bluuebunny/crossref_metadata_2025_split huggingface dataset:
Prevalence of Heparin Antibodies in ICU Patients (The HAICU Study).
Authors: Hergenroeder Georgene W. , Francis John L. , Miller Charles C. , Levine Robert L. 
Published: April 2020

Abstract
BACKGROUND: Heparin-induced thrombocytopenia (HIT) is an antibody-mediated prothrombotic disorder characterized by absolute or relative thrombocytopenia occurring after exposure to heparin. Although thrombocytopenia in HIT patients usually resolves after discontinuing heparin, the risk for thrombosis persists up to 3 months.
PURPOSE: The HAICU study was conducted to determine the prevalence of heparin-induced antibodies and HIT on admission to the intensive care unit (ICU) and their development within a week of hospitalization.
METHODS: Platelet counts and heparin-platelet factor 4 antibodies (GTI ELISA) were measured on admission and again on day 7 ± 2 or discharge on a convenience sample of ICU patients. Patients with new onset thrombocytopenia (unexplained platelet count &lt;100 x109/L or a 50% decrease in count) or a positive ELISA had confirmatory testing for HIT antibodies using a serotonin release assay. HIT was prospectively defined as positive HIT antibodies by both assays or as HIT antibodies with new onset, unexplained thrombocytopenia.
RESULTS: Over 6 months, 118 patients were enrolled from three ICUs. Subjects had an average ICU LOS of 9 +/− 11 days, hospital LOS of 20 +/− 11 days and Apache II Physiology Score of 14 +/− 7; 59% were male. HIT, as defined above, occurred in 3 (3%) patients on admission. After 7.2 ± 2 days, HIT occurred in an additional 9 patients. Overall, 12 of 118 (10%) ICU patients had HIT at or within a week of admission (Table 1). 5 had documented prior exposure to heparin within 100 days of ICU admission, and 4 received heparin during the period when HIT assays were performed. Cases were distributed throughout the ICU’s, yet relatively more often in the neurotrauma and shock-trauma units than the medical unit.
CONCLUSION: Heparin-induced antibodies and HIT are common in the ICU, occurring in 3% of patients on admission and 10% in the first week. Physicians need to be aware of heparin exposure and the possibility of HIT in this population.
Patients Positive for Heparin Antibodies by Type of ICU and Time Point Unit No. of Patients Percent (%) Day of ICU Admission Day 7 +/− 2 TOTAL Percent Positive per ICU (%) NTICU 56 47.5 1 5 6 11 STICU 39 33 2 3 5 13 MICU 23 19.5 0 1 1 4 TOTAL 118 100 3 9 12 10
rFVIIa Treatment and Efficacy Prediction in a Patient with Hermansky-Pudlak Syndrome Type 1 (HPS-1) Using Global Clotting Tests and Flow Cytometry.
Authors: Wegert Wolfgang , Scholz Thomas , Ehrenforth Silke , Mondorf Wolfgang , Kirchmaier Carl M. 
