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      Coagulation and fibrinolysis in hyperparathyroidism secondary to vitamin D deficiency

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          Abstract

          Introduction

          Abnormal coagulation tests have been observed in patients with primary hyperparathyroidism (HPT) suggesting a prothrombotic effect of parathyroid hormone (PTH). Vitamin D deficiency (VIDD) is the most frequent cause of secondary HPT. Aim of our study was to investigate the influence of HPT secondary to moderate-to-severe VIDD and vitamin D replacement on the coagulation and fibrinolysis system.

          Subjects and methods

          Prospective cohort study of patients with vitamin D <25 nmol/L with and without HPT, and a control group of patients on vitamin D suppletion. At baseline and after 2 months of vitamin D suppletion (900,000 IU in 2 months), endocrine and coagulation markers were measured.

          Results

          59 patients with VIDD of which 34 had secondary HPT and 36 controls were included. After 2 months of suppletion, vitamin D increased by 399% (VIDD with HPT), 442% (all patients with VIDD) and 6% (controls). PTH decreased by 34% (VIDD with HPT, P < 0.01 for decrease), 32% (all VIDD, P < 0.01) and increased by 8% in the controls ( P-values: <0.01 for relative changes between VIDD with HPT or all VIDD patients vs controls). Relative changes in PT, aPTT, fibrinogen, Von Willebrand factor, factors VII, VIII and X, thrombin generation, TAFI, clot-lysis time and d-dimer were not different between patients with VIDD with HPT or all VIDD vs controls.

          Discussion

          Secondary HPT due to VIDD does not have a prothrombotic effect. In contrast with previous reports, PTH does not seem to influence coagulation or fibrinolysis, which is relevant because of the high prevalence of VIDD.

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          Most cited references20

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          Bidirectional relation between inflammation and coagulation.

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            Primary hyperparathyroidism and heart disease--a review.

            Primary hyperparathyroidism (pHPT), caused by solitary parathyroid adenomas in 85% of cases and diffuse hyperplasia in most of the remaining cases, overproduces parathyroid hormone (PTH), which mobilizes calcium to the blood stream. Renal stones, osteoporosis and diffuse symptoms of hypercalcaemia, such as constipation, fatigue and weakness are well-known complications. However, in Western Europe and North America, patients with pHPT are nowadays usually discovered during an early, asymptomatic phase of the disease. It has been reported that patients suffering from symptomatic pHPT have increased mortality, mainly due to an overrepresentation of cardiovascular death. pHPT is reported to be associated with hypertension, disturbances in the renin-angiotensin-aldosterone system, and structural and functional alterations in the vascular wall. Recently, studies have indicated an association between pHPT and heart disease, and studies in vitro have produced a number of theoretical approaches. An increased prevalence of cardiac structural abnormalities such as left ventricular hypertrophy (LVH) and valvular and myocardial calcification has been observed. Associations have been found between PTH and LVH, and between LVH and serum calcium. LV systolic function does not seem to be affected in patients with pHPT, whereas any influence on LV diastolic performance needs further evaluation. The aim of this review is to clarify the connection between pHPT and cardiac disease.
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              Parathyroid hormone secretion and action: evidence for discrete receptors for the carboxyl-terminal region and related biological actions of carboxyl- terminal ligands.

              PTH is a major systemic regulator of the concentrations of calcium, phosphate, and active vitamin D metabolites in blood and of cellular activity in bone. Intermittently administered PTH and amino-terminal PTH peptide fragments or analogs also augment bone mass and currently are being introduced into clinical practice as therapies for osteoporosis. The amino-terminal region of PTH is known to be both necessary and sufficient for full activity at PTH/PTHrP receptors (PTH1Rs), which mediate the classical biological actions of the hormone. It is well known that multiple carboxyl-terminal fragments of PTH are present in blood, where they comprise the major form(s) of circulating hormone, but these fragments have long been regarded as inert by-products of PTH metabolism because they neither bind to nor activate PTH1Rs. New in vitro and in vivo evidence, together with older observations extending over the past 20 yr, now points strongly to the existence of novel large carboxyl-terminal PTH fragments in blood and to receptors for these fragments that appear to mediate unique biological actions in bone. This review traces the development of this field in the context of the evolution of our understanding of the "classical" receptor for amino-terminal PTH and the now convincing evidence for these receptors for carboxyl-terminal PTH. The review summarizes current knowledge of the structure, secretion, and metabolism of PTH and its circulating fragments, details available information concerning the pharmacology and actions of carboxyl-terminal PTH receptors, and frames their likely biological and clinical significance. It seems likely that physiological parathyroid regulation of calcium and bone metabolism may involve receptors for circulating carboxy-terminal PTH ligands as well as the action of amino-terminal determinants within the PTH molecule on the classical PTH1R.
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                Author and article information

                Journal
                Endocr Connect
                Endocr Connect
                EC
                Endocrine Connections
                Bioscientifica Ltd (Bristol )
                2049-3614
                February 2018
                09 January 2018
                : 7
                : 2
                : 325-333
                Affiliations
                [1 ]Department of Internal Medicine Medical Center Slotervaart, Amsterdam, the Netherlands
                [2 ]Department of Vascular Medicine Academic Medical Center, University of Amsterdam, Amsterdam, the Netherlands
                [3 ]Laboratory of Experimental Intensive Care and Anesthesiology Academic Medical Center, University of Amsterdam, the Netherlands
                [4 ]Department of Experimental Vascular Medicine Academic Medical Center, University of Amsterdam, Amsterdam, the Netherlands
                [5 ]Department of Plasma Proteins Sanquin Research, Amsterdam, the Netherlands
                [6 ]Clinical Chemistry Laboratory Medical Center Slotervaart, Amsterdam, the Netherlands
                [7 ]Department of Endocrinology and Metabolism Academic Medical Center, University of Amsterdam, Amsterdam, the Netherlands
                Author notes
                Correspondence should be addressed to E Fliers: e.fliers@ 123456amc.uva.nl
                Article
                EC170249
                10.1530/EC-17-0249
                5820989
                29317405
                b39653dd-45c5-40cc-97fe-8d4a29e9d07d
                © 2018 The authors

                This work is licensed under a Creative Commons Attribution-NonCommercial-NoDerivatives 4.0 International License..

                History
                : 15 December 2017
                : 09 January 2018
                Categories
                Research

                coagulation,fibrinolysis,parathyroid hormone,secondary hyperparathyroidism,vitamin d deficiency

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