Direct Anticoagulants Research Articles

Allergy to Rivaroxaban: A Case Report Showing Cross-Reactivity With Other Direct Anticoagulants and the Role of the Basophil Activation Test.

Allergy to Rivaroxaban: A Case Report Showing Cross-Reactivity With Other Direct Anticoagulants and the Role of the Basophil Activation Test.

Potential targets of heparin during progression and metastasis of malignant neoplasms

In the modern world, oncological diseases occupy the leading positions in the structure of mortality. An integrated approach to oncotherapy is not only aimed at immediate affection of malignant tumors, but also directed at reducing the risk of tumor recurrence and metastasis, as well as alleviating side effects of chemotherapy and radiotherapy of the disease. In oncologic disorders, blood viscosity increases, thus being associated with hypercoagulation syndrome. To prevent its consequences, the direct and indirect anticoagulants, especially heparin and its derivatives, are actively used. Biological functions and structural features of heparin make it a potential universal platform of a drug development for broad application, including oncology. With the advent of heparin fractionation technology and preparation of low-molecular weight forms and their derivatives, it has become possible to focus not only on anticoagulant activity but also to obtain fractions with targeted pharmacological activity. Usage of the anticoagulants has shown their antitumor activity in some cases, thus providing a basis for a more detailed study of pharmacotherapeutic effects of this group of drugs. Currently, some data suggest various pathways of interaction between heparin and tumor cells. There are multiple common features in development of a primary tumor and formation of secondary distant metastases, which may be attributed to similar molecular cellular mechanisms. The molecules mediating intercellular interactions, both between the tumor cells and between malignant cells and tumor-associated immune cells (e.g., lymphocytes and macrophages) may serve as targets for heparin thus helping the tumor to evade immune surveillance. The cytokines that stimulate tumor angiogenesis represent another important therapeutic target. Heparin derivatives are able to suppress tumor activity and prevent metastatic processes at various stages by inhibiting heparanase, P-/L-selectin, and angiogenesis activity, modulating the CXCL12-CXCR4 chemokine axis, and regulating OAM activity.This brief review addresses the current understanding and application of the potentially antimetastatic properties of heparin and its derivatives in malignant bone tumors since the heparin-based drugs are used as anticoagulants in arthroplasty of large joints and bone defects in patients with osteosarcoma.

THE SURGEON'S PERSPECTIVE ON PORTAL VEIN THROMBOSIS IN PATIENTS WITH LIVER CIRRHOSIS

The article discusses the key aspects of the etiology, diagnosis, and treatment of portal vein thrombosis in patients with liver cirrhosis. The prevalence of portal vein thrombosis in individuals with liver cirrhosis ranges from 0.6 % to 26 %, with a higher incidence observed in those with decompensated cirrhosis. Symptoms of portal vein thrombosis are often nonspecific. Approximately one-third of patients with this condition experience no symptoms, and the detection of a thrombus is usually an incidental finding during computed tomography or ultrasound examinations.
 Acute portal vein thrombosis is characterized by abdominal pain in the right upper quadrant, non-bloody diarrhea, or acute intestinal obstruction when there is symptomatic dilatation of the superior mesenteric vein. On the other hand, chronic portal vein thrombosis manifests through signs of portal hypertension, such as esophageal and gastric bleeding, deterioration of portal gastropathy, splenomegaly, pancytopenia, and significant ascites.
 The first-line treatment for portal vein thrombosis involves the use of direct and indirect anticoagulants. However, their administration necessitates careful consideration of the risk of intraluminal bleeding, the severity of cirrhosis, and the potential benefits of portal vein recanalization. Mechanical thrombectomy can serve as an alternative to long-term anticoagulant therapy for portal vein thrombosis. In cases of portal vein thrombosis in patients with cirrhosis, after mechanical thrombectomy and thrombolysis, the placement of transjugular intrahepatic portosystemic shunt (TIPS) is often performed.
 To conclude, portal vein thrombosis frequently occurs in patients with liver cirrhosis, and its appearance is challenging to predict due to its multifactorial nature. The preferred initial treatment for acute portal vein thrombosis, in the absence of intraluminal bleeding or intestinal ischemia, involves the use of direct and indirect anticoagulants. Minimally invasive surgical options, such as mechanical thrombectomy, chemical thrombolysis, and TIPS placement (with or without variceal embolization), are currently available. However, due to the heterogeneous nature of the existing data and the lack of randomized controlled trials, definitive recommendations regarding the optimal treatment strategy are not yet available.
 Keywords: cirrhosis, coagulopathy, portal hypertension, portal vein thrombosis, anticoagulants.

