SEOM clinical guidelines on venous thromboembolism (VTE) and cancer (2023).

The Spanish Society of Medical Oncology (SEOM) last published clinical guidelines on venous thromboembolism (VTE) and cancer in 2019, with a partial update in 2020. In this new update to the guidelines, SEOM seeks to incorporate recent evidence, based on a critical review of the literature, to provide practical current recommendations for the prophylactic and therapeutic management of VTE in patients with cancer. Special clinical situations whose management and/or choice of currently recommended therapeutic options (low-molecular-weight heparins [LMWHs] or direct-acting oral anticoagulants [DOACs]) is controversial are included.

[Comment on article "Enoxaparin dose associated with decreased risk of death in COVID-19"]. / Comentario al artículo "Dosis de enoxaparina asociada a disminución de riesgo de muerte en COVID-19".

In this letter to the editor, apropos of the article "Enoxaparin dose associated with decreased risk of death in COVID-19", it is discussed the role of the current thromboprophylactic strategies, as well as the potential role of heparins in the management of COVID-19.

En la presente carta al editor, a propósito del artículo "Dosis de enoxaparina asociada a disminución de riesgo de muerte en COVID-19", se discute el papel de las estrategias de tromboprofilaxis y el potencial rol de las heparinas en relación con la COVID-19.

Coagulopatía, tratamiento anticoagulante en COVID-19 y trombosis posvacunación / Coagulopathy, anticoagulant treatment in COVID-19 and thrombosis postvaccine

Resumen La coagulopatía y la trombosis son situaciones graves que afectan a los pacientes con enfermedad por coronavirus 2019 (COVID-19) que requieren hospitalización. En estos pacientes se alteran mecanismos procoagulantes y fibrinolíticos que condicionan un estado procoagulante progresivo y grave. La anticoagulación oportuna en estos pacientes es importante, pero han surgido preguntas sobre el tipo, la dosis y el momento adecuado de la anticoagulación. Las directrices y documentos de consenso existentes ofrecen sugerencias generales sobre la dosis de heparinas de bajo peso molecular en función de la gravedad de la enfermedad y el riesgo de trombosis, pero todavía falta una relación entre los marcadores de coagulación y el régimen de anticoagulación. Se están llevando a cabo muchos ensayos clínicos que abordan estas cuestiones; se alienta la participación en estos ensayos para determinar las mejores estrategias de tratamiento para los pacientes de COVID-19. Es necesario aumentar los conocimientos con un rápido intercambio para atender adecuadamente a los pacientes en esta pandemia.

Abstract Coagulopathy and thrombosis are serious situations that COVID-19 patients require hospitalization. In these patients, procoagulant and fibrinolytic mechanisms are altered that condition a progressive and severe procoagulant state. Timely anticoagulation in these patients is important, but questions have been raised about the type, dose, and timing of anticoagulation. The guidelines and consensus documents offer general suggestions on the dose of LMWH based on the severity of the disease and the risk of thrombosis, but a relationship between coagulation markers and anticoagulation regimen is still lacking. Many clinical trials are underway that address these issues; Participation in these trials to determine the best treatment strategies for COVID-19 patients is encouraged. Increasing knowledge with rapid exchange is necessary to adequately care for patients in this pandemic.

SEOM clinical guideline of venous thromboembolism (VTE) and cancer (2019).

In 2011, the Spanish Society of Medical Oncology (SEOM) first published a clinical guideline of venous thromboembolism (VTE) and cancer. This guideline was updated in 2014, and since then, multiple studies and clinical trials have changed the landscape of the treatment and prophylaxis of VTE in cancer patients. To incorporate the most recent evidence, including data from direct oral anticoagulants (DOACs) randomized clinical trials, SEOM presents a new update of the guideline.

Outpatient management of incidental pulmonary embolism in cancer patient.

PURPOSE: Incidentally discovered pulmonary embolism is a prevalent clinical problem for cancer patients and contributes significantly to the burden of cancer-associated thrombosis. The aim of this study was to explore if outpatient management of incidental pulmonary embolism (iPE) in cancer patients is effective and can be conducted safely. METHODS/PATIENTS: We performed a prospective observational cohort study in a single Spanish tertiary hospital. Patients diagnosed with iPE and active cancer were enrolled. Between May 2016 and May 2017, 25 consecutive patients were included in the study. RESULTS: All patients were assessed in the emergency room (ER) and started treatment with low-molecular weight heparins (LMWH) being discharged in the following 24 h. Congestive heart failure and right ventricular dysfunction were ruled out, and none of them presented massive PE, active bleeding or any disease-related reason that required hospitalization. The 90-day follow-up visit showed no venous thromboembolism (VTE) recurrence and the major bleeding rate was 4%. Mortality rate at 30 and 90 days was 0%. CONCLUSIONS: Outpatient management for iPE in cancer patients appears to be feasible and safe in selected cancer patients.

