Thrombosis in patients with immune thrombocytopenia: incidence, risk, and clinical outcomes.

Background: There is evidence that patients with immune thrombocytopenia (ITP) are at increased risk of thrombosis. However, the association of clinical- and treatment-related factors with thrombosis remains controversial. Objectives: To evaluate the incidence and impact of risk factors for arterial and venous thromboembolism (VTE) in patients with ITP and characterize the clinical features and management of patients. Methods: We performed a retrospective cohort study (January 1, 2011, to October 30, 2022) of adult patients diagnosed with ITP from an Australian tertiary hospital. The incidence rates of thrombosis were calculated in terms of person-years of follow-up. Multiadjusted Cox regression was used to estimate associations. Results: A total of 220 patients with 1365 person-years of follow-up since ITP diagnosis revealed 26 (11.8%) patients with a total of 37 thrombosis events, 29 (78%) VTE and 8 (22%) arterial thromboembolism (ATE). The incidence rate of thrombosis was 2.71 (95% CI, 1.97-3.72) (0.66 [95% CI, 0.33-1.26] for arterial thromboembolism and 2.05 [95% CI, 1.42-2.95] for VTE) per 100 person-years. Mean age and median time to first thrombosis diagnosis was 56 and 2.13 years, respectively. Age, secondary ITP, lines of therapy, thrombosis risk factors, and thrombopoietin receptor agonist therapy were independently associated with thrombosis. Almost all patients (25 of 26, [96%]) had good ITP disease control prior to thrombosis diagnosis, and antithrombotic therapy was deliverable and well tolerated. Conclusion: Diagnosis of thrombosis in patients with ITP, while infrequent, is of clinical significance. We identified from a heterogeneous real-world cohort that older patients with multiply-treated secondary ITP receiving thrombopoietin receptor agonists are at the highest risk.

Risk Factors for Non-Adherence to Pharmacist or Non-Pharmacist Explanations on Preoperative Medication Discontinuation: A Retrospective Japanese Study.

Purpose: The risk factors for non-adherence to pharmacist or non-pharmacist explanations of preoperative medication discontinuation are unknown. The primary outcome of this study was to determine whether the final explainer's occupation was a risk factor for non-adherence. The secondary outcomes were to determine the risk factors for non-adherence after limiting the departments or adjusting for age. Patients and Methods: We retrospectively examined the data (including patient age, sex, prescription medications, comorbidities, presence of roommate, and number of days between receiving explanation and surgery) of 1132 patients on medications that could affect surgery at a Japanese university hospital between April 1, 2017, and March 31, 2020. The primary endpoint was whether the occupation of the last person explaining medication discontinuation to the patient was an independent risk factor for non-adherence (age ≥65 years vs <65 years). Secondary endpoints included subgroup analyses in urological, gastrointestinal, and otolaryngological areas, as well as a sensitivity analysis (age as a continuous variable) to confirm the validity of the primary endpoint results. A multivariate binary logistic regression identified independent non-adherence risk factors. Results: The main analysis showed that discontinuing two or more medications was a risk factor for non-adherence (adjusted odds ratio (AOR): 1.67; 95% confidence interval (CI): 1.13-2.47; p = 0.01). However, in analyses coordinated by department (urological, gastrointestinal, and otolaryngological), ≥65 (versus <65) years of age was determined as a risk factor for increased nonadherence (AOR: 2.27, 95% CI: 1.11-4.63; p=0.024). Age-adjusted analysis (continuous variables) showed similar results to the primary endpoint (AOR: 1.68, 95% CI: 1.14-2.49, p = 0.009). Conclusion: Two or more medications, and not the final explainer's occupation, were associated with pre-surgery medication non-adherence. To prevent non-adherence, pharmacists and non-pharmacists should educate patients about preoperative medication discontinuation. These findings could help identify high-risk non-adherence patients.

Indicadores hematológicos en pacientes con infección por SARS COV-2 / Hematological indicators in patients with SARS COV-2 infection

Objetivo: Analizar los indicadores hematológicos en pacientes con infección por SARS COV-2. Método: Observacional de tipo descriptiva. Resultados: Se ha encontrado la existencia de un patrón común de exámenes anormales del recuento leucocitario con Neutrófilos elevados en 43.69 % (neutrofilia) y los linfocitos, pero por debajo de los valores normales (linfopenia) en un 20.16 %. Además de monocitopenia en un 13.44%. Conclusión: La detección de Proteína C reactiva elevada y neutrofilia se relaciona con casos severos de COVID-19 en pacientes adultos. Ambas pruebas combinadas tienen una alta especificidad y sensibilidad para predicción temprana de casos se veros de COVID -19.

