Anticoagulation Therapy in Patients with Chronic Kidney Disease.

Patients with chronic kidney disease (CKD) are at increased risk for both thrombotic events and bleeding. The early stages of CKD are mainly associated with prothrombotic tendency, whereas in its more advanced stages, beside the prothrombotic state, platelets can become dysfunctional due to uremic-related toxin exposure leading to an increased bleeding tendency. Patients with CKD usually require anticoagulation therapy for treatment or prevention of thromboembolic diseases. However, this benefit could easily be offset by the risk of anticoagulant-induced bleeding. Treatment of patients with CKD should be based on evidence from randomized clinical trials, but usually CKD patients are excluded from these trials. In the past, unfractionated heparins were the anticoagulant of choice for patients with CKD because of its independence of kidney elimination. However, currently low-molecular-weight heparins have largely replaced the use of unfractionated heparins owing to fewer incidences of heparin-induced thrombocytopenia and bleeding. We undertook this review in order to explain the practical considerations for the management of anticoagulation in these high risk population.

Prophylaxis and treatment of venous thromboembolism based on Japanese clinical guides.

Venous thromboembolism (VTE) has recently increased owing to the westernization of our food habits and an aging society in Japan. The Japanese Guidelines for VTE Prophylaxis were formulated and issued in 2004 and then revised in 2009. The incidence rates of symptomatic perioperative pulmonary thromboembolism (PTE) in Japan are being investigated by the Japanese Society of Anesthesiologists since 2002. The average rate of perioperative PTE was estimated to be 3.1 per 10,000 operations between 2002 and 2011. However, this rate significantly declined after the guidelines for thromboprophylaxis were issued and the management fee for PTE prophylaxis was covered by a health insurance in 2004. The average mortality rate was 17.9%, but it significantly decreased after new anticoagulants were approved in 2008. An anticoagulant, which is effective for both acute and long-term VTE treatment, is clearly beneficial and avoids the need for any form of overlapping therapy. The emerging oral antithrombotic compounds such as direct oral anticoagulants (DOACs), which have the potential to inhibit factor Xa, do not require laboratory monitoring. The oral administration of DOACs results in a benefit-to-risk ratio that is at least comparable with that provided by a conventional treatment with heparin followed by vitamin K antagonists.

[PROCURING OF ІNTRAOPERATIVE HEMOSTASIS IN REVASCULARIZATION INTERVENTIONS].

Results of the hemostasis conduction in conditions of revascularization in 106 patients, оperated on for atherosclerotic affection of aorta and the main arteries of the lower extremities, were adduced. Syndrome of hypercoagulation of traumatic stage of surgical intervention in early postoperative period is developing due to thrombinemia on background of a fibrinolytic system depression. There was proved a necessity to impact on thrombin-fibrinous factor (factor ІІа) of hemocoagulant cascade by application of nonfractionized heparins immediately after conclusion of operative intervention with thromboprophylaxis prolongation, using low-molecular heparins (impact on Ха factor) in accordance to the branch standards.

Chemical prophylaxis to prevent venous thromboembolism in morbid obesity: literature review and dosing recommendations.

Pharmacologic prophylaxis of deep vein thrombosis and venous thromboembolism (VTE) is an important aspect of medical care, particularly in the inpatient setting. Low-molecular weight heparins, heparin, and fondaparinux are commonly used agents to prevent VTE, each of which has well established dosing regimens in patients with normal body mass index. Dosing of these medications in morbidly obese populations (BMI > 40 kg/m(2)) is not as clearly defined in guidelines. This article reviews published data to support specific dosing regimens and monitoring strategies of these agents in this population. The most validated parenteral agent to prevent VTE in morbidly obese hospitalized patients is enoxaparin, dosed at 40 mg subcutaneously (SC) twice daily. If unfractionated heparin is utilized for prophylaxis in morbidly obese patients, a dose of 7500 units SC three times daily should be considered. Monitoring of anti-factor Xa levels to guide prophylactic dosing is an option, although the utility of this lab test is limited, as target anti-Xa ranges for VTE prophylaxis have not been universally defined and trials have not shown a clear link between anti-factor Xa levels and bleeding or thrombotic events. Additional studies are needed to clearly define the most appropriate dosing strategies in patients with moderate obesity (BMI 35-40 mg/m(2)) and those with extreme obesity (BMI > 60 mg/m(2)).

