bluuebunny/crossref_metadata_2025_split huggingface dataset:
Rituximab in the Treatment of Factor VIII Inhibitor.
Authors: Maruscak Mercedes , Cohan Barry , Aghakhanian Linda , Ucar Kalust 
Published: April 2020

Abstract
Rituximab is a monoclonal antibody directed against the CD20 antigen found on both malignant and normal B lymphocytes. It was given FDA approval in 1997 for relapsed or refractory, low grade or follicular, CD20+ non-Hodgkin’s lymphoma. We report the use of selective B-cell depletion with Rituximab on a fifty-nine year old male with acquired Factor VIII inhibitor who failed to respond to convential therapy. The patient presented with compartment syndrome of the left calf due to spontaneous severe hematoma, and was subsequently hospitalized. The patient was found to have a PTT of 86, Factor VIII &lt;3%, and Factor VIII inhibitor 108 b.u. The patient had completed forty-eight weeks of interferon and ribavirin for Hepatitis C one month prior to admission. The PTT was normal nineteen months prior when liver biopsies were obtained. The patient was subsequently diagnosed with acquired Factor VIII deficiency, thought to be secondary to either the Hepatitis C infection or the interferon therapy. He improved with Factor VIII concentrate therapy, but did not spontaneously recover from the inhibitor. He had minimal response to IVIG. Rituxin was subsequently started (intravenously at 375mg/m2) once a week for eight consecutive weeks, and repeated every six months. After four cycles, a consistent response was documented by increased Factor VIII activity (as high as 62%), and decreased Factor VIII inhibitor (stable at &lt;0.5%). The treatment was well tolerated, and no infusion related side effects were observed. The patient did well with no bleeding on maintenance therapy for approximately twenty-one months. Unfortunately, two weeks after completion of the fourth cycle the patient suffered a ruptured AAA, and upon surgical intervention became unresponsive and a right cerebral infarct was identified. The patient’s family subsequently discontinued life support and the patient died. This experience suggests that further investigation of Rituximab therapy in this defined population might benefit similar patients.
Evaluation of Thrombotic Events in Haemophiliacs Undergoing Major Orthopaedic Surgery without Thrombosis Prophylaxis.
Authors: Krause Manuela , von Auer Charis , Kurth Andreas , Boehm Martina , Hovy L. , Scharrer Inge 
Published: April 2020

Abstract
Introduction:Major orthopaedic procedures and the presence of thrombophilia are risk factors of thrombotic events. In patients with haemophilia undergoing hip or knee replacement the importance of thrombosis prophylaxis with heparin in the postoperative period is still unknown. The aim of the present study was to evaluate the occurence of thrombotic events in haemophiliacs undergoing major surgery without thrombosis prophylaxis.
Patients: A total of 32 pts with haemophilia A (severe:27 pts, moderate:4 pts, mild:1pt; median age:47yrs, range:27–73yrs) undergoing hip (n=9)or knee (n=35) replacement were analysed in our haemophilia treatment center. Pts with inhibitors were excluded. Surgical interventions were performed using recombinant (n=37) or plasma-derived (n=7) FVIII for 12 to 15 postoperative days. The median initial dose of FVIII was 82 IU/Kg−1, followed by median FVIII doses of 54 IU/kg−1over the first four days. All pts received thrombosis prophylaxis with graduated compression stockings only. In addition to factor VIII activity, APC resistance, FV G1691A mutation and the FII G20210A variant (FII) were investigated.
Results: No thrombotic events in the postoperative period was dokumented. The median FVIII activity was 153% (range:85–347%), the Body mass index (BMI:kg/m2) was 23.1(range:18.2–30.5). During the first four postoperative days FVIII levels &gt;150% were measured in 24/44 (55%) operative procedures. BMI&gt;25 were shown in 12/32 (38%) pts, and age &gt;40yrs was documented in 23/32 (72%) pts. In 1/30 (3%) pt APC resistance and none of our pts FII were identified.
Conclusion: In our study group elevated FVIII levels and additional risk factors (BMI&gt;25, age&gt;40years) seems not to influence relevantly the occurrence of thrombotic events in pts with haemophilia undergoing hip or knee replacement without thrombosis prophylaxis. Further studies are required to confirm whether a thrombosis prophylaxis with heparin is needed in haemophiliacs undergoing high risk surgery.
Administration of Vaccines to Infants and Children with Hemophilia. A Survey of the Region III Comprehensive Hemophilia Treatment Centers.
Authors: Ritchey Arthur K. 
Published: April 2020