Objective: To analyze hematological indicators in patients with SARS COV-2 infection. Methods: Descriptive observational study. Results: A common pattern of abnormal leukocyte count tests was found with elevated neutrophils in 43.69% (neutrophilia) and lymphocytes, but below normal values (lymphopenia) in 20.16%. In addition to monocytopenia in 13.44%. Conclusion: The detection of elevated C-reactive protein and neutrophilia is associated with severe cases of COVID-19 in adult patients. Both tests combined have high specificity and sensitivity for early prediction of severe cases of COVID -19.

L-Glutamine in sickle cell disease.

L-Glutamine is a conditionally essential amino acid required for synthesis of the pyridines for nucleotides, including nicotinamide adenine dinucleotide (NAD) and glutathione, as well as glutamate, and becomes essential during oxidative stress exposure. The NADH:[NAD⁺ + NADH] (redox) ratio in sickle red blood cells (RBCs) is lower than in normal RBCs, consistent with oxidative stress, therefore glutamine availability is important in sickle cell disease (SCD). RBC glutamine levels vary between SCD studies but the ratio glutamine:glutamate was inversely related to tricuspid regurgitant jet velocity in one. Oral L-glutamine was associated with an increase in NADH and reduction in RBC endothelium adhesion in small studies of SCD patients. In a sickle mouse model, glutamine levels were directly related to cerebral blood flow. Phase II and III randomized, double-blind, controlled trials of L-glutamine 0.6 g/kg/day compared with placebo in children and adults with SCD and = 2 episodes of pain in the previous year provide evidence that L-glutamine is safe and associated with a reduction in painful episodes and in hospitalizations. However, L-glutamine was only tolerated in two-thirds of patients, anemia and hemolysis did not improve and there are few data on mortality and organ complications. Future studies should investigate the effect of other amino acids and total protein intake.

The many roles of tranexamic acid: An overview of the clinical indications for TXA in medical and surgical patients.

Clinically significant bleeding can occur as a consequence of surgery, trauma, obstetric complications, anticoagulation, and a wide variety of disorders of hemostasis. As the causes of bleeding are diverse and not always immediately apparent, the availability of a safe, effective, and non-specific hemostatic agent is vital in a wide range of clinical settings, with antifibrinolytic agents often utilized for this purpose. Tranexamic acid (TXA) is one of the most commonly used and widely researched antifibrinolytic agents; its role in postpartum hemorrhage, menorrhagia, trauma-associated hemorrhage, and surgical bleeding has been well defined. However, the utility of TXA goes beyond these common indications, with accumulating data suggesting its ability to reduce bleeding and improve clinical outcomes in the face of many different hemostatic challenges, without a clear increase in thrombotic risk. Herein, we review the literature and provide practical suggestions for clinical use of TXA across a broad spectrum of bleeding disorders.

Avatrombopag for the treatment of immune thrombocytopenia and thrombocytopenia of chronic liver disease.

Avatrombopag is an orally-administered small molecule thrombopoietin receptor agonist. It was the third thrombopoietin receptor agonist approved for the treatment of immune thrombocytopenia and the first approved to treat periprocedural thrombocytopenia in patients with chronic liver disease (thereby providing an alternative to blood transfusions for these patients). Unlike eltrombopag, avatrombopag does not require a 4 hr food-restricted window around its use and it has not been associated with hepatotoxicity in ITP patients or portal vein thrombosis in patients with chronic liver disease. In ITP patients it can often be dosed less frequently than once daily. It is overall well-tolerated with a side-effect profile similar to placebo in randomized clinical trials. This article will review the clinical development, efficacy, safety, and pharmacology of avatrombopag for use in patients with ITP and thrombocytopenia of chronic liver disease.

Research progress in the biological activities of 3,4,5-trimethoxycinnamic acid (TMCA) derivatives.

TMCA (3,4,5-trimethoxycinnamic acid) ester and amide are privileged structural scaffolds in drug discovery which are widely distributed in natural products and consequently produced diverse therapeutically relevant pharmacological functions. Owing to the potential of TMCA ester and amide analogues as therapeutic agents, researches on chemical syntheses and modifications have been carried out to drug-like candidates with broad range of medicinal properties such as antitumor, antiviral, CNS (central nervous system) agents, antimicrobial, anti-inflammatory and hematologic agents for a long time. At the same time, SAR (structure-activity relationship) studies have draw greater attention among medicinal chemists, and many of the lead compounds were derived for various disease targets. However, there is an urgent need for the medicinal chemists to further exploit the precursor in developing chemical entities with promising bioactivity and druggability. This review concisely summarizes the synthesis and biological activity for TMCA ester and amide analogues. It also comprehensively reveals the relationship of significant biological activities along with SAR studies.

