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1.
J Thromb Haemost ; 22(6): 1640-1648, 2024 Jun.
Article in English | MEDLINE | ID: mdl-38395359

ABSTRACT

BACKGROUND: Relatively little is known about thrombotic adverse events (AEs) of emicizumab in postmarketing real-world settings, particularly in comparison with factor VIII (FVIII) products. A recent European study reported a potentially greater thrombotic risk of emicizumab compared with FVIII products. OBJECTIVES: This drug safety study aims to investigate whether thrombotic AEs are more frequently reported for emicizumab than for FVIII products and if so, whether it is independent of bypassing agents as coreporting drugs using the United States Food and Drug Administration Adverse Event Reporting System data. METHODS: Disproportionality analyses for thrombotic AEs of emicizumab vs FVIII products were conducted. Three signal detection indicators were used: proportional reporting ratio (PRR), reporting odds ratio (ROR), and informational component (IC). RESULTS: During 2018-2022, the proportions of thrombotic AEs among all AEs were 4.07% (97 out of 2383) and 1.44% (134 out of 9324) for emicizumab and FVIII products, respectively: PRR = 2.83 (2.19-3.66), ROR = 2.91 (2.23-3.79), and IC = 1.04 (0.70-1.28). Bypassing agents as coreporting drugs were identified in 36% and 15% of the total thrombotic AE reports associated with emicizumab and FVIII products, respectively. Even after thrombotic AE reports with bypassing agents were excluded, the reporting proportion of thrombotic AEs was still greater for emicizumab than for FVIII products: PRR = 2.19 (1.60-2.99). CONCLUSION: Thrombotic AEs in the United States Food and Drug Administration Adverse Event Reporting System data were about 3 times more frequently reported for emicizumab than for FVIII products. More research and efforts in the future are warranted for monitoring, elucidating, and preventing the potential risk of thrombotic AEs in hemophilia therapy, including emicizumab.


Subject(s)
Adverse Drug Reaction Reporting Systems , Antibodies, Bispecific , Antibodies, Monoclonal, Humanized , Factor VIII , Thrombosis , United States Food and Drug Administration , Humans , United States , Antibodies, Monoclonal, Humanized/adverse effects , Antibodies, Monoclonal, Humanized/therapeutic use , Thrombosis/chemically induced , Thrombosis/epidemiology , Antibodies, Bispecific/adverse effects , Factor VIII/adverse effects , Hemophilia A/drug therapy , Hemophilia A/blood , Risk Factors , Coagulants/adverse effects , Coagulants/therapeutic use , Risk Assessment , Databases, Factual
2.
Cytotherapy ; 26(2): 194-200, 2024 02.
Article in English | MEDLINE | ID: mdl-38127031

ABSTRACT

BACKGROUND AIMS: Mesenchymal stromal cells (MSCs) are multipotent adult cells that can be isolated from tissues including bone marrow [MSC(BM)], adipose [MSC(AT)] and umbilical cord [MSC(CT)]. Previous studies have linked expression of tissue factor (TF) on MSC surfaces to a procoagulant effect. Venous thromboembolism (VTE), immediate blood-mediated inflammatory reaction (IBMIR) and microvascular thrombosis remain a risk with intravascular MSC therapy. We examined the effect of low molecular weight heparin (LMWH) on clinical-grade MSCs using calibrated automated thrombography (CAT). METHODS: Clinical grade MSC(BM)s, MSC(AT)s and MSC(CT)s harvested at passage 4 were added to normal pooled plasma (NPP) to a final concentration of either 400 000 or 50 000 cells/mL. LMWH was added to plasma in increments of 0.1 U/mL. Thrombin generation (TG) was measured using CAT. Flow cytometry was conducted on the cells to measure MSC phenotype and TF load. RESULTS: Presence of MSCs decreased lag time and increased peak TG. All cell lines demonstrated a dose response to LMWH, with MSC(AT) demonstrating the least thrombogenicity and most sensitivity to LMWH. TG was significantly reduced in all cell lines at doses of 0.2 U/mL LMWH and higher. DISCUSSION: All MSC types and concentrations had a decrease in peak thrombin and TG with increasing amounts of LMWH. While this in vitro study cannot determine optimal dosing, it suggests that LMWH can be effectively used to lower the risk of VTE associated with intravascular administration of MSCs. Future in vivo work can be done to determine optimal dosing and effect on IBMIR and VTE.


Subject(s)
Coagulants , Thrombosis , Venous Thromboembolism , Adult , Humans , Heparin, Low-Molecular-Weight/pharmacology , Heparin, Low-Molecular-Weight/therapeutic use , Venous Thromboembolism/drug therapy , Coagulants/therapeutic use , Thrombin/therapeutic use , Heparin/therapeutic use
3.
Blood Coagul Fibrinolysis ; 34(2): 122-128, 2023 Mar 01.
Article in English | MEDLINE | ID: mdl-36719809

ABSTRACT

Emicizumab prophylaxis significantly reduces bleeding episodes in patients with hemophilia A (PwHA). There is little information on coagulant potentials in emicizumab-treated PwHA with infection, however. We encountered an emicizumab-treated PwHA with inhibitor, complicated with Epstein-Barr virus-associated infectious mononucleosis (IM) in phase 1/2 study (ACE001JP/ACE002JP). Although it was a typical clinical course of IM, activated partial thromboplastin time was mildly prolonged but rotational thromboelastometry revealed severely impaired coagulant potential. The blood concentration of emicizumab decreased moderately in the low concentration range, resulting in an increased risk of bleeding and possibly leading to severe ileocecal bleeds requiring coil embolization. The blood concentrations of factors IX/X little decreased and antiemicizumab antibodies did not develop, however. After the influence by IM resolved, his coagulant potentials gradually recovered with the recovery of emicizumab concentration, and parameters by global coagulation assays improved. An IM case for emicizumab-treated PwHA may need to monitor using global coagulation assays.


