scholarly journals Defibrotide Therapy for Sars CoV2 Acute Respiratory Distress Syndrome

Blood ◽  
2021 ◽  
Vol 138 (Supplement 1) ◽  
pp. 3237-3237
Author(s):  
Gregory A Yanik ◽  
David Frame ◽  
Gianni Bruno Scappaticci ◽  
Mary Maliarik ◽  
Steven W Pipe ◽  
...  
Keyword(s):  
Research Funding ◽  
Distress Syndrome ◽  
Study Entry ◽  
Open Label ◽  
Pulmonary Response ◽  
Response Parameter ◽  
Days Of Therapy ◽  
Thrombotic Complications ◽  
Pai 1 ◽  
D Dimer

Abstract Background: SARS-CoV-2 related acute respiratory distress syndrome (ARDS) is associated with endothelial dysfunction and profound dysregulation of the thrombotic/fibrinolytic pathway, with thrombotic complications common in affected patients (pts). Fibrin deposition may be a key feature of the pathobiology, with markedly elevated levels of PAI-1 reported. Defibrotide (DF), a polyanionic naturally-derived polydeoxyribonucelotide with endothelial stabilizing activity, has fibrinolytic, antithrombotic and anti-inflammatory properties, with known activity in reducing PAI-1 levels and inhibiting heparanase. We now report a prospective, open label, safety and tolerability trial of defibrotide for the management of patients with advanced SARS-CoV-2 related ARDS. Patients and Methods: Eligible patients (pts) were ≥18 years in age, with clinical and radiographic signs of ARDS, no signs of active bleeding, a serum D-Dimer > 2X ULN, and a positive PCR-based assay for SARS-CoV-2. Concomitant use of systemic anticoagulants or fibrinolytics was initially precluded, with the study amended to allow prophylactic doses of systemic heparin in its latter stages. Defibrotide (6.25 mg/kg/dose IV q. 6 hours) was administered for a planned 7-day course, with day 1 defined as the first day of study therapy. Therapy was able to be discontinued prior to day 7 in pts who met the pulmonary response parameter at that earlier timepoint. Patients with a partial response to therapy (> 20% reduction in FiO2) by day 7 were allowed to receive an additional 7 days of therapy (14 days total). Response was defined as complete cessation of supplemental O2 support, or ≥ 2 point reduction in WHO ordinal score for 48 consecutive hours by day 7. Patients were recruited from a single center between October 2020 and March 2021. Results: Twelve pts (median 63 years, range 35-73 years) were treated, with 10 of 12 pts on mechanical ventilation (median FiO2 55%, PEEP 18 mmHg), and six on vasopressor support at the time of study entry. Baseline PaO2/FiO2 ratios ranged from 82 - 200 mmHg. The median D-Dimer was 3.25 mcg/ml (range 1.33-12.3 mcg/ml), and fibrinogen 637 mg/dl (range 250-1208 mg/dl) at study entry. Dexamethasone and remdesivir had been administered prior to DF in all pts, with no other SARS-CoV-2 targeted treatment given during DF therapy. Eleven pts received ≤7 days of therapy, with one pt receiving 14 days. The first 9 pts received DF without other concomitant anticoagulants, with the last 3 pts concurrently receiving prophylactic heparin plus DF. No hemorrhagic or bleeding complications occurred during DF therapy, including the 3 pts receiving concurrent heparin prophylaxis. Likewise, no thrombotic complications developed during study therapy, including the 9 patients in which DF was their sole anti-coagulant. All 12 patients were evaluable for response. Four pts met the day 7 pulmonary response parameter, with 2 pts having a complete cessation of O2 support within this period. Three pts died from progressive pulmonary disease, at 11, 17 and 34 days from study entry. The 3 pts (who died) had the lowest baseline PaO2/FiO2 ratios (82-115 mmHg) of all study subjects. Nine pts (75%) remain alive, 64 to 174 days from study entry, all 9 discharged from their primary hospitalization. Day 30 all-cause mortality was 17% (95%CI: 0-35%). Serial coagulation and fibrinolytic assays were available in 7 patients. Total PAI-1 levels decreased from a median 167 ng/ml (range 105-264 ng/ml) to a median 104 ng/ml (range 55-166 ng/ml) by day 4 of therapy, with all 7 subjects showing a decline in PAI-1 levels at that time point. Total tPA levels increased from a median 3.02 ng/ml (range 0.72 - 36.1 ng/ml) at baseline to 4.5 ng/ml (range 1.1-8.2 ng/ml) by day 4 in study subjects. Allowing for the small sample size, baseline PAI-1, tPA or D-Dimer levels did not impact response. One of two patients with a baseline D-Dimer > 10 mcg/ml responded, while both patients with a baseline D-Dimer <2.0 mcg/ml failed to meet the response parameter. Conclusion: The use of DF for the management of SARS-CoV-2-related ARDS proved safe and tolerable in a prospective, open label trial. No hemorrhagic or thrombotic complications were reported during therapy. Outcomes were promising, including an overall survival of 75% in a patient population with a historically high mortality rate. (The study was supported by a research grant from Jazz Pharmaceuticals) Disclosures Yanik: Jazz Pharmaceutical: Research Funding. Pipe: Sangamo Therapeutics: Other: Scientific Advisory Board; ASC Therapeutics: Other: Scientific Advisory Board; Apcintex: Consultancy; Bayer: Consultancy; Biomarin: Consultancy; Catalyst Biosciences: Consultancy; CSL Behring: Consultancy; Freeline: Consultancy; Grifols: Consultancy; HEMA Biologics: Consultancy; Novo Nordisk: Consultancy; Octapharma: Consultancy; Pfizer: Consultancy; Roche: Consultancy; Sanofi: Consultancy; Takeda: Consultancy; Spark Therapeutics: Consultancy; uniQure: Consultancy. Sisson: Translatebio: Other: Data Safety Committee member. Richardson: Celgene/BMS: Consultancy, Research Funding; Karyopharm: Consultancy, Research Funding; Oncopeptides: Consultancy, Research Funding; Janssen: Consultancy; Secura Bio: Consultancy; AstraZeneca: Consultancy; Takeda: Consultancy, Research Funding; Regeneron: Consultancy; AbbVie: Consultancy; Protocol Intelligence: Consultancy; GlaxoSmithKline: Consultancy; Sanofi: Consultancy; Jazz Pharmaceuticals: Consultancy, Research Funding. Lawrence: MDI Therapeutics: Membership on an entity's Board of Directors or advisory committees. OffLabel Disclosure: Defibrotide: Off label use for ARDS