Andexanet Alfa for Reversing Factor Xa Inhibition.

The direct oral anticoagulants (DOACs) have gained popularity recently among both patients and providers for their comparable or better efficacy and safety profiles compared with warfarin and the lack of need for routine monitoring of anticoagulant effect. One obstacle for the more widespread use of the DOACs in clinical practice has been the lack of a reversal agent. Most DOACs act by directly binding to and inhibiting the effects of factor Xa. Andexanet alfa (Andexxa, Portola Pharmaceuticals, San Francisco, CA) is a modified form of factor Xa that acts as a decoy binding entity for DOACs, thereby allowing endogenous factor Xa to perform its normal clotting functions. Andexanet has proven efficacious in clinical trials for reversing the anticoagulant effects of apixaban, edoxaban, and rivaroxaban, although its impact on clinical outcomes has not been adequately studied. Andexanet has a boxed warning for thromboembolic risks, ischemic risks, cardiac arrest, and sudden death, with these adverse events occurring in up to 18% of patients in clinical trials. However, the occurrence of these adverse events needs to be considered in relation to the fragile nature of patients who receive this agent. Because the duration of the DOACs is much less than that of warfarin, it is unclear how many patients would actually need andexanet in clinical practice, because cessation of the DOAC may be all that is needed to effectively manage bleeding. Nonetheless, having andexanet available in cases of DOAC-associated severe or life-threatening bleeding represents a therapeutic advance and should provide an added level of comfort with the clinical use of DOACs.

Oral, direct factor Xa inhibitors in development for the prevention and treatment of thromboembolic diseases.

Anticoagulants are recommended for the prevention and treatment of a wide variety of thromboembolic events. Although existing anticoagulants are effective, their use is limited by parenteral administration or the requirement for frequent monitoring and subsequent dose adjustment. Therefore, there is an urgent need for novel, oral agents with a predictable anticoagulant action. Because of its key position in the coagulation cascade and its limited roles outside of coagulation, Factor Xa has emerged as an attractive target for novel anticoagulants. As a result, the past decade has witnessed an explosion of research into small-molecule, oral, direct Factor Xa inhibitors, and several are now in clinical development. Rivaroxaban, LY517717, YM150, apixaban, PRT054021, and DU-176b, among others, have shown considerable promise; rivaroxaban is currently furthest ahead in its developmental program, having entered phase III in 3 indications. It is hoped that, before long, these anticoagulants will allow us to enter an era of convenient, oral anticoagulation, without the need for regular monitoring or dose adjustment.

DU-176b, an oral, direct Factor Xa antagonist.

Daiichi Sankyo Inc (formerly Daiichi Seiyaku Co Ltd) is developing DU-176b, a direct, orally active Factor Xa inhibitor, as an anticoagulant for the potential treatment of cardiovascular indications, including venous and arterial thrombosis. By January 2005, phase II studies had begun in the US and Europe, and by March 2006, phase II studies had begun in Japan. Phase II trials for the prevention of thromboembolism were ongoing in mid 2007.

Adjusted value of thromboprophylaxis in hospitalized obese patients: A comparative study of two regimens of enoxaparin: The ITOHENOX study.

