Blood coagulation, fibrinolysis, and markers of endothelial dysfunction in systemic sclerosis

doi:10.1053/sarh.2002.50011

Seminars in Arthritis and Rheumatism

Volume 32, Issue 5, April 2003, Pages 285-295

https://doi.org/10.1053/sarh.2002.50011 Get rights and content

Abstract

Objective: To evaluate the coagulative/fibrinolytic cascade and the circulating markers of the endothelial injury in systemic sclerosis (SSc). Method: Plasma was obtained from 29 patients with SSc and tested for thrombin-antithrombin (TAT), fragments 1+2 (F1+2), dermatansulphate (DS), thrombomodulin (TM), lipoprotein (a) [Lp(a)], von Willebrand factor (vWF), tissue type plasminogen activator (tPA), plasminogen activator inhibitor (PAI), D-dimers, intercellular adhesion molecole-1 (ICAM-1), vascular cell adhesion molecule (VCAM), and E-selectin. The data were correlated with lung (forced vital capacity, diffusing lung capacity for carbon monoxide, vital capacity) and skin (skin score) involvement. Results: Coagulation was significantly activated (increase in F1+2, P <.001; TAT, P <.01; and Lp(a), P <.05). TM was not significantly different from controls. vWF was significantly increased (P <.01), and its supranormal multimers increased in more than 50% of patients. DS was significantly increased in diffuse cutaneous SSc (P <.01). Fibrinolysis was impaired as shown by reduced D-dimers (P <.01) and decreased levels of PAI (P < 0.01). The markers of endothelial injury were also significantly elevated. DS correlated significantly with forced vital capacity (P <.01) and forced vital capacity ratio (P <.01). Conclusion: Injury to the endothelium reduces endothelial function, as suggested by impairment of fibrinolysis and activation of the coagulative pathway. The loss of the balance between fibrinolysis and coagulation contributes to vessel engulfment with fibrin and breakdown of vessel patency. The increase of circulating DS suggests that this factor may be a new marker of endothelial injury. Semin Arthritis Rheum 32:285-295. Copyright 2003, Elsevier Inc. All rights reserved.

Section snippets

Patients and methods

We evaluated 29 consecutive nonsmoking patients with SSc, admitted to the Rheumatology Unit of University of Florence (13 patients) and to the Second University of Naples (16 patients) from January 1, 1998, to December 31, 1998.

No differences in clinical features were detected between patients enrolled in the 2 centers (Table 1; patients 1-5,12,19-25 from Florence Center, patients 6-11, 13-18, 26-29 from Naples Center). There were 12 patients who were classified as having diffuse cutaneous SSc

Results

The clinical characteristics of the patients and the results of the circulating parameters are reported in Tables 1 and 2, respectively.

Discussion

Our results show that the coagulative system is activated in patients with dSSc and lSSc , as shown by an increase of TAT and F1+2, which is in agreement with previous reports (8, 25, 26).

The coagulative abnormality is enhanced by the increase of Lp(a), mainly in lSSc. lSSc is characterized by a significant macrovascular involvement and atherosclerosis of the great vessels (27). Lp(a) is a low-density lipoprotein particle bound to apolipoprotein (a) that represents a risk factor of

Acknowledgements

The authors are indebted to the Association for Autoimmune Diseases (APAI) for their continuous support in this work.

