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Concizumab is a monoclonal, humanized IgG4 antibody specific for the Kunitz-2 domain of Tissue Factor Pathway Inhibitor (TFPI). Preclinical studies in vitro or on animal models and in vivo have demonstrated the ability of concizumab to restore thrombin generation, promoting the establishment of a procoagulant action; all these results were subsequently confirmed in the studies of EXPLORER program. Concizumab may represent a new opportunity for the treatment of persons with hemophilia, so there is much anticipation for the results of the ongoing trials still. This review retraces all the studies on concizumab published to date, with a brief discussion about the patient' perspectives.

Background The D-dimer (DD) assay is an essential biological test for the diagnosis and monitoring of thrombotic conditions. DD testing is usually not performed as part of the routine laboratory management of patients with hemophilia (PWH). There is an increasing concern about the risk of thrombotic complications in PWH, which is likely related to age, cardiovascular risk factors, invasive thrombogenic procedures, over-correction of Factor VIII (FVIII) or FIX, or administration of new therapeutic agents mimicking FVIII or rebalancing coagulation. Objective This retrospective study sought to assess the basal DD levels in PWH treated prophylactically with FVIII, and to evaluate potential changes after switching to emicizumab. Method Patients over 18 years of age treated with emicizumab within a single center over the period 2017-2022 were included in the study. Result DD levels were measured in 40 adult PWH (37 severe/ three moderate / two with FVIII inhibitor) with a median age of 46 years (range: 19-82; Q1-Q3: 30,25-56,5), before and at least 3 months after emicizumab initiation. No significant changes were revealed, with DD median values of 257 ng/mL (range: 250-2876; Q1-Q3: 250-493,5) before and 250 ng/mL (range: 50-6205; Q1-Q3: 250-380,25) after the switch (p  =  0.9). Conclusion Most adult PWH on prophylaxis using FVIII display DD levels within the normal range, which remain unchanged after switching to emicizumab. In view of these reassuring results, monitoring of DDs at the start of emicizumab treatment does not appear necessary but could be considered when combined with other bypassing agents or high dose FVIII.

The unprecedented progress in addressing unmet needs in haemophilia care to date includes developing several novel therapies that rebalance haemostasis by restoring thrombin generation in patients with haemophilia A or B with and without inhibitors. These novel therapies are FVIII mimetics, antithrombin interference RNA therapy and several monoclonal antibodies directed against the tissue factor pathway inhibitor (anti-TFPI). In this review, we provide an update on the progress made in developing anti-TFPI therapie. Phase 1 data from the three anti-TFPI studies showed acceptable safety profiles, and currently, available phase 2 data are encouraging. While these data support these molecules' further development progression, there is uncertainty on several aspects of their evolution. Two of the three anti-TFPIs have shown drug-related thrombosis, with one study consequently terminated. None of the thrombotic events is predictable with current monitoring tools, and none correlate with known coagulation parameters. All three anti-TFPIs undergo target mediated drug disposition, which impacts the formulation of dosing regimen fo these therapies. They would require more frequent dosing than some of the extended half-life clotting factor products and antithrombin RNAi therapy. There is no assay to measure the TFPI as the physiological levels are very low, which makes monitoring the impact of the anti-TFPI a challenge. The anti-TFPIs have several advantages, including their bioavailability when administered subcutaneously, their stable pharmacokinetics and their ability to prevent bleeds in haemophilia A or B patients with and without inhibitors. Whether these advantages can be realized will depend on the outcome of the currently ongoing studies.

Thrombosis is a frequent manifestation in patients with systemic lupus erythematosus (SLE), although precise mechanisms remain unclear. This study investigated whether the major physiological trigger of blood coagulation, the tissue factor (TF) pathway, was altered in SLE patients. Furthermore, we investigated potential associations between the TF pathway, the presence of antiphospholipid (APL) antibodies and other abnormalities present in SLE. A total of 101 participants (40 SLE patients and 61 age- and sex-matched controls) were recruited from Tasmania, Australia. Markers of the TF pathway, hypercoagulability, inflammation and endothelial cell damage were measured in plasma. Serum levels of APL antibodies (anti-cardiolipin antibodies [ACL], lupus anticoagulants [LAC], anti-beta2-glycoprotein-1 [anti-β2GP1] and anti-prothrombin antibodies) were also determined. Despite similar TF and TF pathway inhibitor (TFPI) total antigen levels, SLE patients had significantly increased levels of TFPI free antigen (patients vs controls; mean ± SD) (11.6 ± 0.9 ng/mL vs 6.4 ± 0.4 ng/mL; p < 0.001) but significantly reduced TFPI activity (0.66 ± 0.07 U/mL vs 1.22 ± 0.03 U/mL; p < 0.001), compared with healthy controls. Anti-TFPI activity, designated as the ability of isolated IgG fractions to inhibit TFPI activity in normal plasma, was detected in 19/40 (47.5%) of SLE patients and 3/40 (7.5%) of healthy controls. The significant reduction in TFPI activity in SLE patients reflects impaired functional control of the TF pathway. Moreover, SLE patients with a history of thrombosis demonstrated higher levels of TFPI activity compared with patients without a previous thrombotic event (0.97 ± 0.07 U/mL vs 0.53 ± 0.14 U/mL; p = 0.0026). Changes to the TF pathway were not associated with manifestations of SLE such as inflammation or endothelial cell damage. The results from this study suggest hypercoagulability in SLE may (in part) be due to reduced TFPI activity, a mechanism that appears to be independent of other abnormalities in SLE.