Introduction Recombinant fusion protein linking coagulation factor IX (FIX) with albumin (rIX-FP) has been shown to be an effective, well-tolerated treatment for patients with severe hemophilia B who had previously received factor replacement therapy. This study investigated the safety and efficacy of rIX-FP in previously untreated patients (PUPs). Methods Patients with moderately severe/severe hemophilia B (≤2% FIX) previously untreated with FIX replacement products received rIX-FP (25-75 IU/kg) prophylaxis weekly or on-demand treatment over ≥50 exposure days (EDs). Primary outcomes were the number of patients who developed FIX inhibitors and mean incremental recovery (IR) following a 50 IU/kg dose of rIX-FP. Secondary outcomes included incidence of adverse events (AEs) and annualized bleeding rates (ABRs). Results In total, 12 PUPs with a median age of 0 years (range, 0-11 years) were treated with rIX-FP for a median of 50 EDs (6/12 prophylaxis; 6/12 on-demand then prophylaxis). Overall, 11/12 patients did not develop FIX inhibitors; one 11-year-old patient developed an inhibitor against FIX after 8 EDs and was ultimately withdrawn. Mean (standard deviation) IR was 1.2 (0.4, n = 8) (IU/dL)/(IU/kg). Of the 137 treatment-emergent AEs recorded, five were attributed to rIX-FP. On the prophylaxis regimen, median ABR was 1.0 (range, 0-3.9, n = 12). No thromboembolic events or deaths occurred during the study. Conclusion This study provides data to support the safety and efficacy of rIX-FP in PUPs requiring on-demand or prophylactic treatment for moderately severe/severe hemophilia B, consistent with results in previously treated patients. Overall, 1/12 patients developed an inhibitor against FIX.

This post hoc subgroup analysis examined efficacy and safety outcomes with extended thromboprophylaxis rivaroxaban compared with in-hospital enoxaparin in 2,078 patients from the MAGELLAN study who had a hospitalization for heart failure or a history of heart failure and a lower risk of bleeding. A significant 36% reduction in the composite endpoint of asymptomatic proximal deep vein thrombosis (DVT) in the lower extremity, symptomatic DVT in the lower extremity (proximal or distal), symptomatic nonfatal pulmonary embolism, and venous thromboembolism-related death was observed with rivaroxaban. Major bleeding was low in both groups and not significantly increased with rivaroxaban.

Heparin has already been found in a variety of animal tissues but only few of them became effective sources for production of pharmaceutical preparations. Here, we correlate physical-chemical features and anticoagulant activities of structurally similar heparins employed in the past (from bovine lung, HBL), in the present (from porcine intestine, HPI) and in development for future use (from ovine intestine, HOI). Although they indeed have similar composition, our physical-chemical analyses with different chromatography and spectrometric techniques show that both HOI and HBL have molecular size notably lower than HPI and that the proportions of some of their minor saccharide components can vary substantially. Measurements of anticoagulant activities with anti-FIIa and anti-FXa assays confirmed that HPI and HOI have potency similar each other but significantly higher than HBL. Such a lower activity of HBL has been attributed to its reduced molecular size. Considering that HOI also has reduced molecular size, we find that its increased anticoagulant potency might result from an improved affinity to antithrombin (three times higher than HBL) promoted by the high content of N ,3,6-trisulfated glucosamine units, which in turn are directly involved in the heparin-antithrombin binding. Therefore, the anticoagulant activity of different heparins is driven by a balance between different physical-chemical components, especially molecular size and fine-tuning composition. Although such minor but relevant chemical differences reinforce the concept that heparins from different animal sources should indeed be considered as distinct drugs, HOI could be approved for interchangeable use with the gold standard HPI and as a suitable start material for producing new LMWHs.