Clinical and pharmacological approaches to personalization of the prescription of oral anticoagulants: clinical cases

Anticoagulants play an important role in reducing complications and mortality associated with thromboembolic disease. For some time, vitamin K antagonists (VKAs) have been the main drugs used for long-term oral anticoagulant therapy, but because of the significant limitations of VKAs over the past decade, pharmacological research has led to the development of new direct acting oral anticoagulants (DOACs). Direct acting oral anticoagulants have a rapid onset of action with peak levels within 2–4 hours and a half-life of about 12 hours, which is much shorter than that of vitamin K antagonists, a more predictable anticoagulant effect, no need for dose selection, routine laboratory monitoring of pharmacodynamic effects, and a lower frequency of clinically significant drug-drug interactions compared with warfarin. But anticoagulants can still cause serious adverse drug reactions (ADRs) in the form of hemorrhagic complications in hospitalized patients, as confirmed in studies. Currently, clinicalpharmacological technologies of personalized medicine such as pharmacogenetic and pharmacokinetic studies are considered as promising approaches to improve the safety of modern pharmacotherapy, allowing the prediction and prevention of various ADRs. In addition, there are emerging studies showing the importance of genetic features of patients in relation to the metabolism of oral anticoagulants, as well as described clinical situations where different gene polymorphisms, could be responsible for changes in the pharmacokinetics of DOACs. This article reviews clinical cases in which pharmacogenetic testing and therapeutic drug monitoring are used to optimize the clinical efficacy and maximum safety of anticoagulant therapy with apixaban and rivaroxaban.

Pharmacokinetic drug-drug interactions with direct anticoagulants in the management of cancer-associated thrombosis.

Drug-drug interactions (DDIs) are common in cancer management and complicate the choice of anticoagulation in cancer-associated thrombosis. Cancer confers an increased risk of thrombotic events. Also, more bleeding events are observed in those who receive anticoagulation compared to those without cancer. In the treatment of cancer-associated thrombosis, direct oral anticoagulants (DOACs) have been found to be at least as effective as low-molecular weight heparins, which became the standard of care after several trials demonstrated superiority over vitamin K antagonists. Non-inferiority compared to low-molecular weight heparins has been shown for rivaroxaban, edoxaban and apixaban with a signal of fewer recurrent thrombotic events, albeit with an increase in bleeding events. Yet, potentially major pharmacokinetic drug-drug interactions have been identified as a reason to withhold DOACs and to rather choose an alternative. Practical guidance on what constitutes a major pharmacokinetic interaction and/or how to deal with these interactions in clinical practice is limited. Hence, here we have provided a framework to allow clinicians to better deal with pharmacokinetic drug-drug interactions between DOACs and cancer therapies in the management of cancer-associated thrombosis. In this review we have discussed the current literature, how the pharmacokinetic profile links to the label information on DDI, and have provided a practical proposal, applied to a clinical case.

Evolución clínica de los pacientes con FA y diabetes mellitus en la pandemia de COVID-19. Registro REFADI

