Coagulation Disorders in Patients with Abnormal Serum Cortisol Level
Cortisol, a critical hormone produced by the adrenal glands, plays a significant role in maintaining homeostasis, including hemostasis. Its influence on coagulation has been widely studied in conditions of hyperadrenalism, such as Cushing syndrome (CS), where elevated cortisol levels are associated with a hypercoagulable state. However, the hemostatic status in patients with hypoadrenalism, a condition characterized by low cortisol levels, remains poorly understood. This study aimed to evaluate coagulation abnormalities in patients with both hypoadrenalism and hyperadrenalism, providing new insights into the relationship between cortisol levels and hemostasis.
Study Design and Participants
The study was conducted as a retrospective analysis of patients with pituitary adenomas hospitalized in the Department of Neurosurgery at Peking Union Medical College Hospital between 2012 and 2018. The protocol was approved by the hospital’s Ethics Review Board, and all participants provided written informed consent. Patients were categorized into four groups based on their cortisol levels and pituitary function:
- Hyperadrenalism group (hyperA): Patients diagnosed with Cushing disease (CD), characterized by excessive cortisol production.
- Hypoadrenalism group (hypoA): Patients with pituitary adenoma and pre-operative morning serum cortisol levels (MSCL) below 138 nmol/L (5 µg/dL).
- Non-functional pituitary adenoma control group (NFC): Patients with non-functional pituitary adenomas and normal endocrinological results.
- Healthy control group (HC): Healthy individuals who underwent annual physical examinations during the same period.
Exclusion criteria included the use of exogenous glucocorticoids within six months prior to hospitalization or the absence of coagulation test results.
Diagnostic Criteria and Laboratory Methods
The diagnosis of CD was based on clinical symptoms, magnetic resonance imaging (MRI), hormone assays, and pathological immunohistological staining for adrenocorticotropic hormone (ACTH). Non-functional pituitary adenomas were diagnosed based on normal endocrinological results and negative immunohistological staining. Blood samples were collected at 08:00 AM for coagulation and endocrine tests.
Coagulation parameters, including prothrombin time (PT), international normalized ratio (INR), activated partial thromboplastin time (APTT), thrombin time (TT), and fibrinogen levels, were measured using the Sysmex CS-5100 Hemostasis system. Endocrine parameters, such as serum cortisol, ACTH, insulin-like growth factor-1 (IGF-1), and thyroid function, were assessed using direct chemiluminescent immunoassay systems (ADVIA Centaur XP or IMMULITE 2000).
Results
The study included 73 patients in the hypoA group, 136 in the hyperA group, 124 in the NFC group, and 79 in the HC group. No participants had a history of coagulation disorders.
Clinical and Endocrinological Characteristics
Patients in the hypoA group had a mean age of 45.0 years, with 30.1% being female. Systolic blood pressure in hypoA patients was significantly lower than in the NFC group but similar to the HC group. Liver function tests revealed minor differences between hypoA and HC groups, though most values remained within the reference range.
Endocrinological results showed significantly higher MSCL and ACTH levels in the hyperA group and lower levels in the hypoA group compared to the NFC group. Patients with hypoA also had lower levels of free triiodothyronine, thyroxine (T4), free thyroxine, and IGF-1 compared to the NFC group.
Coagulation Test Results
Significant differences were observed in PT, INR, and APTT among the four groups. Patients in the hypoA group had significantly prolonged PT, INR, and APTT compared to the HC group (PT: median 12.1 vs. 11.6 seconds; INR: median 1.034 vs. 0.988; APTT: median 33.6 vs. 28.1 seconds). In contrast, patients in the hyperA group had significantly shorter PT, INR, and APTT compared to the HC group. No significant differences were observed between the NFC and HC groups.
Fibrinogen levels were significantly higher in the NFC and hypoA groups compared to the HC group, but no significant differences were observed between the hyperA and HC groups.
Multivariable Logistic Regression Analysis
Multivariable logistic regression analysis identified several factors associated with hypoA and hyperA. Longer APTT, younger age, lower albumin levels, and lower T4 levels were associated with hypoA. Conversely, shorter APTT, younger age, lower albumin levels, lower T4 levels, higher alanine transaminase (ALT) levels, and female gender were associated with hyperA.
Discussion
This study is the first to comprehensively evaluate coagulation disorders in patients with hypoadrenalism, providing valuable insights into the hemostatic abnormalities associated with abnormal cortisol levels. The findings highlight significant differences in coagulation parameters between patients with hypoA and hyperA, particularly in the intrinsic coagulation pathway.
Hypoadrenalism and Coagulation
Patients with hypoA exhibited prolonged APTT and PT, suggesting impaired intrinsic and extrinsic coagulation pathways. These findings are consistent with the hypothesis that low cortisol levels may lead to reduced levels of coagulation factors, particularly factors VIII and IX, which are critical for the intrinsic pathway. While previous studies have primarily focused on hypercortisolism, this study fills a critical gap by demonstrating the opposite effect in hypoA.
Hyperadrenalism and Coagulation
The results in the hyperA group align with previous studies on Cushing syndrome, which have consistently reported a hypercoagulable state characterized by shortened APTT and increased levels of coagulation factors. The shortened APTT in hyperA patients is likely due to elevated levels of factors VIII and IX, which are known to be influenced by cortisol.
Clinical Implications
The findings have several potential clinical implications. For instance, APTT could serve as a useful marker for monitoring glucocorticoid replacement therapy (GRT) in patients with hypoadrenalism. Currently, GRT dosage is primarily adjusted based on clinical experience, as MSCL is not a reliable indicator of glucocorticoid levels. Prolonged APTT may indicate insufficient glucocorticoid replacement, while shortened APTT may suggest overuse. However, further studies are needed to validate the clinical utility of APTT in this context.
Conclusion
This study demonstrates that coagulation disorders are prevalent in patients with abnormal cortisol levels, with distinct patterns observed in hypoA and hyperA. APTT is significantly prolonged in hypoA and shortened in hyperA, reflecting the opposing effects of cortisol on the intrinsic coagulation pathway. These findings underscore the importance of monitoring coagulation parameters in patients with adrenal dysfunction and suggest potential applications for APTT in guiding glucocorticoid therapy.
doi.org/10.1097/CM9.0000000000001567
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