Identification of Human Kinin-Forming Enzyme Inhibitors from Medicinal Herbs.

The goal of this study was to assess the pharmacological effects of black tea (Camellia sinensis var. assamica) water extract on human kinin-forming enzymes in vitro. Tea is a highly consumed beverage in the world. Factor XII (FXII, Hageman factor)-independent- and -dependent activation of prekallikrein to kallikrein leads to the liberation of bradykinin (BK) from high-molecular-weight kininogen (HK). The excessive BK production causes vascular endothelial and nonvascular smooth muscle cell permeability, leading to angioedema. The prevalence of angiotensin-converting enzyme inhibitor (ACEI)-induced angioedema appears to be through BK. Both histamine and BK are potent inflammatory mediators. However, the treatments for histamine-mediated angioedema are unsuitable for BK-mediated angioedema. We hypothesized that long-term consumption of tea would reduce bradykinin-dependent processes within the systemic and pulmonary vasculature, independent of the anti-inflammatory actions of polyphenols. A purified fraction of the black tea water extract inhibited both kallikrein and activated FXII. The black tea water extracts inhibited factor XII-induced cell migration and inhibited the production of kallikrein on the endothelial cell line. We compared the inhibitory effects of the black tea water extract and twenty-three well-known anti-inflammatory medicinal herbs, in inhibiting both kallikrein and FXII. Surprisingly, arjunglucoside II specifically inhibited the activated factor XII (FXIIa), but not the kallikrein and the activated factor XI. Taken together, the black tea water extract exerts its anti-inflammatory effects, in part, by inhibiting kallikrein and activated FXII, which are part of the plasma kallikrein-kinin system (KKS), and by decreasing BK production. The inhibition of kallikrein and activated FXII represents a unique polyphenol-independent anti-inflammatory mechanism of action for the black tea.

The Safety and Efficacy of Novel Agents Targeting Factors XI and XII in Early Phase Human Trials.

Although anticoagulation without hemorrhage is a primary aim, this vision has remained as yet out of reach. Even despite the superior safety profile of the direct oral anticoagulants, hemorrhage remains a major risk of anticoagulation. Selective inhibition of the contact pathway of coagulation, specifically coagulation factor XI (FXI) and/or factor XII (FXII), has now substantial epidemiologic and preclinical data supporting the notion that these factors contribute to pathologic thrombosis and are yet primarily dispensable for in vivo hemostasis. In this way, targeting FXI and FXII may revolutionize the future anticoagulation landscape. Several drugs are under development for this purpose, including: ISIS 416858, a FXI antisense oligonucleotide which impairs hepatic synthesis of FXI; MAA868, a monoclonal antibody that binds the procoagulant enzymatic site of both zymogen and activated FXI (FXIa); BAY 1213790, a monoclonal antibody that binds the procoagulant enzymatic site of FXIa only; and AB023, a monoclonal antibody that inhibits activated FXII-mediated activation of FXI, along with two small molecules in clinical trials. Each of these drugs have demonstrated favorable safety profiles in their phases 1 and 2 studies to date, with preclinical data also supporting efficacy of abrogating thrombosis in various animal models. Other benefits of some of these drugs include once-monthly dosing and safety in patients with renal or hepatic impairment, while others offer quickly metabolized parenteral options, thus providing more convenient and widely available anticoagulation options. Though still far from the marketplace, drugs targeting FXI and FXII have the potential to usher in a new era of anticoagulation therapy.

Antithrombotic Agents.

Recent advances in our understanding of the contribution of thrombin generation to arterial thrombosis and the role of platelets in venous thrombosis have prompted new treatment paradigms. Nonetheless, bleeding remains the major side effect of such treatments spurring the quest for new antithrombotic regimens with better benefit-risk profiles and for safer anticoagulants for existing and new indications. The aims of this article are to review the results of recent trials aimed at enhancing the benefit-risk profile of antithrombotic therapy and explain how these findings are changing our approach to the management of arterial and venous thrombosis. Focusing on these 2 aspects of thrombosis management, this article discusses 4 advances: (1) the observation that in some indications, lowering the dose of some direct oral anticoagulants reduces the risk of bleeding without compromising efficacy, (2) the recognition that aspirin is not only effective for secondary prevention of atherothrombosis but also for prevention of venous thromboembolism, (3) the finding that dual pathway inhibition with the combination of low-dose rivaroxaban to attenuate thrombin generation plus aspirin to reduce thromboxane A2-mediated platelet activation is superior to aspirin or rivaroxaban alone for prevention of atherothrombosis in patients with coronary or peripheral artery disease, and (4) the development of inhibitors of factor XI or XII as potentially safer anticoagulants.

