bluuebunny/crossref_metadata_2025_split huggingface dataset:
A Prospective Comparision of Intranasal (I.N.) and Subcutaneous (S.C.) Desmopressin (DDAVP) Therapy in Type 2M Von Willebrand Disease (VWD).
Authors: Herbert Scott , Parameswaran Rekha , Shapiro Amy D. , Di Paola Jorge , Winay Jon , Roberson Chris , Greist Anne 
Published: April 2020

Abstract
DDAVP is effective therapy for VWD patients with documented adequate biologic response. Few data evaluating DDAVP exist in the less common type 2M VWD Seventy one members of an Amish kindred diagnosed with type 2 M VWD with abnormal VWF:Rco &lt;35% and C-to-T transition at nucleotide 4120 in exon 28 of the VWF gene have been identified; 11 previously participated in an evaluation of weight-based trial dose of I.N. DDAVP(Stimate® Nasal Spray: 1.5 mg/ml concentration, 2 puffs weight &gt;50 kg); 9/11 were further evaluated for response to S.C. DDAVP (0.3 microgram/kg). These 9 patients included 5 males, 4 females; age range: 21 to 58 years; weight range: 59–101.8 kg. Response utilizing ristocetin cofactor activity (VWF:Rco), factor VIII activity (VIII:C), and VWF antigen (VWF:Ag). Was assessed at 90 minutes post Stimate® administration and at 60 and 120 minutes post S.C. administration; values were also obtained at 4 and 6 hours post S.C. DDAVP to assess pharmacokinetics. Response to DDAVP was defined as VWF:Rco &gt;40%. Five people (55%) responded to Stimate®; three (33%) responded to S.C. DDAVP. There were no major adverse effects. Two males who had responded to I.N. route did not respond to S.C. route; one female who responded to S.C. DDAVP did not respond to Stimate®. Responses fell below 40% at 4 and 6 hours post-dose. Responses to DDAVP are thus observed in a subset of individuals with type 2M VWD. Although all individuals tested exhibit the 4120C&gt;T mutation, the response to DDAVP as measured by VWF: Rco levels varied from 1.7 to 4.9 fold. Therefore response to DDAVP in these patients appears not to be solely based upon the mutation causing the VWD phenotype but may be modified by other environmental and genetic factors. DDAVP responsiveness is an interesting phenotypic trait to be studied. Response may vary based on route of administration; this report highlights the necessity of assessing response to a trial dose by the intended route of administration prior to clinical use. Both I.N. and S.C. DDAVP may be used for minor bleeding episodes in those patients with type 2M VWD with adequate response to a trial dose. Both may be self administered as home based first line hemostatic therapy and are well tolerated.
RESPONSE TO I.N. DDAVP(2005) AGE/SEX WEIGHT(KG) PRE VWF:RCo(%) POST VWF:RCo(%) POST/PRE VWF:RCo RATIO 58/M 94.8 11 42 3.8 26/M 69.7 10 48 4.8 48/M 83.2 14 68 4.9 29/M 79.4 10 28 2.8 49/F 58.8 12 20 1.7 43/F 79 10 35 3.5 21/F 59.2 10 40 4.0 22/F 51.8 10 38 3.8 27/M 76.2 11 52 4.7 RESPONSE TO S.C. DDAVP (2006) AGE/SEX WEIGHT (KG) PRE VWF:RCo(%) PEAK POST VWF:RCo(%) POST/PRE VWF:RCo RATIO 58/M 101.8 13 42 3.2 26/M 72.7 10 33 3.5 48/M 88.1 14 61 4.4 29/M 82.7 10 31 3.1 49/F 70.5 11 21 1.9 43/F 79.5 10 46 4.6 21/F 59 10 49 4.9 22/F 62.7 10 39 3.9 27/M 79 10 37 3.7
Recombinant Factor VIIa Combined with Plasma Factor XIII Stabilize Clot Formation and Increase Clot Stability in Whole Blood from Patients with Severe Hemophilia A.