Thromboprophylaxis is a mainstay of hospital care in patients at high risk of thrombosis. Fixed doses of low-molecular-weight heparin (LMWH) are recommended for thromboprophylaxis in patients admitted to hospital for an acute medical condition. However, the distribution of LMWH is weight-based, and the efficacy of standard doses in obese patients may be decreased. Data for obese patients are mainly available in bariatric surgery with extremely obese patients who are at greater risk of venous thromboembolism than those hospitalized for a medical condition. We conducted a randomized control trial in medically obese inpatients (BMI≥30kg/m2) assessing two regimens of enoxaparin (40mg and 60mg SQ daily) in order to determine whether a stronger dosage would achieve higher anti-Xa level suitable for thromboprophylaxis. Between September 2013 and April 2015, 91 patients were included in the study (mean (±standard deviation) age was 70.4±10.7years, average BMI 37.8±6.4kg/m2). Main indications of thromboprophylaxis were mainly acute infection (50%), acute respiratory failure (10%), acute congestive heart failure (9%) and acute rheumatic disorders (18%). Average anti-Xa activity, measured 4h after the third administration of enoxaparin was 0.25±0.09IU/mL in group 1 (enoxaparin 40mg) and 0.35±0.13IU/mL in group 2 (enoxaparin 60mg) (P<10-3). The proportions of patients with normal anti-Xa activity (between 0.32 and 0.54IU/mL) were 31% (n=11) and 69% (n=24) in group 1 and 2 respectively (P=0.007). The proportions of anti-Xa activity measurement below the normal range were 64% and 36% in group 1 and 2 (P<10-3) respectively. Subgroup analysis focusing on high weight patients (above 100kg, n=45) showed a marked difference in the proportion of patients with normal anti-Xa activity between group 1 (9%) and 2 (44%) (P=0.009). No venous thromboembolism occurred during the study and one patient in group 1 died because of hemorrhagic shock due to a gastric ulcer. Incidence of adverse events was not different between the two groups (P=0.52). In conclusion, the ITOHENOX study shows in medically obese inpatients that thromboprophylaxis with enoxaparin 60mg provides higher control of anti-Xa activity, without more bleeding complications than the standard enoxaparin regimen. This trial is registered with ClinicalTrials.gov, number NCT01707732.

The impact on coagulation of an intravenous loading dose in addition to a subcutaneous regimen of low-molecular-weight heparin in the initial treatment of acute coronary syndromes.

OBJECTIVES: We sought to quantify the impact of adding an intravenous loading dose to a subcutaneous regimen of enoxaparin in patients with an acute coronary syndrome (ACS). BACKGROUND: It is unclear whether an intravenous (i.v.) loading dose of enoxaparin should be added to a subcutaneous (s.c.) regimen in patients with ACS. METHODS: Patients admitted with ACS were randomized to i.v.+s.c.(n = 14) or s.c. alone (n = 11) enoxaparin treatment. Coagulation markers were measured at nine time points during the first 24 h of treatment. RESULTS: The i.v.+s.c. therapy immediately resulted in therapeutic anti-Xa levels, which remained significantly higher for 6 h compared with s.c. alone, without reaching excessively high levels. A rapid decrease of plasma prothrombin fragments 1+2 (F(1+2)) levels was observed as soon as 5 min after the i.v. injection (33% lower; p = 0.007), and these levels remained lower up to 2 h after the start of treatment compared with SQ alone. The ex vivo thrombin generation time was maximally prolonged at 5 min post-injection in the i.v.+s.c. group and remained significantly prolonged up to 6 h post-injection compared with s.c. alone. The tissue factor pathway inhibitor plasma activity was immediately increased by 194% with i.v.+s.c., whereas the maximum increase with s.c. alone was 47% at 3 h. CONCLUSIONS: Therapeutic plasma levels of enoxaparin are achieved significantly earlier by an i.v.+s.c. regimen compared with s.c. alone, without leading to unacceptably high levels. As the risk of thrombotic complications is greatest early after admission, the observed differences in antithrombotic effects may translate into a clinical benefit. However, this remains to be established.

Prevention effect of orally active heparin conjugate on cancer-associated thrombosis.

Thrombogenesis is a major cause of morbidity and mortality in cancer patients. Prophylaxis with low-molecular-weight heparin (LMWH) is recommended for cancer patients, but requires non-parenteral delivery methods for long-term treatments. In this study, we sought to generate a new oligomeric-bile acid conjugate of LMWH that can be used for oral delivery. We first synthesized a tetramer of deoxycholic acid (tetraDOCA), which was site-specifically conjugated at the end saccharide of LMWH. When LMWH-tetraDOCA conjugate (LHe-tetraD) was orally administered at a dose of 5 mg/kg in ICR mice, the maximum anti-factor Xa level was increased up to 0.62±0.05 IU/mL without any evidence of liver toxicity, gastrointestinal damage, or thrombocytopenia. The cancer-associated thrombosis was induced in tumor-bearing mice by local heat application, and the fibrin deposition in tumors was evaluated. The oral administration of LHe-tetraD (either a single dose or multiple daily doses for up to 10 days) in mice substantially abolished the coagulation-dependent tropism of fibrinogen in the heated tumors and significantly decreased hemorrhage, compared to the mice treated with saline or subcutaneous injection of LMWH. Thus, the anticoagulation effect of oral LHe-tetraD invokes the benefits of oral delivery and promises to provide an effective and convenient treatment for cancer patients at risk of thrombosis.