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Systemic vasculitis can be a challenge to differentiate from other forms of vasculopathy. Because treatment for systemic vasculitis is disparate from that for other forms of vasculopathy, clinicians should strive for high diagnostic certainty. This review article aims to highlight the clinical, radiographic, and histologic clues to distinguish systemic vasculitis from mimics. Vasculitis should be considered in patients with preexisting conditions including autoimmune connective tissue diseases, multisystem manifestations, unexplained ischemic events, unusual radiographic findings, or signs of systemic inflammation. A multidisciplinary approach can be used among rheumatologists, vascular cardiologists, radiologists, and vascular interventionalists to raise diagnostic certainty in cases with large- and/or medium-vessel involvement. Recognition of cardiac manifestations, including myocarditis seen in forms of small-vessel vasculitis (eg, eosinophilic granulomatosis with polyangiitis) or coronary arteritis seen in forms of medium-vessel vasculitis (eg, polyarteritis nodosa and Kawasaki disease) is important owing to the associated mortality. Clinical phenotype, radiographic features, laboratory tests, and histology can help to differentiate vasculitis from noninflammatory vasculopathies and define the etiology of the vasculitis to help guide appropriate treatment. Various modalities of imaging can give clues to aid in diagnosis of vasculitis and can be considered in the context of physician preference and patient comorbidity. While conventional angiography can give important details regarding luminal anatomy and pressure gradients in medium- and large-vessel vasculitis, noninvasive imaging modalities such as computed tomographic angiography, magnetic resonance angiography, color Doppler ultrasound, and positron emission tomography/computed tomography are commonly used for both diagnosis and follow-up. Treatment for systemic vasculitis should be coordinated with an experienced rheumatologist.
Il peut être difficile de distinguer la vascularite systémique des autres formes de vasculopathie. Le traitement de la vascularite systémique étant différent de celui des autres formes de vasculopathie, les cliniciens doivent s’efforcer de confirmer le plus possible le diagnostic. La présente synthèse vise à mettre en évidence les indices cliniques, radiographiques et histologiques qui permettent de distinguer la vascularite systémique des autres affections qui lui ressemblent. Une vascularite doit être envisagée chez les personnes atteintes d’affections préexistantes, comme une maladie auto-immune du tissu conjonctif, des manifestations multisystémiques, des événements ischémiques inexpliqués, des observations anormales à la radiographie ou des signes d’inflammation généralisée. Une approche pluridisciplinaire peut être adoptée par les rhumatologues, les cardiologues vasculaires, les radiologues ainsi que les médecins interventionnels spécialisés dans la prise en charge des affections vasculaires afin d’accroître la certitude du diagnostic en cas d’atteinte de vaisseaux sanguins de gros ou de moyen calibre. Étant donné la mortalité qui leur est associée, il est important de déceler les manifestations cardiaques, y compris la myocardite accompagnant certaines formes de vascularite des vaisseaux de petit calibre (p. ex. granulomatose éosinophile avec polyangéite) et la coronarite accompagnant certaines formes de vascularite des vaisseaux de moyen calibre (p. ex., polyartérite noueuse et maladie de Kawasaki). Le phénotype clinique et les caractéristiques radiographiques de la maladie ainsi que les épreuves de laboratoire et l’analyse histologique peuvent aider à différencier la vascularite des vasculopathies non inflammatoires et à déterminer la cause de la vascularite afin d’aiguiller vers le traitement approprié. Diverses techniques d’imagerie peuvent fournir des indices pour faciliter le diagnostic de vascularite et être envisagées selon les préférences du médecin et des affections concomitantes du patient. Bien qu’une angiographie classique puisse donner de précieuses indications au sujet de l’anatomie luminale et des gradients de pression dans les vaisseaux de moyen et de gros calibre atteints par la vascularite, les techniques d’imagerie non invasives comme l’angiographie par tomodensitométrie, l’angiographie par résonance magnétique, l’échographie Doppler couleur ainsi que la tomographie par émission de positons et la tomodensitométrie sont couramment utilisées pour le diagnostic et le suivi. Le traitement de la vascularite systémique doit être coordonné avec un rhumatologue d’expérience.
Evaluation of the direct effects on retinal and choroidal microvascularity of systemic scleroderma
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Citation Excerpt :
Although the cause of Ssc is still not fully known, recent studies have shown that the substantial steps in the disease pathogenesis are the injury to the endothelium and immune activation (Altorok et al., 2014). The cause of fibrosis and vessel obstruction have thought to be caused by endothelial dysfunction (Cerinic et al., 2003). Raynaud's phenomenon is the most common manifestation of the SSc related endothelial dysfunction (Allanore et al., 2015).
Ocular involvement in systemic sclerosis (SSc) has been documented; however it cannot be distinguished from secondary changes due to concomitant hypertension.Therefore, the aim of this prospective cross-sectional study was to demonstrate the direct effects of Ssc on retinal and choroidal microvasculature in patients without hypertension.
47 SSc patients and 44 age- and sex-matched healthy control subjects were enrolled in this study. In fundus examination: Increased vascular tortitis, focal or general arteriolar narrowing, arteriovenous notch, severe exudation, microhemorrhage, and pigment epithelial changes in the retina of SSc patients without hypertension were investigated. Patients with at least two of the above findings were considered to have retinopathy After that, patients were divided into two groups according to the presence of retinopathy in this study. Retinal and choroidal microvasculature were evaluated using optical coherence tomography angiography.
There was a significant decrease in SSc patients with retinopathy in both superficial capillary plexus vessel density (SCP VD) and deep capillary plexus vessel density (DCP VD) compared to the control group. Full avascular zone (FAZ) evaluation tool variables (FAZ area, FAZ perimeter, foveal density) were significantly lower in all Ssc patients than in the healthy control group. It was found that the flow in the 1 mm and 3 mm circular area (Outer Retina 1–3 mm Flow Area) increased significantly in Ssc patients with retinopathy. Choroidal flow (Choriocapillaries 1 mm Flow Area) was statistically lower in Ssc patients with retinopathy.