Published: April 2020

Abstract
The use of hemostatic agents for patients with platelet function related disorders causing impaired clotting is predominantly monitored via clinical parameters to date. For HPS patients, which suffer from a platelet storage pool disease, up to now mainly desmopressin and/or platelet concentrates have been administered as therapeutic agent in case of bleeding or surgery, with variable success. A more recent option is rFVIIa (NovoSeven®, N7), but there are few reports of its use in HPS patients. Before administering, it would be of therapeutical interest to know the maximum efficacy and the patient’s individual response. We investigated the hemostatic efficacy of rFVIIa in a patient with HPS-1 (63 y; 2 mutations: 972delC, T322N), who was undergoing tooth extraction. rFVIIa (90 U/kg body weight bolus) was administered 30 minutes before the procedure. Citrated blood samples were taken before, 15 minutes after rFVIIa administration and after the dental treatment was completed. Platelet rich plasma was generated by centrifugation (750g, 5 min) and the samples assayed using a fluorometric thrombin generation test (TGT), thrombelastography (RoTEG) and flow cytometry (FACS). The TGT was started adding Ca 16,7 mM and fluorogenic substrate. RoTEG was used with Ca, N7, tissue factor separately and combined. From the pre-substitution samples a reference value with rFVIIa, 80 U/ml added in vitro, and a dose-response curve from 0 to 400 U/ml were measured. N7 recovery was evaluated from pre-, post-substitution and the reference values. The TGT showed a presubstitutional residual activity of 50 % of the maximum ETP value, and 100% after substitution. TGT response to N7 was dose-dependent and entered a plateau at 90 % of the value after substitution, from 80 U/ml N7 on. The effect of subsituted rFVIIa persisted 2h after the extraction. Other TGT parameters (peak, time to peak, lag time) changed concordantly. RoTEG changes were most pronounced for Ca 12 mM alone as a trigger, which showed a transient reduction of clotting time and clot formation time after N7 substitution. FACS showed a 2.2fold CD62P increase indicating platelet activation after administration. Altogether, the TGT parameter changes corresponded best to the clinical outcome, as no bleeding events were observed during and 2h after the dental procedure. Thrombin generation may thus be useful to evaluate and predict N7 therapeutic efficacy in HPS patients. More HPS patients have to be treated to confirm these findings.
Human Thrombospondin-1 in Eleven von Willebrand Factor /FVIII Coagulation Factor Concentrates.
Authors: Suiter Tobias M. , Budde Ulrich 
Published: April 2020

Abstract
Von Willebrand factor (VWF) is a multimeric protein that mediates adhesion of platelets to sites of vascular injury and is therefore essential for primary haemostasis. The modulation of VWF multimers size is critical to the control of the hemostatic activity, where the large multimeric forms are most hemostatically active. It has been shown that various proteases, such as Thrombospondin-1 (facilitates reduction of the disufide bonds), are critical in the degradation of VWF multimers. This might be an important aspect for VWF coagulation factor concentrates used in the treatment of von Willebrands disease, best treated with high molecular weight VWF multimers and least content of human TSP-1 (huTSP-1).
Determination of huTSP-1 (ChemiKine EIA Kit der Fa. Chemicon International, USA) were done in 11 commercially available VWF/FVIII-concentrates (3 different batches each) in duplicates. HuTSP-1 content in the VWF/FVIII concentrates varied from 0,08 ug/mL to 12,7 ug/mL (variance in all duplicates less than 15%), as shown in the figure.
The results show a significant difference in huTSP-1 content. VWD patients might receive as much as 250 ug huTSP-1 or even higher during a single treatment course. If the huTSP-1 is still active, requires further investigations.
Figure Figure
Age-Related Reference Values of Molecular Markers in Endothelial Cell Activation, Coagulation and Fibrinolysis in Thai Children Versus Adults.
Authors: Sosothikul Darintr , Lusher Jeanne M. 
Published: April 2020

Abstract
Introduction: The hemostatic system is a developing and changing process relative to age. Although advances in the knowledge of hemostatic mechanisms have led to the development of new methods for measuring peptides or enzyme-inhibitor complexes, there are very limited data concerning normal reference values for these in children.
Objectives: The aim of this study is to distinguish the difference(s) in various endothelial cell activation and hemostatic parameters between children and adults, and to establish the normal range of these parameters in normal children in different age groups.
Materials and Methods: Blood was obtained from 96 normal Thai children and adults whose screening coagulation tests were normal. All children were categorized into 3 age groups: 1–5 yrs, 6–10 yrs, and 11–18 yrs. Endothelial cell activation parameters: von Willebrand Factor Antigen and Activity (VWF:Ag and VWF:Ac) and soluble thrombomodulin (sTM); coagulation parameters: activated Factor VII (FVIIa:C), tissue factor (TF), and Thrombin-Antithrombin Complex (TAT); and fibrinolytic parameters: tissue plasminogen activator (t-PA), plasminogen activator inhibitor (PAI-1), D-dimer, thrombin activatable fibrinolysis inhibitor (TAFIa) and Protein C activity (PC:Ac) were measured.