Subject(s)
Coagulants , Hemophilia A , Infectious Mononucleosis , Humans , Antibodies, Bispecific/pharmacology , Antibodies, Bispecific/therapeutic use , Coagulants/therapeutic use , Epstein-Barr Virus Infections/complications , Epstein-Barr Virus Infections/drug therapy , Factor VIII/therapeutic use , Factor X/therapeutic use , Hemophilia A/complications , Hemophilia A/drug therapy , Hemorrhage/etiology , Herpesvirus 4, Human , Infectious Mononucleosis/complications , Infectious Mononucleosis/drug therapy , Clinical Trials, Phase I as Topic , Clinical Trials, Phase II as Topic , Male
4.
N Engl J Med ; 388(4): 310-318, 2023 01 26.
Article in English | MEDLINE | ID: mdl-36720133

ABSTRACT

BACKGROUND: Efanesoctocog alfa provides high sustained factor VIII activity by overcoming the von Willebrand factor-imposed half-life ceiling. The efficacy, safety, and pharmacokinetics of efanesoctocog alfa for prophylaxis and treatment of bleeding episodes in previously treated patients with severe hemophilia A are unclear. METHODS: We conducted a phase 3 study involving patients 12 years of age or older with severe hemophilia A. In group A, patients received once-weekly prophylaxis with efanesoctocog alfa (50 IU per kilogram of body weight) for 52 weeks. In group B, patients received on-demand treatment with efanesoctocog alfa for 26 weeks, followed by once-weekly prophylaxis with efanesoctocog alfa for 26 weeks. The primary end point was the mean annualized bleeding rate in group A; the key secondary end point was an intrapatient comparison of the annualized bleeding rate during prophylaxis in group A with the rate during prestudy factor VIII prophylaxis. Additional end points included treatment of bleeding episodes, safety, pharmacokinetics, and changes in physical health, pain, and joint health. RESULTS: In group A (133 patients), the median annualized bleeding rate was 0 (interquartile range, 0 to 1.04), and the estimated mean annualized bleeding rate was 0.71 (95% confidence interval [CI], 0.52 to 0.97). The mean annualized bleeding rate decreased from 2.96 (95% CI, 2.00 to 4.37) to 0.69 (95% CI, 0.43 to 1.11), a finding that showed superiority over prestudy factor VIII prophylaxis (P<0.001). A total of 26 patients were enrolled in group B. In the overall population, nearly all bleeding episodes (97%) resolved with one injection of efanesoctocog alfa. Weekly prophylaxis with efanesoctocog alfa provided mean factor VIII activity of more than 40 IU per deciliter for the majority of the week and of 15 IU per deciliter at day 7. Prophylaxis with efanesoctocog alfa for 52 weeks (group A) improved physical health (P<0.001), pain intensity (P = 0.03), and joint health (P = 0.01). In the overall study population, efanesoctocog alfa had an acceptable side-effect profile, and the development of inhibitors to factor VIII was not detected. CONCLUSIONS: In patients with severe hemophilia A, once-weekly efanesoctocog alfa provided superior bleeding prevention to prestudy prophylaxis, normal to near-normal factor VIII activity, and improvements in physical health, pain, and joint health. (Funded by Sanofi and Sobi; XTEND-1 ClinicalTrials.gov number, NCT04161495.).


Subject(s)
Coagulants , Factor VIII , Hemophilia A , Hemorrhage , Humans , Drug Administration Schedule , Half-Life , Hemophilia A/complications , Hemophilia A/drug therapy , Hemorrhage/drug therapy , Hemorrhage/etiology , Hemorrhage/prevention & control , von Willebrand Factor/administration & dosage , von Willebrand Factor/therapeutic use , Chemoprevention , Factor VIII/administration & dosage , Factor VIII/therapeutic use , Coagulants/administration & dosage , Coagulants/therapeutic use , Recombinant Fusion Proteins/administration & dosage , Recombinant Fusion Proteins/therapeutic use
5.
Pediatr Res ; 93(6): 1546-1550, 2023 05.
Article in English | MEDLINE | ID: mdl-36045224

ABSTRACT

BACKGROUND: Hemophilia A (HA) therapy requires intravenous replacement infusions of factor (F) VIII concentrate. Inhibitors are high-affinity immunoglobulin G that are directed against FVIII and thereby render replacement therapy ineffective. This complication has significant prognostic implications. We aimed to examine the immune system involvement in inhibitor formation specifically T-cell excision circles (TRECs) and B-cell excision circles (KRECs), markers of new T and B cells, respectively, and examine them as surrogate markers for inhibitor formation. METHODS: Blood samples were collected from 35 children with severe HA. Children were divided into two groups: with FVIII inhibitors and without FVIII inhibitors. TRECs and KRECs were measured in peripheral blood. RESULTS: A total of 11 patients with inhibitors and 24 without were evaluated. Children with inhibitors had higher levels of TRECs however not statistically significant (p = 0.085). CjKREC levels were higher in the inhibitor patients (p = 0.003). Moreover, the sj/cjKREC ratio was lower in the inhibitor patients (p = 0.015). CONCLUSIONS: Our findings may add to the notion that inhibitor formation is attributed to humoral immunity due to peripheral B-cell expansion and loss of peripheral tolerance. Improved knowledge regarding the involvement of the immune system in the formation of FVIII inhibitors will enable better therapy tailoring in the era of non-replacement therapies. IMPACT: The etiology of FVIII inhibitor formation is multifactorial, in which the immune system plays a pivotal role. Our findings may add to the notion that inhibitor formation is attributed to humoral immunity due to peripheral B-cell expansion and production of antibodies against FVIII. Improved knowledge regarding the involvement of the immune system in the development of FVIII inhibitors will enable the identification of patients prone to inhibitor development and better therapy tailoring in the new era of non-replacement therapies.