We have showed an increase in the outer retina 1–3 mm flow area (circular area of the outer retina fold covering the fovea) despite the decrease in vascular density and choroidal thickness in scleroderma patients with retinopathy. Hence, we first demonstrated that Ssc itself may have an effect on retinal and choroidal microvasculature, independent of hypertension.
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The alteration of vascular permeability and vascular tone are the earliest signs of vascular dysfunction. In addition, activation of platelets and enhanced coagulation with reduced fibrinolysis further contribute to vasculopathy in SSc [6]. The endocannabinoid system (ECS) is composed by the G-protein couple receptors CB1 and CB2, endocannabinoids such as anandamide and 2-arachidonoyl glycerol, and the enzymes that regulated their synthesis and catabolism.
The endocannabinoid system (ECS) may play a role in the pathophysiology of systemic sclerosis (SSc). Cannabinoids acting as dual PPARγ/CB₂ agonists, such as VCE-004.8 and Ajulemic acid (AjA), have been shown to alleviate skin fibrosis and inflammation in SSc models. Since both compounds are being tested in humans, we compared their activities in the bleomycin (BLM) SSc model. Specifically, the pharmacotranscriptomic signature of the compounds was determined by RNA-Seq changes in the skin of BLM mice treated orally with AjA or EHP-101, a lipidic formulation of VCE-004.8. While both compounds down-regulated the expression of genes involved in the inflammatory and fibrotic components of the disease and the pharmacotranscriptomic signatures were similar for both compounds in some pathways, we found key differences between the compounds in vasculogenesis. Additionally, we found 28 specific genes with translation potential by comparing with a list of human scleroderma genes. Immunohistochemical analysis revealed that both compounds prevented fibrosis, collagen accumulation and Tenascin C (TNC) expression. The endothelial CD31⁺/CD34⁺ cells and telocytes were reduced in BLM mice and restored only by EHP-101 treatment. Finally, differences were found in plasmatic biomarker analysis; EHP-101, but not AjA, enhanced the expression of some factors related to angiogenesis and vasculogenesis. Altogether the results indicate that dual PPARγ/CB2 agonists qualify as a novel therapeutic approach for the treatment of SSc and other fibrotic diseases. EHP-101 demonstrated unique mechanisms of action related to the pathophysiology of SSc that could be beneficial in the treatment of this complex disease without current therapeutic options.
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Citation Excerpt :
In particular, vWF showed a positive predictive value of 83% and a negative predictive value of 100%. Interestingly, in all patients with RP, the increased levels of vWF were irrespective of the blood groups, apparently in contrast to what is usually observed in normal subjects, in which blood group 0 is associated with lower levels of vWF than non-0 group (Marasini et al., 1992; Herrick et al., 1996; Cerinic et al., 2003). Our findings of increased levels of vWF irrespective of blood groups could be explained by the presence of an ongoing vasculopathy with diffuse activation of the endothelial cells.
Raynaud's phenomenon (RP) can be the first manifestation of systemic sclerosis (SSc) or other connective tissue diseases (CTDs), often preceding an overt disease by years. It is not known if markers of endothelial damage are detectable in those RP patients who subsequently develop a CTD.
We studied 82 RP patients at their first evaluation to correlate the levels of endothelial markers with the subsequent development of an overt disease 36 months later. We measured plasma levels of tissue-type plasminogen activator (t-PA) and von Willebrand factor (vWF), two markers of endothelial damage, and interleukin-6 (IL-6), a pro-inflammatory cytokine. Thirty sex- and age-matched healthy subjects (HS) served as controls.
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Systemic sclerosis (SSc) is an autoimmune connective tissue disorder characterized by fibroproliferative vasculopathy, immunological abnormalities and progressive fibrosis of multiple organs including the skin. In this study, all English speaking articles concerning the role of endothelial cells (ECs) in SSc vasculopathy and representing biomarkers are systematically reviewed and categorized according to endothelial cell (EC) (dys)function in SSc.
A sensitive search on behalf of the EULAR study group on microcirculation in Rheumatic Diseases was developed in Pubmed, The Cochrane Library and Web of Science to identify articles on SSc vasculopathy and the role of ECs using the following Mesh terms: (systemic sclerosis OR scleroderma) AND pathogenesis AND (endothelial cells OR marker). All selected papers were read and discussed by two independent reviewers. The selection process was based on title, abstract and full text level. Additionally, both reviewers further searched the reference lists of the articles selected for reading on full text level for supplementary papers. These additional articles went through the same selection process.
In total 193 resulting articles were selected and the identified biomarkers were categorized according to description of EC (dys)function in SSc. The most representing and reliable biomarkers described by the selected articles were adhesion molecules for EC activation, anti-endothelial cell antibodies for EC apoptosis, vascular endothelial growth factor (VEGF), its receptor VEGFR-2 and endostatin for disturbed angiogenesis, endothelial progenitors cells for defective vasculogenesis, endothelin-1 for disturbed vascular tone control, Von Willebrand factor for coagulopathy and interleukin (IL)-33 for EC-immune system communication. Emerging, relatively new discovered biomarkers described in the selected articles, are VEGF₁₆₅b, IL-17A and the adipocytokines. Finally, myofibroblasts involved in tissue fibrosis in SSc can derive from ECs or epithelial cells through a process known as endothelial-to-mesenchymal transition.
This systematic review emphasizes the growing evidence that SSc is primarily a vascular disease where EC dysfunction is present and prominent in different aspects of cell survival (activation and apoptosis), angiogenesis and vasculogenesis and where disturbed interactions between ECs and various other cells contribute to SSc vasculopathy.

