehrenstein V, Vandenbroucke JP, Pereira AM & Sorensen HT. Multi- system morbidity and mortality in Cushing’s syndrome: a cohort evaluate the clinical relevance of introducing coagu- study. 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Received 19 March 2015 Revised version received 10 May 2015 Accepted 14 May 2015 European Journal of Endocrinology

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