Subject(s)
B-Lymphocytes , Factor VIII , Hemophilia A , T-Lymphocytes , Humans , Child , Hemophilia A/drug therapy , Factor VIII/therapeutic use , Coagulants/therapeutic use , Immune System
6.
Carbohydr Polym ; 282: 119132, 2022 Apr 15.
Article in English | MEDLINE | ID: mdl-35123764

ABSTRACT

Chitosan has many desirable attributes e.g. antimicrobial properties and promoting wound healing, and is used in various applications. This article first discusses how degree of deacetylation (DD) and molecular weight (MW) impacts on what level of bioactivities chitosan manifests, then introduces the "molecular chain configuration" model to explain various possible mechanisms of antimicrobial interactions between chitosan with different MW and different types of bacteria. Similarly, the possible pathways of how chitosan reacts with cancer and the body's immune system to demonstrate immune and antitumor effects are also discussed by using this model. Moreover, the possible mechanisms of how chitosan enhances coagulation and wound healing are also discussed. With these beneficial bioactivities in mind, the application of chitosan in surgery, tissue engineering and oncology is outlined. This review concludes that as chitosan demonstrates many beneficial bioactivities via multiple mechanisms, it is an important polymer with a promising future in medicine.


Subject(s)
Chitosan , Animals , Anti-Infective Agents/chemistry , Anti-Infective Agents/pharmacology , Anti-Infective Agents/therapeutic use , Antineoplastic Agents/chemistry , Antineoplastic Agents/pharmacology , Antineoplastic Agents/therapeutic use , Chitosan/chemistry , Chitosan/pharmacology , Chitosan/therapeutic use , Coagulants/chemistry , Coagulants/pharmacology , Coagulants/therapeutic use , Humans , Molecular Structure
7.
Sci Rep ; 12(1): 1814, 2022 02 02.
Article in English | MEDLINE | ID: mdl-35110612

ABSTRACT

Data on the use of activated prothrombin complex concentrate (aPCC) for the management of warfarin associated major bleeding is sparse. The objective of the study was to assess the achievement of effective clinical hemostasis using aPCC in patients presenting with major bleeding while on warfarin. We also assessed the safety of the drug. This retrospective study was conducted at a tertiary care teaching center in the USA where patients with major bleeding while receiving warfarin, and received aPCC were included. Efficacy of aPCC in achieving effective hemostasis was assessed according to the International Society of Thrombosis and Hemostasis Scientific and Standardization Subcommittee criteria. Efficacy was also assessed by achieving INR < 1.5 after treatment. The primary safety endpoint was the occurrence of any thromboembolic complications. A total of 67 patients were included in the study. The most common site for bleeding was intracerebral hemorrhage (n = 37, 55.2%), followed by gastrointestinal bleed (n = 26, 38.8%). Clinical hemostasis was achieved in 46 (68.7%) patients and of the 21 (31.3%) patients who did not achieve clinical hemostasis, 16 died. Thirty nine (58.2%) patients achieved INR < 1.5. Five (7.5%) patients developed thromboembolic complications. This study suggests that the use of aPCCs is effective in achieving effective hemostasis in patients on warfarin presenting with major bleeding.


Subject(s)
Anticoagulants/adverse effects , Blood Coagulation Factors/therapeutic use , Cerebral Hemorrhage/drug therapy , Coagulants/therapeutic use , Gastrointestinal Hemorrhage/drug therapy , Vitamin K/antagonists & inhibitors , Warfarin/adverse effects , Aged , Aged, 80 and over , Blood Coagulation Factors/adverse effects , Cerebral Hemorrhage/chemically induced , Cerebral Hemorrhage/diagnosis , Cerebral Hemorrhage/mortality , Coagulants/adverse effects , Female , Gastrointestinal Hemorrhage/chemically induced , Gastrointestinal Hemorrhage/diagnosis , Gastrointestinal Hemorrhage/mortality , Humans , International Normalized Ratio , Male , Middle Aged , Retrospective Studies , Thromboembolism/etiology , Time Factors , Treatment Outcome
8.
Diagn Microbiol Infect Dis ; 102(2): 115592, 2022 Feb.
Article in English | MEDLINE | ID: mdl-34839128

ABSTRACT

Staphylococcus pettenkoferi is a recently described coagulase-negative staphylococcal pathogen. We retrospectively reviewed 25 cases in which S. pettenkoferi was identified in routine cultures (12 blood, 13 other). Most were found with commensal flora and considered clinically insignificant, but its significance was uncertain in two cases from non-healing, deep foot wounds.


Subject(s)
Anti-Bacterial Agents/therapeutic use , Coagulase/therapeutic use , Drug Resistance, Bacterial/drug effects , Sepsis/drug therapy , Staphylococcal Infections/drug therapy , Staphylococcal Infections/epidemiology , Staphylococcus/drug effects , Adult , Aged , Aged, 80 and over , Coagulants/therapeutic use , Female , Humans , Male , Microbial Sensitivity Tests , Middle Aged , Retrospective Studies , Sepsis/epidemiology , Tertiary Care Centers/statistics & numerical data , Tertiary Healthcare/statistics & numerical data , United States/epidemiology
9.
Orthop Surg ; 14(1): 27-34, 2022 Jan.
Article in English | MEDLINE | ID: mdl-34841675

