Endothelial injury and dysfunction with emerging immunotherapies in multiple myeloma, the impact of COVID-19, and endothelial protection with a focus on the evolving role of defibrotide.

Patients with multiple myeloma (MM) were among the groups impacted more severely by the COVID-19 pandemic, with higher rates of severe disease and COVID-19-related mortality. MM and COVID-19, plus post-acute sequelae of SARS-CoV-2 infection, are associated with endothelial dysfunction and injury, with overlapping inflammatory pathways and coagulopathies. Existing treatment options for MM, notably high-dose therapy with autologous stem cell transplantation and novel chimeric antigen receptor (CAR) T-cell therapies and bispecific T-cell engaging antibodies, are also associated with endothelial cell injury and mechanism-related toxicities. These pathologies include cytokine release syndrome (CRS) and neurotoxicity that may be exacerbated by underlying endotheliopathies. In the context of these overlapping risks, prophylaxis and treatment approaches mitigating the inflammatory and pro-coagulant effects of endothelial injury are important considerations for patient management, including cytokine receptor antagonists, thromboprophylaxis with low-molecular-weight heparin and direct oral anticoagulants, and direct endothelial protection with defibrotide in the appropriate clinical settings.

Awareness of venous thromboembolism among patients with cancer: Preliminary findings from a global initiative for World Thrombosis Day.

BACKGROUND: Cancer-associated venous thromboembolism (CAT) has detrimental impact on patients' clinical outcomes and quality of life. Data on CAT education, communication, and awareness among the general cancer population are scanty. METHODS: We present the preliminary results of an ongoing patient-centered survey including 27 items covering major spheres of CAT. The survey, available in 14 languages, was promoted and disseminated online through social networks, email newsletters, websites, and media. RESULTS: As of September 20, 2022, 749 participants from 27 countries completed the survey. Overall, 61.8% (n = 460) of responders were not aware of their risk of CAT. Among those who received information on CAT, 26.2% (n = 56) were informed only at the time of CAT diagnosis. Over two thirds (69.1%, n = 501) of participants received no education on signs and symptoms of venous thromboembolism (VTE); among those who were educated about the possible clinical manifestations, 58.9% (n = 119) were given instructions to seek consultation in case of VTE suspicion. Two hundred twenty-four respondents (30.9%) had a chance to discuss the potential use of primary thromboprophylaxis with health-care providers. Just over half (58.7%, n = 309) were unaware of the risks of bleeding associated with anticoagulation, despite being involved in anticoagulant-related discussions or exposed to anticoagulants. Most responders (85%, n = 612) valued receiving CAT education as highly relevant; however, 51.7% (n = 375) expressed concerns about insufficient time spent and clarity of education received. CONCLUSIONS: This ongoing survey involving cancer patients with diverse ethnic, cultural, and geographical backgrounds highlights important patient knowledge gaps. These findings warrant urgent interventions to improve education and awareness, and reduce CAT burden.

Factor XI Deficiency.

Factor XI (FXI) deficiency (hemophilia C or Rosenthal disease) was first described in the 1950s in a multigenerational family experiencing bleeding related to surgery and dental procedures. Managing patients with FXI deficiency presents several challenges, including a lack of correlation of bleeding symptoms with FXI activity levels, the large volume of fresh frozen plasma required to achieve hemostatic FXI levels, lack of availability of FXI concentrate in certain regions of the world, and the inherent thrombotic risk associated with replacement therapy. This article summarizes presentation, diagnosis, and management of patients with FXI deficiency in a variety of clinical settings.

Prevention of recurrent thromboembolism in myeloproliferative neoplasms: review of literature and focus on direct oral anticoagulants.

Myeloproliferative neoplasms (MPNs), including polycythemia vera (PV), essential thrombocythemia (ET), and primary myelofibrosis (MF) are stem cell clonal neoplasms characterized by expansion of late myeloid cells. Thrombosis risk is elevated in MPNs and contributes significantly to morbidity and mortality. Current consensus guidelines make no specific recommendations regarding anticoagulant choice for the treatment of venous thromboembolism (VTE) in MPNs, with most evidence supporting the use of vitamin K antagonists (VKAs) for secondary prophylaxis. However, direct oral anticoagulants (DOACs) are now increasingly being used, although with limited data on safety and efficacy in MPNs specifically. The widespread adoption of DOACs is based on new, high-quality evidence demonstrating safety and efficacy of DOAC treatment for cancer-associated VTE. However, these studies include few if any MPN patients, and MPNs have disease-specific considerations that may elevate thrombosis and bleeding risk. The purpose of this review is to discuss evidence behind current treatment recommendations for thrombosis in MPNs, with special attention to the use of DOACs.

Apixaban versus Dalteparin for the Treatment of Acute Venous Thromboembolism in Patients with Cancer: The Caravaggio Study.