scholarly journals Bleeding and Thrombosis Are Associated with Endothelial Dysfunction in CAR-T Cell Therapy and Are Increased in Patients Experiencing Neurologic Toxicity

Blood ◽  
2020 ◽  
Vol 136 (Supplement 1) ◽  
pp. 32-33
Author(s):  
Andrew Johnsrud ◽  
Juliana Craig ◽  
John H. Baird ◽  
Jay Y. Spiegel ◽  
Lori S. Muffly ◽  
...  
Keyword(s):  
T Cell ◽  
Research Funding ◽  
Bleeding Events ◽  
Private Company ◽  
T Cell Therapy ◽  
Car T Cell ◽  
Car T ◽  
Thrombotic Complications ◽  
D Dimer ◽  
Support Research

Background Treatment with chimeric antigen receptor (CAR) T cell therapies have shown dramatic, often durable responses for relapsed/refractory B-cell malignancies. However, it can be associated with significant side effects such as cytokine release syndrome (CRS), immune effector-cell associated neurotoxicity syndrome (ICANS) and life-threatening consumptive coagulopathies. The underlying pathobiology of such hemostatic defects and their distinct clinical sequelae remains obscure. This retrospective study aims at quantifying CAR T therapy associated bleeding and thrombotic complications and their association with CRS, ICANS, and laboratory derangements. Methods 130 adult patients with DLBCL or B-ALL treated between 2017-2020 with CD19 CAR-T therapy axicabtagene ciloleucel (N=90) or a bispecific CD 19/22 CAR construct utilizing 4-1BB costimulatory domains (N=40) were analyzed to determine dynamics of coagulation parameters and platelet counts as well as incidences of bleeding or thrombosis in the first three months after CAR T infusion. Events were included if graded ≥ 2 or if intervention was required. Platelet counts and coagulation parameters were collected prior to lymphodepletion (pre-LD), day 0, 3, 7, 14, 21, 28, 60 and 90. Results 12 (9.2%) and 8 (6.2%) patients developed bleeding and thrombotic complications in the first three months after CAR-T infusion, respectively. Events are characterized in Figure 1. All bleeding events occurred between days 0-30 (median 17.5, range 8-30), while thrombotic events occurred between days 2-91 (median day 29, range, 2-91). Two (1.5%) patients experienced both bleeding and thrombosis. Bleeding events coincided with the onset of thrombocytopenia and hypofibrinogenemia, and patients who bled had lower platelet (median 22.5 vs. 47 K/uL; p=0.03) and fibrinogen (median 151 vs. 351 ug/mL; p=0.007) nadirs in the first 30 days compared to those without bleeding. Temporally, the lowest median platelet nadir occurred at day 7 in patients with bleeding events vs. day 21 in patients without bleeding, while timing of fibrinogen nadirs were at day 21 in both. Patients with bleeding episodes were more likely to be older (median age: 70 vs. 60 yrs, p=0.03), have thrombocytopenia prior to lymphodepletion therapy (median 117.5 vs. 174.5 K/uL, p=0.01), and have elevated LDH (lymphoma subgroup; p=0.07). Other lab derangements in the first 30 days seen more frequently in patients with bleeding included prolonged thrombin time (TT) (21% vs. 6%; p=0.02), PT (16% vs. 5%; p=0.06), and elevated d-dimer (16% vs. 3%; p=0.01) indicative of a consumptive process. Thrombotic events were not significantly associated with elevated or peak d-dimer values (median 4.97 vs. 2.37 ug/mL, p=0.20). Interestingly, occurrence or severity of CRS was not associated with bleeding or thrombotic events, nor was it associated with marked derangements in coagulation abnormalities. However, higher grade ICANS (grade > 3) was associated with bleeding (42% vs. 15%; p=0.038), thrombosis (50% vs. 16%; p=0.03), and evidence of endothelial activation including PT prolongation (78% vs. 35%; p<0.001), hypofibrinogenemia (57% vs. 20%; p=0.001), and trend towards elevated d-dimer (70% vs. 46%; p=0.06). 13 (10%) patients received anticoagulation for prophylaxis or therapeutic indications that predated CAR T infusion. Four started anticoagulation secondarily for thrombotic events after CAR-T infusion, and one received tissue plasminogen activator (tPA) for an acute stroke. In this group, no patients developed bleeding complications from anticoagulation. Conclusion Both bleeding (9.2%), and thrombotic (6.2%) events are observed after CAR T cell therapy, with bleeding limited to the first month in our cohort. Notably, ICANS was uniquely associated with PT prolongation, hypofibrinogenemia, and increased fibrin degradation, in addition to both bleeding and thrombosis. These results suggest that a systemic coagulopathy coincides with high grade ICANS and whether these neurologic events truly represent sequelae of widespread vascular dysfunction warrants further investigation. Anticoagulation was safe in the patients whom it was indicated. Risk factors for bleeding and thrombotic complications should be studied prospectively to develop risk-assessment models and clinical guidelines for management of bleeding and thrombosis (including prophylaxis) during CAR T therapy. Disclosures Muffly: Adaptive: Research Funding; Servier: Research Funding; Amgen: Consultancy. Negrin:BioEclipse Therapeutics: Current equity holder in private company; Magenta Therapeutics: Consultancy, Current equity holder in publicly-traded company; KUUR Therapeutics: Consultancy; Biosource: Current equity holder in private company; Amgen: Consultancy; UpToDate: Honoraria. Shizuru:Jasper Therapeutics, Inc: Current equity holder in private company, Membership on an entity's Board of Directors or advisory committees. Meyer:Orca Bio: Research Funding. Shiraz:Kite, a Gilead Company: Research Funding; ORCA BioSystems: Research Funding. Rezvani:Pharmacyclics: Research Funding. Mackall:Apricity Health: Consultancy, Current equity holder in private company; NeoImmune Tech: Consultancy; Nektar Therapeutics: Consultancy; Allogene: Current equity holder in publicly-traded company; BMS: Consultancy; Lyell Immunopharma: Consultancy, Current equity holder in private company. Miklos:Adaptive Biotech: Consultancy, Other: Travel support, Research Funding; Kite-Gilead: Consultancy, Membership on an entity's Board of Directors or advisory committees, Other: Travel support, Research Funding; Juno-Celgene-Bristol-Myers Squibb: Consultancy, Other: Travel support, Research Funding; Allogene Therapeutics Inc.: Research Funding; Novartis: Consultancy, Other: Travel support, Research Funding; Pharmacyclics: Consultancy, Other: Travel support, Patents & Royalties, Research Funding; Janssen: Consultancy, Other: Travel support; Miltenyi Biotec: Research Funding. Sidana:Janssen: Consultancy.