ABSTRACT

OBJECTIVE: To evaluate the operative methods and clinical results of surgical treatment in a case series of 10 patients with hemophilic pseudotumors. METHODS: Ten patients with hemophilic pseudotumors who received surgical resection treatment in our hospital from October 2017 to June 2020 were retrospectively reviewed. All patients were hemophilia A (factor VIII deficiency).The age range was 20-51 years. Preoperative imaging examination revealed the size of irregular mass from 8.2 cm× 3.3 cm× 2.3 cm to 22.3 cm× 15.5 cm× 17.0 cm. With the supplementary of recombinant coagulation factor VIII, five cases received complete resection; one received resection and skin grafting; one received cytoreduction surgery as the pseudotumor closing to iliac vessel and nerve; three cases received complete resection and construction as bone destruction. The perioperative variables were recorded and all the patients were followed in the outpatient clinic. Clinical and radiological assessments were conducted. RESULTS: In these patients, the average intraoperative blood loss volume was 783.1 mL (range, 240-2100 mL). Six patients received blood transfusion during perioperative period. The average duration of surgery was 140.7 min (range, 110-240 min). All wounds healed smoothly and there was no infection or chronic sinus formation. The average length of hospital stay was 16.3 days (range, 12-25 days). There is no iatrogenic vascular nerve injury in our series. Complete follow-up was performed in all patients. Mean follow-up duration was 14.2 months (range, 6-26 months). One patient with pseudotumor in the thigh had a recurrence 1 year after operation, then secondary operation was performed. In three cases who received complete resection and construction, patient 8 obtained bone graft and late fixation. X-ray examination showed bone formation in the lesion at the 2-year follow-ups after operation. Patient 9 underwent knee replacement, his left knee showed flexion deformity in preoparation. At the last follow-up, range of motion was improved from 0° to 40° compared with preoperative status. Patient 10 had pseudotumor in the distal femur, received long bone graft and intramedullary nail fixation. CONCLUSIONS: Surgical resection for hemophilic pseudotumors is an effective and safe method. The choice of surgical procedure must be individualized according to the localization and progress of pseudotumor.


Subject(s)
Bone Diseases/surgery , Hemophilia A/complications , Adult , Blood Loss, Surgical , Bone Diseases/diagnostic imaging , Coagulants/therapeutic use , Factor VIII/therapeutic use , Female , Hemophilia A/drug therapy , Humans , Male , Retrospective Studies , Young Adult
10.
Surg Clin North Am ; 102(1): 53-63, 2022 Feb.
Article in English | MEDLINE | ID: mdl-34800389

ABSTRACT

An increasing number of patients are on anticoagulation for a variety of indications. Patients on anticoagulation who present to the hospital with life-threatening hemorrhage, whether trauma related or not, must be assessed for the reversal of anticoagulation. Identification of the type of anticoagulation, the timing of the most recent usage of anticoagulation, and the efficacy of the anticoagulation all have an impact on whether reversal agents should be used. There are a variety of reversal agents, both nonspecific and specific, that could be used for reversal; however, not all reversal agents work for all anticoagulation medication. As more anticoagulation medications are used and indications expand, providers must be aware of the reversal agents available and the efficacy and indications for these reversal agents.


Subject(s)
Anticoagulants/adverse effects , Coagulants/therapeutic use , Critical Care/methods , Emergency Medical Services/methods , Hemorrhage/drug therapy , Hemorrhage/prevention & control , Perioperative Care/methods , Critical Illness , Drug Administration Schedule , Emergencies , Hemorrhage/etiology , Humans , Surgical Procedures, Operative , Wounds and Injuries/complications , Wounds and Injuries/therapy
11.
Int J Mol Sci ; 22(22)2021 Nov 18.
Article in English | MEDLINE | ID: mdl-34830348

ABSTRACT

Dysfunction of cellular homeostasis can lead to misfolding of proteins thus acquiring conformations prone to polymerization into pathological aggregates. This process is associated with several disorders, including neurodegenerative diseases, such as Parkinson's disease (PD), and endoplasmic reticulum storage disorders (ERSDs), like alpha-1-antitrypsin deficiency (AATD) and hereditary hypofibrinogenemia with hepatic storage (HHHS). Given the shared pathophysiological mechanisms involved in such conditions, it is necessary to deepen our understanding of the basic principles of misfolding and aggregation akin to these diseases which, although heterogeneous in symptomatology, present similarities that could lead to potential mutual treatments. Here, we review: (i) the pathological bases leading to misfolding and aggregation of proteins involved in PD, AATD, and HHHS: alpha-synuclein, alpha-1-antitrypsin, and fibrinogen, respectively, (ii) the evidence linking each protein aggregation to the stress mechanisms occurring in the endoplasmic reticulum (ER) of each pathology, (iii) a comparison of the mechanisms related to dysfunction of proteostasis and regulation of homeostasis between the diseases (such as the unfolded protein response and/or autophagy), (iv) and clinical perspectives regarding possible common treatments focused on improving the defensive responses to protein aggregation for diseases as different as PD, and ERSDs.


Subject(s)
Afibrinogenemia/genetics , Fibrinogen/chemistry , Parkinson Disease/genetics , alpha 1-Antitrypsin Deficiency/genetics , alpha 1-Antitrypsin/chemistry , alpha-Synuclein/chemistry , Afibrinogenemia/drug therapy , Afibrinogenemia/metabolism , Afibrinogenemia/pathology , Animals , Autophagy/drug effects , Autophagy/genetics , Coagulants/therapeutic use , Endoplasmic Reticulum/drug effects , Endoplasmic Reticulum/metabolism , Endoplasmic Reticulum/pathology , Fibrinogen/genetics , Fibrinogen/metabolism , Gene Expression Regulation , Humans , Liver/metabolism , Liver/pathology , Neuroprotective Agents/therapeutic use , Parkinson Disease/drug therapy , Parkinson Disease/metabolism , Parkinson Disease/pathology , Protease Inhibitors/therapeutic use , Protein Aggregates/drug effects , Protein Folding/drug effects , Unfolded Protein Response/drug effects , alpha 1-Antitrypsin/genetics , alpha 1-Antitrypsin/metabolism , alpha 1-Antitrypsin Deficiency/drug therapy , alpha 1-Antitrypsin Deficiency/metabolism , alpha 1-Antitrypsin Deficiency/pathology , alpha-Synuclein/genetics , alpha-Synuclein/metabolism
12.
ACS Appl Mater Interfaces ; 13(37): 44013-44027, 2021 Sep 22.
Article in English | MEDLINE | ID: mdl-34494427