Abstract
There appears to be variability in both recommendations and practice regarding the route of administration of immunizations to infants and children with hemophilia. The CDC Advisory Committee on Immunizations, the American Academy of Pediatrics Red Book, and the Medical and Scientific Advisory Council (MASAC) of the National Hemophilia Foundation all recommend intramuscular vaccination; the risk of bleeding can be minimized by concomitant administration of antihemophilic factor. However, informal discussions among practicing hematologists suggest that common practice is subcutaneous administration.
METHODS: To determine the standard practice regarding immunizations a survey was completed by 12 Hemophilia Treatment Centers in Federal Region III (Mid-Atlantic states). The number of pediatric patients followed in each institution ranged from 9 to 182 (average 73).
RESULTS: All centers have a policy or standard practice regarding the administration of vaccines and 10 of 12 recommend subcutaneous administration of all vaccines. Of the two centers that recommend following manufacturer guidelines one does and one does not routinely recommend concomitant factor administration. One center, whose policy is subcutaneous administration, recommends simultaneous factor administration if the primary care provider insists on intramuscular administration. Half of the centers do not offer immunizations on site; those that do usually offer only hepatitis A and B vaccines. All but one center have seen hematoma formation following immunizations, but none have seen sterile abscesses, necrosis, or granuloma formation. Hematomas have been seen following both subcutaneous and intramuscular injection. Estimates of hematoma formation are difficult to calculate, but one large program (folowing 182 patients) sees about 1 hematoma per year or an estimated 2–5% incidence.
CONCLUSION: Contrary to CDC and MASAC guidelines, it is standard practice at most Hemophilia Treatment Centers in Federal Region III to recommend subcutaneous administration of all vaccines without coverage of factor replacement. Hematoma formation is uncommon and can be seen following either subcutaneous or intramuscular administration. There appears to be little indication for prophylactic factor treatment before vaccine administration.
Management of Refractory Intracranial Hemorrhage in a Coagulopathic Patient with Liver Disease by Using Recombinant Factor VIIa (rFVIIa).
Authors: Leblebisatan Goksel , Sasmaz Ilgen , Mert Kurthan , Ozates Ebru , Antmen Bulent , Kilinc Yurdanur 
Published: April 2020

Abstract
Objective: Coagulopathy resulting from liver pathologies and the hemorrhages secondary to this are the complications observed in chronic liver diseases, fulminant hepatitis, hepatocellular cancer, liver transplantation and other similar conditions. The literature on the use of rFVIIa which was initially used in hemophiliac patients with inhibitors for hemorrhages that can not be managed with conventional methods or operations that can not be performed safely, is increasingly growing. Here we will present a patient that was successfully operated by using rFVIIa for recurrent intracranial hemorrhage secondary to liver disease.
Case: The 7 months old female infant was brought to our clinic due to abdominal distention and bleeding from anus. Her medical history included a treatment by hospitalization in the Regional Hospital when two months old due to high fever, forceful vomiting, foaming at mouth and yellow coloring of skin (convulsion?), operation due to hemorrhage detected at cerebral imaging, two subsequent operations at the same hospital due to hemorrhage upon sudden purple coloring of skin observed 1.5 months later and finally, dismission from hospital following a 25-day monitoring under conditions of intensive care. Following the yellow coloring of eyes, hematemesis, abdominal distention, echhymoses in the back and chest observed in the patient, she was referred to our clinic and her cerebral CT findings revealed pressure effect and subdural hematoma extending from temporal localization to frontoparietal cranium at left and to tentorium superior section and anterior interhemispheric fissure in cranium at posterior, with the widest part reaching 1.5 cm. The patient, for whom an operation was planned, was twice supplemented with platelet suspension at a dose of 10 cc/kg (53000/mm3) for her thrombocytopenia. Despite the administration of Frozen Plasma supplement, PT, PTT and Fibrinogen was detected as 18, 42.8 and 117 mg/dl, respectively and 1.2 mg of Novoseven was administered to the patient once preoperatively and twice postoperatively at a two-hour interval due to her history of postoperative hemorrhage. Upon the preoperative detection of PT, PTT, Fibrinogen as 12.1, 43.1 and 145 mg/dl and KZ and PZ as 6 and 5 minutes respectively, the patient was operated. No new postoperative hemorrhages or other complications were observed. The diagnosis of Gaucher disease was made at the bone marrow examination and the relevant treatment was planned.
Conclusion: rFVIIa can be safely used in high-risk patients with a history of recurrent hemorrhage, for whom no improvement can be achieved in the hemostasis tests.
Analysis of Structural Changes of the Factor VIII Gene: Intron 1 and 22, in Costarrican Families with Severe Haemophilia A.
Authors: Salazar-Sanchez Lizbeth , Jimenez-Cruz Guillermo , Chaverri Pilar , Schroeder Winnie , Wulff Karin , Sandoval Miriam , Auerswald Guenter K.H. , Herrmann Falko H. 
Published: April 2020