Background There is scarce information regarding the prevalence and clinical impact of saddle pulmonary embolism (PE) in patients with cancer. Objectives This study aimed to assess the prevalence, clinical findings, and short-term outcomes of patients with cancer-related saddle PE including acute symptomatic and unsuspected events. Patients/Methods Consecutive patients with cancer-related PE (March 1, 2006–October 31, 2014) were retrospectively reviewed by a chest radiologist to assess PE burden and signs of right ventricular (RV) overload. The clinical outcomes within 30 days were evaluated according to saddle versus nonsaddle PE. Results Thirty-six (12%) out of 289 patients with newly diagnosed cancer-related PE presented with saddle PE. Saddle PE was found in 21 cases (58%) with acute symptomatic PE and the remaining 15 cases (42%) were found as unsuspected findings. Patients with saddle PE had more frequently experienced a previous thrombotic event (31 vs. 13%; p = 0.008), and it occurred more frequently as an acute symptomatic event (58 vs. 39%; p = 0.025) compared with those with nonsaddle PE. Signs of RV overload including RV/left ventricle ratio ≥1 (22 vs. 4%; p < 0.001) and interventricular septum displacement (53 vs. 20%; p < 0.001) were also more common in patients with saddle PE compared with nonsaddle PE. Overall, PE-related mortality, venous thromboembolism recurrence, and major bleeding within 30 days were found to be similar according to saddle versus nonsaddle PE. Conclusion Saddle PE is not uncommon in patients with cancer-related PE including in those with unsuspected PE. Similar 30-day outcomes were found according to saddle versus nonsaddle PE in our cohort.

Platelet contractility drives clot contraction to enhance clot density and stability. Clot contraction is typically studied under static conditions, with fewer studies of wall-adherent platelet clots formed under flow. We tested the effect of inhibitors of ADP and/or thromboxane A2 (TXA2) signaling on clot contraction. Using an eight-channel microfluidic device, we perfused PPACK-treated whole blood (WB) ± acetylsalicylic acid (ASA), 2-methylthioAMP (2-MeSAMP), and/or MRS-2179 over collagen (100/s) for 7.5 min, then stopped flow to observe contraction for 7.5 minutes. Two automated imaging methods scored fluorescent platelet percent contraction over the no-flow observation period: (1) “global” measurement of clot length and (2) “local” changes in surface area coverage of the numerous platelet aggregates within the clot. Total platelet fluorescence intensity (FI) decreased with concomitant decrease in global aggregate contraction when ASA, 2-MeSAMP, and/or MRS-2179 were present. Total platelet FI and global aggregate contraction were highly correlated ( R 2 = 0.87). In contrast, local aggregate contraction was more pronounced than global aggregate contraction across all inhibition conditions. However, ASA significantly reduced local aggregate contraction relative to conditions without TXA2 inhibition. P-selectin display was significantly reduced by ADP and TXA2 inhibition, but there was limited detection of global or local aggregate contraction in P-selectin-positive platelets across all conditions, as expected for densely packed “core” platelets. Our results demonstrate that global aggregate contraction is inhibited by ASA, 2-MeSAMP, and MRS-2179, while ASA more potently inhibited local aggregate contraction. These results help resolve how different platelet antagonists affect global and local clot structure and function.

Heparin is a centennial anticoagulant drug broadly employed for treatment and prophylaxis of thromboembolic conditions. Although unfractionated heparin (UFH) has already been shown to have remarkable pharmacological potential for treating a variety of diseases unrelated with thromboembolism, including cancer, atherosclerosis, inflammation, and virus infections, its high anticoagulant potency makes the doses necessary to exert non-hemostatic effects unsafe due to an elevated bleeding risk. Our group recently developed a new low-anticoagulant bovine heparin (LABH) bearing the same disaccharide building blocks of the UFH gold standard sourced from porcine mucosa (HPI) but with anticoagulant potency approximately 85% lower (approximately 25 and 180 Heparin International Units [IU]/mg). In the present work, we investigated the pharmacokinetics profile, bleeding potential, and anticancer properties of LABH administered subcutaneous into mice. LABH showed pharmacokinetics profile similar to HPI but different from the low-molecular weight heparin (LMWH) enoxaparin and diminished bleeding potential, even at high doses. Subcutaneous treatment with LABH delays the early progression of Lewis lung carcinoma, improves survival, and brings beneficial health outcomes to the mice, without the advent of adverse effects (hemorrhage/mortality) seen in the animals treated with HPI. These results demonstrate that LABH is a promising candidate for prospecting new therapeutic uses for UFH.

