Chemokine Oligomers and the Impact of Fondaparinux Binding.

Heparin, a widely used clinical anticoagulant, is generally well-tolerated; however, approximately 1% of patients develop heparin-induced thrombocytopenia (HIT), a serious side effect. While efforts to understand the role of chemokines in HIT development are ongoing, certain aspects remain less studied, such as the stabilization of chemokine oligomers by heparin. Here, we conducted a combined ion mobility-native mass spectrometry study to investigate the stability of chemokine oligomers and their complexes with fondaparinux, a synthetic heparin analog. Collision-induced dissociation and unfolding experiments provided clarity on the specificity and relevance of chemokine oligomers and their fondaparinux complexes with varying stoichiometries, as well as the stabilizing effects of fondaparinux binding.

Population pharmacokinetics-pharmacodynamics of fondaparinux in dialysis-dependent chronic kidney disease patients undergoing chronic renal replacement therapy.

PURPOSE: Data on the anti-Xa efficacy of fondaparinux in dialysis-dependent chronic kidney disease (DD-CKD) patients are scarce. This study characterizes the pharmacokinetics (PK) and pharmacodynamics (PD) of fondaparinux in DD-CKD patients undergoing renal replacement therapy (RRT), to assess dosing strategies. METHODS: A retrospective, observational study was conducted using data on anti-Xa activity (112 samples) from 12 (3 male and 9 female) DD-CKD patients (median (IQR) age 71 years (63-88), weight 73 kg (59-98.5)). Eleven patients underwent high-flux or low-flux hemodialysis (HD) and one patient underwent peritoneal dialysis. Three patients were also treated with therapeutic plasma exchange (TPE). A non-linear mixed effects analysis was performed using NONMEM 7.3.0. RESULTS: The lab-specific slope of the relationship between fondaparinux concentration and anti-Xa levels was 1.18 IU/µg. In a one-compartment model, clearance (CL) and volume of distribution (Vd) were 0.05289 L/h and 5.55 L, respectively. High-flux HD was found to increase the CL of fondaparinux 2.26 times. TPE also considerably increased CL, but the fold-change could not be accurately estimated. Low-flux HD and peritoneal dialysis did not impact PK parameters. CONCLUSIONS: Model-based simulations showed that standard dosing (2.5 mg three times weekly before HD) results in a median anti-Xa activity of 0.55 IU/mL and 0.98 IU/mL, pre- and post-low-flux HD, respectively. In patients undergoing high-flux HD, these values are approximately 27% lower. Additional caution is warranted with TPE, as this treatment can reduce anti-Xa activity even further.

Fondaparinux Pre-, Peri-, and/or Postpartum for the Prophylaxis/Treatment of Venous Thromboembolism (FondaPPP).

We analyzed data for women who received fondaparinux for ≥7 days during pregnancy. The study retrospectively included women who received fondaparinux pre-, peri- and/or postpartum for ≥7 days for prophylaxis/venous thromboembolism (VTE) treatment at German specialist centers (2004-2010). Data on pregnancy, VTE risk factors, anticoagulant treatment, pregnancy outcome and adverse events were extracted from medical records. 120 women (mean age 31.5 years) were included. Among 84 women with prior pregnancies, 41.0% had ≥1 abortion. Anticoagulation was indicated for prophylaxis in 92.5% cases, including 82.5% women with an elevated VTE risk (82.8% thrombophilia, 34.2% VTE history). All women received low-molecular-weight heparin (LMWH) as first-line therapy; 3 also unfractionated heparin. Treatment changed to fondaparinux, due to heparin allergy (41.7%) or heparin-induced thrombocytopenia (10.0%). Fondaparinux was generally well tolerated. Adverse events included bleeding events (n = 5), abortion (n = 2), premature births (n = 2), stillbirth (n = 1), arrested labors (n = 2), injection site erythema (n = 4) and unspecified drug hypersensitivity (n = 6). No VTE events or increased liver enzymes occurred during treatment. In this retrospective study, fondaparinux was effective and well tolerated. Trial registration: ClinicalTrials.gov NCT01004939.

Effective use of fondaparinux in patient with unresponsiveness to nadroparin.

WHAT IS KNOWN AND OBJECTIVE: Fondaparinux exhibits a similar mechanism of action as LMWH. Since both of these drugs bind to antithrombin and increase its affinity to factor Xa, fondaparinux is not expected to be an effective alternative anticoagulant to LMWH in case of LMWH resistance. CASE SUMMARY: We report on a case of effective anticoagulation using fondaparinux following total unresponsiveness to high doses of nadroparin administered twice daily, as confirmed via repeated anti-Xa measurements. The antithrombin levels were within the normal range. WHAT IS NEW AND CONCLUSION: To the best of our knowledge, this is the first report of the effective use of fondaparinux in the case of unresponsiveness to LMWH.

Glycosaminoglycans bind human IL-27 and regulate its activity.

