A Study on Correlation between D-Dimer Levels and TSH in Elderly Euthyroid Patients to Evaluate Potential Coagulopathic Tendencies View PDF

Thyroid hormones namely T3 (triiodothyronine) and T4 (thyroxine or tetraiodothyronine) primarily sustain basal metabolic rate (BMR) and are essential for growth, neuronal development, reproduction and regulation of carbohydrate, lipid and energy metabolism. Consequently, disorders of the thyroid especially hypothyroidism and hyperthyroidism are common conditions with potentially devastating health consequences that affect all populations worldwide [1]. Hyperthyroidism is characterized by increased thyroid hormone synthesis and secretion from the thyroid gland [2]. It usually manifests with increased excitability and fine tremors, heat intolerance, increased sweating, weight loss, fatigue, etc. Hypothyroidism results from low levels of thyroid hormones with varied manifestations such as cold intolerance, atherosclerosis, insulin resistance, etc [3]. Recent studies suggest that hyperthyroidism enhances coagulation and increases the risk of thrombosis [4]. D-dimer is a soluble fibrin degradation product that results from the systematic degradation of vascular thrombi by fibrinolytic pathway. It functions as an indirect marker of fibrinolysis and displays unique properties as a biological marker of hemostatic anomalies, due to which serves as a valuable marker of activation of coagulation and fibrinolysis in several clinical scenarios [5]. According to recent studies, hyperthyroidism is regarded to be associated with hypercoagulability and hypo-fibrinolysis, whereas the hemostatic profile in hypothyroidism is ambiguous [6]. Low platelet count, aggregationagglutination, von-Willebrand factor antigen level decreased levels of coagulation factors VIII, IX, XI, VII, and plasminogen activator-1 are detected in overt hypothyroidism, rendering a hypo-coagulable nature; while elevated fibrinogen levels implicated in subclinical hypothyroidism and autoimmune thyroid disease renders a hypercoagulable propensity [7]. Hence, there is ample evidence that indicated hypercoagulable and hypo-coagulable tendencies in hyperthyroidism and hypothyroidism. However, there are almost no studies to our knowledge that have been done on euthyroid subjects to assess whether TSH levels (primarily used in the diagnosis of thyroid disorders) in the extremes of euthyroid reference spectrum can lead to a potential hypercoagulable or hypocoagulable state, especially in the vulnerable population such as the elderly. Hence, we intend to know more about the risk of a potential hypercoagulable state in the susceptible population (especially the elderly) by studying D dimer levels in a spectrum of elderly euthyroid patients and assessing whether TSH levels (which are primarily used to diagnose thyroid disorders) have any correlation with D-dimer levels (not just in thyroid disorders but also in the euthyroid state). The importance of contributions of such factors can facilitate doctors in developing appropriate treatment regimens for patients with thyroid problems, with suspicion of coagulopathy in mind.

Objective

To study correlation between D-dimer levels and TSH in elderly patients and evaluate coagulopathic tendencies.

Type of study: Cross-sectional study.

Sample population: Elderly south Indian individuals aged 50-92 years visiting the respective tertiary care hospital for clinical tests under study.

Criteria for choosing subjects: Subjects were chosen such that they were aged between 50-92 years and not afflicted with any chronic hepatic, pulmonary or renal afflictions, or any inflammatory autoimmune diseases like AIDS or rheumatoid arthritis. Subjects on medications or thyroid supplements were excluded from the study

Sample size: A total of 30 subjects who met the above-mentioned criteria were chosen.

Duration of study: One month.

Method: Subjects chosen as per inclusion criteria were first informed regarding the study via an informed consent form. Only after receiving their signed approval for participation in the study, the subjects matching selection criteria were taken into consideration.

Normality of the data distribution of D-Dimer levels and TSH levels was first assessed as per Shapiro Wilk test

Whereas the middle horizontal line represents the median TSH level, the vand lower bounds of the box represent the 75th and the 25th centile of TSH levels respectively, and the upper and lower extent of the whiskers represent the Tukey limits for TSH levels in each of the groups.

The Shapiro-Wilk test indicated that the data distribution was not normal (non-Gaussian) distribution. Hence, Spearman’s correlation coefficient (non-parametric test) was employed to check the correlation between TSH levels and D-Dimer levels in elderly euthyroid subjects.

Spearman’s rho correlation coefficient test showing a negative correlation between D-Dimer and TSH levels in elderly euthyroid subjects which is statistically significant at the 0.05 level.

The test indicated that there is a negative correlation between D-Dimer and TSH levels in elderly euthyroid subjects which is statistically significant at the 0.05 level, suggesting that a decrease in TSH levels (thus indicating a shift towards hyperthyroidism) is associated with a concomitant increase in D-Dimer levels, implicating a proclivity for a hypercoagulable haemostatic state whereas an increase in TSH levels (thus indicating a shift towards hypothyroidism) are similarly associated with a concomitant decrease in D-Dimer levels, implicating a proclivity for a potential hypo-coagulable state.

Low T3 and T4 levels cause TSH levels to increase via a feedback mechanism. TSH acts on the thyroid gland and stimulates the release of T3 and T4. T3 and T4 in turn exert negative feedback mechanisms on TSH release. As for the elevated D-Dimer dependent procoagulant proclivity, in-vitro and clinical evidence implicate multiple mechanisms for this risk. Genomic functions of T3 via a nuclear thyroid hormone receptor have been suggested, but recent evidence indicates that nongenomic mechanisms initiated at the receptor for L-thyroxine (T4) on platelet integrin, αvβ3 are of a prothrombotic predisposition [4]. It is also possible that thyroid hormone stimulates the platelet-endothelial cell dynamics involved in local thrombus formation. Effects of TSH and resultant release of thyroid hormones not just at the receptor signaling level but at the physiological level on the the heart may also indirectly influence hemostasis. Hyperthyroidism leads to a higher incidence of atrial fibrillation and atrial flutter, and at least partially by that mechanism can result in a higher risk of cerebral arterial thrombosis. In addition, compressive manifestations of goitre on developing venous thrombosis have been ascribed to local stasis of blood because of tumor cell proliferation and neoplastic expansion [8]. Another study reviewed both hyper- and mild-to-moderate hypothyroidism to conclude that they are associated with prothrombotic plasma fibrin clot phenotype and that restoration of euthyroidism had improved fibrin clot properties with a return to normalcy of ex-vivo plasma fibrin clot permeability (Ks) in hyperthyroid and lysis tendency in hypothyroid patients [9]. Thyroxine released after TSH level elevation also increases the activity of HMG CoA reductase leading to increased synthesis of cholesterol. This increased risk of cholesterol-plaque mediated atherosclerosis could also lead to an increase in D-Dimer levels.

Our study confirms that TSH levels in euthyroid elderly individuals correlate negatively with TSH levels. This finding is beneficial for doctors in that they can suspect a risk of potential hypercoagulable state in the euthyroid elderly and provide prompt and appropriate therapy for the same.

No funding sources.

None declared.

The study was approved by the Institutional Ethics Committee.

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