Tests Children’s Age Range Adults (Mean ± SD) 1–5 yr (n=19) 6–10 yr (n=26) 11–18 yr (n=25) (n=25) ANOVA *p ≤ 0.05 compared with adults; **p ≤ 0.001 compared with adults VWF:Ag (%) 93.3 ± 25.7 110.3 ± 27.1 98.4 ± 31.0 100.5 ± 25.2 VWF:Ac (%) 72.1 ± 18.9 91.1 ± 20.6 82.0 ± 24.2 84.7 ± 21.8 sTM (ng/mL) 3.9 ± 1.6** 3.1 ± 0.9 3.1 ± 1.3 2.4 ± 1.1 Fibrinogen (mg/dL) 360.7 ± 56.9 384.4 ± 78.9 410.1 ± 109.4 360.7 ± 51.0 FVIIa:C (%) 68.0 ± 23.8 69.9 ± 23.1 75.0 ± 22.9 75.6 ± 19.7 TF (pg/mL) 218.8 ± 57.8** 152.7 ± 38.2 144.5 ± 46.7 126.6 ± 42.2 TAT (ug/L) 4.5 ± 3.3 2.2 ± 0.7 2.4 ± 1.2 3.7 ± 4.9 t-PA (ng/mL) 1.32 ± 0.56 1.19 ± 0.48 1.16 ± 0.28 1.27 ± 0.32 PAI-1 (ng/mL) 22.8 ± 13.2 29.4 ± 14.2* 27.3 ± 18.3 18.8 ± 11.9 D-dimer (mg/L) 0.52 ± 0.42* 0.44 ± 0.46 0.28 ± 0.33 0.21 ± 0.09 TAFIa μg/mL) ( 40.6 ± 9.7 44.4 ± 6.9 46.1 ± 6.1 42.2 ± 5.7 Protein C:Ac (%) 87.2 ± 18.3* 101.7 ± 15.6 101.1 ± 22.5 102.4 ± 17.4
As seen in the Table, children in all age groups showed no significant difference in mean levels of VWF:Ag and Ac, fibrinogen, FVIIa:C, TAT, t-PA and TAFIa compared to adults. However, compared to adults, children aged 1–5 had significantly higher mean values of sTM (p=0.001), TF (p=&lt; 0.001), and D-dimer (p = 0.015) whereas they had significantly lower mean levels of PC:Ac (p=0.023). The mean levels of PAI-1 in children of all groups were high, especially in children in the 6–10 yr age group (p = 0.032). These data indicate a physiologic difference in endothelial cell activation and hemostatic system between children and adults. Our data will serve as a useful reference guide in interpreting test results from children with suspected bleeding disorders.
Plasma Coagulation on Microparticles Is Modulated by Water Activity. Relevance to Inflammation-Mediated Disruption of the Extracellular Matrix.
Authors: McGee Maria P. , Li Lynne , Ollero Jorge 
Published: April 2020

Abstract
The microenvironment of extravascular spaces influences the reactivities of extravasated plasma proteins. During inflammation, the structural and physicochemical characteristics of peri- and extra-vascular spaces can change widely depending on the severity of extracellular matrix disruption. Plasma extravasation after limited vascular injury results in transient changes in water activity (aw) and fibrin deposition.