ABSTRACT

Synergetic therapy includes the combination of two or more conventional therapeutic approaches and can be used for tumor treatment by combining the advantages and avoiding the drawbacks of each type of treatment. In the present study, truncated tissue factor (tTF)-EG3287 fusion protein-encapsulated gold nanorod (GNR)-virus-inspired mesoporous silica core-shell nanoparticles (vinyl hybrid silica nanoparticles; VSNP) (GNR@VSNP-tTF-EG3287) were synthesized to achieve synergetic therapy by utilizing selective vascular thrombosis therapy (SVTT) and photothermal therapy (PTT). By integrating the targeted coagulation activity of tTF-EG3287 and the high tumor ablation effect of GNR@VSNP, local hyperthermia could induce a high percentage of apoptosis of vascular endothelial cells by using near-infrared light. This provided additional phospholipid sites for tTF-EG3287 and enhanced its procoagulant activity in vitro. In addition, the nanoparticles, which had unique topological viral structures, exhibited superior cellular uptake properties leading to significant antitumor efficacy. The in vivo antitumor results further demonstrated an interaction between SVTT and PTT, whereas the synergetic therapy (SVTT and PTT) achieved an enhanced effect, which was superior to the respective treatment efficacy of each modality or the additive effect of their individual efficacies. In summary, the synthesized GNR@VSNP-tTF-EG3287 exerted synergetic effects and enhanced the antitumor efficiency by avoiding multiple injections and suboptimal administration. These effects simultaneously affected both tumor blood supply and cancer cell proliferation. The data suggested that the integration of SVTT induced by tTF-EG3287 and PTT could provide potential strategies for synergetic tumor therapy.


Subject(s)
Antineoplastic Agents/therapeutic use , Coagulants/therapeutic use , Nanotubes/chemistry , Neoplasms/drug therapy , Recombinant Fusion Proteins/therapeutic use , Animals , Antineoplastic Agents/chemistry , Antineoplastic Agents/toxicity , Apoptosis/drug effects , Coagulants/chemistry , Female , Gold/chemistry , Gold/radiation effects , Gold/toxicity , Hep G2 Cells , Human Umbilical Vein Endothelial Cells , Humans , Infrared Rays , Mice, Inbred BALB C , Mice, Nude , Nanotubes/radiation effects , Nanotubes/toxicity , Peptide Fragments/chemistry , Peptide Fragments/therapeutic use , Photothermal Therapy , Porosity , Rabbits , Recombinant Fusion Proteins/chemistry , Silicon Dioxide/chemistry , Silicon Dioxide/radiation effects , Silicon Dioxide/toxicity , Thromboplastin/chemistry , Thromboplastin/therapeutic use , Thrombosis/chemically induced , Vascular Endothelial Growth Factor A/chemistry , Vascular Endothelial Growth Factor A/therapeutic use , Xenograft Model Antitumor Assays
13.
Lancet Haematol ; 8(7): e492-e502, 2021 Jul.
Article in English | MEDLINE | ID: mdl-34171280

ABSTRACT

BACKGROUND: Dosing of replacement therapy with factor VIII concentrate in patients with haemophilia A in the perioperative setting is challenging. Underdosing and overdosing of factor VIII concentrate should be avoided to minimise risk of perioperative bleeding and treatment costs. We hypothesised that dosing of factor VIII concentrate on the basis of a patient's pharmacokinetic profile instead of bodyweight, which is standard treatment, would reduce factor VIII consumption and improve the accuracy of attained factor VIII levels. METHODS: In this open-label, multicentre, randomised, controlled trial (OPTI-CLOT), patients were recruited from nine centres in Rotterdam, Groningen, Utrecht, Nijmegen, The Hague, Leiden, Amsterdam, Eindhoven, and Maastricht in The Netherlands. Eligible patients were aged 12 years or older with severe or moderate haemophilia A (severe haemophilia was defined as factor VIII concentrations of <0·01 IU/mL, and moderate haemophilia as 0·01-0·05 IU/mL), without factor VIII inhibitors, and planned for elective low or medium risk surgery as defined by surgical risk score. Patients were randomly assigned (1:1) using a web-based randomisation system and treatment minimisation, stratified by method of administration of factor VIII concentrate (continuous infusion vs bolus administration) and risk level of surgery (low and medium risk surgery), to the pharmacokinetic-guided or standard treatment group. The primary endpoint was total amount of infused factor VIII concentrate (IU per kg bodyweight) during perioperative period (from day of surgery up to 14 days after surgery). Analysis was by intention to treat and the safety analysis population comprised all participants who underwent surgery with factor VIII concentrate. This study is registered with the Netherlands Trial Registry, NL3955, and is now closed to accrual. FINDINGS: Between May 1, 2014, and March 1, 2020, 98 patients were assessed for eligibility and 66 were enrolled in the trial and randomly assigned to the pharmacokinetic-guided treatment group (34 [52%]) or the standard treatment group (32 [48%]). Median age was 49·1 years (IQR 35·0 to 62·1) and all participants were male. No difference was seen in consumption of factor VIII concentrate during the perioperative period between groups (mean consumption of 365 IU/kg [SD 202] in pharmacokinetic-guided treatment group vs 379 IU/kg [202] in standard treatment group; adjusted difference -6 IU/kg [95% CI -88 to 100]). Postoperative bleeding occurred in six (18%) of 34 patients in the pharmacokinetic-guided treatment group and three (9%) of 32 in the standard treatment group. One grade 4 postoperative bleeding event occurred, which was in one (3%) patient in the standard treatment group. No treatment-related deaths occurred. INTERPRETATION: Although perioperative pharmacokinetic-guided dosing is safe, it leads to similar perioperative factor VIII consumption when compared with standard treatment. However, pharmacokinetic-guided dosing showed an improvement in obtaining factor VIII concentrations within the desired perioperative factor VIII range. These findings provide support to further investigation of pharmacokinetic-guided dosing in perioperative haemophilia care. FUNDING: Dutch Research Council (NWO)-ZonMw and Takeda.