Authors: Sorensen Benny , Rojkjaer Rasmus , Ingerslev Jorgen 
Published: April 2020

Abstract
Patients with severe hemophlia A and inhibitors suffer from significantly compromised clot formation as well as reduced clot stability. Recombinant factor VIIa (rFVIIa - NovoSeven®, Novo Nordisk, Bagsvaerd, Denmark) has proven safe and efficacious for securing haemostasis in hemophilia patients with inhibitors. Recently, it was proposed that the reduced thrombin generation in severe haemophilia hinders sufficient activation of factor XIII and thereby result in insufficient covalent lateralization of fibrin (Blood2005; 106: 11, Abstract 321). The present study aimed at exploring the effect of rFVIIa and rFVIIa + plasma-derived FXIII (Haematological Technologies Inc) on whole blood clot (WB) formation and WB clot stability in severe hemophilia A. In total, 14 patients with a verified FVIII:C &lt; 0.01 IU/ml were enrolled. Ex vivo studies were performed with rFVIIa (2 μg/ml), rFVIIa+FXIII (2+10 μg/ml), and a buffer control. Dynamic WB coagulation profiles describing initiation (clotting time=CT[sec]), propagation (maximum velocity=MaxVel [mm*100/sec]) and clot strength (maximum clot firmness=MCF[mm*100]) were recorded using thrombelastography and activation with a minute amount of tissue factor (TF, Innovin, final dilution 1:50000). WB clot stability was evaluated using a reaction mixture containing TF and tPA (1nM), followed by evaluation of the MCF and the total area under the elasticity curve after 120 min analysis time (AUEC[mm*100*sec]). Data are presented as mean and Wilcoxon statistical results. In the absence of tPA, Both rFVIIa+FXIII and rFVIIa significantly shortened the CT (Buffer=1424, rFVIIa+FXIII=739 (p=0.010), rFVIIa=881, (p=0.0005)) and accelerated WB MaxVel (Buffer=3.8, rFVIIa+FXIII=10.5 (p=0.0001), rFVIIa=9.2, (p=0.0002)). The standard deviation (SD) of the CT was significant lower in WB spiked with rFVIIa+FXIII than rFVIIa (Buffer SD=697, rFVIIa+FXIII SD=289 vs rFVIIa SD=655, p=0.007). In the absence of tPA, rFVIIa+FXIII increased the MCF significantly more than rFVIIa (Buffer=4441, rFVIIa+FXIII=6414 vs rFVIIa=5943, p=0.04) and the SD of the MCF was significant lower in WB spiked with rFVIIa+FXIII than rFVIIa (Buffer SD=2174, rFVIIa+FXIII SD=331 vs rFVIIa SD=948, p=0.0006). In the presence of tPA, rFVIIa+FXIII induced higher clot strength and stability than rFVIIa alone (MCF: Buffer=1313, rFVIIa+FXIII=3295 vs rFVIIa=3023, p=0.10 (N.S.); AUEC: Buffer=3.8*106, rFVIIa+FXIII=12.8*106 vs rFVIIa=10.2*106, p=0.0269). In conclusion, both rFVIIa (2μg/mL) and FXIII (10 μg/ml) added to rFVIIa (2 μg/ml), significantly increased WB clot formation and stability in this ex vivo evaluation of the clotting potential of WB from patients with severe hemophilia A.
Immunoregulatory Mechanisms of PF4/Heparin Antibody Production In Vivo.
