Sepsis is a severe systemic inflammatory response to infection that manifests with widespread inflammation as well as endothelial and coagulation dysfunction that may lead to hypotension, organ failure, shock, and death. Disseminated intravascular coagulation (DIC) is a complication of sepsis involving systemic activation of the fibrinolytic and coagulation pathways that can lead to multi-organ dysfunction, thrombosis, and bleeding, with a 2-fold increase in mortality. This study demonstrates the diagnostic and prognostic value of profiling various biomarkers of inflammation and infection in patients with sepsis-associated DIC to assess the severity of illness. Deidentified samples were obtained from adult patients with sepsis and suspected DIC. Platelet count, prothrombin time, D-dimer, and fibrinogen levels were used to assign International Society of Thrombosis and Hemostasis DIC scores to plasma samples from 103 patients with sepsis and suspected DIC. Using commercially available enzyme-linked immunosorbent assay, chromogenic assay, and RANDOX Biochip methods, levels of procalcitonin (PCT), extracellular nucleosomes, interleukin (IL) 6, IL-8, IL-10, and tumor necrosis factor α (TNFα) were measured in patients with sepsis and DIC and compared to levels in healthy individuals. Elevated levels of PCT, IL-6, IL-8, IL-10, and TNFα were observed in most patients with sepsis and DIC. Additionally, the levels of these markers show significant positive correlations with each other and with DIC score. Currently, no single biomarker can effectively diagnose DIC in patients with sepsis. This study lays the groundwork for the development of a diagnostic algorithm using several markers of inflammation and infection and DIC score as parameters in assessing severity of sepsis-associated coagulopathy in a clinical setting.

The aim of this study was to investigate the utility of the neutrophil-to-lymphocyte ratio (NLR) and platelet-to-lymphocyte ratio (PLR) to predict all-cause mortality in patients presenting with acute pulmonary embolism (PE). Three hundred consecutive patients with acute PE between March 2016 and December 2018 were retrospectively analyzed. We identified 191 patients who met the study inclusion criteria. Twenty-eight patients died during the study period. There was a significant difference in PLR, but not NLR, between patients with low risk, submassive, and massive risk PE (P = .02 and P = .58, respectively, by the Kruskal-Wallis test). Elevated NLR and PLR were associated with all-cause mortality (P < .01 and P < .01, respectively). Neutrophil-to-lymphocyte ratio of 5.46 was associated with all-cause mortality with sensitivity of 75.0% and specificity of 66.9% (area under the curve [AUC]: 0.692 [95% confidence interval, CI]: 0.568-0.816); P < .01). Platelet-to-lymphocyte ratio of 256.6 was associated with all-cause mortality with sensitivity of 53.6% and specificity of 82.2% (AUC: 0.693 [95% CI: 0.580-0.805]; P < .01). Neutrophil-to-lymphocyte ratio and PLR are simple biomarkers that are readily available from routine laboratory values and may be useful components of PE risk prediction models.

Since the discovery of heparin nearly a century ago, there have been large gaps in the development of anticoagulants. The discovery of warfarin was the first step toward using oral anticoagulants, but warfarin use has been associated with its own challenges from the perspectives of the prescribing physician and the patient. Warfarin, along with other coumarins, has a narrow therapeutic index, requires frequent monitoring, exhibits interindividual response variations, and is associated with several adverse effects. Frequent drug and food interactions contribute to potential safety and efficacy compromise. The indications for use of oral anticoagulants have increased, as these drugs are used not only for thrombosis management but also for cardiovascular indications, producing more challenges for oral anticoagulant use. Factor Xa and thrombin targeting has provided a rational approach to develop new oral anticoagulants with improvements over warfarin. In this review, the pharmacology of warfarin and the pharmacology of the newly developed oral anti-Xa and antithrombin agents are discussed.