Subject(s)
Coagulants/therapeutic use , Factor VIII/therapeutic use , Hemophilia A/drug therapy , Adult , Coagulants/pharmacokinetics , Drug Administration Schedule , Elective Surgical Procedures , Factor VIII/pharmacokinetics , Hemophilia A/pathology , Humans , Male , Middle Aged , Perioperative Care , Severity of Illness Index , Treatment Outcome
14.
J Manag Care Spec Pharm ; 27(8): 996-1008, 2021 Aug.
Article in English | MEDLINE | ID: mdl-33843253

ABSTRACT

BACKGROUND: The landscape for hemophilia A prophylaxis is rapidly expanding from factor VIII replacement therapy to include novel treatments such as nonfactor replacement therapies that may enhance coagulation (e.g., emicizumab) or inhibit anticoagulant pathways (e.g., fitusiran and concizumab). For payers, this expansion presents challenges in balancing well-established treatments with new options that cost more and have lesser known real-world safety and efficacy. OBJECTIVE: To evaluate likely coverage practices for hemophilia A prophylaxis therapies among U.S. payers given evolving real-world data on safety and efficacy. METHODS: A 3-round modified Delphi process was conducted with representatives of U.S. commercial health plans who had considerable expertise in managing populations of patients with hemophilia. Round 1 consisted of an online questionnaire; round 2 involved an online discussion about the aggregated results from round 1; and round 3 allowed participants to revise their responses from round 1 based on insights gained during round 2. Questions elicited ratings, rankings, and estimates on access restrictions based on given safety and efficacy information for hemophilia A prophylaxis therapies. Consensus was reached if ≥ 74% of panelists (14 of 19) were within 1 SD of the median group estimate during round 3. RESULTS: 19 Payers participated in the research. Among them, 94% dealt with commercial insurance, 94% with Medicare, and 81% with Medicaid; 79% had spent ≥ 5 years in their current role. Panelists reported limited access restrictions on hemophilia A prophylaxis therapies; the most common restrictions were prior authorization (n = 16, 84%) and quantity level limits (n = 13, 67%). Tiering and step therapy were reported by 7 respondents (39%). Respondents agreed that there was an 80% median likelihood that ≥ 9 additional patients with any safety event (e.g., thrombotic event, death) per year would trigger access restrictions, with the median likelihood of restrictions increasing to 95% for another ≥ 10 patients with safety events per year. Respondents also agreed that > 5 thrombotic events requiring treatment per patient per year would have a 98% median likelihood of leading to access restrictions and that ≥ 5 years of real-world safety and efficacy data would be highly likely (95% median likelihood) to affect coverage decisions. Noncoverage was highly unlikely (ranked fifth or sixth of 6 by 14 respondents), as was no restriction-coverage parity (ranked sixth of 6 by 10 respondents). All else being equal, cost continues to affect access policies, with respondents agreeing that a 13%-30% difference in net cost may lead to preferred formulary treatment for a drug with superior efficacy and noninferior safety, inferior efficacy and noninferior safety, or noninferior efficacy and inferior safety. CONCLUSIONS: Payers prefer treatments with well-understood efficacy, safety, and cost over newer treatments with uncertain long-term effects. Relatively unrestricted access to legacy and new hemophilia A prophylaxis will likely continue unless additional real-world safety concerns or major cost differences emerge. DISCLOSURES: Financial support for this study was provided by Takeda Pharmaceutical Company, which was involved in study concept and design. Graf, Tuly, Harley, and Pednekar are employees of PRECISIONheor, a research consultancy to the health and life sciences industries that was contracted by Takeda to conduct this study and write the manuscript. Batt served as a consultant on this project through PRECISIONheor.


Subject(s)
Coagulants/economics , Coagulants/therapeutic use , Hemophilia A/drug therapy , Insurance Coverage , Organizational Policy , Delphi Technique , Drug Costs , Humans , Interviews as Topic , Qualitative Research , Surveys and Questionnaires , United States
15.
Int J Mol Sci ; 22(4)2021 Feb 22.
Article in English | MEDLINE | ID: mdl-33671748

ABSTRACT

Fibrinogen is the first coagulation protein to reach critically low levels during traumatic haemorrhage. There have been no differential effects on clinical outcomes between the two main sources of fibrinogen replacement: cryoprecipitate and fibrinogen concentrate (Fg-C). However, the constituents of these sources are very different. The aim of this study was to determine whether these give rise to any differences in clot stability that may occur during trauma haemorrhage. Fibrinogen deficient plasma (FDP) was spiked with fibrinogen from cryoprecipitate or Fg-C. A panel of coagulation factors, rotational thromboelastography (ROTEM), thrombin generation (TG), clot lysis and confocal microscopy were performed to measure clot strength and stability. Increasing concentrations of fibrinogen from Fg-C or cryoprecipitate added to FDP strongly correlated with Clauss fibrinogen, demonstrating good recovery of fibrinogen (r2 = 0.99). A marked increase in Factor VIII, XIII and α2-antiplasmin was observed in cryoprecipitate (p < 0.05). Increasing concentrations of fibrinogen from both sources were strongly correlated with ROTEM parameters (r2 = 0.78-0.98). Cryoprecipitate therapy improved TG potential, increased fibrinolytic resistance and formed more homogeneous fibrin clots, compared to Fg-C. In summary, our data indicate that cryoprecipitate may be a superior source of fibrinogen to successfully control bleeding in trauma coagulopathy. However, these different products require evaluation in a clinical setting.