Advances in Antithrombotic Therapy.

Thrombosis remains a major cause of morbidity and mortality. Consequently, advances in antithrombotic therapy are needed to reduce the disease burden. This article focuses on 2 such advances. First, the prevention of atherothrombosis in patients with coronary or peripheral artery disease, which has been enhanced by the finding that the combination of low-dose rivaroxaban plus aspirin is superior to aspirin alone for prevention of recurrent ischemic events. However, this benefit comes at the cost of increased bleeding albeit not fatal bleeding. To overcome this problem, the second advance is the identification of factor XI as a target for new anticoagulants that are potentially safer than those currently available.

Anticoagulant and Antithrombotic Properties of Three Structurally Correlated Sea Urchin Sulfated Glycans and Their Low-Molecular-Weight Derivatives.

The anticoagulant and antithrombotic properties of three structurally correlated sea urchin-derived 3-linked sulfated α-glycans and their low molecular-weight derivatives were screened comparatively through various in vitro and in vivo methods. These methods include activated partial thromboplastin time, the inhibitory activity of antithrombin over thrombin and factor Xa, venous antithrombosis, the inhibition of platelet aggregation, the activation of factor XII, and bleeding. While the 2-sulfated fucan from Strongylocentrotus franciscanus was observed to be poorly active in most assays, the 4-sulfated fucan from Lytechinus variegatus, the 2-sulfated galactan from Echinometra lucunter and their derivatives showed multiple effects. All marine compounds showed no capacity to activate factor XII and similar low bleeding tendencies regardless of the dose concentrations used to achieve the highest antithrombotic effect observed. The 2-sulfated galactan showed the best combination of results. Our work improves the background about the structure-function relationship of the marine sulfated glycans in anticoagulation and antithrombosis. Besides confirming the negative effect of the 2-sulfated fucose and the positive effect of the 2-sulfated galactose on anticoagulation in vitro, our results also demonstrate the importance of this set of structural requirements on antithrombosis in vivo, and further support the involvement of high-molecular weight and 4-sulfated fucose in both activities.

A critical role for plasma kallikrein in the pathogenesis of autoantibody-induced arthritis.

The plasma kallikrein-kinin system (KKS) consists of serine proteases, prekallikrein (pKal) and factor XII (FXII), and a cofactor, high-MW kininogen (HK). Upon activation, activated pKal and FXII cleave HK to release bradykinin. Activation of this system has been noted in patients with rheumatoid arthritis, and its pathogenic role has been characterized in animal arthritic models. In this study, we generated 2 knockout mouse strains that lacked pKal and HK and determined the role of KKS in autoantibody-induced arthritis. In a K/BxN serum transfer-induced arthritis (STIA) model, mice that lacked HK, pKal, or bradykinin receptors displayed protective phenotypes in joint swelling, histologic changes in inflammation, and cytokine production; however, FXII-deficient mice developed normal arthritis. Inhibition of Kal ameliorated arthritis severity and incidence at early stage STIA and reduced the levels of major cytokines in joints. In addition to releasing bradykinin from HK, Kal directly activated monocytes to produce proinflammatory cytokines, up-regulated their C5aR and FcRIII expression, and released C5a. Immune complex increased pKal activity, which led to HK cleavage. The absence of HK is associated with a decrease in joint vasopermeability. Thus, we identify a critical role for Kal in autoantibody-induced arthritis with pleiotropic effects, which suggests that it is a new target for the inhibition of arthritis.-Yang, A., Zhou, J., Wang, B., Dai, J., Colman, R. W., Song, W., Wu, Y. A critical role for plasma kallikrein in the pathogenesis of autoantibody-induced arthritis.

Emerging Therapies in Hereditary Angioedema.

Remarkable progress has been made in the treatment of bradykinin-mediated angioedema with the advent of multiple new therapies. Patients now have effective medications available for prophylaxis and treatment of acute attacks. However, hereditary angioedema is a burdensome disease that can lead to debilitating and dangerous angioedema episodes associated with significant costs for individuals and society. The burden of treatment must be addressed regarding medication administration difficulties, treatment complications, and adverse side effects. New therapies are being investigated and may offer solutions to these challenges. This article reviews the emerging therapeutic options for the treatment of HAE.