Open-Label, Prospective, Multicentre, Phase I/II Study of AOP2014, a Novel PEG-Proline-Interferon Alpha-2b in Patients with Polycythemia Vera: Update from an Ongoing Study

Blood ◽  
2011 ◽  
Vol 118 (21) ◽  
pp. 1747-1747
Author(s):  
Heinz Gisslinger ◽  
Robert Kralovics ◽  
Renate Schoder ◽  
Bettina Gisslinger ◽  
Veronika Buxhofer-Ausch ◽  
...  
Keyword(s):  
Platelet Count ◽  
Phase I ◽  
Polycythemia Vera ◽  
Dose Level ◽  
Dose Escalation ◽  
Research Funding ◽  
Study Entry ◽  
Molecular Response ◽  
Open Label ◽  
Multicentre Phase

Abstract Abstract 1747 Background. IFN-alpha (IFN) is reported to induce molecular response in patients with chronic myeloproliferative neoplasms and may therefore improve survival. However, the use of conventional and pegylated IFNs is limited by toxicity, leading to treatment withdrawals in a substantial proportion of patients. In polycythemia vera (PV), recently published phase II data indicate occurence of grade 3 and 4 toxicities in 20%, and toxicity-related discontinuations in 22–24% of patients administered once weekly with pegylated IFNs. Results from large-scale randomized studies of IFNs in PV are not available. AOP2014 is a next generation long-acting IFNa-2b, consisting predominantly of only one isoform as opposed to other commercially available pegylated interferons. AOP2014 is expected to have pharmacokinetic and pharmacodynamic profiles which may allow a reduced dosing frequency compared to other pegylated IFNs, potentially leading to improved tolerability, better compliance, and, finally, favourable long-term treatment outcomes. Study design. This is an open-label, prospective, multicentre, phase I/II dose escalation study of AOP2014 to determine the maximum tolerated dose (MTD), safety and efficacy in PV. Inclusion criteria are: age ≥18 years, confirmed diagnosis of PV (WHO, 2008, or the PSVG plus JAK2 positivity). Both newly diagnosed and pre-treated (cytoreduction) patients are eligible; hydroxyurea (HU) is allowed until the first application of AOP2014. If abnormally elevated prior to entry, sustained hematocrit (Hct) ≤45% is to be achieved by phlebotomy prior to the first administration. 3+3 dose escalation with cohort extension after MTD definition is being utilized. Intra-patient dose escalation to the dose level, previously established to be safe, is encouraged. MTD is defined as the highest dose level at which no more than 1 of 6 subjects experience a DLT during the first treatment period (2 weeks). Complete hematological response (CR) is defined by Hct <45%, platelet count ≤400*109/L, WBC count ≤10*109/L, normal spleen size, and absence of thromboembolic events. Partial response (PR) is defined as haematocrit <45% without phlebotomy but with persistent splenomegaly or elevated (>400*109/L) platelet count, or reduction of phlebotomy requirements by at least 50%. Evaluation of toxicities and JAK2 allele burden quantication will be performed. Results. 20 patients have been included to date, M/F ratio was 16/4, median age 58 years (range 44–83). Median time from diagnosis to inclusion was 19 months (range 0–170). 