Rivaroxaban: a novel oral anticoagulant for the prevention and treatment of several thrombosis-mediated conditions.

The development of rivaroxaban (XARELTO®) is an important new medical advance in the field of oral anticoagulation. Thrombosis-mediated conditions constitute a major burden for patients, healthcare systems, and society. For more than 60 years, the prevention and treatment of these conditions have been dominated by oral vitamin K antagonists (such as warfarin) and the injectable heparins. Thrombosis can lead to several conditions, including deep vein thrombosis, pulmonary embolism, myocardial infarction, stroke, and/or death. Prevention and treatment of thrombosis with an effective, convenient-to-use oral anticoagulant with a favorable safety profile is critical, especially in an aging society in which the risk of thrombosis, and the potential for bleeding complications, is increasing. Rivaroxaban acts to prevent and treat thrombosis by potently inhibiting coagulation Factor Xa in the blood. Factor Xa converts prothrombin to thrombin, which initiates the formation of blood clots by converting fibrinogen to clot-forming fibrin and leads to platelet activation. After a large and novel clinical development program in over 75,000 patients to date, rivaroxaban has received approval for multiple indications in the United States, European Union, and other countries worldwide to prevent and treat several thrombosis-mediated conditions. This review will highlight some of the unique aspects of the rivaroxaban development program.

Clinical management of rivaroxaban-treated patients.

INTRODUCTION: Until recently, only vitamin K antagonists (VKAs) were used for long-term anticoagulation. New oral anticoagulants, with pharmacokinetic and pharmacodynamic characteristics different to VKAs, are now available for some indications. Rivaroxaban (Xarelto®) is an oral Factor Xa inhibitor approved in many countries for long-term treatment of patients with atrial fibrillation or venous thromboembolism. This article is addressed to all professionals involved in the management of treated patients to highlight the characteristics of rivaroxaban and provide practical guidance on management of treated patients. AREAS COVERED: This article is based on a consensus of specialists involved in the management of anticoagulant treatment, including thrombosis experts, cardiologists, neurologists, emergency medicine specialists, and general practitioners. The authors performed a nonsystematic review of the literature, and expressed guidance statements based on the results of the review as well as personal experience. EXPERT OPINION: Availability of new anticoagulant drugs, including rivaroxaban, is an important step forward to allow easier, more effective, and safer long-term anticoagulation in patients in whom adequate anticoagulation is currently denied due to the limitations of VKAs. However, given their totally new properties, associated risks, and expected broad clinical use, expert professionals and manufacturers must urgently tackle a series of issues.

Increased heparanase level and procoagulant activity in orthopedic surgery patients receiving prophylactic dose of enoxaparin.

BACKGROUND: Orthopedic hip and knee surgeries are followed by a hypercoagulable state. Heparanase is implicated in inflammation, coagulation activation and angiogenesis. Recently, heparanase was shown to directly interact with tissue factor (TF) and to enhance the generation of factor Xa (Nadir et al., Haematologica, 2010). In addition, an assay assessing heparanase procoagulant activity has been lately developed (Nadir et al., Thromb Res, 2011). In the present study heparanase level and procoagulant activity in patients undergoing orthopedic surgery were assessed. METHODS: The study group included 50 orthopedic patients. 31 patients underwent hip surgery and 19 had knee operation. 15 individuals suffered from traumatic hip fractures and 35 had osteoarthrosis of hip or knee joints. All patients received prophylactic dose of enoxaparin starting 6-8 hours post operation and lasting for 5 weeks. Plasma samples were drawn preoperatively and at 1 hour, 1 week and 1 month post operation. Samples were tested for heparanase levels by ELISA and TF/heparanase complex activity, TF activity, heparanase procoagulant activity, factor Xa and thrombin levels using chromogenic substrates. RESULTS: Heparanase levels were significantly higher 1 hour and 1 week post operatively compared to preoperative levels (p<0.05, p<0.005, respectively). The most dramatic changes were observed in heparanase procoagulant activity reaching a 2 fold increase 1 week postoperatively and 1.7 fold increase 1month after surgery (p<0.0001, p<0.0001, respectively). Levels of factor Xa and thrombin did not significantly change. CONCLUSIONS: Heparanase is involved in coagulation activation of orthopedic surgery patients. Heparanase procoagulant activity is highest 1 week postoperatively and remains high 1month after operation. Considering extending prophylactic anticoagulant therapy or evaluating heparanase procoagulant activity may potentially prevent late thrombotic events.