Imminent risk of a global shortage of heparin caused by the African Swine Fever afflicting the Chinese pig herd.

Most of the unfractionated and low-molecular-weight heparins available worldwide are produced by Chinese companies from porcine mucosa. China is the world's largest producer of pork and thus has plenty of raw material to produce heparins. However, the deadly African Swine Fever (ASF) outbreaks afflicting China since August 2018 may cause extensive losses to the pig herd, with serious consequences for the global supply of heparins. In 2008, a sudden shortage of heparin's raw material resulting from a viral disease in Chinese pigs prompted adulterations responsible for 80 deaths and hundreds of adverse events. This incident revealed the fragility of such a supply chain, which is mostly based on raw material from a single animal from a single country. A worldwide introduction of bovine mucosa heparins manufactured in different countries certainly is a feasible way to mitigate eventual shortages of these life-saving anticoagulants caused by local veterinary problems such as the ASF threatening China now.

Efficacy and Safety of a Biosimilar Versus Branded Enoxaparin in the Prevention of Venous Thromboembolism Following Major Abdominal Surgery: A Randomized, Prospective, Single-Blinded, Multicenter Clinical Trial.

Several biosimilar versions of enoxaparin are already approved and in use globally. Analytical characterization can establish good quality control in manufacturing, but they may not assure similarity in clinical outcomes between biosimilar and branded enoxaparin. This study evaluated the efficacy and safety of biosimilar Cristália versus branded Sanofi enoxaparin in venous thromboembolism (VTE) prevention in patients undergoing major abdominal surgery at risk for VTE. In this randomized, prospective single-blind study, we compared Cristália enoxaparin (Ce), a biosimilar version, versus branded Sanofi enoxaparin (Se; at a dose of 40 mg subcutaneously per day postoperatively from 7 to 10 days) in 243 patients submitted to major abdominal surgery at risk for VTE for VTE prevention. The primary efficacy outcome was occurrence of VTE or death related to VTE. The principal safety outcomes were a combination of major bleeding and clinically relevant non-major bleeding. Bilateral duplex scanning of the legs was performed from days 10 to 14, and follow-ups were performed up to 60 days after surgery. The incidence of VTE was 4.9% in the Cristália group and 1.1% in the Sanofi group (absolute risk difference = 3.80%, 95% confidence interval [CI]: -1.4%-9.0%) yielding noninferiority since the 95% CI does not reach the prespecified value Δ = 20%. Clinically significant bleeding occurred in 9.9% in the Cristália group and in 5.5% in the Sanofi group (n.s. ). In conclusion, this study suggests that 40 mg once daily of Ce, a biosimilar enoxaparin, is as effective and safe as the branded Sanofi enoxaparin in the prophylaxis of VTE in patients submitted to major abdominal surgery at risk for VTE.

Structural and functional analyses of biosimilar enoxaparins available in Brazil.

Biosimilar enoxaparins have been available for clinical use in Brazil since 2009. Although their use has reduced costs of treatment expenses, their implementation still raises some concerns about efficiency, safety, regularity and reproducibility of batches. We undertook structural and functional analyses on over 90 batches of pharmaceutical-active ingredient, and 330 ones of the final products of biosimilar enoxaparins available in the Brazilian market between 2009 and 2014. Besides a nationwide-scale analysis, we have also employed methods that go beyond those recommended by the standard pharmacopeias. We have used high-resolution 2D NMR, detailed assessment of the anticoagulant and antithrombotic properties, check of side effects in experimental animals after continuous administration, and analyses of individual composing oligosaccharides. The 1D 1H NMR spectra of all batches of biosimilar enoxaparins are fairly coincident, and the resultant average spectrum is quite identical to that from the original drug. This structural equality was also assured by highly resolved 2D NMR spectra. The anticoagulant activity, determined by diverse assays and the in vivo antithrombotic and bleeding effects of the biosimilar version were confirmed as equal as of the parental enoxaparins. Structure and function of the composing oligosaccharides were identical in both enoxaparin types. No side effect was observed after continuous subcutaneous administration to rats for 30 days at the dose of 2 mg kg⁻¹ body weight. Biosimilar enoxaparins available in Brazil fulfilled the requirement of the five items defined by FDA-USA for approval of this type of drug.

