The role of oxidative stress in acute ischemic stroke-related thrombosis (November 2022)

Available treatments for ischemic stroke are mainly limited to thrombolysis and/or thrombectomy, therefore there would be a benefit of new therapeutic treatments. Intravascular oxidative stress (OS) has been found to be closely linked with stroke-related thrombosis, as it promotes initial thrombus formation by damaging endothelial cells and platelets, and influences thrombus maturation and stability. This review looked at the mechanisms and biomarkers by which oxidative stress promotes stroke-related thrombosis.

Oxidative stress refers to a harmful state in which the body produces free radicals including reactive oxygen species (ROS) and reactive nitrogen species (RNS). There is increasing research regarding the roles of ROS/RNS in platelet function and stroke-related thrombosis. Upon platelets stimulation, enzymes involved in platelet ROS production are motivated and can produce free radicals. Nitric oxide (NO) has a vital role in mediating normal endothelial function, and the reduced synthesis and activation of NO are believed to be one of the earliest and most important events that start endothelial dysfunction and thrombosis.

Progression and recurrence of stroke are linked with the development of thrombus formation and arterial reocclusion. Redox biomarkers with high specificity and easy detection features may be critical tools for predicting the incidence of stroke and observing its progress and prognosis. Lipid peroxidation products (derived from polyunsaturated fatty acids) are extensively used as biomarkers for OS and are significant factors in stroke-related thrombosis. Redox imbalance caused by excessive oxidant generation or insufficient antioxidant storage may lead to OS, therefore the levels of antioxidants may also serve as indirect biomarkers of OS. Myeloperoxidase (MPO) is an essential part of endothelial dysfunction and platelets activation; and as another source of oxidative stress.

Platelet redox imbalance in Hypercholesterolemia: A big problem for a small cell (September 2022)

Oxidative stress results from an imbalance between the synthesis of ROS and neutralising antioxidants, and the role of ROS for intracellular signalling has been well established in several cell lines, including platelets. Evidence shows that increased intraplatelet ROS synthesis and impaired ROS neutralisation are implicated in the thrombotic process. A prothrombotic phenotype is associated with a number of metabolic disorders related to dyslipidemia, including atherosclerosis, with low density lipoprotein cholesterol (LDL-C) being recognised as a key player in the pathogenesis of atherosclerosis.

Dyslipidemia is a relevant risk factor for the development of atherosclerosis due to the prolonged accumulation of lipid-rich plaque in arteries. Changes to the lipid profile are associated with both increased oxidative stress and the generation of oxidized lipids, which exert an important role in promoting atherogenesis through their influence on endothelial and vascular smooth muscle cells, and platelet hyperreactivity.

The redox balance depends on the ROS production and action of antioxidants. Hypercholesterolemia determines increased ROS levels not only by increasing the activity of redox enzymes, but also by impairing the protective function of antioxidant enzymes. Oxidative stress plays an important role in platelet activation, and several studies have evaluated the presumed association between dietary antioxidant nutrients in dyslipidemia and protection against cardiovascular disease and specifically the effects of antioxidants on platelet function. Even though platelets are the smallest blood cells, monitoring platelet biomarkers of oxidative stress and antioxidant status could help to assess the problem of prothrombotic predisposition for patients at high cardiovascular risk.

Risk factors for Post-Thrombotic Syndrome in patients with a first proximal deep venous thrombosis treated with direct oral anticoagulants (August 2022)

The aim of this study was to investigate patients with a first episode of proximal DVT treated with DOACs to determine the incidence and influencing risk factors for post-thrombotic syndrome (PTS). The cohort comprised of 769 individuals, 46.8% had unprovoked DVT and 28.2% with thrombophilia.

The most prescribed anticoagulant was rivaroxaban (43.3%) with 88.3% of patients undertaking treatment for >3 months; and 19.8% of patients had PTS. At the completion of the follow-up period (36 months), incidence of PTS was mild=87%, moderate=7.2% and severe=3.9%. Patients with PTS commonly had DVT in the femoral and/or iliac veins (72.4%) and 46.7% had an unprovoked episode. Thrombophilia was diagnosed in 31.6% of patients; and 31.6% were diagnosed with Thrombophilia.