Authors: Arepally Gowthami , Qi Rui , Suvarna Shayela 
Published: April 2020

Abstract
Heparin-Induced Thrombocytopenia (HIT) is a prothrombotic disorder caused by antibodies directed to complexes of platelet factor 4 (PF4) and heparin. Little is known about the immune basis of HIT, such as why serologic responses develop commonly in certain clinical settings or why immune responses may be transient in humans. To gain insight into the immune mechanisms governing PF4/heparin antibody production in vivo, we initiated studies in a recently developed murine immunization model of HIT, in which mice are injected with PF4/heparin antigen by retro-orbital injection daily for five days without adjuvant. PF4/heparin antibody development in mice is monitored weekly by a murine PF4/heparin (mP+H) ELISA. Immunizations of identical doses of PF4/heparin antigen in BALB/c and C57BL/6 (C57) mice resulted in marked strain-dependent differences in immune susceptibility, temporal kinetics and secondary recall. BALB/c mice showed more variable sensitization to mP+H injections (See Figure below) and manifested lower peak antibody levels (mean peak A450nm± SD: 0.153±0.1) than C57 mice (0.91±0.73). Time course of antibody formation was also strain-dependent. Peak antibody levels occurred ~ 45 days after start of immunization in BALB/c mice as compared to 15 days in C57 mice. Antigen rechallenge with one dose of antigen 65–85 days after primary sensitization revealed presence of variable immune recall in BALB/c mice (increased antibody levels in 3/7 mice) as compared to uniform recall in C57 mice (5/5 mice). We then initiated studies to investigate the immunoregulatory mechanisms underlying strain-dependent responses to mP+H antigen. Because isotype switching and expression of IgG subclasses is influenced by T helper (Th) cell subsets, we examined IgG subclasses in BALB/c and C57 mice as a surrogate marker of Th cytokine expression. C57 mice showed IgG2b&gt;IgG1 anti-mP+H indicative of Th1 cytokine response, while BALB/c mice showed an IgG1&gt;IgG2a response, a Th2 predominant response. Taken together, these findings of strain-dependent differences to mP+H indicate that variable expression of human HIT may be similarly governed by differences in peripheral immunoregulatory mechanisms.
Figure Figure
Improved Clinical Outcome and ADAMTS13 Activity after Concurrent Cyclosporine and Plasma Exchange in TTP.
Authors: Cataland Spero R. , Kraut Eric H. , Benson Don , Ferketich Amy K. , Horne April , Jin Ming , George James N. , Wu Haifeng M. 
Published: April 2020

Abstract
We previously reported that concurrent cyclosporine and plasma exchange(CSA/PE) is superior to corticosteroids and PE for acute TTP in terms of a decreased exacerbation rate (0% v. 47%) after stopping PE.(ASH 2005,Abstract# 1235) We now present similar data and serial analysis of ADAMTS13 activity and inhibitor concentration from two patient cohorts treated with CSA/PE.
Patients: Ten patients failing initial therapy with corticosteroids and PE (exacerbations or refractory) were treated with CSA/PE. This study led to a second cohort study of upfront therapy with CSA/PE in 11 patients with acute TTP.
Methods: CSA (2–3 mg/kg) orally was administered concurrent with daily PE. After remission (normal platelet count and LDH), 2 additional exchanges were performed on an every other day schedule. CSA was administered for 6 months and discontinued.
Results: In the exacerbation/refractory patients, 9/10 achieved remission after a median of 11 exchanges. One patient suffered an exacerbation and required one additional exchange to achieve a sustained (&gt;30 d.) remission. Four patients relapsed 2,3,7, and 10 months after completing 6 months of CSA. In the CSA/PE upfront group, 10/11 achieved remission. One patient died of infectious and disease-related complications. Remission occurred after a median of 5 exchanges. No patients(0/10) suffered an exacerbation. Three patients recurred, 2 while taking CSA and one 2 weeks after stopping CSA. Median ADAMTS13 activity and the change in inhibitor concentration over time for all CSA/PE patients is shown in Figure 1.
Conclusions: CSA/PE improves clinical outcome and prevents exacerbations after tapering PE. CSA/PE also increased in vitro ADAMTS13 activity and suppressed the inhibitor, with both occurring well after the last PE. These findings coupled with the decline in median ADAMT13 activity after discontinuing CSA(Fig. 2) suggest the improvement in ADAMTS13 activity was a result of CSA therapy.