Introduction and objectivesTo analyze the evolution of patients with atrial fibrillation (AF) and diabetes in the mid-term follow-up during the COVID-19 pandemic and to describe its impact on this population. MethodsMulticenter and prospective registry that included patients with AF and diabetes attended in cardiology clinics. A multivariate analysis was performed to determine the variables associated with the occurrence of clinical events and mortality. Recruitment was performed in February-December 2019. ResultsThe evolution of 633 patients, 96,2% of those included in the REFADI registry with a median follow-up of 835 days was analyzed (mean age 73.8±8.5 years, 54.3% male, CHA2DS2-VASc 4,34±1,4, HAS-BLED 2,47±0,96) were analyzed. The proportion of anticoagulated patients remained constant (95.6% vs 94.5%; P=.24). There was a decrease in the prescription of vitamin K antagonists (from 31.4% to 19.7%; P <.01), and an increase in the use of direct anticoagulants (from 62.0% to 70.3%; P <.01). During the follow-up there was an increase in the prescription of SGLT2 inhibitors (from 20.0% to 25.5%; P <.01) and GLP1 agonists (from 4.2% to 9.1%; P <.01). During this period, 17.2% of patients died, the majority from cardiovascular causes, 6.4% from COVID-19, 2.8% from stroke, and 1.8% from hemorrhage. Older age, lower ejection fraction, lower hemoglobin levels, and especially lower direct anticoagulants prescription were associated with mortality. ConclusionsPatients with AF and diabetes have a high thromboembolic risk and a high risk of developing complications, especially of cardiovascular origin.

A clinical case of a complicated course of immunoglobulin A vasculitis with long-term nephritis: peculiarities of treatment

Immunoglobulin A vasculitis is the most common systemic vasculitis in children. Its course can be mild, involving only the skin and not requiring medical intervention, as well as severe, recurrent, long-lasting — when the gastrointestinal tract and kidneys are involved. Nephritis is the most often cause the disease severity, although abdominal pain usually affects the well-being of the child. We present a clinical case of immunoglobulin A vasculitis in a 6-year-old girl who had an acute onset with severe abdominal syndrome and vomiting that preceded the appearance of the rash. The use of direct anticoagulants led to gastric bleeding. Treatment with corticosteroids had a positive effect on the abdominal syndrome, but did not prevent the development of kidney injury with hematuria and moderate proteinuria. Nephritis had a stable persistent course. Recurrences of rashes and abdominal pain were observed. Long-term corticosteroid therapy and renoprotection using angiotensin-converting enzyme inhibitors allowed partial control of the disease. The presented clinical case confirms that the course of immunoglobulin A vasculitis can be long, with frequent relapses of skin manifestations, abdominal syndrome, transformation into glomerulonephritis, even in the presence of only moderate hematuria and proteinuria. Skin manifestations and nephritis cannot be always completely controlled by the first-line therapy, which requires a balanced decision regarding the escalation of treatment, taking into account biopsy data, kidney function, and severity of proteinuria. Renoprotection with angiotensin-converting enzyme inhibitors or angiotensin receptor blockers can prevent secondary kidney injury. The implementation of European guidelines in the treatment of immunoglobulin A vasculitis, including that associated with nephritis, will allow unifying the approaches to patient management, detecting kidney damage timely and carrying out appropriate treatment measures.

Is the use of direct anticoagulants justified after lower extremity revascularization surgery?

Is the use of direct anticoagulants justified after lower extremity revascularization surgery?

Thromboprophylaxis in COVID-19

Abstract The SARS-CoV-2 pandemic and its specific respiratory pathology has generated extensive research that has highlighted the specific nature of the disease (COVID-19). Thrombotic processes in the macrocirculation and microcirculation were among the first reported, accompanying respiratory (pulmonary) manifestations. Of the COVID-19 complications, thrombosis in the venous system (venous thrombosis and pulmonary embolism) and the atrial system (stroke) are the most numerous and severe in terms of evolution and prognosis. The prophylaxis of thrombotic processes in COVID-19, initially empirical, has gained a scientific basis based on research and experience of clinicians. The current paper presents general data on macro- and microcirculatory thrombosis and the rationale for thromboprophylaxis. Thromboprophylaxis in non-hospitalized COVID-19 patients, “non-critical” and “critical” hospitalized patients and possible post-hospital thromboprophylaxis are presented. Heparins (HGMM and HNF) are the most commonly indicated and used antithrombotic agents. Other antithrombotic agents - antiplatelets and direct anticoagulants (oral - DOAC) have a very limited and possibly negative role in thromboprophylaxis in COVID-19.