This work investigates whether changes in aw influence either pro- or anticoagulant pathways assembled on procoagulant microparticles. Based on conclusions from in vivo models indicating that factor Xa (fXa) concentration is the limiting factor in prothrombinase assembly we modeled the extravascular coagulation process in vitro, using plasma as the matrix; controlling aw as the independent variable; and measuring the fXa generation rate as the dependent variable. Initial rates of fXa generation were measured in human plasma (1/100 final dilution) containing procoagulant particles and 200 nM factor X. Water activity levels decreased from 0 to 0.8 atm relative to isosmolar plasma (~7 atm) with polyethylene glycol 8000 (~26 Å radius), while all reactant concentrations remained constant. Procoagulant particles were either recombinant tissue factor (TF) in PC/PS vesicles (at a mol ratio of 1/2666) or microvesicles collected from the monocytoid cell line THP-1 after 24-hour stimulation with endotoxin (1ug/ml). As the reaction environment’s aw progressively decreased, fXa generation rate first increased, and then decreased. Rate/aw profiles followed nearly symmetrical peaks with a maximum at ~0.2 atm and minimum at ~0.7 atm. Similar profiles were obtained with cell-derived procoagulant microvesicles. At each aw level, the fXa generation rate increased exponentially with TF concentration (25–100 pM). Activation and inhibition indices of ~1.5 and ~2.1, calculated as the ratio between the maximal and baseline and the maximal and minimal rates did not change significantly with TF concentration. Rates increased with added factor VIII (~2 units/ml) indicating fIX activation and a contribution of the intrinsic pathway protease to fXa generation. Furthermore, reaction rates changed with hirudin suggesting that thrombin-mediated regulatory loops also affect the rate profiles. Results in this simple model of extravascular coagulation indicate that aw modulates the rate of coagulation reactions stimulating or inhibiting them depending on whether the reaction environment’s aw is high or low. This conclusion in turn predicts that immediately after limited plasma extravasation coagulation rates accelerate with the decrease in aw as it tend to equilibrate with aw in the extravascular spaces. Continued water adsorption by an intact extracellular matrix would equilibrate aw and decrease coagulation rates. However, in a structurally damaged matrix with compromised water sorption ability, rates may remain longer at the higher level.
Variations in Ex-Vivo Assessments of Hemostasis.
Authors: Gabriel Don A. , Skolnick Brett E. , Rojkjaer Lisa Payne , Seremetis Stephanie V. 
Published: April 2020

Abstract
Previous studies have described differences in hemostasis between Caucasians and African-American subjects, suggesting that ethnicity may influence parameters used to monitor hemostasis. During the course of post-hoc analyses of data from an ex-vivo model to evaluate hemostasis in healthy, non-coagulopathic individuals, evidence of ethnic variability was noted. In this study, ex-vivo assessments of hemostasis were conducted using the thromboelastograph assay (TEG), and Hemodyne Hemostasis Analyzer (HHA). These instruments provide an assessment of platelet function and clot formation. All the subjects enrolled in this trial were healthy male volunteers between the ages of 18 and 45 years. Of the 48 subjects enrolled, 34 (71%) were Caucasians and 14 (29%) were African-Americans. Analyses were performed comparing blood loss volume (assessed by systematic recording of filter paper weights), duration of bleeding, TEG and HHA tracings between the two groups. There were no significant differences in blood loss volume and duration. However in the African-American subjects, TEG analyses demonstrated a significantly higher clot growth rate and maximum clot amplitude strength, while HHA analyses demonstrated a significantly higher platelet contractile force. These observations suggest that ethnic differences in coagulation parameters may exist that could influence techniques or instruments used to evaluate hemostasis. These observations require further investigation. In addition, these observation may provide a useful avenue for further investigation of the apparent enhanced coagulability in the African-American population.
Ex-vivo Assessments of Hemostasis African-American Caucasian n=14 n=31 Mean ± SD Mean ± SD p-value NS, Not statistically significant Blood loss volume (g) 2.19 ± 1.16 2.58 ± 1.84 NS Bleeding duration (mins) 21.07 ± 7.52 20.0 ± 7.21 NS TEG results Coagulation onset time (R, mins) 4.93 ± 0.72 5.40 ± 0.89 NS Time to 20 mm clot strength (K, mins) 1.59 ± 0.25 1.95 ± 0.29 0.0004 Clot growth rate (A, degrees) 67.17 ± 3.78 63.15 ± 3.69 0.0017 Max. clot amp. Strength (MA, mm) 61.07 ± 3.89 57.63 ± 3.96 0.0096 HHA results Clot elastic modulus (CEM, Kdynes/cm2) 20.01 ± 5.80 15.87 ± 7.51 NS Platelet contractile force (PCF, Kdynes) 5.50 ± 1.11 4.42 ± 1.44 0.0165
Effect of Recombinant Activated Factor VII (rFVIIa) on Platelet and Clotting Systems in Healthy Volunteers.