Table 1. Presenting ADAMTS13 and Inhibitor Data N Med. ADAMTS13% Prior to Initial Therapy Med. ADAMTS13% Prior to CSA and PE Med. Inhibitor Conc. Prior to Initial Therapy(ug/mL) Med. Inhibitor Conc. Prior to CSA and PE(ug/mL) Remission Rate Exacerbation (30 d. Recurrence) Rate CSA and PE Exacerbation and Refractory 10 2 (0–8) 4 (0–20) 587 (275–1,111) 3,173 (372–9,845) 9/10 1/10 CSA and PE Upfront Therapy 11 N/A 2 (0–60) N/A 571 (147–4,988) 10/11 0/10 Table 2. Effect CSA and PE on ADAMTS13 Activity and Inhibitor Concentration. Time (weeks) 0 4 10 24 CSA and PE Exac. and Refractory N 9 9 7 8 Median ADAMTS13 % 4 (0–20) 24 (4–39) 42 (5–72) 49 (7–116) Median Inhibitor Conc. (ug/mL) 3,173 (372–9,845) 294 (165–6,548) 191 (41–4,228) 204 (55–756) CSA and PE Upfront Therapy N 10 8 5 4 Median ADAMTS13% 2 (0–60) 20 (5–104) 32 (4–37) 49 (7–116) Median Inhibitor Conc. (ug/mL) 571 (147–4,988) 270 (82–2,637) 302 (110–378) 204 (55–756) Figure Figure
Dapsone as Second-Line Drug in Non-Splenectomized Patients with Chronic Idiopathic Thrombocytopenic Purpura (ITP): A Highly Cost Effective Option in a Developing Country.
Authors: Sharma Ajay , Nair Velu , Das Satya R. , Mishra D.K. , Kotwal J. , Agarwal Mohan B. 
Published: April 2020

Abstract
The management of chronic refractory ITP continues to be a frustrating experience for the patients as well as treating hematologists. Many patients relapse after steroid therapy as well as splenectomy. Even though latter modality leaves them susceptible to life-threatening infections, without making them symptom free. Immunoglobulins and anti-D vaccine do show a good but brief response. Retuximab is a newer drug to be used in ITP, but it is out of reach for most of the patients in a developing country like India. Of late Dapsone has been seen to be an effective drug in such situations and probably acts through reticulo-endothelial blockade.
We report the efficacy of Dapsone in 46 consecutively treated patients in our hospital, who had continued to be symptomatic despite adequate steroid therapy. They were chosen to be treated with Dapsone without being subjected to splenectomy. Their median age was 21 years(range : 8–46 years). The patients having associated connective tissue disorders were excluded. All the patients were screened for hemolytic tendency and splenectomy. Dapsone was started at an initial dose of 50 mg/day and escalated to100 mg/day, if the response was sub-optimal. Children received 25 mg/day initially and subsequent dose was adjusted to a minimal level required to achieve symptom free status. The aim of the therapy was to eliminate purpura rather than to achieve a particular level of platelet count. The duration of treatment ranged from six months to 48 months.36 patients (80%) showed an overall response with disappearance of purpura and a significant rise (&gt; 40,000/cmm) in platelet count. Treatment was well tolerated and no adverse effects were encountered even though dose related hemolysis has been reported. The drug was continued in 36 responders for a median period of 32 months and they all continued to be asymptomatic throughout. The treatment was intentionally withdrawn in 12 responders, but thrombocytopenia recurred in all these patients. In our experience Dapsone provided an inexpensive and well tolerated alternative for patients with ITP who showed suboptimal response to steroid therapy. The splenectomy was successfully avoided in these patients. Its use is cost effective as well. Both these factors make this a great boon to the patients in a developing country. We recommend that all patients be started on Dapsone once they fail to show response to steroids. Splenectomy should be reserved for the patients who do not respond to Dapsone.
Single Dose of Anti-CD20 Monoclonal Antibody (Rituximab) Treatment in Adults with Refractory Immune Thrombocytopenic Purpura (ITP).