[Hemorrhage under direct oral anticoagulants : Occurrence and treatment in intensive care patients]. / Blutungen unter direkten oralen Antikoagulanzien : Auftreten und Therapie bei Intensivpatienten.

The use of anticoagulants is associated with an increased risk of bleeding and nevertheless bleeding complications can be lifethreatening. The focus is on bleeding under direct oral anticoagulants (DOAC) because antidotes and specific measures are lacking for some DOACs. Furthermore, routinely carried out clotting tests cannot be used to determine the degree of anticoagulation under DOACs. Therefore, it becomes difficult to determine whether the coagulation inhibition effect is present. This article presents the treatment of hemorrhage in patients with DOACs in the intensive care unit. Further, the indications for DOACS and details of administration and monitoring are presented.

Patients with Moderate and Severe Traumatic Brain Injury: Impact of Preinjury Platelet Inhibitor or Warfarin Treatment.

OBJECTIVE: We aimed to examine the effect of preinjury antithrombotic medication on clinical and radiologic neuroworsening in traumatic brain injury (TBI) and study the effect on outcome. METHODS: A total of 184 consecutive patients ≥50 years old with moderate and severe TBI admitted to a level 1 trauma center were included. Neuroworsening was assessed clinically by using the Glasgow Coma Scale (GCS) score and radiologically by using the Rotterdam CT score on repeated time points. Functional outcome was assessed with the Glasgow Outcome Scale Extended 6 months after injury. RESULTS: The platelet inhibitor group (mean age, 77.3 years; n = 43) and the warfarin group (mean age, 73.2 years; n = 20) were significantly older than the nonuser group (mean age, 63.7 years; n = 121; P ≤ 0.001). In the platelet inhibitor group 74% and in the warfarin group, 85% were injured by falls. Platelet inhibitors were not significantly associated with clinical or radiologic neuroworsening (P = 0.37-1.00), whereas warfarin increased the frequency of worsening in GCS score (P = 0.001-0.028) and Rotterdam CT score (P = 0.004). In-hospital mortality was higher in the platelet inhibitor group (28%; P = 0.030) and the warfarin group (50%; P < 0.001) compared with the nonuser group (13%). Platelet inhibitors did not predict mortality or worse outcome after adjustment for age, preinjury disability, GCS score, and Rotterdam CT score, whereas warfarin predicted both mortality and worse outcome. CONCLUSIONS: In this study of patients with moderate and severe TBI, preinjury platelet inhibitors did not cause neuroworsening or predict higher mortality or worse outcome. In contrast, preinjury warfarin caused neuroworsening and was an independent risk factor for mortality and worse outcome at 6 months. Hence, fall prevention and liberal use of computed tomography examinations is important in this patient group.

Phase 1 dose-escalating study to evaluate the safety, pharmacokinetics, and pharmacodynamics of a recombinant factor Xa variant (FXaI16L ).

Essentials FXaI16L is a recombinant zymogen-like variant of activated coagulation factor X (FXa). A phase 1 dose escalation clinical trial of FXaI16L was conducted in healthy adults. FXaI16L was safe and tolerated at doses up to 5 µg/kg; no dose-limiting toxicity was observed. Data support further development of FXaI16L for patients with acute hemorrhagic conditions. SUMMARY: Background FXaI16L (PF-05230907) is a zymogen-like variant of activated factor X (FXa). It shows enhanced resistance to inactivation by endogenous inhibitors as compared with wild-type FXa, and restores hemostatic activity in non-clinical models of various bleeding conditions. Objectives To evaluate the safety, pharmacokinetics and pharmacodynamics of FXaI16L by performing a phase 1, first-in-human, dose-escalation clinical trial in healthy adult volunteers. Methods Participants were assigned to one of six ascending single-dose cohorts (0.1, 0.3, 1, 2, 3 or 5 µg kg-1 ), each planned to comprise six volunteers treated with FXaI16L and two treated with placebo. Assessments included safety monitoring, pharmacokinetic and pharmacodynamic (PD) analyses, and immunogenicity testing. Results The trial enrolled 49 male volunteers. Administration of a single intravenous bolus dose of FXaI16L was safe and tolerated at all dose levels tested, with no dose-limiting toxicity or serious adverse events. FXaI16L plasma levels appeared to increase dose-proportionally, with a half-life of ~ 4 min. Treatment-related PD changes were observed for activated partial thromboplastin time, thrombin generation assay, thrombin-antithrombin complexes, prothrombin fragment 1 + 2, and D-dimer. One volunteer had a weak and transient non-neutralizing antidrug antibody response, which did not cross-react with native FX or native FXa. Conclusions FXaI16L was safe and tolerated, and showed a pharmacologic effect in healthy adults when administered at doses up to 5 µg kg-1 . The safety profile, pharmacokinetics and pharmacodynamics observed in this clinical trial support the further development of FXaI16L for hemostatic treatment in individuals with acute hemorrhagic conditions.