Subject(s)
Blood Coagulation Disorders/therapy , Coagulants/therapeutic use , Fibrinogen/therapeutic use , Hemorrhage/complications , Blood Coagulation Disorders/etiology , Coagulants/administration & dosage , Dose-Response Relationship, Drug , Factor VIII/therapeutic use , Fibrinogen/administration & dosage , Fibrinolysis , Hemorrhage/therapy , Humans , Microscopy, Confocal , Thrombelastography , Thrombin/metabolism , Thrombosis/chemically induced
16.
Thromb Haemost ; 121(12): 1588-1598, 2021 12.
Article in English | MEDLINE | ID: mdl-33742435

ABSTRACT

Clinical parameters have been extensively studied in factor (F) VII deficiency, but the knowledge of molecular mechanisms of this disease is scarce. We report on three probands with intracranial bleeds at an early age, one of which had concomitant high titer of FVII inhibitor. The aim of the present study was to identify the causative mutations and to elucidate the underlying molecular mechanisms. All nine F7 exons were sequenced in the probands and the closest family members. A homozygous deletion in exon 1, leading to a frame shift and generation of a premature stop codon (p.C10Pfs*16), was found in proband 1. Probands 2 and 3 (siblings) were homozygous for a missense mutation in exon 8, resulting in a glycine (G) to arginine (R) substitution at amino acid 240 (p.G240R). All probands had severely reduced FVII activity (FVII:C < 1 IU/dL). Treatment consisted of recombinant FVIIa and/or plasma concentrate, and proband 1 developed a FVII inhibitor shortly after initiation of treatment. The FVII variants were overexpressed in mammalian cell lines. No FVII protein was produced in cells expressing the p.C10Pfs*16 variant, and the inhibitor development in proband 1 was likely linked to the complete absence of circulating FVII. Structural analysis suggested that the G to R substitution in FVII found in probands 2 and 3 would destabilize the protein structure, and cell studies demonstrated a defective intracellular transport and increased endoplasmic reticulum stress. The molecular mechanism underlying the p.G240R variant could be reduced secretion caused by protein destabilization and misfolding.


Subject(s)
Codon, Nonsense , Factor VII/genetics , Hemostasis/genetics , Homozygote , Intracranial Hemorrhages/genetics , Mutation, Missense , Age of Onset , Animals , CHO Cells , Coagulants/therapeutic use , Cricetulus , Endoplasmic Reticulum Stress , Exons , Factor VII/metabolism , Factor VIIa/therapeutic use , Genetic Predisposition to Disease , HEK293 Cells , Hemostasis/drug effects , Humans , Intracranial Hemorrhages/blood , Intracranial Hemorrhages/diagnosis , Intracranial Hemorrhages/drug therapy , Models, Molecular , Phenotype , Recombinant Proteins/therapeutic use , Treatment Outcome
17.
Am J Surg ; 222(2): 264-269, 2021 08.
Article in English | MEDLINE | ID: mdl-33612255

ABSTRACT

BACKGROUND: Drug-specific agents for the reversal of direct oral anticoagulants (DOACs) were recently approved. We hypothesized that the approval of these reversal agents would lead improved outcomes for trauma patients taking DOACs. METHODS: A multicenter, prospective (2015-2018), observational study of all adult trauma patients taking DOACs who were admitted to one of fifteen participating trauma centers was performed. The primary outcome was mortality. RESULTS: For 606 trauma patients on DOACs, those reversed were older (78 vs. 74, p = 0.007), more severely injured (ISS: 16 vs. 5, p < 0.0001), had more severe head injuries (Head AIS: 2.9 vs. 1.3, p < 0.0001), and higher mortality (11% vs. 3%, p = 0.001). Patients who received drug-specific agents (idarucizumab, andexanet alfa) had higher mortality (30% vs. 8%, p = 0.04) than those reversed with factor concentrates. However, the low usage of drug-specific reversal agents limits our ability to assess their efficacy and safety. CONCLUSIONS: DOAC reversal was not independently associated with mortality. At present, the overall usage of drug-specific reversal agents is too sparing to meaningfully assess outcomes in trauma.


Subject(s)
Coagulants/therapeutic use , Factor Xa Inhibitors/administration & dosage , Hemorrhage/prevention & control , Wounds and Injuries/therapy , Adult , Aged , Aged, 80 and over , Antibodies, Monoclonal, Humanized/therapeutic use , Blood Coagulation Factors/therapeutic use , Factor Xa/therapeutic use , Female , Humans , Injury Severity Score , Male , Prospective Studies , Recombinant Proteins/therapeutic use , Survival Rate , Trauma Centers , Wounds and Injuries/complications , Wounds and Injuries/mortality
18.
Thromb Haemost ; 121(11): 1400-1408, 2021 Nov.
Article in English | MEDLINE | ID: mdl-33581698

