Coagulopathy in Cushing’s Syndrome

A hypercoagulable state and its consequent increased incidence of thromboembolic complications are reported in patients with Cushing’s syndrome (CS). These alterations are related to cortisol excess that induces prothrombotic changes in blood by several and complex mechanisms including increased levels of clotting factors, mainly factor VIII and von Willebrand factor (VWF) and impaired fibrinolytic capacity. However, it has recently been observed that the increase in VWF levels is not a constant feature of CS and that VWF response to glucocorticoids is genetically determined and depends on the presence of particular polymorphisms in the VWF gene promoter. The risk of venous thromboembolism is moreover enhanced in patients with CS by additional endogenous and exogenous risk factors such as obesity, bed rest, surgery and invasive diagnostic procedures like inferior petrosal sinus (IPS) sampling. In line with all these data, patients with active CS should be treated as having a prothrombotic disorder and undergo antithrombotic prophylaxis during IPS sampling. Special care should be taken in the imPublished online: September 10, 2010 Marco Boscaro Clinica di Endocrinologia Azienda Ospedaliero-Universitaria, Ospedali Riuniti di Ancona IT–60100 Ancona (Italy) Tel. +39 071 88 7061, Fax +39 071 88 7300, E-Mail m.boscaro @ univpm.it © 2010 S. Karger AG, Basel 0028–3835/10/0925–0055$26.00/0 Accessible online at: www.karger.com/nen D ow nl oa de d by : 54 .7 0. 40 .1 1 10 /6 /2 01 7 4: 33 :4 8 A M Trementino /Arnaldi /Appolloni / Daidone /Scaroni /Casonato /Boscaro Neuroendocrinology 2010;92(suppl 1):55–59 56 ence of particular polymorphisms in the von Willebrand factor (VWF) gene promoter plays a role in determining thrombotic risk. Finally, additional endogenous (e.g. hyperhomocysteinemia, obesity) and exogenous (e.g. bed rest, surgery, invasive diagnostic procedures) factors may contribute and enhance the thromboembolic risk of patients with hypercortisolism. In this short review, we discuss coagulation alterations in CS focusing on our personal experience and on mechanisms by which glucocorticoids may influence hemostatic parameters. Quantitative Alterations: Increased Clotting Factors and Impaired Fibrinolysis Whereas little is known about the effect of cortisol on platelet count and function, it is certain that the hypercoagulable state in CS is related to an increase in plasma clotting factors, especially factor VIII and VWF and, to a minor extent, to a defective fibrinolysis ( fig. 1 ). In addition to plasma VWF and factor VIII, some studies have shown higher levels of other coagulation factors such as factors IX, XI, and XII [5–16] . We demonstrated that both increased clotting factors and defective fibrinolytic potential are related to the increased concentration of cortisol in the blood. High levels of glucocorticoids stimulate the endothelial production of VWF with a concomitant increase of factor VIII, which is transported in blood by the VWF, and impairs fibrinolytic capacity upregulating the synthesis of plasminogen activator inhibitor type 1 (PAI-1) [9–14] . In 1982, Dal Bo Zanon et al. [11] showed that active CS is associated with increased levels of factor VIII. They investigated 13 women and 2 men affected by CS every 30– 50 days after treatment for 11 months: in these patients, circulating cortisol and factor VIII were significantly increased before treatment and decreased slowly after treatment to become normal in 3–4 months. The increase in VWF correlated well with cortisol levels. In 1999, we studied the clotting profile in 20 patients with CS before and after surgical treatment [12] . In line with previous studies, plasma levels of factor VIII and VWF were markedly increased in these patients before surgery. In cured patients, an additional and significant increase during the first month after surgery was followed by a progressive decrease until a complete normalization within 12 months. This study confirmed the presence of quantitative alterations in clotting profile due to cortisol excess and their reversibility after the resolution of hypercortisolism, and identified a period of additional thrombotic risk early after surgery as a result of the worsening of the hemostatic pattern, exposing patients to a further and higher risk of thromboembolic complications. The fibrinolytic system also plays a key role in the pathogenesis of venous thromboembolic disorders, and in patients with CS an impaired fibrinolytic capacity was described [13] , mainly due to a decrease in tissue plasminogen activator (t-PA) antigen and increase in PAI-1. However, a case-control study did not find any significant difference in plasma PAI-1 and t-PA levels between CS patients and controls [14]. More recently, Erem et al. [15] reported increased levels of PAI-1 in CS patients compared with healthy subjects and decreased levels of the tissue factor pathway inhibitor that contributes to the hypofibrinolytic state of these patients and consequently to their increased thromboembolic risk. In this study, PAI-1 was also found to be positively correlated with midnight serum cortisol levels, a finding that emphasizes the strict relationship between these alterations and cortisol excess. A shortening of the activated thromboplastin time was observed in our and in the majority of published clinical studies, whereas other coagulation parameters (prothrombin time, bleeding time, and platelet aggregation) were unchanged. A significant inverse correlation between activated thromboplastin time and urinary free cortisol levels was also observed [16] . Intrinsic pathway