Implementing a clinical pharmacy service in hematology / Implementação de um serviço farmacêutico clínico em hematologia

ABSTRACT Objective: To implement a clinical pharmacy service focused on the comprehensive review of antineoplastic drugs used in therapy of hematological diseases. Methods: An interventional study was conducted in a Brazilian tertiary teaching hospital in two different periods, with and without a clinical pharmacy service, respectively. This service consisted of an antineoplastic prescription validation (analysis of patients' characteristics, laboratory tests, compliance with the therapeutic protocol and with pharmacotechnical parameters). When problems were detected, the pharmacist intervened with the physician or another health professional responsible for the patient. Inpatients and outpatients with hematological diseases were included. Results: We found an increased detection of drug-related problem by 106.5% after implementing the service. Comparing the two periods, an increase in patients' age (26.7 years versus 17.6 years), a predominance of outpatients (54% versus 38%), and an increase in multiple myeloma (13% versus 4%) and non-Hodgkin lymphoma (16% versus 3%) was noted. The most commonly found problems were related to dose (33% versus 25%) and cycle day (14% versus 30%). With regard to clinical impact, the majority had a significant impact (71% versus 58%), and in one patient from the second period could have been fatal. The main pharmaceutical interventions were dose adjustment (35% versus 25%) and drug withdrawal (33% versus 40%). Conclusion: The pharmacy service contributed to increase the detection and resolution of drug-related problems, and it was an effective method to promote the safe and rational use of antineoplastic drugs.

RESUMO Objetivo: Implementar um serviço farmacêutico clínico centrado na revisão completa dos antineoplásicos utilizados no tratamento de doenças hematológicas. Métodos: Estudo intervencional conduzido em um hospital universitário terciário brasileiro em dois períodos distintos, com base na ausência e na presença do serviço farmacêutico clínico, respectivamente. O referido serviço consistiu na validação farmacêutica de prescrição de medicamentos antineoplásicos (análise de características do paciente, exames laboratoriais, conformidade com o protocolo terapêutico e parâmetros farmacotécnicos). Após a detecção dos problemas, o farmacêutico interveio junto ao médico ou outro profissional de saúde responsável pelo paciente. Foram incluídos pacientes internados e ambulatoriais com doenças hematológicas. Resultados: Observou-se um aumento de 106,5% na detecção de problemas relacionados com medicamentos após a implementação do serviço. Comparando-se os dois períodos, verificou-se aumento na idade dos pacientes (26,7 anos versus 17,6 anos), predomínio de pacientes ambulatoriais (54% versus 38%) e aumento de mieloma múltiplo (13% versus 4%) e linfoma não Hodgkin (16% versus 3%). Os problemas mais comumente encontrados foram relacionados à dose (33% versus 25%) e ao dia do ciclo (14% versus 30%). Quanto ao impacto clínico, a maioria apresentou impacto significante (71% versus 58%) e um poderia ter sido fatal no segundo período. As principais intervenções farmacêuticas realizadas foram ajuste de dose (35% versus 25%) e suspensão de medicamento (33% versus 40%). Conclusão: O serviço farmacêutico contribuiu para o aumento da detecção e resolução de problemas relacionados com medicamentos, tratando-se de um método efetivo para promover o uso seguro e racional de medicamentos antineoplásicos.

Os novos anticoagulantes orais na prática clínica / The new oral anticoagulants in clinicalpractice

Na tradição mitológica grega, Cila e Caribdis eram dois monstros marinhos que moravam nos lados opostos do estreito de Messina, entre a Calábria e a Sicília na Itália. Navegar nesse mar tornava-se extremamente difícil, desde que esses monstros estavam muito próximos, e tentar se afastar de Cila implicava passar muito próximo de Caribdis, e vice-versa. Esse cenário imaginário bem retrata a dificuldade que se encontra na prática clínica quando, no complexo cenário do mundo real, pesando entre o benefícioe o risco, deve-se indicar a anticoagulação aos pacientes. Os antagonistas da vitamina K foram a única classe de anticoagulantes orais disponíveis para os médicos por décadas. No entanto, com a recente entrada no mercado nacional de novos anticoagulantes orais, como dabigatran, rivaroxaban e apixaban, os clínicos têm agora uma escolha mais ampla. Este artigo busca fornecer uma revisão concisa desses novos medicamentos e uma abordagem prática para o seu uso clínico.