Risk factors associated with PTS included obesity (1.7-fold increased risk). Proximal localisation of thrombosis in the femoral and/or iliac veins increased risk of developing PTS by 1.2-fold. Other risk factors measured in the study – age, gender, malignancy, DVT transient risk factors, unprovoked DVT thrombophilia, blood group and duration of anticoagulant treatment, were not significantly linked with PTS.

The findings show the risk of PTS is not negligible in patients with proximal DVT, notwithstanding the use of DOACs. As other studies show inconclusive results, further investigation is needed to ascertain the incidence and predisposing risk factors of PTS and the ideal therapy.

Antithrombotic therapy for venous thromboembolism (June 2022)

Despite the high prevalence of VTE, 25% to 40% of all VTE events are idiopathic, making diagnosis and prevention difficult. This clinical guideline synopsis provides recommendations for VTE antithrombotic therapy. The guidelines oversight committee of the American College of CHEST Physicians formed a panel of experts (general internists, thrombosis specialists, pulmonologists, haematologists, methodologists, and medical librarians); here is a list of their main suggestions and strength of evidence:

  • Low-risk PE – receive outpatient treatment (strong recommendation, low certainty of evidence)
  • DOACs – use to treat acute VTE for the 3-month treatment phase (strong recommendation, moderate evidence)
  • Oral Xa inhibitors – use to treat acute VTE in a patient with cancer for both the initial and extended treatment phases (strong recommendation, moderate evidence)
  • Acute VTE – treat with full dose DOACs for 3 months (strong recommendation, moderate evidence) followed by reduced-dose DOACs for extended therapy if indicated (weak recommendation, moderate evidence)
  • Major or minor transient risk factors - extended anticoagulation therapy beyond 3 months is not routinely recommended (strong recommendation, moderate evidence)

Consensus on prevention and treatment of cancer-associated thrombosis (CAT) in controversial clinical situations with low levels of evidence (June 2022)

CAT causes increased hospitalisation, morbidity and mortality rates; and delays in cancer treatment. This review provides recommendations and treatment processes for the following complex and clinically relevant situations.

  • VTE prophylaxis in ambulatory cancer patients with pancreatic cancer.
  • Lung cancer with molecular alterations.
  • During antineoplastic treatment with antiangiogenics
  • Chemotherapy
  • Protracted VTE treatment
  • Drugs
  • Situations of high bleeding risk
  • Recurrent VTE

This review analysed several guidelines and articles and has provided useful advice and practical recommendations including: primary thromboprophylaxis in patients with lung cancer (ALK/ROS1) translocations or pancreatic cancer receiving ambulatory chemotherapy must be appraised; anticoagulation beyond 6 months is recommended with metastatic tumours, on active treatment, high risk of recurrent VTE without bleeding risk; LMWH and DOACs should be used cautiously in gastrointestinal cancers; with recurrent VTE, the presence of active cancer, infra-therapeutic dose, and anticoagulant treatment failure must be ruled out.

Pharmacological profile of asundexian, a novel, orally bioavailable inhibitor of factor XIa (June 2022)

Activated coagulation factor XI (FXIa) contributes to the development and propagation of thrombosis and as it plays a small role in haemostasis it is a useful antithrombotic target. The aim of the study was to evaluate the pharmacology of asundexian which is a small molecule inhibitor targeting FXIa.

The study found asundexian reduced FXIa activity, thrombin generation triggered by contact activation or low concentrations of tissue factor, and prolonged activated partial thromboplastin time. When administered before or during thrombus formation, asundexian reduced thrombus weight.

Asundexian alone or in combination with antiplatelet drugs did not increase bleeding times or blood loss in any of the models studied. This research demonstrates asundexian is an effective oral FXIa inhibitor with antithrombotic efficacy in both arterial and venous thrombosis models in prevention and intervention settings, without increasing bleeding.