Abstract 12256: Symptomatic Supratherapeutic International Normalized Ratio on Rivaroxaban: A Case Report and a Systematic Review

Rivaroxaban is a direct oral anticoagulant that works by inhibiting factor Xa. Direct anticoagulants have largely replaced direct vitamin K inhibitors (VKAs) due to the increased risk of major hemorrhages and the need for regular monitoring and dose adjustments. However, there have been multiple reports of elevated international normalized ratio (INR) and incidents of bleeding in patients on rivaroxaban, which brings into question the potential need for monitoring. The purpose of this review is to differentiate the patients that may benefit from regular monitoring and to propose future directions for implementation of monitoring. Here we report a case of an INR of 4.8 in a patient who presented with a gastrointestinal bleed and a drop of five gm/dL in hemoglobin four days after starting rivaroxaban following right femoral popliteal bypass graft stenting. The patient had no liver or kidney abnormalities and was not taking any medication or consuming any foods that could introduce any significant drug interaction. Additionally, we conducted a systematic review of similar reports in the literature with the goal of identifying the factors that could influence rivaroxaban’s levels in the blood or its influence on the INR. We reviewed PubMed using keywords including; “rivaroxaban”, “anti-Xa”, “DOAC”, “elevated”, “INR”, “bleeding”, “hemorrhage”, “pharmacology”, and “pharmacokinetics”. The literature revealed reports of INRs up to 5.2. Reviewing the pharmacokinetics of rivaroxaban indicated possibly higher drug levels in Caucasians, patients with a low body mass index (BMI), and patients with polymorphisms in the genes coding for CYP3A4, CYP2J2, or p-glycoprotein, assuming no renal or liver disease and no significant drug-drug or drug-food interactions. INR can be falsely normal if the thromboplastin reagent used to monitor the INR on warfarin is not sensitive to the changes in INR due to rivaroxaban. We suggest finding a thromboplastin reagent that is sensitive to INR changes with rivaroxaban, which could yield clinically relevant INRs on rivaroxaban allowing for accurate monitoring. We then suggest conducting studies to evaluate the cost effectiveness of regular monitoring in at-risk patients.

Use of Direct Oral Anticoagulant and Associated Bleeding and Thrombotic Complication after Lower Extremity Bypass.

Therapeutic anticoagulation with either a vitamin K antagonist (VKA) or direct anticoagulant (DOAC) is often newly prescribed to patients undergoing lower extremity bypass (LEB) to aid in graft patency when risk factors for thrombosis are present or to treat postoperative venous thromboembolism or atrial fibrillation. There is a gap in knowledge as to how DOAC usage impacts postoperative outcomes compared with the standard-of-care VKAs. To determine temporal trends in DOAC prescription after infrainguinal LEB, impact on length of stay (LOS), and associated bleeding and thrombotic complications, patients undergoing elective LEB were identified from the Vascular Quality Initiative between January 2013 and May 2019. Postoperative bleeding, LOS, and graft occlusion for patients receiving VKA compared with DOAC were evaluated. A total of 24,459 LEBs were performed during the study period. Among 2,656 patients newly prescribed an anticoagulant, 78.0% (n = 2,072) received VKA and 22.0% (n = 584) received a DOAC, with DOAC use increasing throughout the study period. There was no significant difference in postoperative bleeding (VKA 2.3%, DOAC 1.7%, p = 0.413) or graft occlusion (VKA 1.2%, DOAC 1.4%, p = 0.762) between the anticoagulant classes. LOS was shorter in the DOAC group than in the VKA group (5.7 vs 6.8 days; p &lt; 0.001). This analysis demonstrates that DOAC use is increasing with time in Vascular Quality Initiative centers. DOACs are a safe and comparable alternative to VKAs in the postoperative setting with similar rates of bleeding complications and early graft patency and are associated with a reduced postoperative LOS.

Cost-of-Illness Analysis of Long-Term Health Care Resource Use and Disease Burden in Patients With Pulmonary Embolism: Insights From the PREFER in VTE Registry.