Tromboprofilaxis en pacientes no quirúrgicos internados en un hospital general / Venous thromboembolism prevention in non-surgical adult patients admitted in a general hospital

Los pacientes adultos internados por una enfermedad no quirúrgica tienen un riesgo alto de padecer una tromboembolia venosa y pueden desarrollar alguna forma de esta enfermedad cuando no reciben un tratamiento preventivo adecuado. Los objetivos de este estudio prospectivo, analítico, observacional y transversal, fueron: 1) determinar cuál es el porcentaje de pacientes adultos internados por una enfermedad aguda no quirúrgica en el Hospital de Clínicas José de San Martín, Universidad de Buenos Aires, que tienen indicación de tromboprofilaxis, 2) establecer cuántos de ellos reciben un tratamiento preventivo para la tromboembolia venosa, y 3) comprobar cuántos estaban medicados con alguna forma de tromboprofilaxis sin tener causas que justificaran este tratamiento. Se estudiaron 93 pacientes durante un lapso de 72 horas consecutivas. Se encontró que el 90.3% de ellos necesitaba un tratamiento preventivo para la tromboembolia venosa y el 76.2% de estos enfermos recibían tromboprofilaxis farmacológica. Un 33.3% de los pacientes internados tenía indicado un tratamiento farmacológico preventivo sin tener una causa que justificara esta prescripción. El porcentaje encontrado de pacientes tratados con tromboprofilaxis es más alto que el comunicado en otros estudios observacionales.(AU)

Adult patients hospitalized for a non-surgical condition, usually have a high risk of venous thromboembolism and may develop some form of this disease when they do not receive appropriate preventive treatment. The objectives of this prospective, analytical, observational and cross-sectional study were: 1) to determine what percentage of adult patients hospitalized for a non-surgical acute condition at the Hospital de Clínicas José de San Martín, Universidad de Buenos Aires, had indication for preventive thromboprophylaxis, 2) to establish how many of them had been prescribed a preventive treatment of venous thromboembolism, 3) to establish how many of them had been prescribed a preventive treatment of venous thromboembolism without having reasons to justify the treatment. The study was performed on 93 patients for 72 consecutive hours. It resulted in 90.3% in need of preventive treatment for venous thromboembolism and 76.2% of these patients had received pharmacological thromboprophylaxis. A 33.3% of the studied patients had received preventive pharmacological treatment without having a proper indication. In this study, the percentage of patients treated is higher than in those reported in other published observational studies.(AU)

Tromboprofilaxis en pacientes no quirúrgicos internados en un hospital general / Venous thromboembolism prevention in non-surgical adult patients admitted in a general hospital

Los pacientes adultos internados por una enfermedad no quirúrgica tienen un riesgo alto de padecer una tromboembolia venosa y pueden desarrollar alguna forma de esta enfermedad cuando no reciben un tratamiento preventivo adecuado. Los objetivos de este estudio prospectivo, analítico, observacional y transversal, fueron: 1) determinar cuál es el porcentaje de pacientes adultos internados por una enfermedad aguda no quirúrgica en el Hospital de Clínicas José de San Martín, Universidad de Buenos Aires, que tienen indicación de tromboprofilaxis, 2) establecer cuántos de ellos reciben un tratamiento preventivo para la tromboembolia venosa, y 3) comprobar cuántos estaban medicados con alguna forma de tromboprofilaxis sin tener causas que justificaran este tratamiento. Se estudiaron 93 pacientes durante un lapso de 72 horas consecutivas. Se encontró que el 90.3% de ellos necesitaba un tratamiento preventivo para la tromboembolia venosa y el 76.2% de estos enfermos recibían tromboprofilaxis farmacológica. Un 33.3% de los pacientes internados tenía indicado un tratamiento farmacológico preventivo sin tener una causa que justificara esta prescripción. El porcentaje encontrado de pacientes tratados con tromboprofilaxis es más alto que el comunicado en otros estudios observacionales.