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^*: Marco Matucci Cerinic, MD, PhD: Professor of Medicine; S Generini MD, PhD: Fellow in Rheumatology; A. Pignone, MD, PhD: Associate Professor of Medicine; S Guiducci, MD; A. Del Rosso, MD, PhD: Department of Medicine, Division of Rheumatology, University of Florence, Italy; G. Valentini, MD: Professor of Rheumatology; S. D'Angelo, MD: Fellow in Rheumatology; G. Cuomo, MD: Fellow in Rheumatology, Department of Clinical and Experimental Internal Medicine “F Magrassi,” Rheumatology Unit, II University of Naples, Italy; F. Marongiu, MD: Professor of Medicine; G. G. Sorano, MD: L. Fenu, MD: Institute of Internal Medicine, University of Cagliari, Italy; S. Cinotti, BsC; M. Morfini, MD: Department of Hematology and Hemophilia Center, University of Florence, Italy; D. Das, MD: Professor of Cardiology; R. Kalfin, PhD: Department of Cardiology, University Connecticut Health Center, Farmington, CT.

^**: Address reprint requests to Marco Matucci Cerinic, MD, PhD, Department of Medicine, Division of Rheumatology “Villa Monna Tessa,” viale Pieraccini 18, 50139 Italy. E-mail: [email protected]