Background As mortality from pulmonary embolism (PE) decreases, the personal and societal costs among survivors are receiving increasing attention. Detailing this burden would support an efficient public health resource allocation. We aimed to provide estimates for the economic and disease burden of PE also accounting for long-term health care use and both direct and indirect costs beyond the acute phase. Methods and Results This is a cost-of-illness analysis with a bottom-up approach based on data from the PREFER in VTE registry (Prevention of Thromboembolic Events-European Registry in Venous Thromboembolism). We calculated direct (clinical events and anticoagulation) and indirect costs (loss of productivity) of an acute PE event and its 12-month follow-up in 2020 Euros. We estimated a disability weight for the 12-month post-PE status and corresponding disability adjusted life years presumably owing to PE. Disease-specific costs in the first year of follow-up after an incident PE case ranged between 9135 Euros and 10 620 Euros. The proportion of indirect costs was 42% to 49% of total costs. Costs were lowest in patients with ongoing cancer, mainly because productivity loss was less evident in this already burdened population. The calculated disability weight for survivors who were cancer free 12 months post-PE was 0.017, and the estimated disability adjusted life years per incident case were 1.17. Conclusions The economic burden imposed by PE to society and affected patients is considerable, and productivity loss is its main driver. The disease burden from PE is remarkable and translates to the loss of roughly 1.2 years of healthy life per incident PE case.

Rapidly progressing dyspnea and retiform purpura

Rapidly progressing dyspnea and retiform purpura

Reduction of major adverse and major cardiovascular events in patients with atrial fibrillation and stent implantation treated with left atrial occlusion device vs oral anticoagulants strategy

Abstract Background Treatment of patients with Nonvalvular Atrial Fibrillation (NVAF) who need coronary stent implantation is a challenge. Although trials have shown “direct anticoagulants (DOAC) indefinitely plus clopidogrel for one year” strategy reduces bleeding events in comparison to triple therapy, especially with warfarin, many questions remain about the safety and efficacy of this strategy. Purpose This study compared the events in patients who received left atrial appendage occlusion (LAAO) and antiplatelet therapy (APT) with those who were treated with oral anticoagulants (OAC) (including DOAC) and APT. Methods 207 consecutive patients with NVAF who underwent coronary stent implantation (most of them for NSTEACS), were analysed. 146 were treated with OAC (75 with acenocoumarol, 71 with DOAC) and 61 with LAAO during a mean follow-up of 35 months. Furthermore, they received APT according to the clinical cardiologist criteria (Figure 1). Results There were no significant differences in variables like age (average 75.7 years-old) hypertension, diabetes, gender, permanent or paroximal AF or a history of stroke or thromboembolisms between groups. But there were more unfavourable characteristics in LAAO group with significant differences in the percentage of history of coronary artery disease (43.2% vs 75,4% p= &amp;lt;0.001), CHA2DS2-VASc (4.07±1.70 vs 4.56±1.53 p=0.033), history of relevant bleedings (BARC ≥2) (8.9% vs 49.2% p&amp;lt;0.001), history of high bleeding risks defined as previous bleedings or HASBLED ≥3 (19.9% vs 62.3% p&amp;lt;0.001) and HAS-BLED (1.63±1.09 vs 2.49±1.18, p&amp;lt;0.001), between OAC and LAAO groups respectively. Observed total death, stroke/TIA and relevant bleedings incidence rates (expressed per 100 patient-years) were higher in OAC- than in LAAO-group: 10.86 vs. 6.96% (HR: 1.56; p=0.183), 4.59 vs. 1.27% (HR: 3.61; p=0.084), 12.43 vs. 4.57% (HR: 2.72; p=0.014), respectively. The composite events of MAE and MCVE (defined as in Figure 1 and 2) were also significantly higher: 23.40 vs. 9.8% (HR: 2.40; p=0.002) (Figure 2, left) and 7.41 vs. 1.9% (HR: 3.90; p=0.025) (Figure 2, right), respectively. Conclusions In patients with NVAF receiving coronary stents, a LAAO strategy with APT, shows better results in MAE and MCVE than treatment with OAC (DOAC included) plus APT strategy in a long term-follow-up, despite more unfavourable variables in LAAO group. Funding Acknowledgement Type of funding sources: None.