Adult patients hospitalized for a non-surgical condition, usually have a high risk of venous thromboembolism and may develop some form of this disease when they do not receive appropriate preventive treatment. The objectives of this prospective, analytical, observational and cross-sectional study were: 1) to determine what percentage of adult patients hospitalized for a non-surgical acute condition at the Hospital de Clínicas José de San Martín, Universidad de Buenos Aires, had indication for preventive thromboprophylaxis, 2) to establish how many of them had been prescribed a preventive treatment of venous thromboembolism, 3) to establish how many of them had been prescribed a preventive treatment of venous thromboembolism without having reasons to justify the treatment. The study was performed on 93 patients for 72 consecutive hours. It resulted in 90.3% in need of preventive treatment for venous thromboembolism and 76.2% of these patients had received pharmacological thromboprophylaxis. A 33.3% of the studied patients had received preventive pharmacological treatment without having a proper indication. In this study, the percentage of patients treated is higher than in those reported in other published observational studies.

Avaliação comparativa da atividade biológica de heparinas não fracionadas pelas metodologias de inibição da coagulação do plasma ovino (ICPO) e de tempo de tromboplastina parcial ativada (TTPA) / Comparative study on the biological activity of non-fractionated heparin by using sheep plasma coagulation inhibition assay (SPCIA) and activated partial thromboplastin time (APTT) methodologies

O objetivo deste trabalho foi realizar o estudo comparativo entre os métodos ICPO e TTPA, para avaliar a eficácia da implantação do TTPA como método para a avaliação da segurança e eficácia de heparinas não fracionadas em produtos farmacêuticos. Foram avaliados, comparativamente, cinco lotes de diferentes fabricantes de heparinas não fracionadas (polissacarídeo sulfatado usado como droga anticoagulante), de origem suína ou bovina, testadas com base no 5º Padrão Internacional de Heparina. Esses produtos foram provenientes de coletas efetuadas pelas autoridades sanitárias para análise no Instituto Nacional de Controle de Qualidade em Saúde (INCQS). As amostras foram analisadas quanto à pureza e potência anticoagulante, por meio de duas metodologias: inibição da coagulação do plasma ovino (ICPO) e tempo de tromboplastina parcial ativada (TTPA). Houve boa concordância entre as duas metodologias, sendo que a técnica TTPA apresentou ser mais simples, rápida e objetiva, quando da utilização do coagulômetro para a medição do tempo de formação de coágulos, em detrimento da leitura subjetiva dos graus de coagulação no ensaio de ICPO. A implantação e a execução do TTPA em paralelo à utilização do ICPO garantirão o aumento de sensibilidade técnica na avaliação da segurança e eficácia de heparinas não fracionadas.(AU)

The aim of this study was to compare the methods of SPCIA and APTT to evaluate the effectiveness of the implementation of APTT as a method for assessing the safety and efficacy of unfractionated heparins in pharmaceuticals. Five lots of non-fractionated heparins (a sulfated polysaccharide used as anticoagulant) from porcine or bovine origin, and from different producers were comparatively evaluated. They were tested based on the 5th International Standard for Heparin, and they were collected by the Brazilian sanitary authorities for evaluating their purity and anticoagulant potency at the National Institute for Quality Control in Health (INCQS). Two methodologies were employed: sheep plasma coagulation inhibition assay (SPCIA) and activated partial thromboplastin time technique (APTT). An excellent correlation between the both methodologies was found, and it showed that technique is easier, faster and objective due to the use of a coagulometer for measuring the clot-forming time, instead of SPCIA assay which uses the subjective visual determination of the coagulation degree. The implementation and execution of APTT technique and the concomitant use of SPCIA assay will improve the technique sensitivity for assessing the non-fractionated heparins safety and efficacy.(AU)

Nadroparina cálcica: una revisión de su farmacología básica y clínica / Nadroparin calcium: a review of its basic and clinical pharmacology