Abstract
Hemophilia A (HA) is X-chromosome linked bleeding disorders caused by deficiency of the coagulation factor VIII. The disease is caused by Factor VIII gene intron 22 inversion in approximately 50% of the patients and by intron 1 inversion in 5% of the patients. Both inversions occur as a result of intrachromosomal recombination between homologous region, in intron 1 or 22 and their extragenic copy located telomeric to the FVIII gene. The goal of the present study was to analyze the presence of these mutations in 15 HA severe Costarrican families.
Methods: We studied 122 unrelated HA patients and obligate or possible carriers for the presence of intron 22 or intron 1 by Southern blotting and polymerase chain reaction (PCR).
Results: We found altered intron 22 restriction profiles by Southern analyses in 14 of the families, 12 cases type 1 (Figure 1) and 2 cases type 2 inversion. During the screening for intron 1 inversion among the HA patient, who were intron 22 inversion negative, we did not identified this mutation.
Interpretation and Conclusions: This report is the first in our haemophilia families dealing with mutations in the intron 22 and intron 1. Our data highlight the importance of the analysis of intron 22 inversion for the association with development of inhibitors in the HA patients and we are continuous searching of intron 1 mutation. This will benefit both genetic counselling and the study of the relationship between genotype and inhibitor development.
Fig. 1 Southern blot of HA-I showing the intron 22 inversion of the factor VIII gene. Lane 1 and 2 normal Lane 3: heterozygote carrier and lane 4: patient with the altered fragment, (inversion of the intron 22). Fig. 1. Southern blot of HA-I showing the intron 22 inversion of the factor VIII gene. Lane 1 and 2 normal Lane 3: heterozygote carrier and lane 4: patient with the altered fragment, (inversion of the intron 22).
Peginterferon Alfa 2a: Treatment Option for Coagulopathy Associated with Vascular Malformation?.
Authors: von Auer Charis , Krause Manuela , Miesbach Wolfgang , Scharrer Inge 
Published: April 2020