Oral anticoagulant therapy: Antithrombotic Therapy and Prevention of Thrombosis, 9th ed: American College of Chest Physicians Evidence-Based Clinical Practice Guidelines.

BACKGROUND: The objective of this article is to summarize the published literature concerning the pharmacokinetics and pharmacodynamics of oral anticoagulant drugs that are currently available for clinical use and other aspects related to their management. METHODS: We carried out a standard review of published articles focusing on the laboratory and clinical characteristics of the vitamin K antagonists; the direct thrombin inhibitor, dabigatran etexilate; and the direct factor Xa inhibitor, rivaroxaban RESULTS: The antithrombotic effect of each oral anticoagulant drug, the interactions, and the monitoring of anticoagulation intensity are described in detail and discussed without providing specific recommendations. Moreover, we describe and discuss the clinical applications and optimal dosages of oral anticoagulant therapies, practical issues related to their initiation and monitoring, adverse events such as bleeding and other potential side effects, and available strategies for reversal. CONCLUSIONS: There is a large amount of evidence on laboratory and clinical characteristics of vitamin K antagonists. A growing body of evidence is becoming available on the first new oral anticoagulant drugs available for clinical use, dabigatran and rivaroxaban.

Modification of biological parameters after treatment with recombinant factor VIIa in a patient with thrombocytopathy due to storage pool disease.

Patients with thrombocytopathy due to storage pool disease mostly suffer from mild bleeding diathesis. However surgical interventions can lead to excess bleeding. We describe how treatment with recombinant factor VIIa (Novoseven) during a surgical procedure in a boy with SPD leads to an immediate rise in PF-4, thereby activating factor Xa on the platelet surface, leading to active thrombin generation.

Low molecular weight heparin (dalteparin) for the treatment of venous thromboembolism in pregnancy.

OBJECTIVE: To evaluate the effect and dose of dalteparin given to pregnant women with acute venous thromboembolism. DESIGN: An observational study of pregnant women in Norway. SETTING: Delivery and haematological departments in Norway. POPULATION: Twenty women, aged 22-41 years, with acute venous thromboembolism verified by objective means. METHODS: Patients were treated with dalteparin from diagnosis until delivery. Treatment was monitored with anti-activated factor Xa (anti-Xa) activity, and the dose was adjusted to achieve target 0.5-1.0 U/mL 2-3 hours post-injection. MAIN OUTCOME MEASURES: Anti-Xa activity and side effects. RESULT: None of the patients suffered recurrent venous thromboembolism or major bleeding complications. In 9 of 13 women starting with conventional dose of dalteparin (100 iu/kg bd), dose escalation was necessary to reach target anti-Xa activity. None of the six women who started with 105-118 iu/kg bd required dose escalation. One woman who started with 133 iu/kg bd required dose reduction. Bioaccumulation of dalteparin was not observed. CONCLUSION: Our study suggests that dalteparin may be used for the treatment of acute venous thromboembolism in pregnancy. Approximately 10-20% higher doses of dalteparin may be needed as compared with non-pregnant individuals.

Safety and efficacy of single bolus anticoagulation with enoxaparin for chronic hemodialysis. Results of an open-label post-certification study.

