bluuebunny/crossref_metadata_2025_split huggingface dataset:
Acquired Hemophilia A: A Single Institution’s Experience.
Authors: Randhawa Devinderpal , Sidhom Ibrahim , Guron Gunwant , Layne Trevor 
Published: April 2020

Abstract
Background: Acquired Hemophilia A (AH) due to factor VIII inhibitor is a rare life threatening disorder. If not diagnosed and treated urgently, significant mortality and morbidity results. AH can occur in setting of old age, autoimmune diseases, pregnancy, medication, malignancy, and lymphoproliferatve disorders. In majority of cases it is idiopathic.
Objective: Review the treatment modalities and outcome of AH patients at our institution.
Methods: A retrospective review of the data pertaining to patients who were diagnosed with AH at our institution between 1993–2004.
Results: There were 5 patients diagnosed with AH, 3 female and 2 male. The median age was 67 years (range 30–84 years) the setting for development of AH in these patients was as follows: 1- postpartum, 1-HIV, 3 idiopathic. All patients presented with varying degree of spontaneous hemorrhage. The median Factor VIII inhibitor level was 16 Bethesda Unit (BU)(range 7. 2–31). Acute control of hemorrhage was achieved in all patients using either FEIBA (Factor eight inhibitor bypass activity) alone (1 patient), FEIBA and Novo seven (VIIa)(4 patients). Chronic immunosuppressive therapy was given as follows: Steroid alone (2 patients), Steroid and IVIG (1 patients), Steroid and Cyclophospamide (1 patient) and Steroid, Cyclophospamide and Rituximab (1 patient). Complete remission (CR) was obtained in 4 patients and with the final patient still receiving treatment. In one patient, the dose of Cyclophospamide was decreased due to Leucopenia. The median time to elimination of inhibitors was 5 month (range 1–10 month). There have been no mortalities.
Conclusions: AH is a life threatening condition if not promptly diagnosed and treated, mortality remains significantly high. Treatment with factors replacement and immunosuppressive therapy was effective in all our patients
Venous Thromboembolism (VTE) in Hematologic Malignancies(HM).
Authors: Korin Jorge D. , Tartas Norma E. , Ferro Hugo , Barazzutti Lucia M. , Kordich Lucia C. , Porterie Pablo , Avalos Julio Cesar Sanchez 
Published: April 2020

Abstract
In our series of consecutive patients (p) with objectively diagnosed VTE, cancer constitutes the most frequent ethiology (25%) followed by idiopathic (24%), clinical causes (22%), orthopedics and trauma (16%), general surgery (7%), obstetric entities (3%) and others (3%). Among the neoplastic subtypes, HM are the most prevalent ones followed by prostatic, colonic, lung and CNS cancers. A recent publication (Blom et al, JAMA2005; 293:715) shows this previously undisclosed high tendency of HM for provoking VTE. Our current study describes the experience with this association from 1996 to 2005, excluding central vein catheter thrombosis. Out of 531 p with VTE, 138 have cancer and 34 of them, HM, with the following distribution: plasma cells discrasias (PCD) 9 (4 on treatment with thalidomide), diffuse large cell lymphomas (DLCL) 8, indolent lymphomas (IL) 6, CLL 5, mantle cell lymphoma 1, Burkitt lymphoma 1, RAEB 1, AML 1, myelofibrosis 1, P vera 1. In 25/34 p, the HM was previously known at diagnosis of VTE and mostly active or on treatment. In the other 9 p, the clinical presentation was as an idiopathic VTE, and during follow-up the following HM were disclosed: PCD: 3, CLL: 2, DLCL: 1, IL: 1, myelofibrosis: 1, RAEB: 1. Table 1
Comments:
PCD and DLCL constitute the two HM more frequently associated with VTE. However, the contribution of less agressive neoplasms such as indolent lymphomas and CLL is not negligible As in solid tumors, recurrences are high, specially when anticoagulated patients are off-therapy In spite of more chemotherapy related-thrombocytopenia and bone marrow involvement, bleeding rates do not differ of those observed in solid tumors Given the frequent association with VTE, and the probable heterogeneity in the thrombophilic potency of these different entities collectively grouped as HM, prospective multicentric studies are clearly needed to identify groups of patients with HM suitable for primary prophylaxis of VTE. Such studies should also be designed to provide further clue about the use of LMWH instead of oral anticoagulants for secondary prophylaxis in HM.
Table 1. Main clinical findings in patients able to be evaluated during follow-up Events Hematologic Malignancies Solid Neoplasms Recurrences 6/28 (21.4%) 5 off anticoagulation 15/106 (14.1%) 7 off anticoagulation (p=ns) Major bleeding 2/28 (7.1%) 10/106 (9.4%) (p=ns)
Proteinase-Activated Receptor 1, 3 Expression in Primary Human Carcinoma Cells.
Authors: Xie Wan-Zhuo , Huang He , Cai Zhen , Lin Mao-Fang , Gieseler Frank 
Published: April 2020