COVID-19 has proven to be particularly challenging given the complex pathogenesis of SARS-CoV-2. Early data have demonstrated how the host response to this novel coronavirus leads to the proliferation of pro-inflammatory cytokines, massive endothelial damage, and generalized vascular manifestations. While SARS-CoV-2 primarily targets the upper and lower respiratory tract, other organ systems are also affected. SARS-CoV-2 relies on 2 host cell receptors for successful attachment: angiotensin-converting enzyme 2 and transmembrane protease serine 2. Clinicopathologic reports have demonstrated associations between severe COVID-19 and viral coagulopathy, resulting in pulmonary embolism; venous, arterial, and microvascular thrombosis; lung endothelial injury; and associated thrombotic complications leading to acute respiratory distress syndrome. Viral coagulopathy is not novel given similar observations with SARS classic, including the consumption of platelets, generation of thrombin, and increased fibrin degradation product exhibiting overt disseminated intravascular coagulation–like syndrome. The specific mechanism(s) behind the thrombotic complications in COVID-19 patients has yet to be fully understood. Parenteral anticoagulants, such as heparin and low-molecular-weights heparins, are widely used in the management of COVID-19 patients. Beyond the primary (anticoagulant) effects of these agents, they may exhibit antiviral, anti-inflammatory, and cytoprotective effects. Direct oral anticoagulants and antiplatelet agents are also useful in the management of these patients. Tissue plasminogen activator and other fibrinolytic modalities may also be helpful in the overall management. Catheter-directed thrombolysis can be used in patients developing pulmonary embolism. Further investigations are required to understand the molecular and cellular mechanisms involved in the pathogenesis of COVID-19-associated thrombotic complications.

It is now widely accepted that various low-molecular-weight heparins (LMWHs) exhibit specific molecular and structural attributes that are determined by the type of manufacturing process used. For example, enoxaparin, which is prepared by benzylation followed by alkaline hydrolysis of unfractionated heparin (UFH), exhibits a double bond at the nonreducing end and the presence of a unique bicyclic structure namely 1,6 anhydromanno glucose or mannose, or both, at the reducing end. Similarly, the other LMWHs, such as dalteparin, nadroparin, tinzaparin, and parnaparin, exhibit specific structural characteristics that may contribute to their own unique biochemical and pharmacological profiles. These unique features may not exhibit any major influence on the routinely determined anti-Xa and anti-IIa activities. However, these may have an impact on the pharmacokinetics and other biological actions such as the interactions with growth factors, blood components, and vascular cells. This is the reason for the initial caution for the noninterchangeability of the anti-Xa adjusted dosing of the different LMWHs. Although the nonanticoagulant biological effects of these drugs are poorly understood at this time, they are now recognized as contributing significantly to the overall therapeutic effects of these drugs. Because some of these drugs have proved to be effective in the management of cancer-associated thrombosis and exhibit improvements in mortality outcome, these LMWHs may also produce several other effects by modulating inflammatory processes, apoptosis, and other regulatory functions related to cellular functions at different levels. Thus, the interactions of these LMWHs with antithrombin and heparin cofactor II are not the only determinants of their biological actions. Release of tissue factor pathway inhibitor (TFPI), regulation of cytokines, nitric oxide, and eicosanoids contribute to their individuality. Such properties are not only dependent on the oligosaccharide sequence and consensus sites but also depend mainly on microchemical and structural attributes in these drugs. European Pharmacopoeia (EP) and the World Health Organization (WHO) have developed guidelines to characterize these agents in terms of their molecular and biological profile. Regulatory agencies such as the U.S. Food and Drug Administration (FDA) and European Medicines Agency (EMEA) consider each of these drugs as distinct pharmacological agents. This has prompted the requirement for product-specific clinical data for the approval of their use in various clinical indications. There is a clear concern regarding the development of potential generic versions of branded products and the submissions by generic manufacturers for the regulatory approval of generic interchangeability that refers to the substitution of an apparent chemically identical and bioequivalent versions of the branded LMWHs. Currently, there are no regulatory guidelines or consensus opinions on the acceptance of generic versions of the branded products. Because the LMWHs represent not only a biological entity but also product-specific molecular and structural attributes, the acceptance of a generic version must be based on clearly defined guidelines stipulating minimal molecular and structural, biological, and clinical validation requirements. It is therefore to be stressed that each of the LMWHs is a distinct drug entity that characteristically exhibits a product-based therapeutic spectrum in different thrombotic and nonthrombotic disorders. Thus, until the establishment of valid regulatory guidelines for the generic interchangeability of the commercially available LMWHs is completed, generic substitutes are not recommended.