Authors: Tanaka Eri , Hayashi Shuji , Fujimaki Katsumichi , Fujita Hiroyuki 
Published: April 2020

Abstract
Refractory Immune Thrombocytopenic Purpura (ITP) is a difficult disease to treat effectively and the mortality approaches nearly 10% over 10 years. Moreover, the side effect profile of chronic steroid administration is undesirable due to the multi-systemic actions of these drugs. Recently, it has been reported in the literature that Rituximab is effective treatment for chronic ITP and it has been used at a dose of 375mg/m2 weekly for up to four weeks, as with lymphoma therapy. Rituximab is an expensive treatment, but according to previous data, patients treated with this drug have responded with increased and sustained platelet counts following only one infusion. Based on this, we treated five refractory ITP patients with single-dose Rituximab and all responded well.
Patient 1 is with a 15 year history of ITP and Patient 2 is with a 34 year long history of ITP. Following treatment with Rituximab, although there was an interval of up to 7 months, both eventually responded well. Patient 3 is a 93 year old male who presented to our hospital with an acute presentation of ITP which involved severe gastrointestinal bleeding and this proved to be refractory to both steroids and intravenous immunoglobulins, but responded very quickly to Rituximab within 24 days. Patient 4 is a 75 year old female with diabetes mellitus and three-vessel coronary artery disease who presented with a bleeding diathesis. She was treated with steroids, intravenous immunoglobulins, danazol and azathioprine but with no response. Single-dose Rituximab was effective within 20 days with an improvement in platelet counts. Patient 5 is a 51 year old male with a six year history of ITP who presented to our hospital with massive intraabdominal and gastrointestinal bleeding and after Rituximab therapy his platelet count responded appropriately after 45 days.
These patient responses were not associated with prior response to therapy, age, previous splenectomy, duration of ITP or platelet count. All patients tolerated treatment well except one patient who developed SLE-nephrotic syndrome 15 months later although it cannot be proven that such therapy induced this collagen-vascular diseases because Rituximab can be used to actually treat such conditions. Three patients remained in remission for more than one year after just one dose of the Rituximab therapy. Even from our small number of refractory ITP patients treated with Rituximab, it is our experience that single-dose treatment is also effective in some cases of refractory ITP and its effect may continue to provide long-term remission whereby it is now possible to decrease and even stop long-term steroid treatment in such patients.
Management of Fetal Alloimmune Thrombocytopenia (AIT): Treatment of 30 Cases in Which the Previous Sibling Suffered an IntraCranial Hemorrhage (ICH).
Authors: Hung Crystal , Wissert Megan , Primiani Andrea , Berkowitz Richard , McFarland Janice G. , Bussel James B. 
Published: April 2020

Abstract
Prevention of fetal-perinatal ICH is the primary goal of antenatal therapy for AIT. When there was an ICH in a prior pregnancy, these fetuses are at virtually 100% risk for a recurrent ICH. Current antenatal treatments given to the mother are intravenous gammaglobulin (IVIG), oral steroids, or both. Two consecutive studies examined risk-based therapy by tailoring therapeutic interventions according to the course of the previous affected sibling with ICH.
Thirty patients with AIT were divided into 4 groups based on the timing of the sibling’s ICH (see Figs. 1 & 2, including abbreviations). In the Extremely High Risk (EHR), Very HR (VHR), HR1, and HR2 arms, an adequate initial response was defined as an Fetal Platelet Count (FPC) ≥30 × 109/L at the time of the first Fetal Blood Sampling (FBS). Repeat FBS was done 3–8 weeks later. If the platelet count did not increase, therapy was intensified (“salvage”) by adding prednisone or additiional IVIG. There were 5 ICHs (see Table), 3 of which were failures of antenatal therapy. One ICH occurred in an EHR patient prior to the use of 2g/kg/wk of IVIG as did one of the 2 ICHs in the HR1 study; both of these hemorrhages occurred on IVIG + pred prior to 30 weeks. Both previous siblings had had early antenatal ICHs. The second HR1 patient with ICH was initially on IVIG alone, added pred when repeat FBS was not possible because of premature contractions, and delivered at 35 weeks with a birth platelet count (BPC) of 14 × 109/L; a Grade I intraventricular ICH was noted on the first day of life. The other 2 ICHs occurred in a VHR infant delivered at 24 weeks gestation with a BPC of 248 × 109/L and in a HR2 35.7 week old infant with a BPC of 137 × 109/L. The effectiveness of the treatment strategy was demonstrated because all groups’ mean BPC was &gt;50 × 109/L; 3 of 4 groups’ mean BPC was &gt;100 × 109/L.