9 patients were pre-treated with HU prior to study entry. Median number of phlebotomies in the past 3 months prior to inclusion was 1 (range 0–4), a total of 13 patients were regularly phlebotomized at least once in three months prior to study entry. Six patients had a history of thrombotic complications. Median Hct at baseline was 46% in males (range 46–52) and 42% in females (range 41–43). Median WBC and platelet counts were 11.3*109/L (range 4.7–17.8) and 366*109/L (range 148–1016), respectively. Twelve patients (60%) had splenomegaly. Dose levels of 50, 100, 150, 225, 300, 360 and 450 microgramm once in two weeks were investigated. The median reported treatment duration is 24 weeks (range 0–33). After 10 weeks of treatment (14 evaluable patients), 64% of patients had hematological response (2 CR; 7 PR), one patient needed to be phlebotomized. At 18 weeks (9 evaluable patients), 1 patient had CR and 4 – PR, overall response (CR+PR) was 56%; at 28 weeks (8 evaluable patients), 1 patient had CR and 5 PR, overall response was 63%. The only evaluable patient at week 34 had CR. Starting from week 18, no patient required phlebotomy. Mainly grade 1 and 2 adverse events were reported. Administration site reactions developed in 11 patients, all of mild intensity and recovered within 72h. The most frequent adverse reactions were muscle and joint pain and gastrointestinal toxicities (12 and 6 patients, respectively). Fever and depression were observed in 5 and 2 patients, respectively. Drug-related adverse event (depression) was the reason of treatment discontinuation in one patient. Molecular response data are still undergoing evaluation. Conclusion. Response rate of above 60% at six month already observed in the phase I dose finding part suggests that AOP2014 has promising efficacy and good tolerability profile in PV. Updated results will be presented as the trial progresses. Disclosures: Gisslinger: AOP Orphan Pharmaceuticals AG: Research Funding, Speakers Bureau; Novartis: Speakers Bureau; Celgene Austria: Research Funding, Speakers Bureau. Kralovics:(7) AOP Orphan Pharmaceuticals AG: Research Funding. Schoder:AOP Orphan Pharmaceuticals AG: Research Funding. Gisslinger:AOP Orphan Pharmaceuticals AG: Research Funding. Buxhofer-Ausch:AOP Orphan Pharmaceuticals AG: Research Funding. Strecker:AOP Orphan Pharmaceuticals AG: Research Funding. Wolf:AOP Orphan Pharmaceuticals AG: Research Funding. Willenbacher:AOP Orphan Pharmaceuticals AG: Research Funding. Greil:AOP Orphan Pharmaceuticals AG: Research Funding. Egle:AOP Orphan Pharmaceuticals AG: Research Funding. Melchardt:AOP Orphan Pharmaceuticals AG: Research Funding. Burgstaller:AOP Orphan Pharmaceuticals AG: Research Funding. Tarmann:AOP Orphan Pharmaceuticals AG: Employment. Wachter:AOP Orphan Pharmaceuticals AG: Employment. Zahriychuk:AOP Orphan Pharmaceuticals AG: Employment. Thaler:AOP Orphan Pharmaceuticals AG: Research Funding.

Results of PX-171-003-A1, An Open-Label, Single-Arm, Phase 2 (Ph 2) Study of Carfilzomib (CFZ) In Patients (pts) with Relapsed and Refractory Multiple Myeloma (MM)

Blood ◽  
2010 ◽  
Vol 116 (21) ◽  
pp. 985-985 ◽  
Author(s):  
David Samuel diCapua Siegel ◽  
Thomas Martin ◽  
Michael Wang ◽  
Ravi Vij ◽  
Andrzej J Jakubowiak ◽  
...  
Keyword(s):  
Multiple Myeloma ◽  
Side Effects ◽  
Board Of Directors ◽  
Clinical Benefit ◽  
Research Funding ◽  
Single Agent ◽  
Study Entry ◽  
Open Label ◽  
Advisory Committees ◽  
Ortho Biotech