Objectives Thrombotic and bleeding complications are common in COVID-19 disease. In a prospective study, we performed a comprehensive panel of tests to predict the risk of bleeding and thrombosis in patients admitted with hypoxic respiratory failure due to severe COVID-19 infection. Methods We performed a single center (step down and intensive care unit [ICU] at a quaternary care academic hospital) prospective study. Sequentially enrolled adult (!18 years) patients were admitted with acute hypoxic respiratory failure due to COVID-19 between June 2020 and November 2020. Several laboratory markers of coagulopathy were tested after informed and written consent. Results Thirty-three patients were enrolled. In addition to platelet counts, prothrombin time, and activated partial thromboplastin time, a series of protocol laboratories were collected within 24 hours of admission. These included Protein C, Protein S, Antithrombin III, ADAMTS13, fibrinogen, ferritin, haptoglobin, and peripheral Giemsa smear. Patients were then monitored for the development of hematological (thrombotic and bleeding) events and followed for 30 days after discharge. Twenty-four patients (73%) required ICU admissions. At least one laboratory abnormality was detected in 100% of study patients. Nine patients (27%) suffered from significant hematological events, and four patients had a clinically significant bleeding event requiring transfusion. No significant association was observed between abnormalities of coagulation parameters and the incidence of hematologic events. However, a higher SOFA score (10.89 AE 3.48 vs. 6.92 AE 4.10, p 0.016) and CKD (5/9 [22.2%] vs. 2/24 [12.5%] p 0.009) at baseline were associated with the development of hematologic events. 33.3% of patients died at 30 days. Mortality was similar in those with and without hematological events. Reduced ADAMTS13 level was significantly associated with mortality.

Abstract Background Patients undergoing systemic cancer therapy are susceptible to developing venous thromboembolism (VTE). The most pertinent prognostic factors for VTE remain unclear. This systematic review aims to summarize prognostic factors associated with VTE in this population. Methods MEDLINE, Embase, and CENTRAL databases were searched for observational or randomized studies that used multivariable analysis adjusted for tumor type and/or metastatic disease to model the risk of VTE. Adjusted effect estimates for each prognostic factor were collected for all of the included studies. Risk of bias was assessed using the Quality in Prognostic Factor Studies (QUIPS) tool. Results From 5,988 search results, 15 eligible studies and 42 prognostic factors were identified. A total of 8,554 patients of whom 456 (5.33%) developed VTE were included. Fourteen studies had a high risk of bias and one study had a moderate risk. The most commonly reported prognostic factors include age, gender, tumor site, metastasis, performance status, and systemic therapy type. Poor performance status and the use of platinum-based chemotherapy compounds were associated with an increased risk of VTE across the majority of studies. The evidence to suggest that the other prognostic factors identified were associated with VTE development was inconclusive. Several individual studies identified novel biomarkers for VTE. Heterogeneity in statistical methods and prognostic factor definitions across studies precluded meta-analysis. Conclusion Overall, many prognostic factors were identified; however, the evidence for association with development of VTE for most of the factors is inconclusive. Findings were limited by high heterogeneity and risk of bias in the included studies.

Background Patients undergoing systemic cancer therapy are susceptible to developing venous thromboembolism (VTE). The most pertinent prognostic factors for VTE remain unclear. This systematic review aims to summarize prognostic factors associated with VTE in this population. Methods MEDLINE, Embase, and CENTRAL databases were searched for observational or randomized studies that used multivariable analysis adjusted for tumor type and/or metastatic disease to model the risk of VTE. Adjusted effect estimates for each prognostic factor were collected for all of the included studies. Risk of bias was assessed using the Quality in Prognostic Factor Studies (QUIPS) tool. Results From 5,988 search results, 15 eligible studies and 42 prognostic factors were identified. A total of 8,554 patients of whom 456 (5.33%) developed VTE were included. Fourteen studies had a high risk of bias and one study had a moderate risk. The most commonly reported prognostic factors include age, gender, tumor site, metastasis, performance status, and systemic therapy type. Poor performance status and the use of platinum-based chemotherapy compounds were associated with an increased risk of VTE across the majority of studies. The evidence to suggest that the other prognostic factors identified were associated with VTE development was inconclusive. Several individual studies identified novel biomarkers for VTE. Heterogeneity in statistical methods and prognostic factor definitions across studies precluded meta-analysis. Conclusion Overall, many prognostic factors were identified; however, the evidence for association with development of VTE for most of the factors is inconclusive. Findings were limited by high heterogeneity and risk of bias in the included studies.