Oral Rivaroxaban Treatment for L-asparaginase-induced Deep Thrombophlebitis in Lower Extremity / 임상소아혈액종양

We are reporting our experience of oral rivaroxaban (Xarelto(R)) treatment for L-asparaginase (L-ASP)-induced deep vein thrombophlebitis in the lower extremity developed during childhood acute lymphoblastic leukemia (ALL) chemotherapy, with a brief review of the literature. A 16-year-old boy was admitted to our institution with right lower leg pain and gait difficulties. He was diagnosed with ALL and started chemotherapy protocol. He had been under a chemotherapy course of delayed intensification (DI)-1. We began antibiotics treatment for possible inflammation including cellulitis of the leg and planned an MRI scan. The MRI scan indicated thrombophlebitis of the right posterior calf deep veins. Subsequent DVT CT and coagulation profiles showed other abnormal findings. Coagulation factor assay were noted with decreased levels of multi factors; Factor II 45%, Factor IX 35.3 %, Factor X 30%, Factor XI 19%, Factor XII 22%, and anti-coagulants levels were decreased also with variant degrees; Protein C Activity 51%, Protein C Ag 54.5%, Protein S Activity 35%, Protein S Antigen, total 27.1%, Protein S Antigen, free 41.7%. Low molecular heparin (LMWH) treatment was initiated and the patient was switched to oral rivaroxaban (Xarelto(R)). After 6 weeks treatment, abnormal coagulation profiles and MRI scan showed improvement. Furthermore, the patient had no other symptoms or recurrence of thrombotic events. There was no significant adverse reaction to rivaroxaban in this patient.

Oral Rivaroxaban Treatment for L-asparaginase-induced Deep Thrombophlebitis in Lower Extremity / 임상소아혈액종양

We are reporting our experience of oral rivaroxaban (Xarelto(R)) treatment for L-asparaginase (L-ASP)-induced deep vein thrombophlebitis in the lower extremity developed during childhood acute lymphoblastic leukemia (ALL) chemotherapy, with a brief review of the literature. A 16-year-old boy was admitted to our institution with right lower leg pain and gait difficulties. He was diagnosed with ALL and started chemotherapy protocol. He had been under a chemotherapy course of delayed intensification (DI)-1. We began antibiotics treatment for possible inflammation including cellulitis of the leg and planned an MRI scan. The MRI scan indicated thrombophlebitis of the right posterior calf deep veins. Subsequent DVT CT and coagulation profiles showed other abnormal findings. Coagulation factor assay were noted with decreased levels of multi factors; Factor II 45%, Factor IX 35.3 %, Factor X 30%, Factor XI 19%, Factor XII 22%, and anti-coagulants levels were decreased also with variant degrees; Protein C Activity 51%, Protein C Ag 54.5%, Protein S Activity 35%, Protein S Antigen, total 27.1%, Protein S Antigen, free 41.7%. Low molecular heparin (LMWH) treatment was initiated and the patient was switched to oral rivaroxaban (Xarelto(R)). After 6 weeks treatment, abnormal coagulation profiles and MRI scan showed improvement. Furthermore, the patient had no other symptoms or recurrence of thrombotic events. There was no significant adverse reaction to rivaroxaban in this patient.

Experimental study on the hemostatc activity of Pollen Typhae: a traditional folk medicine used by external and oral application.

Pollen Typhae is the traditional Chinese herbal medicine widely used to treat the hemorrhagic diseases both by external and oral application. The present study examines the hemostatic properties and its components of Pollen Typhae. Pollen extract significantly reduced prothrombin time (PT), activated partial prothrombin time (APTT) and recalcification time. Pollen extract directly activated factor XII in the coagulation cascade. Acidic polysaccharide in the pollen that adsorbed to the diethylaminoethyl (DEAE) column was the causative agent of factor XII activation. These results suggested that an electronegative charge attributed to an acidic polysaccharide in the pollen extract contributed to the hemostatic activity. We then examined the hemostatic activity of administered pollen extract in the mouse tail bleeding model. Tail bleeding was significantly decreased after oral administration of the pollen extract, whereas the acidic polysaccharide fraction did not affect the duration of tail bleeding. These results suggest that the oral anticoagulant effect of Pollen Typhae is attributed to compounds other than acidic polysaccharides. We concluded that the activation of the intrinsic coagulation pathway by the acidic polysaccharide contributes to the external hemostatic property of Pollen Typhae, and the action of components such as flavonoids that possess anticoagulant activity are causative agent when orally administered.