IL-27 is a cytokine of the IL-12 family, composed of EBI3 and IL-27p28. IL-27 regulates immune responses and also other physiological processes including hematopoiesis, angiogenesis, and bone formation. Its receptor, composed of IL-27Rα and gp130, activates the STAT pathway. Here, we show that different glycosaminoglycans (GAGs) modulate human IL-27 activity in vitro. We find that soluble heparin and heparan sulfate efficiently inhibit human IL-27 activity as shown by decreased STAT signaling and downstream biological effects. In contrast, membrane-bound heparan sulfate seems to positively regulate IL-27 activity. Our biochemical studies demonstrate that soluble GAGs directly bind to human IL-27, consistent with in silico analyses, and prevent its binding to IL-27Rα. Although murine IL-27 also bound to GAGs in vitro, its activity was less efficiently inhibited by soluble GAGs. Lastly, we show that two heparin-derivatives, low molecular weight heparin and fondaparinux, that like unfractionated heparin are used in clinics, had weaker or no effect on human IL-27 activity. Together, our data identify GAGs as new players in the regulation of human IL-27 activity that might act under physiological conditions and may also have a clinical impact in heparin-treated patients.

Anticoagulant therapy in the treatment of splanchnic vein thrombosis associated to acute pancreatitis: a 3-year single-centre experience.

Splanchnic vein thrombosis (SVT) is a possible complication of acute pancreatitis (AP). There are no precise guidelines on the use of anticoagulant therapy (AT) in these patients. The aim of the study was to determine the safety and the efficacy of AT in AP-associated SVT. Two hundred twenty-one patients were retrospectively and consecutively enrolled from the Pancreatic Outpatient Clinic of the "A. Gemelli" hospital. Patients had a diagnosis of AP and a diagnostic imaging to evaluate whether they had or not SVT. Twenty-seven out of 221 AP patients had SVT (12.21%) and AT therapy was administered to 16 patients (59.3%), for 5.2 ± 2.2 months. A therapeutic dose of low molecular weight heparin was administered (100 UI/kg b.i.d.) at the diagnosis, with fondaparinux 7.5 mg/day, or vitamin K antagonist, or the novel direct oral anti-coagulants, upon discharge. The presence of SVT resulted significantly associated to male sex (p = 0.002). The recanalization rates were 11/16 (68.7%) in patients who received AT, and 3/11 (27.3%) in patients who did not receive it. There was a significant difference between the recanalization rates with and without AT (p = 0.03, OR 5.87). No SVT recurrence was registered during follow-up. No treated patient developed haemorrhagic complications after AT. No deaths were recorded, either in the group undergoing AT or in the one that was not. In conclusion, AT in AP-associated SVT appears to be safe and effective; yet prospective clinical trials are needed to confirm our results.

From unfractionated heparin to pentasaccharide: Paradigm of rigorous science growing in the understanding of the in vivo thrombin generation.

Following a chance discovery made by a medical student who was searching for a clot-promoting activity in tissue extracts, it took 15-20 years to attain the therapeutic use of standard unfractionated heparin (UFH), due to problems with the purification and extraction of the active material. Soon it was found that: 1) thrombin inactivation by UFH was associated with the formation of molecular complexes between antithrombin and the activated forms of factor X (FXa) and thrombin, 2) low-molecular-weight fractions of UFH lose their antithrombin activity while still interacting with FXa, 3) a pentasaccharide sequence of UHF increases FXa (but not thrombin) inactivation by antithrombin. Low-molecular-weight heparins (LMWHs) with little effect on thrombin and strongly active versus FXa were then developed. In patients, LMWHs (and the pentasaccharide sequence) came up as a useful class of drugs to prevent and treat thrombosis, their greatest advantage over UFH being the convenience of the once/twice daily subcutaneous injections at a fixed dose without any laboratory monitoring. In addition to providing major information on in vivo modulation of thrombin generation, the heparin saga served as a paradigm to support an alternative coagulation scheme that includes platelets and tissue factor as integral parts of the model. Forthcoming work with this scheme - also supported by studies in hemophilia and rare bleeding disorders - is expected to provide major hints for understanding why some patients benefit more than others from the small amount of thrombin they form and directions to tailor prevention and treatment of thromboembolic disorders.

The clinical use of Fondaparinux: A synthetic heparin pentasaccharide.

Fondaparinux is a synthetic heparin pentasaccharide with a sequence identical to that found in anticoagulant heparin. It is a pure compound with a molecular weight of 1728Da. Fondaparinux catalyzes the conformational change of a serpin or serine protease inhibitor antithrombin III to accelerate the suicidal inactivation of factor Xa over 340-fold, which in turn inhibits thrombin generation in the coagulating signal transduction pathway. Fondaparinux does not inhibit thrombin activity, release tissue factor pathway inhibitor, or possess other properties of heparin such as anti-inflammatory, anti-viral, anti-angiogenesis, anti-neoplastic, and anti-metastatic effects though high affinity interactions with a variety of proteases, protease inhibitors, chemokines, cytokines, growth factors, and their respective receptors. Low antithrombin III levels in blood circulation also affects the efficacy of Fondaparinux. Thus, Fondaparinux represents a refined use of the anti-factor Xa property of heparin. As an anti-factor Xa drug, Fondaparinux has complete bioavailability subcutaneously, instant onset of action, a half-life of 15-20h, and a direct renal excretion without any metabolism. Fondaparinux has been shown to be superior to low molecular weight heparin in preventing deep vein thrombosis. Clinically, Fondaparinux is used for the prevention of deep vein thrombosis in patients who have had orthopedic surgery as well as for the treatment of deep vein thrombosis and pulmonary embolism with limitations of use in elderly, low weight, renal impaired patients and in those receiving spinal anesthesia. Clinical studies showed that Fondaparinux acts in prevention and treatment of venous thromboembolism and in ischemic heart disease without significant risk of bleeding.