Abstract Abstract 985 Introduction: CFZ is a novel and highly selective epoxyketone proteasome inhibitor currently in clinical development for the treatment of multiple myeloma (MM). Ph 1 and 2 studies with CFZ have demonstrated durable single-agent antitumor activity in pts with relapsed or refractory (R/R) MM. The present study, PX-171-003-A1, was an open-label, single-arm Ph 2b trial and enrolled patients with multiply relapsed MM whose disease was refractory (defined as <25% response on, or progression during or <60 days after completion of, therapy) to their last treatment regimen. Patients must have received ≥2 prior therapies including: 1) bortezomib (BTZ) and either thalidomide (THAL) or lenalidomide (LEN), and 2) an alkylating agent. Materials and Methods: Pts received CFZ at 20 mg/m2 on a QDx2 schedule (Days 1, 2, 8, 9, 15, and 16 every 28 days) in cycle (C) 1 and were dose escalated to 27 mg/m2 on the same schedule thereafter for up to 12 C. Pts completing 12 C were eligible to enter an extension study (PX-171-010). The primary endpoint was overall response rate (ORR) (≥ partial response [PR]). Secondary endpoints included: clinical benefit response (CBR) (ORR + Minimal response [MR]), duration of response for ≥PR (DOR), overall survival (OS), time to progression (TTP), progression free survival (PFS), and safety. Responses and progression were determined according to the International Myeloma Working Group (IMWG) criteria and were assessed and confirmed by an Independent Response Committee (IRC). Results: 266 pts were enrolled with a median duration of MM of 5.4 years including 83% whose disease had progressed on or within 60 d of last therapy and 17% whose disease had achieved <25 % response to the regimen immediately preceding study entry. Of the 266 pts enrolled pts, 257 were evaluable for response; 9 patients were considered not evaluable based on missing baseline or lacking at least one post-baseline M-protein. An ORR (≥PR) of 24% with a median DOR of 7.4 mo (range 6.2–10.3) was determined. Responses are detailed in the table. The CBR (ORR + MR) was 36%. Median DOR of pts with MRs was 6.3 months, indicating that long-term MRs were observed. An additional 32% (83 pts) achieved SD for at least 6 wks. To date, 79 pts (30%) completed ≥6 C and >11% of pts have completed all 12 C of protocol specified therapy and most have entered the extension protocol; 15 pts remain on study (all >10 C). OS and TTP data for the overall population will also be reported. The enrolled pts in this study were heavily pretreated having received a median of 5 prior lines of therapy (range 1–20, median of 13 anti-myeloma agents). 85% of pts had received at least 2 and 37% had received at least 3 drugs in the regimen just prior to entering the study. Prior anti-myeloma agents included 99.6% (265/266 pts) BTZ (median 2 prior regimens containing BTZ), 99.6% either THAL (74%) or LEN (94%), 98% corticosteroids, 91% alkylating agents, and 74% stem cell transplant; 65% of pts were refractory to BTZ at any point in time prior to study entry. The most common treatment-emergent adverse events ≥ Grade (G) 3 regardless of relationship to study drug were predominantly hematologic and included thrombocytopenia (22%), anemia (20%), lymphopenia (10%), pneumonia (8%), neutropenia (8%), fatigue (7%), hyponatremia (5%), and hypercalcemia (5%). Although 206 pts (77%) had G1/2 peripheral neuropathy (PN) at baseline, new onset PN was infrequent and G ≥3 PN occurred in <1%. Interestingly, in this subset of patients, efficacy response was nearly identical to that seen in the full study population with an ORR (≥PR) of 24%. Conclusions: Single-agent CFZ achieved durable responses in pts with R/R MM whose disease had relapsed after all available therapies including BTZ and immunomodulatory agents. The CBR and median DOR achieved with this steroid-sparing regimen establish that CFZ has the potential to offer substantial clinical benefit to patients with relapsed or refractory disease. CFZ was well-tolerated and side effects were clinically manageable with no new or unexpected toxicities observed. Importantly, exacerbation of pre-existing PN was uncommon. Cumulative side effects were not observed, allowing prolonged single-agent dosing for chronic disease control. Disclosures: Siegel: Millenium: Consultancy, Honoraria; Celgene: Consultancy, Honoraria. Martin:Celgene: Honoraria; Onyx: Consultancy. Wang:Celgene: Research Funding; Onyx: Research Funding; Millenium: Research Funding; Novartis: Research Funding. Vij:Onyx: Honoraria. Jakubowiak:Millennium Pharmaceuticals, Inc.: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Celgene: Consultancy, Honoraria; Centocor Ortho Biotech: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Exelixis: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Bristol-Myers Squibb: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees. Jagannath:Millenium, OrthoBiotec, Celgene, Merck, Onyx: Honoraria; Imedex, Medicom World Wide, Optum Health Education, PER Group: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau. Lonial:Millennium: Consultancy, Research Funding; Celgene: Consultancy, Research Funding; Novartis: Consultancy, Research Funding; BMS: Consultancy, Research Funding; Onyx: Consultancy, Research Funding. Kukreti:Celgene: Honoraria; Roche: Honoraria; Ortho Biotech: Honoraria. Alsina:Millenium: Consultancy, Research Funding; Celgene: Research Funding; Novartis: Consultancy. Zonder:Millenium: Consultancy, Honoraria, Research Funding; Cephalon: Research Funding; Celgene: Honoraria. Wong:Onyx Pharmaceuticals: Employment. Vallone:Onyx Pharmaceuticals: Employment. Chang:Onyx Pharmaceuticals: Employment. Kauffman:Onyx Pharmaceuticals: Employment. Stewart:Millennium: Consultancy; Celgene: Honoraria. Singhal:Celgene: Speakers Bureau; Takeda/Millenium: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Onyx : Research Funding.

