Scientific Calendar June 2021

Antiphospholipid syndrome (APS) is an acquired prothrombotic autoimmune disorder defined by arterial or venous thrombosis and/or pregnancy morbidity in patients who exhibit a persistent presence of antiphospholipid antibodies (aPL) – mostly IgG and IgM subtypes, but more rarely also IgA. [1] According to revised Sapporo criteria, APS is diagnosed based on clinical and laboratory criteria summarised in Table 1. Definite APS is considered present if at least one of the clinical and one of the laboratory criteria are met.

Table 1 Summary of classification criteria for APS according to Sydney revised Sapporo criteria classification

The syndrome can either be associated with an existing autoimmune disease, in which case it is called ‘secondary APS’ or, if there is no evidence of an existing underlying disease, it is called ‘primary APS’.

Most patients have primary APS (53%), while the others have secondary APS with underlying autoimmune diseases such as systemic lupus erythematosus (SLE), lupus-like syndrome, Sjögren’s syndrome or rheumatoid arthritis. Apart from the primary autoimmune diseases, several other diseases are associated with the development of aPLs. Most of them are infections and lymphoproliferative disorders.

The most common type of infection is viral, followed by bacterial, parasitic and fungal. Human immunodeficiency virus (HIV) and hepatitis C (HCV) viruses were the most frequent infections reported primarily in cases that developed thromboembolic events in the presence of aPLs. [2] ACA antibodies and anti-β2-GPI antibodies, mainly IgG and IgM isotypes, are most commonly detected in patients with HCV infections.

In most cases, these antibodies are transient (detectable for less than six months) without clinical consequences, but patients with persistent antibodies often show clinical features that meet the classification criteria for definite APS. Interestingly, anti-β2GPI antibodies are more transient and without clinical consequences in HCV-negative patients, whereas in HCV patients they appear to be associated with clinical features of persistent APS and/or catastrophic APS (CAPS). [2]

Patients with HCV are generally at a higher risk of developing clinical features that meet the classification criteria for CAPS and exhibit thrombocytopenia, peripheral thrombosis, stroke, myocardial infarction and renal vessel occlusion as main clinical features similarly found in patients with APS. [2]

The question as to whether aPLs associated with HCV are responsible for thrombotic events, i.e. lead to the development of (definite) APS, or whether there are other causes for the thrombosis, has been controversial until now.

The hypothesis that HCV-associated aPLs are responsible for the development of APS is based on the assumption that these antibodies are causally associated with thrombosis in other clinical situations (e.g. in patients with primary SLE). [3]

This assumption is however not supported by other published studies reporting that, for example, ACA antibodies could be detected, but only with low titres and often without β2GPI dependence (considered to be 'non-pathogenic'). The latter however seems to have since been refuted by an increasing number of case reports of patients showing that ACA, LA and anti-β2GPI with clinical consequences can occur in HCV-infected individuals and not just as a transient, non-pathogenic process. [2, 4-6]

Another hypothesis is that aPLs are a by-product of HCV infection but are not involved in the development of thrombotic events. This is based on the observation that even in the absence of a thrombotic event, higher prothrombin fragments F1 + 2 concentrations are detected in patients with HCV infection than in patients with another underlying disease (e.g. hepatitis B), regardless of whether aPLs were detected or not. It is therefore assumed that HCV itself, more so than the suspected APS, plays a role in thrombotic events that occur in chronic hepatitis, as there are indications that viruses also have procoagulant properties. [7]

Furthermore, antinuclear antibodies, cryoglobulins, hypocomplementemia, and rheumatoid factor are other findings that are common to both patients with APS and those with HCV. Cryoglobulinemia is closely linked to HCV infection, but it can also play a role in the development of secondary APS-related traits. [8]

The large number of patient cases with partly controversial conclusions as to whether or not HCV infection is possibly related to the pathogenesis of APS makes it difficult to make a recommendation for systematic aPL screening in patients with infections. Attending physicians should therefore be aware of a possible link in patients with signs and symptoms of infection and clinical features of APS. Furthermore, as most of the literature on the association between APS and HCV is from the interferon treatment era, predating the massive scale up of direct acting antiviral (DAA) treatment, it is not known what impact DAAs will have on this association.

[1] Miyakis S, Lockshin MD, Atsumi T, Branch DW, Brey RL, Cervera R, Derksen RH, De Groot PG, Koike T, Meroni PL, Reber G, Shoenfeld Y, Tincani A, Vlachoyiannopoulos PG, Krilis SA. International consensus statement on an update of the classification criteria for definite antiphospholipid syndrome (APS). J Thromb Haemost 2006; 4: 295–306.

[2] Noha Abdel-Wahab et al. Systematic Review of Case Reports of Antiphospholipid Syndrome Following Infection. Lupus. 2016 December; 25(14): 1520–1531.

[3] Love PE, Santoro SA. Antiphospholipid antibodies: anticardiolipin and the lupus anticoagulant in systemic lupus erythematosus and in non-SLE disorders: prevalence and clinical significance. Ann Intern Med 1990; 112: 682-698.

[4] Arruda VR, Bizzacchi JM, Metze IL. Hairy cell leukemia and multiple autoimmune manifestations in a human immunodeficiency virus-infected patient. Ann Hematol. 1993; 66:325–7. [PubMed: 7686405]

[5] Brown P, Crane L. Avascular necrosis of bone in patients with human immunodeficiency virus infection: report of 6 cases and review of the literature. Clinical Infectious Diseases. 2001; 32:1221–6. [PubMed: 11283813]

[6] R A Asherson, R Cervera. Antiphospholipid antibodies and infections. Ann Rheum Dis 2003; 62:388–393.

[7] Violi F et al. Letter to the editor: Hepatitis C Virus, Antiphospholipid Antibodies, and Thrombosis. Hepatology. March 1997. 782.

[8] Ramos-Casals M et al. Clinical Features Related to Antiphospholipid Syndrome in Patients with Chronic Viral Infections (Hepatitis C Virus/HIV Infection): Description of 82 Cases. Clinical Infectious Diseases 2004; 38:1009–16.