Abstract
We applied peginterferon alfa 2a for off label use therapy in a 44 year old male patient (pat.) with extensive venous malformation (VM) and associated localized intravascular coagulation (LIC). Since birth he had huge VMs in the left leg and left lower abdomen. During surgery and tooth extraction he had severe bleeding complications. In 2003 he reported a sensation of continually growing VMs and requested for therapy.
Clinical findings (examination, contrast medium CT) showed no considerable growth of VMs in comparison to former examinations. Laboratory findings were low fibrinogen, low factor VIII activity (FVIII:C) and factor XIII activity (FXIII:C), prolonged aPTT, mild thrombocytopenia and elevated d-dimers. Vascular surgeons disadvised another surgery. LMWH therapy had been carried out before and was ineffective considering coagulopathy and sizereduction of vascular malformations. Considering antiproliferative properties we decided for off label use therapy with peginterferon alfa 2a (Pegasys), 180 μg once a week. Therapy started September 2004 and was applied for 16 weeks. Laboratory tests, clinical examination and photo documentation were done before, during and after therapy.
During and after therapy laboratory findings showed normalization of fibrinogen, FVIII:C levels, aPTT and rising FXIII:C levels. We saw no significant change of VMs in clinical examination and photographs. The pat. reported no sense of vascular size reduction but also no sense of growing malformations. Due to interferon side effects such as lowered blood count, therapy was finished after 16 weeks.
In conclusion the LIC in the VMs seemed to improve under interferon therapy with normalization of fibrinogen and FVIII:C. Even though there was no significant size reduction of VMs yet, this therapy could be an important treatment option for normalization of coagulation parameters e.g. before surgery. In our patient interferon therapy seemed to be more effective than LMWH therapy. In literature only heparin was reported to be effective in coagulopathies associated with VMs, not interferon. Therefore the positive laboratory findings in our patient are remarkable.
Factor VIII Inhibitors in Haemophilia A Patients Who Are Considered as Previously Treated Patients.
Authors: von Auer Charis , Oldenburg Johannes , Krause Manuela , Miesbach Wolfgang , Scharrer Inge ,   PTT- Study Group Germany
Published: April 2020

Abstract
Previously treated patients (PTP), who have not developed an inhibitor (inh.) so far, are considered to be tolerant to factor VIII and at low risk for inh. development. Therefore inh. detection in a PTP should raise concerns about the concomitant variables such as product neo-antigenicity or way of application.
To find out about the current situation regarding inh. development in PTP in Germany, we conduct a retrospective study. A questionnaire was sent to 87 haemophilia treating centers, so far 46 of them answered. 28 PTP-inh. developments during the last 5 years were reported. Age of the patient (median 35), severity of haemophilia A (18 severe, 2 moderate, 8 mild), exposuer days (median 30) and gene mutation (intron-22-inversions 31%, large deletions 13%, missense mutations 25%, stop mutation 6%, small deletion 13%) were recorded. 8 different factor VIII concentrates were given during inh. development (5 plasma derived, 3 recombinant). Way of application (16 times bolus infusion, 3 times continuous infusion, 5 times both), former change of product, infused amount until inh. development, inh. characteristic, concomitant diseases and medication were registered.
In conclusion most of the patients were over 18 years old (17/28) when the inh. developed. Most of them had severe haemophilia A (18/28) and had at least one change of product before inh. detection. Our data are still too small to draw any conclusion concerning product neo-antigenicity or treatment modalities. Nevertheless it became obvious that inh. development in PTP is still a serious and underestimated problem in haemophilia treatment today. Secondly data showed that there is a variety of PTP definitions in Germany, referring to age of pat, number of exposure days and former change of product. An international definition for PTP would be helpful. A national haemophilia register would make it easier to evaluate data in the future and a prospective, not product related study should be conducted.
Thromboembolism in Children with Sarcoma.
Authors: Athale Uma H. , Cox Stephanie , Siciliano Sabrina , Chan Anthony K.C. 
Published: April 2020