BACKGROUND: Low-molecular-weight heparin (LMWH) is supposed to be advantageous compared to unfractionated heparin for chronic hemodialysis (HD) with respect to lipid and bone metabolism, polymorphonuclear cell stimulation, induction of antibody-mediated thrombocytopenia, and aldosterone suppression. Due to longer biological half-life, LMWH offers the possibility of single bolus administration. METHODS: To assess safety and efficacy of single bolus anticoagulation with enoxaparin for chronic HD, 781 stable HD patients from 79 German dialysis centers (mean age 62 years; 31% ESRD due to diabetes mellitus) were monitored by clinical and laboratory parameters for 32 weeks. Additionally, in a single dialysis center, 22 chronic HD patients were investigated by molecular markers of coagulation during chronic HD under conditions of single bolus or continuous anticoagulation regimens. Anti-Xa activity and the thrombin- antithrombin-III complex (TAT) were determined before the enoxaparin bolus, after 15 min, 2 h, and at the end of HD in venous and arterial blood lines. RESULTS: Chronic HD was performed in 24,117 HD treatments with enoxaparin at a median dose of 70.1 IU/kg (5,000 IU median total dose) for single bolus anticoagulation. In 83.0% of HD treatments, enoxaparin was given as single bolus. In 98.3% of patients no adverse event was reported. No drug-related severe adverse event occurred. Significant clotting problems were observed in only 0.3% of HD treatments with single bolus anticoagulation. As assessed in 257 HD treatments, essentially identical anti-Xa levels were detected at the end of HD with single bolus (50 IU/kg) or continuous (mean total dose 43 IU/kg) anticoagulation regimens. Bolus anticoagulation resulted in higher TAT generation at the end of HD. However, this was not associated with increased macroscopic clot formation. CONCLUSION: Single bolus anticoagulation with enoxaparin was safe and effective for chronic HD. For a duration of 4 h HD, a median dose of 70 IU/kg can be recommended for regular use, which is in accordance with the manufacturer's instructions for use of enoxaparin recommending a range of 50-100 IU/kg.

Low-molecular-weight heparin for the prevention and treatment of venous thromboembolism in pregnancy.

PURPOSE OF REVIEW: Low-molecular-weight heparins (LMWHs) have largely replaced unfractionated heparins for both prophylaxis and treatment of venous thromboembolism in nonpregnant patients. However, until recently, evidence in pregnant women was lacking, despite the increasing use of LMWHs during pregnancy in clinical practice. This review covers recent literature on the use of LMWHs in relation to pregnancy. RECENT FINDINGS: The main areas covered in this review are the use of LMWHs in both prophylaxis and treatment of venous thromboembolism in pregnancy. The review also considers issues relating to monitoring of LMWHs in pregnancy, and safety from both a maternal and a fetal perspective. SUMMARY: The available evidence demonstrates that LMWHs are of at least equivalent efficacy but have a better safety profile compared with unfractionated heparins in both prophylaxis and treatment of maternal venous thromboembolism, and are more convenient to administer. There is no consensus with respect to whether these agents require monitoring during pregnancy other than periodic checking of the platelet count. The clinical implication from the available evidence is that LMWHs should now be regarded as the anticoagulant agents of choice for both prophylaxis and treatment of maternal venous thromboembolism.

Recombinant nematode anticoagulant protein c2 and other inhibitors targeting blood coagulation factor VIIa/tissue factor.

Originally isolated from a haematophagous hookworm, recombinant nematode anticoagulant protein c2 (rNAPc2) is an 85-amino acid protein with potent anticoagulant properties. Unlike conventional anticoagulants that attenuate blood coagulation via inhibition of thrombin or activated factor X (FXa) at the downstream portion of the cascade, rNAPc2 is a potent inhibitor of the activated factor VII/tissue factor complex (FVIIa/TF), the key physiological initiator of blood coagulation. Its mechanism of action requires prerequisite binding to circulating FXa or zymogen factor X (FX) to form a binary complex prior to its interaction and inhibition of membrane-bound FVIIa/TF. The binding of rNAPc2 to FX results in an elimination half-life of longer than 50 h following either subcutaneous or intravenous administration. Recombinant NAPc2, like other inhibitors of FVIIa/TF including tissue factor pathway inhibitor (TFPI) and active site-blocked FVIIa (ASIS, FFR-rFVIIa or FVIIai), may have a promising role in the prevention and treatment of venous and arterial thrombosis, as well as potential efficacy in the management of disseminated intravascular coagulopathies because of their potent and selective inhibition of FVIIa/TF.