Objetivo. Evaluar críticamente la información sobre la farmacología básica y clínica de la nadroparina cálcica. Fuente de datos. Se hizo una búsqueda en la literatura científica de octubre de 1985 a septiembre de 2010, en las bases de datos electrónicas: Pubmed, Cochrane, MDConsult,Scielo y Medscape, y en el Instituto Nacional de Vigilancia de Medicamentos y Alimentos (INVIMA).Selección de estudios. Se incluyeron los estudios publicados en inglés, español o francés, realizados en humanos y animales de experimentación, en los que se revisarala farmacología básica y clínica de la nadroparina cálcica. Extracción y síntesis de datos. Se revisaron 792 resúmenes y se seleccionaron 60artículos que cumplieron los criterios de inclusión, de acuerdo con un método se resolvieron todas las discrepancias por discusión y consenso.Conclusión. En algunos estudios la nadroparina cálcica ha mostrado una eficacia igual o superior a la de la heparina no fraccionada y la de un placebo. Sin embargo, la información evaluada no es lo suficientemente sólida para considerar superior lanadroparina frente a las otras heparinas de bajo peso molecular. La literatura científica muestra que, en general, el tratamiento con estas últimas es más seguro y costo-efectivo que con heparina no fraccionada. No existen pruebas suficientes, fuertes y concluyentes para calificar la nadroparina cálcica como superior aotras heparinas de bajo peso molecular en el tratamiento antitrombótico. Las de bajo peso molecular han demostrado una reducción significativaen la angiogénesis tumoral y un aumento en la supervivencia de pacientes con enfermedades oncológicas. Sin embargo, se requieren más investigaciones para caracterizar y comprender mejor este nuevo hallazgo...

Objective: To evaluate critically the evidence on the basic and clinical pharmacology of nadroparin calcium.Data source: We conducted a literature review from October 1985 to September 2010 in the electronic databases: Pubmed, Cochrane,MD Cosult, Medscape, Scielo and Instituto Nacional de Vigilancia de Medicamentos y Alimentos (INVIMA).Study selection: Studies published in English, Spanish or French made in humans and animals for experimentation which reviewed the basic and clinical pharmacology of nadroparin calcium wereincluded. Data extraction and synthesis: 792 abstracts were reviewed by authors and 60 papers were selected that met inclusion criteria according to a standardized method All discrepancies were resolved by discussion and consensus. Conclusion: Some studies have shown that the efficacy of nadroparin calcium is equal or superior to unfractionated heparin (UFH) and placebo, however, the strength of assessed evidencehas been insufficient for considering nadroparin calcium superior to other low molecular weight heparins (LMWH). Literature shows that LMWHstherapy is more cost-effective and safer than UFH therapy in general. It does not exist enough, strong and conclusive evidence for considering antithrombotic nadroparin calcium therapy greater to other LMWHs. LMWHs have shown a significantreduction in tumor angiogenesis and increased survival in oncology patients. To conduct further research is necessary to characterize and understand better this new finding...

Biological potency evaluation and physicochemical characterization of unfractionated heparins

Unfractionated heparins are used clinically as anticoagulants. The biological potency of thirteen samples of raw material and pharmaceutical formulations were assessed utilizing the 5th International Standard of heparin using the sheep plasma coagulation inhibition assay, activated partial thromboplastin time, anti-factor Xa assay, and anti-factor IIa assay, resulting in mean potencies of 101.15 percent, 96.15 percent, 98.15 percent and 99.37 percent, respectively. The samples were also evaluated by the protamine neutralization test giving results within the range of 92 - 138 IU/mg. The anti-factor IIa assay was performed showing reproducibility and significant correlation with the pharmacopoeial assays, thus demonstrating it to be a feasible alternative to the sheep plasma coagulation inhibition assay. Moreover, an analysis by nuclear magnetic resonance and capillary electrophoresis showed some peaks attributable to oversulfated chondroitin sulfate. The results show that batch-to-batch variations and the quality of samples contributed to improvements in the quality control of pharmaceutical products and to assure the safe use and clinical efficacy of this biological medicine.

As heparinas não fracionadas são utilizadas clinicamente como anticoagulantes. A potência biológica de 13 amostras de matérias-primas e produtos farmacêuticos foram avaliadas em relação ao 5ª Padrão Internacional de heparina pelos ensaios da inibição da coagulação do plasma ovino, tempo de tromboplastina parcial ativada, anti-fator Xa e anti-fator IIa, que forneceram potências médias de 101,15 por cento, 96,15 por cento, 98,15 por cento e 99,37 por cento, respectivamente. As amostras foram também submetidas ao teste de neutralização pela protamina que apresentou resultados entre 92-138 UI/mg. Demonstrou-se reprodutibilidade e correlação significativa do ensaio do anti-fator IIa com os farmacopeicos, constituindo-se em alternativa ao ensaio da inibição da coagulação do plasma ovino. Além disso, as análises realizadas por ressonância magnética nuclear e eletroforese capilar mostraram picos correspondentesà condroitina supersulfatada. Os resultados mostraram variações lote-a-lote e a qualidade das amostras contribuindo para aprimorar o controle de qualidade dos produtos farmacêuticos e garantir a segurança e eficácia terapêutica desses produtos biológicos.