The Antiphospholipid Syndrome

Ronald A. Asherson

• Publisher: CRC Press
• Year: 2018
• ISBN:
  9781351094023
• Edition: 1
• Topic: Medicina
• Subtopic: Immunologia

Written by the foremost researchers in the field, this book gathers together in a single source the many important clinical associations of antiphospholipid antibodies. Antibody-related clotting mechanisms and their relationship to conditions such as recurrent strokes, chorea, multi infarct dementias, a variety of spinal syndromes, Addison's Disease, recurrent miscarriages, and many more are discussed in depth. The importance of these antibodies in 'Primary, ' 'Secondary, ' and 'Catastrophic' Antiphospholipid Syndrome is highlighted. Each chapter is devoted to a specific internal system and the clinical effects this syndrome has on that system.
This authoritative book is an essential addition to medical libraries as well as an invaluable reference for general physicians, internists, rheumatologists, neurologists, cardiologists, nephrologists, endocrinologists, gastroenterologists, pulmonologists, dermatologists, and obstetricians.

Section II

Clinical and Laboratory Features of the Antiphospholipid Syndrome

Ronald A. Asherson and Ricard Cervera, Eds.

Chapter	9
Thrombotic Manifestations in the Antiphospholipid Syndrome — An Overview
Josep Ordi-Ros, Alberto Selva O’Callaghan, and Miguel Vilardell Tarrés

TABLE OF CONTENTS

I.	Introduction
II.	Studies on Venous and Arterial Thrombosis
III.	Venous and Arterial Thrombosis and Antiphospholipid Antibody-Related Disorders
IV.	Role of Antiphospholipid Antibodies in Thrombosis
V.	Vascular Syndromes with Antiphospholipid Antibodies
	A.	Central Nervous System Complications
	B.	Cardiac Complications
	C.	Hepatic Complications
	D.	Renal Complications
	E.	Skin Complications
VI.	Future Developments
References

I. INTRODUCTION

Antiphospholipid antibodies (aPL) are a family of immunoglobulins (IgG, IgM, IgA, or mixtures) which were originally thought to recognize anionic phospholipids (PL). Recent evidence supports specificity of aPL for protein-PL complexes rather than PL alone.^1,2 Some studies suggest aPL recognize proteins (β₂-glycoprotein I, prothrombin) in the absence of PL.³ In these studies, the protein targets for aPL have been exposed to negatively charged surfaces, allowing for potential reconfiguration of the protein and exposure of neoepitopes. A variety of proteins have been implicated as targets for aPL. These include: β₂-glycoprotein I, prothrombin, protein C, protein S, and placental anticoagulant protein. Therefore, it can be hypothesized that aPL are always directed against a combination of negatively charged phospholipids and a phospholipid-binding protein. The laboratory identification of aPL offers a plausible explanation for the remarkable clinical and laboratory heterogeneity of these antibodies.

The increased interest in the identification of aPL has been stimulated by the recognition of a number of clinical findings associated with the presence of these antibodies. Venous and arterial thromboembolic events, recurrent spontaneous fetal losses, thrombocytopenia, valvular heart disease, and dermatological manifestations such as skin necrosis, ulceration, or livedo reticularis have been described in association with aPL. Whether aPL are a cause, a consequence, or a coincidence remains unresolved. Recent prospective clinical studies as well as animal models have provided support for a causative role of aPL in the above enumerated clinical complications.⁴

The antiphospholipid syndrome (APS) is a disorder involving recurrent arterial or venous thrombosis, recurrent pregnancy losses, and thrombocytopenia associated with the presence of phospholipid-binding antibodies, including lupus anticoagulant (LA) and anticardiolipin antibodies (aCL). Antiphospholipid syndrome may arise as a primary disease⁵ or in patients with SLE (systemic lupus erythematosus) or other autoimmune, infectious, or neoplastic disorders (secondary APS). Our present knowledge about APS is derived from retrospective case series, case control studies, prospective follow-up studies, and very few therapeutic clinical trials. Patients in these investigations consistently presented broad laboratory and clinical heterogeneity. Thus, we still have to identify the risk factors that stratify patients according to the varying likelihood of developing clinical complications and that will enable us to focus future therapeutic clinical trials more appropriately.