^***: 0049-0172/03/3205-0002$30.00/0

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Blood coagulation, fibrinolysis, and markers of endothelial dysfunction in systemic sclerosis*,**,***

Abstract

Section snippets

Patients and methods

Results

Discussion

Acknowledgements

J Am Acad Dermatol

Fibrinolysis

Fibrinolysis

J Dermatol Sci

J Biol Chem

Thromb Res

Blood

Blood

Thromb Res

Vascular involvement: pathogenesis

Arterial thrombosis in scleroderma

Br J Dermatol

Venous blood fibrinolysis and fibrinolytic potential in primary Raynaud's phenomenon and systemic sclerosis associated with Raynaud's phenomenon

Cutaneous and plasma fibrinolytic activity in systemic sclerosis: evidence of a normal plasminogen activation

Int J Dermatol

Cutaneous fibrinolytic activity in scleroderma

Clin Exp Rheumatol

von Willebrand factor, thrombomodulin, thromboxane, thromboglobulin and markers of fibrinolysis in primary Raynaud's phenomenon and systemic sclerosis

Ann Rheum Dis

The coagulation/fibrinolysis balance in systemic sclerosis: evidence for a haematological stress sindrome

Br J Rheumatol

Scleroderma (systemic sclerosis): classification, subsets and pathogenesis

J Rheumatol

Detection of the prothrombotic state due to procoagulant imbalance

Eur J Haemost

Determination of human thrombin-antithrombin III complex in plasma with an enzyme-linked immunosorbent assay

Thromb Haemost

Determination of human prothrombin activation fragment 1+2 and TAT in plasma with antibody against a synthetic peptide

Thromb Haemost

Activation of heparin cofactor II by dermatan sulphate

J Biol Chem

A simple method to measure dermatan sulphate at sub-microgram conceentration in plasma

Thromb Haemost

Circulating thrombomodulin as a novel endothelial cell marker: comparison of its behaviour with von Willebrand factor and tissue type plasminogen activator

Am J Hematol

Increased factor VIII/von Willebrand factor antigen and von Willebrand factor activity in scleroderma and in Raynaud's phenomenon

Ann Int Med

von Willebrand Factor levels in hypertrophic osteoarthropathy

J Rheumatol

Subunit composition of plasma von Willebrand factor. Cleavage is present in normal individuals, increased in IIA and IIB von Willebrand disease, but minimal in variants with aberrant structure of individual oligomers (types IIC, IID, and IIE)

J Clin Invest

A new adaptation of COA-SET PAI measurement of low inhibitor concentration in plasma

Fibrinolysis

Measurement of cross-linked fibrin derivatives in plasma: an immunoassay using monoclonal antibodies

J Clin Pathol

Anti-endothelial cell antibodies in systemic sclerosis: significant association with vascular involvement and alveolo-capillary impairment

Clin Exp Rheumatol

A modified scleroderma skin scoring method

Clin Exp Rheumatol

The clinical significance of coagulation abnormalities in systemic sclerosis (scleroderma)

J Rheumatol

Increased prevalence of symptomatic macrovascular disease in systemic sclerosis

Ann Rheum Dis

Detection and quantitation of lipoprotein (a) in the arterial wall of 107 coronary artery patients

Arteriosclerosis

Serum lipoprotein (a) and apolipoprotein (a) phenotypes in patients with rheumatoid arthritis

Arthritis Rheum

Lipoprotein (a) levels in systemic lupus erythematosus

J Rheumatol

Elevated plasma lipoprotein (a) level and its association with impaired fibrinolysis in patients with antiphospholipid syndrome

J Rheumatol

Factors influencing the accumulation in fibrous plaques of lipid derived from low density lipoprotein (a)

Atherosclerosis

Blood coagulation, fibrinolysis, and markers of endothelial dysfunction in systemic sclerosis,,