Thrombosis and Haemostasis Pathophysiology of the Antiphospholipid Antibody Syndrome

The antiphospholipid syndrome is characterized by antibodies directed against phospholipid-binding proteins and phospholipids attached to cell membrane receptors, mitochondria, oxidized lipoproteins, and activated complement components. When antibodies bind to these complex antigens, cells are activated and the coagulation and complement cascades are triggered, culminating in thrombotic events and pregnancy morbidity that further define the syndrome. The phospholipid-binding proteins most often involved are annexins II and V, β2-glycoprotein I, prothrombin, and cardiolipin. A distinguishing feature of the antiphospholipid syndrome is the “lupus anticoagulant”. This is not a single entity but rather a family of antibodies directed against complex antigens consisting of β2-glycoprotein I and/or prothrombin bound to an anionic phospholipid. Although these antibodies prolong in vitro clotting times by competing with clotting factors for phospholipid binding sites, they are not associated with clinical bleeding. Rather, they are thrombogenic because they augment thrombin production in vivo by concentrating prothrombin on phospholipid surfaces. Other antiphospholipid antibodies decrease the clot-inhibitory properties of the endothelium and enhance platelet adherence and aggregation. Some are atherogenic because they increase lipid peroxidation by reducing paraoxonase activity, and others impair fetal nutrition by diminishing placental antithrombotic and fibrinolytic activity. This plethora of destructive autoantibodies is currently managed with immunomodulatory agents, but new approaches to treatment might include vaccines against specific autoantigens, blocking the antibodies generated by exposure to cytoplasmic DNA, and selective targeting of aberrant B-cells to reduce or eliminate autoantibody production. Corresponding Author: Affiliations: David Green, Northwestern University Feinberg School of Medicine, Medicine/Hematology/Oncology, Chicago, United States Submission Date: 2021-09-01 Accepted Date: 2021-11-03 Publication Date: Ac ce pt ed M an us cr ip t Th is a rt ic le is p ro te ct ed b y co py rig ht . A ll rig ht s re se rv ed . 2021-11-18 Pathophysiology of Antiphospholipid Syndrome Pathophysiology of Antiphospholipid Syndrome Abstract The antiphospholipid syndrome is characterized by antibodies directed against phospholipidbinding proteins and phospholipids attached to cell membrane receptors, mitochondria, oxidizedThe antiphospholipid syndrome is characterized by antibodies directed against phospholipidbinding proteins and phospholipids attached to cell membrane receptors, mitochondria, oxidized lipoproteins, and activated complement components. When antibodies bind to these complex antigens, cells are activated and the coagulation and complement cascades are triggered, culminating in thrombotic events and pregnancy morbidity that further define the syndrome. The phospholipid-binding proteins most often involved are annexins II and V, β2-glycoprotein I, prothrombin, and cardiolipin. A distinguishing feature of the antiphospholipid syndrome is the “lupus anticoagulant”. This is not a single entity but rather a family of antibodies directed against complex antigens consisting of β2-glycoprotein I and/or prothrombin bound to an anionic phospholipid. Although these antibodies prolong in vitro clotting times by competing with clotting factors for phospholipid binding sites, they are not associated with clinical bleeding. Rather, they are thrombogenic because they augment thrombin production in vivo by concentrating prothrombin on phospholipid surfaces. Other antiphospholipid antibodies decrease the clot-inhibitory properties of the endothelium and enhance platelet adherence and aggregation. Some are atherogenic because they increase lipid peroxidation by reducing paraoxonase activity, and others impair fetal nutrition by diminishing placental antithrombotic and fibrinolytic activity. This plethora of destructive autoantibodies is currently managed with immunomodulatory agents, but new approaches to treatment might include vaccines against specific autoantigens, blocking the antibodies generated by exposure to cytoplasmic DNA, and selective targeting of aberrant B-cells to reduce or eliminate autoantibody production. 