Prothrombin Is Responsible for the Lupus Cofactor Phenomenon in a Patient with Lupus Anticoagulant/Hypoprothrombinemia Syndrome

Abstract

Lupus anticoagulant is a misnomer as it is commonly associated with thromboembolic events. In few cases, the name retains its literal meaning when it characterizes patients with a bleeding disorder. We describe a patient with lupus anticoagulant, hypoprothrombinemia, and major bleeding (lupus anticoagulant/hypoprothrombinemia syndrome). Immunological studies revealed a huge amount of circulating monoclonal immunoglobulin M lambda (IgMλ) antiphosphatidylserine/prothrombin antibodies (14,400 U/mL). Affinity purified monoclonal antibodies (440 U/mL) prolonged the coagulation time of normal plasma by 12.2 seconds (diluted Russell viper venom time) and 25.5 seconds (silica clotting time). The original patient's plasma mixed 1:1 with normal plasma showed a marked prolongation of coagulation times (lupus cofactor) from a ratio of 2.94 to 5.23 in diluted Russel viper venom time and from 2.30 to 3.00 using the silica clotting time. Human prothrombin added to original patient's plasma caused a marked prolongation of coagulation times in diluted Russell viper venom test thus unequivocally explaining the lupus cofactor phenomenon. In conclusion, we have shown that lupus anticoagulant/hypoprothrombinemia syndrome is attributable to monoclonal IgMλ antibodies directed to phosphatidylserine/prothrombin and that prothrombin is the protein responsible for the observed lupus cofactor phenomenon.

Testing for Lupus Anticoagulants

“…This is thought to arise due to a deficiency of a cofactor required by LA to exert their in vitro anticoagulant effect, which is replenished in the mixing test. Candidates for the cofactor are, perhaps unsurprisingly, prothrombin 98 and β2GPI, 99 while the prozone effect is an alternative explanation. 100 Practically speaking, guidelines from the British Society of Haematology (BSH) and the ISTH suggest immediately reflexing to confirm and mixing tests upon finding an elevated screen.…”

“…This is thought to arise due to a deficiency of a cofactor required by LA to exert their in vitro anticoagulant effect, which is replenished in the mixing test. Candidates for the cofactor are, perhaps unsurprisingly, prothrombin 98 and β2GPI, 99 while the prozone effect is an alternative explanation. 100…”

Diagnostic Challenges on the Laboratory Detection of Lupus Anticoagulant

“…Although in most situations this procedure might be valid, there are certain types of LA that behave peculiarly. To express their anticoagulant activity, they require a plasma co-factor (called lupus co-factor [12]) that could be occasionally absent in the patient plasma. In this situation LA cannot prolong adequately the clotting time of the screen procedure but the prolongation becomes much more evident in the mix procedure when the normal plasma provides adequate amount of the missing co-factor.…”

“…In those instances, skipping the mix procedure increases the chance of missing the diagnosis of this particular type of LA. The identity of the lupus co-factor has not yet been accurately established although there are hints that favor prothrombin (factor II) as the most probable candidate [12]. The incidence of this peculiar lupus co-factor in the general population of patients positive for LA is unknown and is probably rare.…”

Thrombin generation assay and lupus anticoagulant synergically distinguish populations of patients with antiphospholipid antibodies

“…In fact, LA is a functional assay that analyses the prolongation of clotting time caused by aPL. The LA phenomenon is thought to be caused mostly by antibodies directed against the β2GPI and, more recently, aPS/PT 6 19 20. However, the actual contribution of aPS/PT antibodies on LA phenomenon and its potential significance, is debated.…”