Abstract
The coagulation system is regularly activated in patients with cancer, especially with lung cancer and gastrointestinal tumors. Up to 30% of these patients suffer from thromboembolic complications. Obviously, activation of thrombin occurs in the natural course of cancer. During tumor progression, many patients develop malignant effusions; treatment is complicated by increased resistance of tumor cells to chemotherapy. Thrombin-mediated activation of cellular receptor(s), such as proteinase-activated receptor-1(PAR-1), plays an important role in tumor growth, local progression, and distant metastasis. Our hypothesis is, that tumor cells that express PAR-1 have a survival benefit if they are activated by thrombin within the malignant effusion. We harvested primary cancer cells from pleural and peritoneal effusions of 110 patients with different carcinomas. In 22 cases we were able to establish long time cultures (2 pancreatic, 4 colon, 3 SCLC, 5 NSCLC, 3 mesothelioma, 1 gastric, 1 rectum, 1 breast, 1 melanoma and 1 NHL). We detected PAR-1, 3 expression using reverse transcription-polymerase chain reaction (RT-PCR) and fluorescence activated cell sorting (FACS) scan. We found that in 76% the primary cancer cells were PAR-1 positive using RT-PCR assays, and in 70% the expression of PAR-1 receptor was positive using FACS scan. In contrast, we found that PCR for PAR-3 was positive in only 37.5% and the expression of the receptor in 6%. As a sign of thrombin activation, we regularly found increased levels of prothrombin fragment F1+2 in the malignant effusions compared to serum of patients (12.0 +/− 4.1 nmol/L vs 1.9 +/− 0.4 nmol/L).
In summary, we found that most of the primary cancer cells in malignant effusions exhibit a positive PAR-1 expression, but PAR-3 expression is low. Also, thrombin is activated in most malignant effusions as shown by prothrombin fragment 1+2 elevation. Further experiments will show if these cell-biological mechanisms aggravate cellular resistance in primary tumor cells found in malignant effusion in end-stage cancer. Therapeutic consequences, such as therapeutic thrombin inhibition in addition to chemotherapy are discussed.
High Prevalence of Antibodies to the Heparin-Platelet Factor 4 Complex in Hemodialysis Patients.
Authors: Carrier Marc , Knoll Greg , Kovacs Michael , Rodger Marc A. 
Published: April 2020

Abstract
Heparin-induced thrombocytopenia is a serious complication of systemic heparin therapy. Patients with this disorder develop antibodies to the heparin-platelet factor 4 (H-PF4) complex. Patients with H-PF4 antibodies are at higher risk of venous and arterial thrombosis independently of the platelet count. Hemodialysis (HD) patients are repeatedly exposed to heparin to prevent thrombosis of the extra-corporeal circuit. However, thrombosis remains a frequent complication of vascular access, which accounts for up to 20% of all hospitalization in HD patients. Studies to date on H-PF4 antibody and vascular access thrombosis in HD patients have produced conflicting data but have been limited by small sample sizes. We sough to determine the prevalence of H-PF4 antibodies in a large cohort of HD patients and the correlation with vascular access thrombosis.
Pre-dialysis blood samples were drawn on 419 HD patients; 107 cases with access thrombosis and 312 controls that never had access thrombosis. H-PF4 antibodies were measured twice using an ELISA (GTI PF4 Enhanced, GTI Diagnostics). The average of the two measurements was used in this analysis. All patients received unfractionated heparin while on dialysis. The mean age was 64 16 yrs with 62% male patients. Antibodies to H-PF4 were positive in 54 (12.9%) patients. H-PF4 antibodies were present in 10 (10.5%) of patients with confirmed access thrombosis and in 44 (15.1%) of controls. Hemodialysis with repeated exposure to systemic unfractionated heparin is associated with a high prevalence of H-PF4 antibodies. Although H-PF4 antibodies contribute to hypercoagulability leading to thrombotic complications, our results are not supporting a correlation between H-PF4 antibodies and vascular access thrombosis. Given the potential for venous and arterial thrombosis and the implications of our findings further investigations are needed in this population.
A Case Illustrating That Cancer Tips the Scale of Thrombosis.
Authors: Scott Emma C. , Cohn Jeffrey , Heitner Stephen 
Published: April 2020