scholarly journals Circulating Plasminogen Activator Inhibitor-1 (PAI-1) Is Reduced By In Vivo Thrombin Generation and Subsequent Formation of Activated Protein C (APC)

Blood ◽  
2019 ◽  
Vol 134 (Supplement_1) ◽  
pp. 2389-2389
Author(s):  
Sara Reda ◽  
Franziska Isabelle Winterhagen ◽  
Christina Berens ◽  
Jens Müller ◽  
Johannes Oldenburg ◽  
...  
Keyword(s):  
Board Of Directors ◽  
Plasma Levels ◽  
Research Funding ◽  
The Other ◽  
Healthy Controls ◽  
Advisory Committees ◽  
Pai 1 ◽  
D Dimer ◽  
Thrombin Formation

Background: APC has been suggested to contribute to a hyperfibrinolytic state in various acquired coagulation disorders, including coagulopathies induced by trauma and sepsis. However, in vivo evidence for the proposed underlying mechanism of proteolytic degradation of PAI-1 by APC remains inconclusive. Recently, we have shown increased APC generation in response to in vivo thrombin formation in carriers of the factor V Leiden mutation (FVL). In this approach of stimulated hemostasis activity pattern evaluation (SHAPE), in vivo thrombin formation was triggered by low-dose administration of recombinant activated factor VII (rFVIIa). Aim of the present study was to investigate the resulting effects on the fibrinolytic system. Methods: The study population consisted of 30 FVL carriers (thereof 13 with a history of venous thromboembolism) and 15 healthy controls. Blood samples were collected immediately before and during a period of 8 hours following injection of 15 µg/kg rFVIIa. Plasma levels of APC were quantified using an oligonucleotide-based enzyme capture assay (OECA). Other monitored parameters included plasma levels of prothrombin activation fragment 1+2 (F1+2), tissue-type plasminogen (t-PA), PAI-1, plasminogen, α2-antiplasmin, plasmin-α2-antiplasmin complexes (PAP), soluble fibrin monomers, d-dimer, and thrombin-activatable fibrinolysis inhibitor (TAFI). Results: At baseline, FVL carriers showed higher median levels of APC in comparison to the controls (1.39 vs. 0.86 pmol/L, P=.001), higher PAI-1 levels (30.1 vs. 15.3 ng/mL, P=.002) and lower plasminogen levels (94.8 vs. 110.4%, P=6·10-4). The other baseline parameters did not differ significantly. In both cohorts a comparable increase of F1+2 was observed after administration of rFVIIa, whereas APC increased more (P=.004) in FVL carriers (by 6.40 pmol/L) than in healthy controls (by 2.14 pmol/L), Concurrently, median PAI-1 levels decreased more (P=.007) in FVL carriers (by 19.8 pmol/L) than in healthy controls (by 8.0 pmol/L) (Figure 1). TAFI levels decreased temporarily, from 104.8 to 94.4% (P=.007) in FVL carriers and from 105.0 to 92.1% (P=2·10-4) in healthy controls. PAP levels increased from 164 to 209 ng/mL (P<10-4) in FVL carriers and from 154 to 189 ng/mL (P=.023) in the control group. The extent of these changes did not differ between the two cohorts. D-dimer level increased only in FVL carriers, from 0.34 to 0.41 mg/L (P=.008). t-PA and the other parameters did not show significant changes after rFVIIa administration. Conclusion: Increased APC formation rates in FVL carriers were associated with a greater decline of PAI-1 levels in the absence of interfering changes in t-PA levels. These data provide further in vivo evidence that APC down-regulates PAI-1. Overall, the SHAPE approach utilized here does not induce a significant profibrinolytic response, even in patients with thrombophilia. Disclosures Reda: Grifols: Honoraria; Shire: Honoraria. Winterhagen:SOBI: Honoraria. Berens:Pfizer: Honoraria; Shire: Honoraria; Biotest: Honoraria; CSL Behring: Honoraria; Novo Nordisk: Honoraria; Baxter: Honoraria. Müller:NovoNordisk: Membership on an entity's Board of Directors or advisory committees; Bayer: Membership on an entity's Board of Directors or advisory committees; Siemens: Membership on an entity's Board of Directors or advisory committees; Roche: Membership on an entity's Board of Directors or advisory committees. Oldenburg:CSL Behring: Consultancy, Research Funding, Speakers Bureau; NovoNordisk: Consultancy, Honoraria, Research Funding; Bayer: Consultancy, Research Funding, Speakers Bureau; Swedish Orphan Biovitrum: Consultancy, Speakers Bureau; Grifols: Consultancy, Speakers Bureau; Takeda (Shire): Consultancy, Research Funding, Speakers Bureau; Chugai: Consultancy, Speakers Bureau; Roche: Consultancy, Speakers Bureau; Biotest: Consultancy, Research Funding, Speakers Bureau; Octapharma: Consultancy, Research Funding, Speakers Bureau; Pfizer: Consultancy, Speakers Bureau. Rühl:CSL Behring: Honoraria; Bayer: Honoraria; Shire: Honoraria; SOBI: Honoraria; Sanofi Genzyme: Honoraria; Grifols: Honoraria.