1 Ac ce pt ed M an us cr ip t Th is a rt ic le is p ro te ct ed b y co py rig ht . A ll rig ht s re se rv ed . Pathophysiology of Antiphospholipid Syndrome Introduction In 1983 Hughes et al described a syndrome that included arterial and venous thromboses, strokes, and obstetrical disorders, and was associated with an anti-lipid antibody, the lupus anticoagulant (LAC). Despite its name, the LAC was observed to be a strong risk factor for thrombosis rather than bleeding, but why it behaved in this fashion was unclear. During the past 40 years, the LAC was associated with anti-phosphatidylserine/prothrombin(anti-PS/PT) antibodies, and a variety of other autoantibodies were identified that are directed against complexes of phospholipid, β2-glycoprotein I (β2-GPI), and other phospholipid-binding proteins. LAC and other autoantibodies that bind to phospholipid-binding proteins are designated antiphospholipid antibodies (APA), and contribute to the distinctive pathologic features of the antiphospholipid syndrome (APS).In this review, the several phospholipidbinding proteins are described, and the cellular receptors and other tissues that bind them are identified. Autoantibodies target these complexes and trigger pathologic processes that bring about thrombosis, premature atherosclerosis, and pregnancy morbidity. APS is classified as primary (no underlying disorder) or secondary (to infection, neoplasm, or other autoimmune disease). In a series of 100 patients with LAC, Triplett et al reported that 34% were drug-associated (chlorpromazine, quinidine, phenytoin, procainamide), 13% autoimmune, 10% infections, and 43% miscellaneous. Greaves classifies APS as secondary if it occurs in association with SLE or other connective tissue disorder, and primary if there is no underlying disorder. Campbell et al distinguish anticardiolipin antibodies (ACA) from individuals with primary APS from ACA in patients with syphilis; the former is specific for phosphatidylserine 2 Ac ce pt ed M an us cr ip t Th is a rt ic le is p ro te ct ed b y co py rig ht . A ll rig ht s re se rv ed . Pathophysiology of Antiphospholipid Syndrome (PS) and enhances agonist-induced platelet activation and aggregation. Although APA are present in 62% of patients with syphilis, leprosy, and human immunodeficiency virus infection, autoantibodies to tissue factor pathway inhibitor (anti-TFPI) are observed in ≤ 10% versus 38% in those with primary APS. Fewer thrombotic complications might be anticipated because thrombogenic autoantibodies are infrequent in secondary APS, but recent experience with Covid19 suggests this is not always the case. Antiphospholipid Syndrome Secondary to Covid-19 Infection In April, 2020, Zhang et al reported cerebral infarcts and antibodies to anti-β2-GPI and cardiolipin in three patients, and Harzallah et al detected LAC in 45% of 56 patients with Covid-19 infection. Another study found 31 of 34 patients had LAC, and the factor XII level was less than 50 IU/deciliter in 7% of 216 patients. Decreased factor XII has been observed previously in 20.9% of patients with LAC. An examination of serum samples from 172 hospitalized coronavirus patients reported high-titer antiphospholipid antibodies in 30%; most were IgM and directed against cardiolipin in 7.6%, β2-GPI in 4.1%, and phosphatidylserine/ prothrombin in 12%. Higher APA titers were associated with higher platelet counts, the release of more neutrophil extracellular traps (NETS), and more severe respiratory disease; injection of the antibodies into mice accelerated venous thrombosis. The incidence of confirmed venous thromboembolism in hospitalized Covid-19 patients is 4.8% and total thrombotic complications 9.5%, but in those requiring intensive care, thrombosis rates can be as high as 31% and correlate with evidence of antibody-induced platelet PS externalization and apoptosis. Autopsy data reveal megakaryocytes and platelet-fibrin thrombi in the lungs, heart, and kidneys. However, major thrombotic events are not associated with the APA, and the β2glycoprotein I (β2-GPI) epitopes targeted by the antibodies differ from those observed in patients 3 Ac ce pt ed M an us cr ip t Th is a rt ic le is p ro te ct ed b y co py rig ht . A ll rig ht s re se rv ed . Pathophysiology of Antiphospholipid Syndrome with APS. Although the high incidence of thrombosis appears to be related to the presence of APA, other factors associated with severe inflammation such as cytokines, complement factors, and NETS might be contributory. There appears to be little distinction between primary and secondary APS when clinical outcomes (thrombosis, strokes, organ damage) are considered. Phospholipid-binding Proteins (Table 1)