Antithrombotic Therapy for Venous Thromboembolic Disease

Direct oral anti–activated factor X and antithrombin agents have largely replaced vitamin K antagonists as the standard of care in treatment of venous thromboembolism. However, gaps in efficacy and safety persist, notably in end‐stage renal disease, implantable heart valves or assist devices, extracorporeal support of the circulation, and antiphospholipid syndrome. Inhibition of coagulation factor XI (FXI) emerges as a promising new therapeutic target. Antisense oligonucleotides offer potential advantages as a prophylactic or therapeutic modality, with one dose‐finding trial in orthopedic surgery already published. In addition, monoclonal antibodies blocking activation and/or activity of activated factor XI are investigated, as are small‐molecule inhibitors with rapid offset of action. Further potential targets include upstream components of the contact pathway such as factor XII, polyphosphates, or kallikrein. Finally, catheter‐directed, pharmacomechanical antithrombotic strategies have been developed for high‐ and intermediate‐risk pulmonary embolism, and large randomized trials aiming to validate their efficacy, safety, and prognostic impact are about to start.

Oral delivery of therapeutics is extremely challenging. The digestive system is designed in a way that naturally allows the degradation of proteins or peptides into small molecules prior to absorption. For systemic absorption, the intact drug molecules must traverse the impending harsh gastrointestinal environment. Technologies, such as enteric coating, with oral dosage formulation strategies have successfully provided the protection of non-peptide based therapeutics against the harsh, acidic condition of the stomach. However, these technologies showed limited success on the protection of therapeutic proteins and peptides. Importantly, inherent permeability coefficient of the therapeutics is still a major problem that has remained unresolved for decades. Addressing this issue in the context, we summarize the strategies that are developed in enhancing the intestinal permeability of a drug molecule either by modifying the intestinal epithelium or by modifying the drug itself. These modifications have been pursued by using a group of molecules that can be conjugated to the drug molecule to alter the cell permeability of the drug or mixed with the drug molecule to alter the epithelial barrier function, in order to achieve the effective drug permeation. This article will address the current trends and future perspectives of the oral delivery strategies.

Over a 7-year period, the chart records of six pregnant women with cardiac diseases at potential risk of thromboembolism were reviewed. All six patients survived and recovered well eventually. LMWH and beta-adrenergic blocker were effective to deal with atrial fibrillation. Digitalis and dobutamine were beneficial to prevent heart failure resulted from degenerated porcine valve and dilated cardiomyopathy. In a patient with mechanical mitral valve, low-dose warfarin did not cause fetal malformation, and was effective to prevent thrombus formation. Protamine sulfate was safely administered to neutralize intravenous heparin effect before vaginal delivery. Life-threatening postpartum pulmonary hemorrhage occurred as a result of pulmonary hypertension with an aberrant right pulmonary artery, absolutely necessitating a long-term cardiopulmonary bypass resuscitation. Patient with primary pulmonary hypertension gave birth safely with forceps assistance under epidural anesthesia. From literatures reviewed and successful experiences presented here, prenatal correction of the underlying cardiac malformation, precise switch of anticoagulant administration, optimizing cardiac function, early delivery prior to heart failure, postpartum fluid restriction, minimized peripartum blood loss, and meticulously intensive cares are essential to achieve satisfactory outcomes.

The development of orally active heparin will have tremendous clinical importance since it can be used to effectively prevent deep vein thrombosis (DVT) in a long-term chronic treatment. We developed in this study a new orally active heparin derivative (Db-LHD), which has heparin chemically conjugated with deoxycholic acid and DMSO molecules by secondary interactions. Db-LHD was prepared in the powder form in soft capsules. When we administered Db-LHD capsules to monkeys, its oral physiological availability was increased up to 16.6%. The maximum anti-FXa activity at 5 mg/kg of Db-LHD was more than twice the minimum effective anti-FXa activity (MEC, 0.1 IU/mL) for preventing DVT, and the anti-FXa activity in plasma was maintained for 10 h above the MEC in monkeys. Also, we evaluated anti-thrombogenic effect of Db-LHD in a rat thrombosis model. A subcutaneous administration of enoxaparin (100 IU/kg), which was the highest recommended dose for the prevention of venous thromboembolism, reduced thrombus formation by 38.9 ± 14.2%. On the other hand, 5 mg/kg (425 IU/kg) of orally administered Db-LHD reduced thrombus formation by 51.0 ± 2.0. We propose a new orally active heparin, Db-LHD, in a solid dosage form to effectively prevent DVT and PE.