International and national guidelines recommend low-molecular-weight heparin for the treatment of venous thromboembolism (VTE) in patients with cancer. The aim of the Caravaggio study is to assess whether oral apixaban is non-inferior to subcutaneous dalteparin for the treatment of acute proximal deep vein thrombosis and/or pulmonary embolism in patients with cancer. The study is an investigator-initiated, multi-national, prospective, randomized, open-label with blind end-point evaluation (PROBE), non-inferiority clinical trial (NCT03045406). Consecutive patients are randomized to receive oral apixaban or subcutaneous dalteparin for 6 months. Apixaban is given at a dose of 10 mg twice daily for the first 7 days and then 5 mg twice daily; dalteparin is given at a dose of 200 IU/kg for the first month and then 150 IU/kg once daily. The primary outcome of the study is objectively confirmed recurrent VTE as assessed by a central independent adjudication committee unaware of study treatment allocation. The primary safety outcome is major bleeding defined according to the guidelines of the International Society of Thrombosis and Haemostasis. Assuming a 6-month incidence of the primary outcome of 7% with dalteparin and an upper limit of the two-sided 95% confidence interval of the hazard ratio below the pre-specified margin of 2.00, 1,168 patients will be randomized considering an up to 20% loss in total patient-years (ß = 80%; α one-sided = 0.025). The Caravaggio study has the potential, along with other recently performed or on-going studies, to make less cumbersome the management of VTE in patients with cancer by replacing parenteral with oral anticoagulation.

Type A aortic dissection in a patient on dabigatran: hemostasis post circulatory arrest.

We present a successful case of prevention of postoperative hemorrhage in a 70-year-old male on dabigatran, who developed an acute type A aortic dissection and subsequently underwent an emergent ascending aortic replacement.

Anticoagulation for noncardiac indications in neurologic patients: comparative use of non-vitamin k oral anticoagulants, low-molecular-weight heparins, and warfarin.

OPINION STATEMENT: Patients with neurologic disorders may develop a wide variety of thromboembolic events, both as a primary manifestation and as a consequence of their underlying neurologic condition. There are many available options for anticoagulation, ranging from warfarin to the parenteral subcutaneously administered anticoagulants to the non-vitamin K oral anticoagulants (NOACs). Warfarin is orally available, well-studied, and easily reversible in the setting of bleeding, but has a prolonged onset of action, measured in days, and equally slow offset; requires frequent monitoring for dose titration; and has multiple drug-drug and food-drug interactions. Parenteral heparin-based anticoagulants are well-studied and have more predictable pharmacokinetics but are often more expensive, only partially reversible, and require daily injections, which can be difficult for patients to tolerate over long periods of time. The NOACs are easy to administer and have predictable pharmacokinetics but are expensive, not easily reversible, and are not as extensively studied. Specific agents are preferable in some defined neurologic conditions. For acute ischemic stroke, we do not recommend immediate anticoagulation with any agent. For patients with intracranial malignancy (either primary or metastatic), we recommend a low-molecular-weight heparin (LMWH) rather than warfarin or a NOAC. For thromboembolic disease in the setting of spinal cord injury, warfarin, LMWH, or the NOACs are reasonable options. In the setting of VTE or stroke related to antiphospholipid antibody syndrome (APS), we recommend long-term warfarin anticoagulation with an INR goal of 2-3, pending the results of ongoing research involving the NOACs. For cerebral venous sinus thrombosis not related to malignancy or APS, we recommend the use of LMWH in the acute setting, followed by at least three months of warfarin. In this article, we discuss the pharmacology, pathophysiology, and comparative research that served as a basis for our recommendations.

Dabigatran: a review of clinical and pharmacoeconomic evidence.

Dabigatran etexilate is the first commercially available oral direct thrombin inhibitor. A single trial has studied patients at risk for stroke associated with nonvalvular atrial fibrillation; in this trial, dabigatran 150 mg twice a day met the criteria for superiority over warfarin in preventing stroke and systemic embolism while reducing the rate of hemorrhagic stroke with a similar risk of major bleeding. For the treatment of venous thromboembolism, dabigatran 150 mg twice a day had comparable efficacy and safety versus warfarin. In contrast, dabigatran was less effective than enoxaparin 30 mg twice a day in venous thromboembolism prevention in orthopedic surgery. Advantages of dabigatran over warfarin include its lack of need for routine laboratory monitoring, a fixed-dose regimen, and potentially fewer clinically important drug interactions. Concerns include higher incidences of dyspepsia and gastrointestinal bleeding, twice-daily dosing, and lack of effective antidote. Additional drawbacks include higher drug cost versus warfarin, accumulation in case of renal impairment, higher discontinuation rates due to adverse events, and limited long-term safety and trial data. From a payer perspective, overall costs will be higher with dabigatran compared with warfarin, but dabigatran does meet the threshold to be considered a cost-effective therapy. In addition, the lack of need for regular laboratory monitoring is a quality of life advantage for patients on dabigatran. These observations suggest that dabigatran is a valuable addition to the therapeutic armamentarium for stroke prevention in selected patients with atrial fibrillation although caution should be exercised given the limited data on this agent and higher cost.