Abstract
Background: Thromboembolism (TE) is one of the common causes of death in adults with cancer. Cancer is a major risk factor in children with TE and over 40% of children with central venous line (CVL)-related deep venous thrombosis (DVT) had underlying cancer. However, the epidemiology of TE in children with cancer, especially in association with childhood solid tumors is still unknown.
Objective: To define the prevalence and epidemiology of TE in association with sarcoma in children.
Methods: Hospital records of children ≤18 years of age with sarcoma diagnosed and treated at McMaster Children’s Hospital during January 1990 to September 2004 were reviewed for demographic details, details of diagnosis and therapy for sarcoma, and details of diagnosis and management of TE. Statistical analysis was performed using Fisher’s exact test.
Results: Seven of 63 (11.11%) patients with sarcoma developed TE (Table). Six patients had DVT and one patient had right atrial thrombosis. All, but one, patients had central venous line (CVL); three patients had CVL-associated DVT. Four of 28 girls (14.29%; 95% CI 5.7, 31.49) developed TE. Six of 36 patients ≥ 12 years of age developed TE (16.67%; 95% CI 7.87, 31.89) compared to 1 out of 27 (3.7%; 95% CI 0.66, 18.28) patients &lt;12 years of age (p =0.222). Three out of 16 patients with metastatic disease at diagnosis developed TE (18.75%; 95% CI 6.59, 43.01) compared to 4 out of 47 (8.51%; 95% CI 3.36,19.93) (p=0.356) patients with localized disease. Six patients received anticoagulant therapy; one of these six patients required thrombectomy. Four patients received secondary thromboprophylaxis. One patient had recurrence of TE while being off of anticoagulant. Although none of the patients died because of TE or TE-related complication, patients with TE were at high risk for adverse outcome. Four out of 7 (57.1%) patients with TE have died compared to 22 of 56 (39.3%) patients without TE.
Conclusions: TE is a significant complication in children with sarcoma and may increase the risk of overall adverse outcome. Older patients and patients with Ewing’s sarcoma seem to be at are at higher, albeit statistically non-significant, risk of TE compared to younger patients and those with other types of sarcoma. Prospective studies of larger patient-populations are needed to define the epidemiology of TE in association with childhood sarcoma.
Type of Sarcoma N Patients with TE % TE (95% CI) * Comparison of Ewing’s sarcoma versus rest of patients, p = 0.184 Osteosarcoma 23 1/23 4.35 (0.77, 20.99) Ewing’s sarcoma 19 4/19 21.05 (8.51, 43.33) Rhabdomyosarcoma 14 1/14 7.14 (1.27, 31.47) Other 7 1/7 14.29 (2.57, 51.31) Overall 63 7/63 11.11 (5.99, 21.20)
The Spectrum of Hypercoagulable States in Minority Patients with Unexplained Thrombosis.
Authors: Ghuman Damanjit K. , Cohen Alice J. 
Published: April 2020

Abstract
The association of genetic risk factors with hypercoagulable states in minority populations has not been well defined. With an estimated prevalence of anywhere between 2-15% in healthy individuals, activated protein C resistance (APCR/Factor V Leiden) is considered to be the most common risk factor for venous thromboembolism( VTE) in the white population. It has also been postulated that this mutation is extremely rare in non-white populations. The prevalence of the prothrombin gene mutation G20210A in the white population is estimated at 0.7–4%, protein C and S deficiencies at 2% each and antithrombin III deficiency at 0.1–0.5% but unknown in Blacks with VTE though case control studies have identified protein C and protein S deficiencies in this population. This study is a retrospective review of all patients with thrombophilia registered at the Hemophilia Treatment Center between 1999–2005. 45/164(27%) of patients with thrombophilia were identified to be from minority groups. Of these minority patients 23/45(51%) had an identifiable primary hypercoagulable state. This group included 7/23(30%) males and 16/23(70%) females. The mean age of the patients was 35 years (range 12–80 years ). 4/23( 17%) were smokers and only 4/23(17%) had a family history of thrombosis with no documented hypercoagulable states in any family members. The majority of the patients were of African American descent 16/23(69%), 5/23(22%) were Hispanic and 2/23(9%) were Asians. 16/23(69%) of the patients had documented deep venous thrombosis/pulmonary embolus, 1/23(4%) had arterial thrombosis, 3/23(13%) had fetal loss, and 2/23(9%) were asymptomatic. APCR was the most common diagnosis in 8/23(35%) of the patients, followed by antiphospholipid antibody syndrome in 7/23(30%) of the patients. Protein S deficiency was diagnosed in 5/23(22%), hyperhomocysteinemia in 4/23(17%), Protein C deficiency in 1/23(4%), antithrombin III in 1/23(4%), and prothrombin gene mutation in 1/23(4%) of the patients. 4/23(17%) of the patients were found to have two coexisting hypercoagulable diagnoses. Recurrent VTE occurred in 7/23(30%) of the patients.
Conclusion: Primary hypercoagulable states are not rare in minorities. In this study, APCR was found to be the most common identified abnormality, followed by antiphospholipid antibody and protein S deficiency. Similar to the white population, thrombophilia in minorities occurred more commonly in young female patients. Work up for primary hypercoagulable states should be considered in minority patients with unexplained thrombosis. Further studies are warranted to determine the true prevalence of hypercoagulable states in minority populations.