ABSTRACT

INTRODUCTION: FVIII inhibitor development is the most serious contemporary treatment complication in haemophilia A, particularly in previously untreated patients (PUPs). No inhibitors developed in clinical trials in previously treated patients treated with simoctocog alfa (Nuwiq), a fourth-generation recombinant FVIII produced in a human cell line. METHODS: The NuProtect study investigated the immunogenicity of simoctocog alfa in PUPs. NuProtect was a prospective, multinational, open-label, non-controlled, phase III study. PUPs with severe haemophilia A (FVIII:C <1%) of any age and ethnicity were treated with simoctocog alfa for 100 exposure days or a maximum of 5 years. Patients were true PUPs without prior exposure to FVIII concentrates or blood components. Inhibitor titres were measured with the Nijmegen-modified Bethesda assay; cut-off for positivity was 0.6 BU mL-1 (≥0.6 to <5 low-titre, ≥5 high titre). RESULTS: A total of 108 PUPs with a median age at first treatment of 12.0 months (interquartile range: 8.0-23.5) were treated with simoctocog alfa. F8 mutation type was known for 102 patients (94.4%) of whom 90 (88.2%) had null F8 mutations and 12 (11.8%) had non-null mutations. Of 105 PUPs evaluable for inhibitor development, 28 (26.7%) developed inhibitors; 17 high titre (16.2%) and 11 low titre (10.5%). No PUPs with non-null F8 mutations developed inhibitors. CONCLUSION: In the NuProtect study, the rate of inhibitor development in PUPs with severe haemophilia A treated with simoctocog alfa was lower than the rate reported for hamster-cell-derived recombinant factor VIII products in other recent clinical trials. No inhibitors were reported in PUPs with non-null F8 mutations.


Subject(s)
Antibodies/blood , Coagulants/therapeutic use , Factor VIII/therapeutic use , Hemophilia A/drug therapy , Hemorrhage/prevention & control , Coagulants/immunology , Factor VIII/genetics , Factor VIII/immunology , Genetic Predisposition to Disease , Hemophilia A/blood , Hemophilia A/genetics , Hemorrhage/blood , Hemorrhage/diagnosis , Hemorrhage/genetics , Humans , Infant , Male , Mutation , Prospective Studies , Recombinant Proteins/immunology , Recombinant Proteins/therapeutic use , Severity of Illness Index , Time Factors , Treatment Outcome
19.
Pediatr Blood Cancer ; 68(5): e28934, 2021 05.
Article in English | MEDLINE | ID: mdl-33577709

ABSTRACT

Hemophilia A and B are inherited hemorrhagic disorders that result from alterations in the coagulation cascade. Aside from spontaneous bleeding, the main complication of hemophilia is hemarthrosis. Progress over the last three decades, specifically prophylaxis using recombinant factor, has prevented hemarthrosis and lengthened patient life expectancies. However, many treatments require frequent dosing up to three times a week, and alloantibodies (inhibitors) against replacement factor continues to be an issue. These problems call for novel treatments for patients with hemophilia. Although there has been progress in extended half-life factors and mimetics of factor VIII, an alternative treatment methodology is to rebalance the activities of pro- and anticoagulant factors through inhibition of the natural anticoagulants: antithrombin, tissue factor pathway inhibitor, protein C, and protein S. This review will explore the efficacy of targeting these inhibitory pathways from preclinical development through clinical trials, and delve into concerns of thrombotic risk.


Subject(s)
Blood Coagulation/drug effects , Hemophilia A/drug therapy , Animals , Coagulants/therapeutic use , Humans
20.
J Surg Res ; 260: 369-376, 2021 04.
Article in English | MEDLINE | ID: mdl-33388533

ABSTRACT

BACKGROUND: Patients on warfarin with traumatic intracranial hemorrhage often have the warfarin effects pharmacologically reversed. We compared outcomes among patients who received 4-factor prothrombin complex concentrate (PCC), fresh frozen plasma (FFP), or no reversal to assess the real-world impact of PCC on elderly patients with traumatic intracranial hemorrhage (ICH). MATERIALS AND METHODS: This was a retrospective analysis of 150 patients on preinjury warfarin. Data were manually abstracted from the electronic medical record of an academic level 1 trauma center for patients admitted between January 2013 and December 2018. Outcomes were ICH progression on follow-up computed tomography scan, mortality, need for surgical intervention, and trends in the use of reversal agents. RESULTS: Of 150 patients eligible for analysis, 41 received FFP, 60 PCC, and 49 were not reversed. On multivariable analysis, patients not reversed [OR 0.25 95% CI (0.31-0.85)] and women [OR 0.38 95% CI (0.17-0.88)] were less likely to experience progression of their initial bleed on follow-up computed tomography while subdural hemorrhage increased the risk [OR 3.69 95% CI (1.27-10.73)]. There was no difference between groups in terms of mortality or need for surgery. Over time use of reversal with PCC increased while use of FFP and not reversing warfarin declined (P < 0.001). CONCLUSIONS: Male gender and using a reversal agent were associated with progression of ICH. Choice of reversal did not impact the need for surgery, hospital length of stay, or mortality. Some ICH patients may not require warfarin reversal and may bias studies, especially retrospective studies of warfarin reversal.


Subject(s)
Anticoagulants/adverse effects , Blood Coagulation Factors/therapeutic use , Coagulants/therapeutic use , Intracranial Hemorrhage, Traumatic/therapy , Plasma , Practice Patterns, Physicians'/trends , Warfarin/adverse effects , Aged , Aged, 80 and over , Blood Coagulation Factors/economics , Coagulants/economics , Connecticut , Female , Follow-Up Studies , Hospital Costs/statistics & numerical data , Humans , Intracranial Hemorrhage, Traumatic/diagnostic imaging , Intracranial Hemorrhage, Traumatic/economics , Intracranial Hemorrhage, Traumatic/mortality , Linear Models , Logistic Models , Male , Multivariate Analysis , Practice Patterns, Physicians'/economics , Retrospective Studies , Tomography, X-Ray Computed , Trauma Centers/economics , Treatment Outcome
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