II. STUDIES ON VENOUS AND ARTERIAL THROMBOSIS

A recent literature review and meta-analysis (Medline 1966 to 1989) to determine the prevalence of aPL, LA, and aCL in SLE and in non-SLE disorders and to evaluate the clinical significance of these autoantibodies as they relate to thromboembolic events, neuropsychiatric disorders, thrombocytopenia and fetal loss has been published. The results of this study of a predominantly retrospective series suggest that, for certain persons (patients with SLE or closely related disorders), aPL may be important risk factors for thrombosis, neurologic disease, thrombocytopenia, and fetal loss. Standardized tests for LA and aCL, as well as long-term, prospective clinical studies, are needed to determine the prognostic value of antiphospholipid antibodies.⁶ This analysis of 29 published series, comprising over 1000 patients with SLE, yielded an average frequency of 34% for LA and 44% for anticardiolipin antibodies. A statistically significant association existed between the presence of either antibody and a history of thrombosis. Contrary to prevailing opinion, no association between aPL and thrombosis has been shown conclusively in patients with non-SLE disorders.

The strength of the association between aPL and thrombosis has been estimated in retrospective studies, and the risk for aPL patients of developing ischemic stroke ranged from 2.33 to 10.6, while the risk for venous thromboembolism ranged between 2.7 and 11.9, compared with matched control subjects.⁷

Case control studies also have demonstrated that the association of aCL with venous thromboembolic disease was stronger in the presence of the following laboratory features: high levels and persistency of aCL IgG class and β₂-glycoprotein I (β₂-GPI) dependence. Serum protein β₂-GPI has recently been shown to act as a cofactor for aCL binding to phospholipids.⁸ The study group comprised 100 patients developing ischemic stroke and 90 with venous thromboembolism. Their baseline aCL levels were compared with those of matched controls. aCL levels above the 95th percentile (33GPL) were significant risk factors for venous thromboembolism but not for ischemic stroke. The importance of this study lies in the fact that it showed the presence of aCL before occurrence of the thrombotic event.⁹

The Antiphospholipid Antibodies (APA) Stroke Study Group evaluated 75 patients with cerebral or ocular ischaemia and reported 26 patients with recurrent stroke or transient ischemic attack, with a mean time of recurrence of 1.18 years. The total incidence was 18.7% per year for complete stroke and 15.2% per year for transient ischemic attacks. Recurrent events were increased by concomitant hypertension and coronary artery disease and decreased by treatment with antiplatelet drugs.¹⁰

Muir et al.¹¹ have carried out a prospective controlled study of 262 unselected patients with acute stroke and 226 controls to assess the prevalence and relationship to age and vascular risk factors of aCL. They found no evidence to support the hypothesis that aCL is an independent risk factor for stroke in young people. The increase in IgG titre with age and number of vascular risk factors in stroke patients suggests that aCL may be a nonspecific accompaniment of vascular disease and that routine testing for aCL in stroke patients is not justified.

The question whether primary APS (PAPS) or APS secondary to SLE were differently associated with recurrent thrombosis has been tackled recently;¹² 114 patients with a history of thrombosis and positive APA tests were followed for an average of 2 years. The total incidence of thrombosis was 3.5% per year, with no real difference between primary and SLE-associated APS. This confirms the data collected by the Italian Registry Group of aPL that has completed a 4-year prospective follow-up of 360 cases. The total incidence of thrombosis was 2.5% per year, and a history of thrombosis was the most important risk factor for subsequent vascular events.¹³

Other prospective studies in survivors of myocardial infarction were designed to assess the relationship between aPL and subsequent cardiovascular events. Antiphospholipid antibodies were consistently more common in postinfarction patients than in control subjects. Hamsten¹⁴ in 1986 reported a positive correlation between aCL and reinfarction, but this association was not always found by other authors.^{15, 16, 17, 18} In a multivariate analysis adjusted for major cardiovascular risk factors, aPL levels were not i...

Table of contents

• Cover
• Title Page
• Copyright Page
• Dedication
• Table of Contents
• Section I: EPIDEMIOLOGIC AND PATHOPHYSIOLOGIC ASPECTS OF THE ANTIPHOSPHOLIPID SYNDROME
• Section II: CLINICAL AND LABORATORY FEATURES OF THE ANTIPHOSPHOLIPID SYNDROME
• Section III: MANAGEMENT AND PROGNOSIS OF THE ANTIPHOSPHOLIPID SYNDROME
• Index