Von Willebrand factor and cancer: Another piece of the puzzle

Von Willebrand factor and cancer: Another piece of the puzzle

S3122 Portal Vein Thrombosis Post Laparoscopic Sleeve Gastrectomy

Introduction: Portal vein thrombosis (PVT) is a clot formation in one of the branches of the portal vein. It is a well-known complication in patients with cirrhosis or post-abdominal surgery. Data on PVT post laparoscopic bariatric surgeries are scarce. Here we present a case of PVT post laparoscopic sleeve gastrectomy. Case Description/Methods: A 43- years-old female with a known past medical history of hypertension, Asthma, and obesity underwent a robotic-assisted laparoscopic sleeve gastrectomy. She presented to the Emergency Department (ED) complaining of Abdominal pain 2 days after the sleeve gastrectomy operation. The patient reported doing well postoperatively till 2 days when she developed sudden epigastric abdominal pain and generalized abdominal discomfort, associated with nausea and anorexia. On arrival at the ED, her vital signs were stable and liver enzymes were normal. She had RUQ tenderness on the physical exam without guarding or rebound. The patient then had a Computed tomography (CT) of the abdomen and pelvis with IV contrast which showed occlusive left portal vein thrombosis extending to branches. She was started on oral direct Anticoagulant (DOAC) with Rivaroxaban. She had complete hypercoagulable work up with hematology which was unremarkable (Figure 1). Discussion: PVT is a well-described complication of cirrhosis. in non-cirrhotic patients, the etiology of PVT can be due to systemic or local factors. A hypercoagulable state such as Factor V Leiden, antithrombin III deficiency, protein C and S deficiency, or Methylenetetrahydrofolate reductase (MTHFR) mutation is associated with higher thrombosis risk. Local factors include direct manipulation of portosystemic vessels such as during splenectomy with resultant endothelial damage and increase vascular thrombogenicity. A gastric sleeve is less likely to cause PVT since it only involves the short gastric vein. However, with the use of laparoscopic surgical techniques, there has been an increase in reported PVT. It is suspected that an increase in intra-abdominal pressure during carbon dioxide insufflation causes a pro-thrombotic state by decreasing venous and portal blood flow. The diagnosis of PVT post-operatively requires a high level of suspicion and can be made with abdominal imaging such as Ultrasound with color doppler or CT with IV contrast. The treatment is usually anticoagulation with the goal of recanalization of the portal vein on repeat imaging to prevent the development of non-cirrhotic portal hypertension in these patients.Figure 1.: Color doppler showing left portal vein thrombosis.

Caracterización epidemiológica del estudio REFLEJA: estrategias de prevención del ictus en mujeres con fibrilación auricular

Introduction and objectivesEvaluation of differences in stroke prevention strategies in women in a prospective atrial fibrillation (AF) cohort. MethodsThe REFLEJA study included all outpatients with AF evaluated between October 2017 and October 2018 from a Spanish tertiary hospital center. The use and type of oral anticoagulation (OAC) and rhythm control strategies were analyzed. ResultsOf the 1499 patients included (age 73.8±11.1 years), 48.1% were women, having a higher CHA2DS2-VASc than men (2.90±1.62 vs 4.11±1.34; P<.001), and a similar use of antiarrhythmics (9.8 vs 12.2%; P=.15), although there was a lower indication for electrical cardioversion (8.6 vs 2.5%; P<.001) and catheter ablation (3.3 vs 1.5%; P=.036). The use of OAC was higher in women (91 vs 95.3%; P=.002) although less with direct anticoagulants (DOAC)(67.1 vs 60.1%; P=.012) and without differences in the use of reduced doses (13.2 vs 20%; P=.065). Previous stroke, previous electrical cardioversion, CHA2DS2-VASc ≥ 2, and de novo AF were predictors of greater use of DOAC, while chronic kidney disease, high bleeding risk (HAS-BLED ≥ 3), or moderate-severe non-rheumatic valvular heart disease were associated with a lower prescription. ConclusionsThe female population of the REFLEJA study presented a more unfavorable clinical profile than that of the men, with less rhythm control, although female sex was not independently associated with less use of OACs or NOAC.