In the tradition Greek mythological, Scylla and Charybdis were two sea monsters placed on opposite sides of the strait of Messina, between Calabria and Sicily in Italy. To navigate at this sea was extremely difficult since these monsters were very close to each other and attempts to avoid Scylla implied passing very closed to Charybdis and vice versa. This imaginary scenario well depicts the difficulties that a practicing physician may encounter when, in the complex setting of "real-world" assessing between benefits and risks, should recommend the anticoagulation for ours patients. Vitamin K antagonists were the only class of oral anticoagulants available to clinicians for decades. However, given the recent approval and availability of new oral anticoagulants, such as dabigatran, rivaroxaban and apixaban, clinicians now have a broader choice. This article provides a concise review of these medications and a practical approach to their clinical use.

Dabigatran versus warfarin after bioprosthesis valve replacement for the management of atrial fibrillation postoperatively: protocol.

BACKGROUND: Warfarin and similar vitamin K antagonists have been the standard therapy for patients with mechanical or biological valve prosthesis and atrial fibrillation (AF). Even with the appropriate use of therapy, some studies have reported that there is a high incidence of thromboembolic events, 1%-4% per year. Furthermore, a bleeding risk is significant, ranging from 2% to 9% per year, according to some studies. OBJECTIVE: The objective of our study was to examine the effect of dabigatran etexilate versus dose-adjusted warfarin for the prevention of intracardiac thrombus in persistent or permanent AF at least 3 months after aortic and/or mitral bioprosthesis replacement. METHODS: Dabigatran versus warfarin after bioprosthesis valve replacement for the management of atrial fibrillation postoperatively (DAWA) is a phase 2, prospective, open label, randomized exploratory pilot study. The main variable to be observed in this study is intracardiac thrombus. From August 2013 to April 2015, 100 patients, at least 3 months after aortic and/or mitral bioprosthesis replacement and permanent or persistent AF postoperatively, who match eligibility criteria will be selected from Ana Nery Hospital in Salvador-Bahia with a follow-up of three months. Patients were randomly assigned in a 1:1 ratio to receive either dabigatran etexilate or warfarin. RESULTS: Although the present study has no statistic power to proof non-inferiority, it is expected that the dabigatran etexilate group will be protected as well as the warfarin group from intracardiac thrombus, without increasing the bleeding rates, since we are using safer doses (110 mg bid). The lack of necessity of monitoring INR is also another factor that contributes to a better adherence to the new drug and it can make all the difference in the manner of doing anticoagulation for patients with similar clinical characteristics. CONCLUSIONS: The study is in the recruitment phase. It is possible that dabigatran etexilate is as effective as warfarin in preventing the emergence of intracardiac thrombus in patients with AF and mitral and/or aortic bioprosthesis. TRIAL REGISTRATION: Clinicaltrials.gov NCT01868243; http://clinicaltrials.gov/ct2/show/NCT01868243 (Archived by WebCite at http://www.webcitation/6OABiuasd).

Antithrombotic medicines following intracerebral haemorrhage: where's the evidence?

The use of antithrombotic medicines in patients who have a history of intracerebral haemorrhage is widely perceived as being contraindicated. However, many patients with intracerebral haemorrhage may suffer from conditions for which antithrombotic medicines are indicated. Such scenarios represent a therapeutic dilemma whereby treating infers an increased risk of recurrent intracerebral haemorrhage, but not treating infers an increase of thrombotic complications. Despite the importance of this dilemma, there is very little guidance for prescribers. This perspective review considered previous systematic reviews that addressed this issue, together with recently published research findings from the Tayside Stroke Cohort. Systematic reviews of experimental and observational studies have concluded that there is a marked lack of data on which to judge the safety of oral anticoagulant agents following intracerebral haemorrhage. In addition, the limited data available regarding the use of antiplatelet medicines following intracerebral haemorrhage provide no evidence that they are harmful, and again further data are required. In the absence of such data, a decision analysis approach has been proposed. This considers the findings of other studies to infer the likely impact of using antithrombotic agents in patients with intracerebral haemorrhage. The success of this approach is contingent on the availability of reliable data that describe the rate of recurrent intracerebral haemorrhage; however, published data on this varies widely. There are a number of factors that conspire against researchers addressing this issue. The current paucity of evidence to guide prescribers faced with this therapeutic dilemma seems likely to remain for some time.