One Month Follow-up of Haemostatic Variables in Patients Undergoing Aortocoronary Bypass Surgery

1995 ◽  
Vol 73 (03) ◽  
pp. 356-361 ◽  
Author(s):  
L Mannucci ◽  
P S Gerometta ◽  
L Mussoni ◽  
C Antona ◽  
A Parolari ◽  
...  
Keyword(s):  
Cardiopulmonary Bypass ◽  
Bypass Surgery ◽  
Fibrinolytic System ◽  
Aortocoronary Bypass ◽  
Protamine Sulphate ◽  
Aortocoronary Bypass Surgery ◽  
Intraoperative Period ◽  
Pai 1 ◽  
D Dimer

SummaryIt is already known that activation of the coagulation and fibrinolytic system occurs in patients undergoing cardiopulmonary bypass (CPB). We have thus studied twenty patients (10 treated with aprotinin during CPB and 10 untreated) both during the intraoperative period and during thirty days follow up. In untreated patients D-dimer levels increased 4-fold during CPB and the levels were above baseline for the whole follow up (p<0.0001). D-dimer levels were reduced in aprotinin treated patients in comparison to untreated patients (p = 0.0172); levels then gradually increased to the values of the untreated patients over the following 24 h later and remained higher during the thirty day follow up. The behavior of haemostatic variables in the 24 h after CPB did not vary between untreated and aprotinin treated patients. In particular, five minutes after protamine sulphate administration, levels of F1 + 2 and TAT rose significantly (p = 0.0054, p = 0.0022 respectively), whereas fibrinogen significantly decreased (p<0.0001) and PAI-1 antigen levels were reduced. Two days after CPB the concentrations of F1 + 2 and TAT lowered, whereas fibrinogen and PAI-1 antigen levels increased. On the 5th, 8th and 30th days after CPB, F1 + 2 and TAT levels remained higher than those reported at baseline in both groups of patients, whereas fibrinogen levels increased over basal levels in aprotinin treated patients only.Thus, in addition to the activation of the coagulation and fibrinolytic system occurring during the intraoperative period, in patients undergoing CPB, there are alterations of haemostatic variables up to thirty days from surgery.

Aktivierungs- und Umsatzmarker der Hämostase im Verlauf der akuten tiefen Beinyenenthrombose

1995 ◽  
Vol 15 (02) ◽  
pp. 87-91 ◽  
Author(s):  
Ch. Burstein ◽  
S. Bitter ◽  
M. Kundt ◽  
M. Freund ◽  
O. Anders
Keyword(s):  
Thrombolytische Therapie ◽  
Pai 1 ◽  
D Dimer

ZusammenfassungIn einer prospektiven Untersuchung wurde das Verhalten von Thrombin-Antithrombin-lll-(TAT-)Komplex, D-Dimer, Plasminogenaktivator-lnhibitor-1 (PAI-1) und weiteren Parametern der Hämostase bei 50 Patienten mit spontaner tiefer Beinvenenthrombose bei Stellung der Diagnose während der initialen Behandlung und bei der ambulanten Kontrolle untersucht: 37 Patienten erhielten eine thrombolytische Therapie, davon 31 Patienten mit Streptokinase in ultrahoher Dosierung (UHSK) und sechs Patienten mit Urokinase; 13 Patienten wurden mit einer Heparininfusion behandelt.Im Vergleich zu den Patienten mit einer Heparintherapie führte die thrombolytische Therapie zu einem Anstieg von TAT (p <0,05), D-Dimer (p <0,01) und von PAI-1 (p <0,05). Bei vier Patienten trat eine Rethrombose nach Thrombolyse auf. Nach fibrinolytischer Therapie wurde eine Aktivierung der Gerinnung und eine erhöhte Aktivität von PAI-1 nachgewiesen, die für die Entstehung einer Rethrombose von Bedeutung sein können.

Influence of insulin-induced hypoglycemia on the hemostatic and fibrinolytic system in patients with hypothalamicpituitary disorders

1998 ◽  
Vol 18 (02) ◽  
pp. 74-79
Author(s):  
K.-H. Zurborn ◽  
H. D. Bruhn ◽  
H. Mönig
Keyword(s):  
Factor Viii ◽  
Plasminogen Activator ◽  
Tolerance Test ◽  
Insulin Tolerance Test ◽  
Fibrinolytic System ◽  
Tissue Type ◽  
Insulin Tolerance ◽  
Factor Viii Antigen ◽  
Pai 1 ◽  
D Dimer

SummaryIn order to study the acute and prolonged effects of hypoglycemia on the hemostatic and fibrinolytic system we measured prothrombin fragment (F1+2), thrombin-antithrombin III complex (TAT), platelet factor 4 (PF4), β-thromboglobulin (âTG), factor VIII antigen (F VIII antigen), D-dimer, tissue-type plasminogen activator (t-PA) antigen, and plasminogen activator inhibitor (PAI-1) in 22 patients during insulin tolerance test. F1+2 and TAT increased significantly 15 and 90 minutes after administration of insulin, as did PF4 and âTG. At 4 and 24 hours, these parameters were not different from baseline. Factor VIII antigen was not significantly altered. D-dimer concentration did not change. However, the D-dimer/TAT ratio significantly decreased at 15 and 90 minutes but increased markedly above baseline at 4 and 24 hours. t-PA antigen was also found to be elevated at 15 and 90 minutes but had returned to baseline at 4 and 24 hours. PAI-1 concentration did not change. We conclude from these data that both coagulation and fibrinolysis are activated in the short-term response to acute insulin-induced hypoglycemia, followed by a prolonged activation of fibrinolysis. Our study may explain why patients undergoing insulin tolerance test, despite marked clotting and platelet activation, almost never develop thromboembolic complications.