Further investigations are warranted to establish the clinical relevance of these preclinical findings. The efficacy and safety of asundexian are currently being investigated in a number of phase II studies. (Conflict of interest – research funded by Bayer AG; authors associated with Bayer AG)

Making anticoagulation safer (April 2022)

This commentary discusses oral anticoagulants and their use for the prevention or treatment of thrombosis by inhibiting the proteases FXa or thrombin or by lowering the plasma concentrations of their precursors (factor X and prothrombin). Despite the effectiveness of these anticoagulants, the increased risk of bleeding is a common factor.

FXa and thrombin are at the core of the system that stems bleeding after blood vessel injury and anticoagulants targeting these proteases, therefore, can compromise haemostasis, and bleeding restricts the intensity of anticoagulation that can be tolerated. Therefore, safer and more efficient antithrombotic therapies are required.

Factor XI (FXI) is the precursor of FXIa, and part of the coagulation pathway, and despite FXI having a limited role in haemostasis, there is evidence that FXI contributes to thrombosis, and particularly to VTE and ischaemic stroke. Research by Piccini et al. (see article below) found that the FXIa inhibitor anticoagulant drug asundexian was effective and had reductions in all bleeding events. Results from this study add to the emerging evidence that justifies pursuing antithrombotic strategies that target FXI or FXIa.

Safety of the oral factor XIa inhibitor asundexian compared with apixaban in patients with atrial fibrillation (PACIFIC-AF): a multicentre, randomised, double-blind, double-dummy, dose-finding phase 2 study (April 2022)

Current treatments recommended for AF is direct oral anticoagulants (DOACs) due to their safety and efficacy over vitamin K antagonists. Based on results from observational data from patients with inherited factor XI deficiency, the researchers hypothesised that treatment with asundexian would lead to less bleeding compared to DOACs. This research compared the DOAC, apixaban with the activated coagulation factor XIa inhibitor asundexian, which might reduce thrombosis and with minimal effect on haemostasis.

The study was between January 2020 to June 2021, with 753 patients from 93 sites in 14 countries starting the treatment phase. There were three treatment groups – 249 receiving 20mg of asundexian; 254 receiving 50mg of asundexian; and 250 participants receiving the standard dosing of 5mg twice daily of apixaban. At the end of the treatment phase, 671 completed and 82 did not due to various reasons – adverse events (38), death (6), withdrawal (12), non-adherence (1) and other reasons (25).

The main outcome was the composite of major bleeding or clinically relevant non-major bleeding according to International Society on Thrombosis and Haemostasis criteria. At the end of the treatment phase there were three events from the asundexian 20mg group: one event from the asundexian 50mg group, and six events from the apixaban group.

Therefore, the study concluded that asundexian treatment resulted in significantly lower rates of bleeding compared to apixaban, the drug is well tolerated with only 1 in 20 participants discontinuing the treatment due to an adverse event. In conclusion, these results demonstrate the efficacy of FXIa as a therapeutic target and provides a rationale for further larger clinical trials with asundexian.

Inherited thrombophilia in the era of direct oral anticoagulants (Feb 2022)

Recent research investigated which thrombophilia testing methods and the affect direct oral anticoagulants (DOAC) may have on patients, as determining who to test and how to use the results is not simple. The review found that thrombophilia testing can be impacted by DOACs, which may cause false-negative results and may be significantly affected by even small amounts of DOACs.

Several strategies have been proposed to minimize the impact of residual DOACs on coagulation assays, however none of the approaches are optimal. A method to overcome the problem is to remove DOAC from the plasma sample without influencing its coagulant property. To avoid this interference, adsorbent agents are able to remove DOAC from a plasma sample. The adsorbent procedure appears to be an effective and simple way to overcome the interference of DOACs in coagulation tests and should soon facilitate the interpretation of thrombophilia screening tests in patients taking DOACs.