Medical management of vascular anomalies of the head and neck.

Depending on impairment, treatment of vascular anomalies is decided on a case-by-case basis in pluridisciplinary consultations. Interventional treatments, especially surgery and sclerotherapy, are usually partially efficient and management of patients with vascular anomalies increasingly involves the use of medical drugs. The most common vascular tumor is infantile hemangioma where first-line medical treatment, when necessary, is propranolol. Kasabach-Merritt phenomenon is now largely treated with sirolimus whereas first-line treatment of coagulation disorders associated with venous malformations is based on low-molecular-weight heparins or direct anticoagulants. Sirolimus is the standard treatment for painful inflammatory manifestations of low-flow vascular malformations such capillary, venous, and lymphatic malformations that can occur singly or in combination but PIK3CA inhibitors, originally developed in oncology, have shown promising results in patients with PIK3CA-related overgrowth spectrum. Currently, medical treatments are poorly developed for high-flow malformations such as arteriovenous malformations. However, new research aimed at delineating the different arteriovenous malformations based on molecular findings has given new hope for future development of targeted therapies.

Testing for Lupus Anticoagulants.

Lupus anticoagulant (LA) is one of the three criteria antiphospholipid antibodies (aPLs) employed in classification, and by default diagnosis, of antiphospholipid syndrome (APS). Detection of LA is not via calibrated assays but is based on functional behavior of the antibodies in a medley of coagulation assays. A prolonged clotting time in a screening test is followed by demonstration of phospholipid dependence and inhibitory properties in confirmatory and mixing tests, respectively, which are modifications of the parent screening test. Complications arise because no single screening test is sensitive to every LA, and no test is specific for LA, because they are prone to interference by other causes of elevated clotting times. Several screening tests are available but the pairing of dilute Russell's viper venom time (dRVVT) with LA-sensitive activated partial thromboplastin time (aPTT) is widely used and recommended because it is proven to have good detection rates. Nonetheless, judicious use of other assays can improve diagnostic performance, such as dilute prothrombin time to find LA unreactive with dRVVT and aPTT, and the recently validated Taipan snake venom time with ecarin time confirmatory test that are unaffected by vitamin K antagonist and direct factor Xa inhibitor anticoagulation. Expert body guidelines and their updates have improved harmonization of laboratory practices, although some issues continue to attract debate, such as the place of mixing tests in the medley hierarchy, and areas of data manipulation such as assay cut-offs and ratio generation. This article reviews current practices and challenges in the laboratory detection of LA.

Preparation, characterization, and pharmacokinetics of rivaroxaban cocrystals with enhanced in vitro and in vivo properties in beagle dogs

Rivaroxaban (RIV) is a direct Factor Xa inhibitor anticoagulant, but the oral bioavailability of RIV is estimated to be only 60% due to its poor solubility. The aim of the present study was to improve the solubility and bioavailability of RIV. Five cocrystals—p-hydroxybenzoic acid (HBA), 2,4-dihydroxybenzoic acid (DBA), nicotinamide (NA), isonicotinamide (IA), and succinic acid (SA)—were used as cofomers and were successfully obtained and characterized by powder X-ray diffraction, thermal analysis, and Fourier transform infrared spectra. RIV-DBA and RIV-HBA cocrystals showed obvious improvements in solubility, dissolution (under sink conditions), and intrinsic dissolution rates versus RIV. Moreover, the dissolution of RIV-HBA, RIV-DBA, and RIV-SA cocrystals under non-sink conditions showed obvious “spring and parachute” patterns. The in vitro permeability levels in a Caco-2 cell model of RIV-DBA and RIV-IA cocrystals were significantly improved versus RIV. Pharmacokinetic studies in beagle dogs showed that RIV-DBA and RIV-HBA cocrystals had higher bioavailability than RIV. The enhancements in solubility and bioavailability indicate the potential of RIV cocrystals as a better candidate for the treatment of thrombosis versus RIV.