scholarly journals Trial of aerosolised surfactant for preterm infants with respiratory distress syndrome

2021 ◽  
pp. fetalneonatal-2021-321645
Author(s):  
Luke Jardine ◽  
Kei Lui ◽  
Helen G Liley ◽  
Timothy Schindler ◽  
James Fink ◽  
...  
Keyword(s):  
Respiratory Distress Syndrome ◽  
Respiratory Distress ◽  
Preterm Infants ◽  
Distress Syndrome ◽  
Failure Criteria ◽  
Open Label ◽  
Dose Escalation Study ◽  
Safety Issues ◽  
Label Dose ◽  
Historical Controls

ObjectiveTo evaluate the safety of an aerosolised surfactant, SF-RI 1, administered via nasal continuous positive airway pressure (nCPAP) and a prototype breath synchronisation device (AeroFact), to preterm infants with respiratory distress syndrome (RDS).DesignMulticentre, open-label, dose-escalation study with historical controls.SettingNewborn intensive care units at Mater Mothers’ Hospital, Brisbane, and Royal Hospital for Women, Sydney, Australia.PatientsInfants 26 weeks through 30 weeks gestation who required nCPAP 6–8 cmH2O and fraction of inspired oxygen (FiO2) <0.30 at <2 hours of age.InterventionsIn part 1, infants received a single dose of 216 mg/kg of aerosolised surfactant. In part 2, infants could receive up to four doses of aerosolised surfactant. Three historical control infants were matched for each enrolled infant.Main outcome measuresTreatment failure was defined as Respiratory Severity Score (FiO2×cmH2O nCPAP) >2.4, nCPAP >8 cmH2O, arterial carbon dioxide >65 mm Hg, pH <7.20 or three severe apnoeas within 6 hours during the first 72 hours of life. Other outcomes included tolerance of the AeroFact treatment and complications of prematurity.Results10 infants were enrolled in part 1 and 21 in part 2 and were compared with 93 historical controls. No safety issues were identified. In part 2, 6 of 21 (29%) AeroFact-treated infants compared with 30 of 63 (48%) control infants met failure criteria. Kaplan-Meier analysis of patients in part 2 showed a trend towards decreased rate of study failure in the AeroFact-treated infants compared with historical controls (p=0.10).ConclusionThe AeroFact system can safely deliver aerosolised surfactant to preterm infants with RDS who are on nCPAP.Trial registration numberACTRN12617001458325.

FGL1 as a modulator of plasma D‐dimer levels: exome‐wide marker analysis of plasma tPA, PAI‐1 and D‐dimer

2021 ◽  
Author(s):  
Florian Thibord ◽  
Ci Song ◽  
Jack Pattee ◽  
Benjamin A.T. Rodriguez ◽  
Ming‐Huei Chen ◽  
...  
Keyword(s):  
Marker Analysis ◽  
Pai 1 ◽  
D Dimer

Hemostatic Parameters and Platelet Activation Marker Expression in Cyanotic and Acyanotic Pediatric Patients Undergoing Cardiac Surgery in the Presence of Tranexamic Acid

2000 ◽  
Vol 83 (01) ◽  
pp. 54-59 ◽  
Author(s):  
Elena Levin ◽  
John Wu ◽  
John Alexander ◽  
Clayton Reichart ◽  
Suvro Sett ◽  
...  
Keyword(s):  
Cardiac Surgery ◽  
Blood Loss ◽  
Tranexamic Acid ◽  
Platelet Activation ◽  
Pediatric Patients ◽  
Factor Xiiia ◽  
Congenital Defects ◽  
Plasma Factor ◽  
Pai 1 ◽  
D Dimer

SummaryWe have investigated hemostatic parameters including platelet activation in 56 pediatric patients with or without cyanosis undergoing cardiopulmonary bypass (CPB) and cardiac surgery to repair congenital defects. Patients were participants in a study assessing the effects of tranexamic acid on surgery-related blood loss. Parameters monitored included blood loss, prothrombin F1.2, thrombin-antithrombin complexes, t-PA, PAI-1, plasminogen, fibrin D-dimer, and plasma factor XIII. Additionally, flow cytometry monitored platelet degranulation (P-selectin or CD63), as well as surface-bound fibrinogen, von Willebrand factor and factor XIIIa. Cyanotic patients had evidence of supranormal coagulation activation as both fibrin D-dimer and PAI-1 levels were elevated prior to surgery. While the extent of expression of Pselectin or CD63 was not informative, platelet-associated factor XIIIa was elevated in cyanotic patients at baseline. In both patient groups, CPB altered platelet activation state and coagulation status irrespective of the use of tranexamic acid.

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