Authors: Gabriel Don A. , Skolnick Brett E. , Seremetis Stephanie , Leese Philip , Mathews David 
Published: April 2020

Abstract
The generation of thrombin is a critical step in clot formation and securing hemostasis. Inadequate thrombin generation may result in excessive bleeding, while uncontrolled thrombin production has the potential to induce thromboses. Recombinant FVIIa has been shown to control bleeding in hemophilia patients with inhibitors to coagulation factors VIII and IX, and several other clinical conditions in which life- and limb-threatening bleeding may occur. However, for non-hemophilia patients the dose and dosing regimen still require refinement. The use of ex-vivo assessment systems (Thromboelastograph assay, Hemodyne Hemostasis Analyzer) to generate an in vitro model of hemostasis may be useful to determine the effect of rFVIIa on the dynamics of clot formation, particularly in a patient population where clinical trials are difficult. A series of pilot studies were performed to establish an optimal punch biopsy location and biopsy size to create an effective bleeding site for further study. The current study (48 subjects consented for an IRB approved protocol) examined, in an ascending dose-escalation manner, the effect of an individual dose of rFVIIa on bleeding time, blood loss volume, coagulation parameters and coagulation status in healthy volunteers. All patients underwent three punch biopsies: the first (baseline biopsy) with no treatment, the second and third biopsy with either a low or high rFVIIa dose administered prior to biopsy. The treatment pair sequences were placebo/10, 10/20, 20/40, 40/80, 80/120, and 120/160 μg/kg. Blood samples were drawn 15 minutes pre-, 15 minutes post-, 1 hour and 5 hours post-biopsy to conduct ex-vivo assessments of hemostasis. The results indicate that overall there was a trend towards an increase in platelet contractile force and clot elastic modulus with an apparent maximal effect at 1 hour post-biopsy. At the higher doses this effect, although reduced, does not return to pre-treatment values by 5 hours post-biopsy. For the lower doses these values decreased to levels comparable to those at pre-treatment. These observations are consistent with the reports of a dose-related half-life of rFVIIa. These data imply that the administration of rFVIIa may have an effect in non-coagulopathic individuals. Although the heterogenity observed in this sample of patients may limit interpretations, it is proposed that this ex-vivo model with further refinements may be useful for evaluating the effects of future pro-hemostatic agents.
Figure Figure
Prophylactic Use of rFVIIa in a Young Hemophilia A Patient with Factor VIII Inhibitor.
Authors: Borel-Derlon Annie , Slaoui Mounia , Gautier Philippe , Guillon Patricia 
Published: April 2020

Abstract
The prevention of bleeding by prophylaxis regimen particularly for joint rehabilitation, could be considered a more effective treatment for hemophilia patients. In hemophiliacs with factor VIII inhibitor (F VIII inh) prophylaxis is not generally proposed because the bypassing agents for these patients may be less effective than F VIII concentrates. We report the regimen and results of a 6 months rFVIIa (Recombinant factor VIIa) prophylaxis, in a young hemophilia A patient (4 years old), with F VIII inh and immune tolerance induction (ITI) treatment and compared, with rFVIIa, the on demand treatment results for the 6 months prior to prophylaxis. After 2 years of a high dose regimen ITI, the FVIII inh titer was less than 50 BU and the immune tolerance treatment remains on going. Due to the development of a right knee target joint the rFVIIa prophylaxis was decided as an active rehabilitation approach to prevent the development of chronic arthropathy as well as to improve the quality of life of the child. During the 6 months period, prior to the initiation of rFVIIa prophylaxis 22 bleeds occurred i.e., 9 right knee hemarthrosis and 13 other joint bleedings and hematoma including elbow, wrist, ankle, foot, arm and chest. These bleeds were all treated with rFVIIa with a dose ranging from 100 to 200 μg/kg depending on the severity of the episodes and the duration of treatment ranged from 1 to 8 days. After 6 recurrent right knee hemarthrosis, a lavage of the joint was performed and prophylaxis with rFVIIa was subsequently initiated. A 120 μg/kg rFVIIa injection was performed 3 times a week concomitantly with the ITI treatment infusion and just before the physiotherapy course. During the 6 months of prophylaxis regimen we observed 9 bleeds with 3 major post traumatic bleedings which were treated by one 200 μg/kg/day rFVIIa injection which was resolved in one to three days. This prophylaxis treatment was effective for the arthropathy evolution and permitted the patient to return to school on a regular basis compared to the previous year. The total dose of on demand rFVIIa treatment used before prophylaxis was 458 mg/6 months. This amount decreased by 25% during the six months of prophylaxis with rFVIIa to reach 343 mg. The results of this significant observation led us to conclude that rFVIIa could be effectively used as prophylactic treatment in patients with FVIII inh and administered safely via a portacath device even in cases of high doses, as demonstrated in this young patient. This prevention approach resulted in a decrease of bleeding episodes, injections, and a significant improvement in the quality of life.
