Antiprothrombin antibodies are heterogeneous and their clinical relevance depends on the method of detection applied. Positive results on the aPS/PT test can serve as a marker of thrombotic events in patients with autoimmune diseases.

In 2012, the Japan Gastroenterological Endoscopy Society published "Guidelines for Gastroenterological Endoscopy in Patients Undergoing Antithrombotic Treatment" concerning thromboembolism associated with antithrombotic therapy withdrawal. Since then, physicians have started prescribing oral anticoagulants, creating a need for standards reflecting their use in clinical practice. Therefore, new findings regarding anticoagulants are included in this appendix. However, the evidence levels are low for many statements contained herein and these appended guidelines still need to be verified in clinical settings.

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␤ 2 -Glycoprotein I (␤ 2 -GPI) is proteolytically cleaved by plasmin in domain V (nicked ␤ 2 -GPI), being unable to bind to phospholipids. This cleavage may occur in vivo and elevated plasma levels of nicked ␤ 2 -GPI were detected in patients with massive plasmin generation and fibrinolysis turnover. In this study, we report higher prevalence of elevated ratio of nicked ␤ 2 -GPI against total ␤ 2 -GPI in patients with ischemic stroke (63%) and healthy subjects with lacunar infarct (27%) when compared to healthy subjects with normal findings on magnetic resonance imaging (8%), suggesting that nicked ␤ 2 -GPI might have a physiologic role beyond that of its parent molecule in patients with thrombosis. Several inhibitors of extrinsic fibrinolysis are known, but a negative feedback regulator has not been yet documented. We demonstrate that nicked ␤ 2 -GPI binds to Glu-plasminogen with K D of 0.37 ؋ 10 ؊6 M, presumably mediated by the interaction between the fifth domain of nicked ␤ 2 -GPI and the fifth kringle domain of Glu-plasminogen. Nicked ␤ 2 -GPI also suppressed plasmin generation up to 70% in the presence of tissue plasminogen activator, plasminogen, and fibrin. Intact ␤ 2 -GPI lacks these properties. These data suggest that ␤ 2 -GPI/plasmin-nicked ␤ 2 -GPI controls extrinsic fibrinolysis via a negative feedback pathway loop. Introduction␤ 2 -Glycoprotein I (␤ 2 -GPI), also known as apolipoprotein H, is a phospholipid-binding plasma protein. Phospholipid-bound ␤ 2 -GPI is one of the major target antigens for antiphospholipid antibodies 1-3 present in patients with antiphospholipid syndrome (APS), an autoimmune disorder characterized by arterial/venous thrombosis and pregnancy morbidity. 4 ␤ 2 -GPI has 5 homologous short consensus repeats, designated as domains I to V. Domains of ␤ 2 -GPI structurally resemble each other, except that domain V has an extra C-terminal loop and a positively charged lysine cluster. In 1993, Hunt et al 5 reported that ␤ 2 -GPI is proteolytically cleaved between Lys317 and Thr318 in domain V (nicked ␤ 2 -GPI), being unable to bind to phospholipids. This cleavage is generated by factor Xa or by plasmin, with plasmin being more effective. 6 A large number of reports have detailed the in vitro properties of ␤ 2 -GPI as a natural anticoagulant/procoagulant regulator by inhibiting phospholipid-dependent reactions, such as prothrombinase and tenase activity on platelets or phospholipid vesicles, 7,8 factor XII activation, 9 and anticoagulant activity of activated protein C. 10,11 Apart from specific hemostatic functions, ␤ 2 -GPI activates lipoprotein lipase, 12 lowers the triglyceride level, 13 binds to oxidized low-density lipoprotein to prevent the progression of atherosclerosis, 14 and binds to nonself particles or apoptotic bodies to allow their clearance. [15][16][17] Little attention has been given to the functions of the nicked form of ␤ 2 -GPI because its phospholipidbinding activity was thought to exert the physiologic or pathologic functions of ␤ 2 -GPI.Fibrinolytic reactions ...

The presence of anti-PS/PT greatly correlated with increased thrombin generation in APS patients. The in vitro effects of monoclonal antibody 231D on thrombin generation are "biaxial" according to the FVa/FXa balance. These data may serve as a clue to understanding the LAC paradox and the thrombogenic properties of anti-PS/PT.

To cite this article: Kumano O, Ieko M, Naito S, Yoshida M, Takahashi N. APTT reagent with ellagic acid as activator shows adequate lupus anticoagulant sensitivity in comparison to silica-based reagent. J Thromb Haemost 2012; 10: 2338-43.Summary. Background: Lupus anticoagulant (LA) is an antibody that interferes with phospholipid-dependent coagulation reactions. Activated partial thromboplastin time (APTT) is widely used as a test for LA screening. APTT reagents are composed of activators, such as silica or ellagic acid, and phospholipids, and APTT reagents with silica are recommended for LA screening because of greater sensitivity. However, the effects of activators on LA activity have not been adequately investigated. Objectives: In this study, we examined whether an ellagic acid-based reagent was highly sensitive to LA in a low phospholipid condition and useful for LA screening. Methods: Silica-based (SL) and ellagic acid-based (EA) reagents were prepared inhouse with the same composition and concentration of phospholipids, while the commercial APTT reagents APTT-SLA (SLA), Actin FSL (FSL), APTT-SP (SP) and PTT-LA (PTT) were also included in the study. Results: The normal reference ranges for SL and EA were 30.1-47.0 and 28.0-40.2 s, respectively, while the cut-off index values for circulating anticoagulant activity (ICA) calculated from the results obtained with SL, EA, SLA, FSL, SP and PTT were 12. 9, 11.5, 13.2, 15.6, 14.3 and 14.0, respectively. The sensitivity of those reagents based on those cut-off values was 91%, 96%, 68%, 46%, 91% and 86%, respectively. Conclusions: Our results showed that the ellagic acid-based reagent was more sensitive to LA than silica-based reagents in a low phospholipid condition and had adequate sensitivity to detect LA. We concluded that the sensitivity of APTT reagents for LA is dependent on phospholipid concentration and not the activator.

Acquired hemophilia A (AHA), which is caused by autoantibodies against coagulation factor VIII (FVIII) is a rare, life-threatening bleeding disorder, the incidence of which appears to be increasing in Japan as the population ages. However, the clinical characteristics, treatment, and outcomes of AHA remain difficult to establish due to the rarity of this disease. We retrospectively analyzed data from 25 patients (median age 73 years; range 24-92 years; male n = 15) diagnosed with AHA between 1999 and 2015 at Gunma University Hospital. We identified autoimmune diseases and malignancy as underlying conditions in four and three patients, respectively. Factor VIII activity was significantly decreased in all patients (median 2.0%; range <1.0-8.0) by FVIII inhibitor (median 47.0 BU/mL; range 2.0-1010). Among 71 bleeding events, subcutaneous or intramuscular hemorrhage was the most prevalent. Seventeen patients required bypassing agents. Twenty-two (91.7%) of 24 patients treated with immunosuppressive agents achieved complete response (CR) during a median of 57.5 days (range 19-714 days). Although three patients (12%) relapsed and seven (28%) died of infection, none of the deaths were related to bleeding. Although most of our patients achieved CR after immunosuppressive therapy, the rate of infection-related mortality was unsatisfactorily high.