The fact that 20 of 30 of the patients required salvage therapy, and that overall, the BPC was greater than the initial FPC in all arms, attests to the need for monitoring of the FPC and for intensification of therapy in these HR patients. Comparing HR1 to HR2, starting therapy earlier than 20–24 weeks in the HR2 arm appeared to substantially increase the BPC. Antenatal therapy with IVIG 1–2g/kg/wk beginning at approximately 12 weeks gestation was effective in preventing ICH in the highest risk pregnancies in 25 of 30 cases. In the future, treatment may start with IVIG 2g/kg/wk and automatically add prednisone at 24–30 weeks for optimal response. This could also allow avoidance of FBS until at least 32 weeks.
Summary # of Patients # Requiring Salvage Mean FPC at 1st FBS (K) Mean Gestational Age at Birth (weeks) Mean BPC (K) # of ICHs # of Fetal Demises EHR 4 3 23 32.5 155 1 1 VHR 15 11 74.6 33.6 122 2 0 HR1 8 5 21.8 33.1 68.4 2 1 HR2 3 1 54 33.2 122 0 0 Figure Figure
Platelets Mediate Clearance of Lymphocytic Choriomeningitis Virus Infection Preventing Lethal Hemorrhage.
Authors: Iannacone Matteo , Sitia Giovanni , Isogawa Masanori , Whitmire Jason K. , Marchese Patrizia , Chisari Francis V. , Ruggeri Zaverio M. , Guidotti Luca G. 
Published: April 2020

Abstract
Lymphocytic choriomeningitis virus (LCMV) is a noncytopathic mouse pathogen of the arenaviridae family. Acute LCMV infection in adult mice has been extensively studied and found to be systemic, essentially asymptomatic and associated with a bone marrow aplasia that produces a transient pancytopenic state. The initial lymphopenia is rapidly reversed, such that within one week of LCMV exposure the mice display lymphocytosis and clear the infection through a response mediated by virus-specific cytotoxic T cells (CTLs). In spite of the thrombocytopenia, the occurrence of hemorrhage in these animals has not been previously investigated, likely because of the lack of overt bleeding symptoms. Other arenaviruses (such as Lassa and Junin) produce systemic infections in humans and cause hemorrhagic diseases that are often lethal. Hemorrhage, mostly mucosal and cutaneous, occurs in the context of profound thrombocytopenia (characteristic of Junin infection) and/or platelet dysfunction (characteristic of Lassa infection), but without disseminated intravascular coagulation (DIC) or other coagulation defects. The pathogenesis of arenavirus infections in humans remains elusive, although disease severity has been associated with the extent of hemorrhage, impaired cellular immunity and lack of viral clearance. We recently showed that platelets may contribute to viral pathogenesis by facilitating the accumulation of virus-specific CTLs at sites of infection. Thus, we reasoned that the thrombocytopenia and/or platelet dysfunction that typify arenavirus infections in humans might not only predispose to the development of hemorrhage but also compromise CTL-mediated viral clearance. Here we report our studies based on the model of LCMV infection in mice. We found that normal inbred mice infected with different isolates of LCMV develop thrombocytopenia associated with decreased platelet function, but show only limited mucosal hemorrhage prior to CD8+ T cell-mediated viral clearance. In contrast, mice depleted of platelets, but not those given anticoagulant treatment, fail to produce a normal CD8+ T cell response or clear LCMV; instead, they develop an interferon (IFN)-α/β-dependent lethal hemorrhagic infection. Transfusion of normal but not activation-blocked platelets into these animals restored the CD8+ T cell responses and allowed clearance of the infection, preventing hemorrhage and death. These results indicate that activated platelets are required for CD8+ T cells to clear LCMV infection and for protecting the host against the induction of an IFN-α/β-dependent, lethal hemorrhagic diathesis.