A New Formulation of Recombinant Human Factor IX Is Bioequivalent to BeneFIX: A Double-Blind, Randomized, Crossover Pharmacokinetic and Open-Label Safety and Efficacy Study.
Authors: Powell Jerry Sherman , Lambert Thierry , Navarro F. Hernández , Recht Michael , Sullivan Sharon T. , Udata Chandrasekhar , Lilly Leslie C. , Roth David A. ,   The rFIX-R Study Group
Published: April 2020

Abstract
A new formulation (rFIX-R) of BeneFIX has been developed to reduce the possibility of RBC agglutination, a phenomenon associated with the low ionic strength of the reconstituted drug product. The new formulation contains NaCl to increase the ionic strength and the recombinant factor IX concentration is increased for the 1000 IU strength and a new 2000 IU strength by reconstituting all strengths in 5 mL, facilitating the administration of larger doses in decreased volumes. Thirty-four (34) previously treated (≥150 exposure days [EDs]) males (≥12 years) with moderately severe/severe hemophilia B (FIX:C ≤2%) were enrolled and treated in this 2 part study. In the randomized, double-blind, crossover pharmacokinetic (PK) period of the study, the PK characteristics of rFIX-R were compared with those of the currently available formulation of BeneFIX. Subjects received either rFIX-R or BeneFIX as a 75 IU/kg bolus infusion over 10 minutes after a suitable washout. Blood samples were collected at defined times over 72 hours to measure pre-/post-infusion plasma factor IX activity. Subjects then received the alternate treatment following the same procedure. The mean plasma factor IX activity-versus-time profile after the infusion of rFIX-R was essentially identical to that seen with BeneFIX. From the 26 evaluable subjects, the mean PK parameter estimates of factor IX activity establish bioequivalence of the products since the 90% confidence intervals for rFIX-R to BeneFIX ratios of the geometric means of Cmax and AUCs fell within the bioequivalence interval of 80% to 125%.
Figure Figure
In the open-label treatment period, subjects used rFIX-R for on-demand control of bleeding, routine prophylaxis, and/or surgical prophylaxis for 6- to 12-months to achieve at least 30 EDs. The plasma factor IX activity-versus-time profile was recharacterized after 6 months of rFIX-R treatment and was unchanged compared with the baseline rFIX-R PK profile. Over 1000 infusions (&gt;3,500,000 IU of rFIX-R) have been administered with no serious adverse events related to rFIX-R. No clinically significant adverse events related to rFIX-R have been reported, including FIX inhibitor development, allergic-type manifestations, or thrombotic complications. One subject, with a prior history of frequent RBC agglutination, reported two instances without any associated adverse events. The overall results of this study demonstrate the safety of rFIX-R and the bioequivalence of the new formulation and BeneFIX. Since bioequivalence is the most important surrogate endpoint for efficacy, these data predict a favorable rFIX-R efficacy profile, consistent with that of BeneFIX, but with increased convenience in that larger doses can be administered using decreased volumes relative to BeneFIX.