Abstract
Background: There are many causes of thrombosis in cancer, including cancer itself, the release of TNF, IL-1 &IL-6 causing endothelial damage, the interaction between tumor cells and macrophages activates platelets, factors X11 &X. Cysteine proteases &tissue factor, in the tumor cells have pro-coagulant activity (Bick, R. New Engl J of Med. Volume 349. July 2003). Chemotherapy, hormonal therapy and indwelling central venous catheters also increase the risk of thrombosis. There is a RR of 4.1 for patients with cancer who did not have chemotherapy and 6.5 for patients with cancer who had chemotherapy (Heit et al. Arch Intern Med. 2000; 160: 809–815).
Factor V Leiden mutation causes partial resistance to the inactivating effects of activated protein C. 5% of the population carries this mutation and it is present in 20% of patients with a 1st venous thrombotic episode. The risk of venous thrombosis is 3–8 fold. The prothrombin mutation is less common and the relative risk of thrombosis is about 2.0. In a large case control study it was found that carriers of the Factor V Leiden or the prothrombin mutation who also had cancer had an approximately 12–17 times increased risk of thrombosis; compared to an overall 7 times risk in patients with malignancy alone (Blom et al. JAMA. Feb 9, 2005. Vol 293, No 6).
Case history: A 54 year old caucasion female was diagnosed with stage 1 infiltrating ductal carcinoma after palpating a lump in her left breast. The tumor was 1.6 cm, ER negative, PR negative and HER-2 negative. Lumpectomy and axillary node dissection revealed no residual carcinoma in the breast and no involvement of eleven lymph nodes. She completed 4 cycles of Cytoxan and Adriamycin successfully and was to start radiation therapy. 1 week after completing chemotherapy she had a focal seizure with tonicclonic movements of her right arm and no loss of consciousness. An MRI showed cortical infarcts, which were originally thought to be metastatic hemorrhages, in the left parietal and frontal areas and right parietal area. A follow up MRI showed considerable improvement of the cortical lesions, with no evidence of any metastatic cancer. Subsequently, she developed bilateral DVTs for which an IVC filter was placed as it was felt that she was not a candidate for anticoagulation given her recent CNS hemorrhage. She was also found to have bilateral pulmonary emboli on CT scan of the chest. Two other underlying disorders predisposing to thrombosis were found- Factor V Leiden mutation and the prothrombin gene mutation. Further imaging confirmed a thrombotic etiology for her CNS event, and coumadin was started.
Conclusion: This case demonstrates the magnitude of the effect of cancer on thrombosis. This patient had 2 prothrombotic mutations, was a smoker, who had been on the OCP for 10 years prior to menopause, yet had no thrombotic episodes until she developed cancer. Also of interest is that the thrombotic episodes occurred shortly after completion of chemotherapy- another prothrombotic factor.
Genetic Basis of Inherited Thrombophilia in Korea: A Single-Institution Experience.
Authors: Kim Hee-Jin , Kim Duk-Kyung , Bang Sung-Hwan , Kim Jong-Won , Kim Sun-Hee 
Published: April 2020

Abstract
Background: Inherited thrombophilia (HT) is a condition that genetically imposes a risk to develop thrombosis. It has been known that the genetic basis of IT is different between Caucasians and Asians; factor V Leiden mutation (R506Q) and the prothrombin gene mutation G20210A are major causes of HT among Caucasians, while they are extremely rare among Asians. Thus the deficiency of anticoagulant factors such as protein C (PC), protein S (PS), and antithrombin (AT) are believed to play a major role in Asians. Genetic study is important to confirm the diagnosis, since there are many acquired conditions including anticoagulant therapy that may mimic inherited form of deficiency. In this study, consecutive patients with a clinical and laboratory suspicion of IT were recruited for genetic diagnosis at a single institution, Samsung Medical Center, Seoul, Korea.
Materials and Methods: From December 2004 to July 2005, a total of 15 patients had presumptive diagnosis of IT; seven were suspected to have PC deficiency (activity, 43~ 51%), four PS deficiency (free Ag; 12~38%), and four AT deficiency (activity, 63~67%). All exons and their flanking sequences of the PROC gene, PROS1, or SERPINC1 were directly sequenced and analyzed.
Results: All seven patients with PC deficiency were shown to have a mutation in PROC. Of note, four of them had a common missense mutation, and the haplotype analysis using polymorphic markers showed that it is a mutation hot focus rather than a founder effect. Two other mutations were novel. Two of four patients with PS deficiency had a mutation in PROS1, each of which was novel. Three of four AT deficiency had a mutation in SERPINC1; one with a novel splice mutation and two shared a common splice mutation, which has not been reported, either. Overall, nine mutation carriers were detected through family study.
Conclusion: This study revealed the genetic basis, mutation spectrum, and the mutation detection rate of IT in consecutive Korean patients. Since diverse (known or novel) mutations underlie genetic deficiency of anticoagulants in Koreans, genetic studies employing direct sequencing for the whole gene are necessary to confirm the diagnosis, and for further family studies.
Correlation between Antifactor Xa Activity and Thrombin Generation Time, Platelet Contractile Force and Clot Elastic Modulus Following Enoxaparin Exposure in Patients with and without Renal Dysfunction.
Authors: Brophy Donald F. , Martin Erika J. , Gehr Todd W.B. , Best Al M. , Carr Marcus E. 
Published: April 2020

Abstract
Patients with renal dysfunction that receive hemodialysis (HD) are highly sensitive to low molecular weight heparin (LMWH) drugs such as Enoxaparin. There have been numerous reports of hemorrhagic effects with these drugs in this population. Although current guidelines recommend judicious monitoring of antifactor Xa activity in HD patients to prevent adverse events, this parameter is poorly correlated to efficacy and toxicity. Newer, more specific parameters such as thrombin generation time (TGT), platelet contractile force (PCF) and clot elastic modulus (CEM) may play a role in monitoring LMWH drugs in high-risk populations such as those with renal dysfunction. To determine the utility of monitoring TGT, PCF and CEM for this purpose, we conducted a prospective clinical trial in 8 non-thrombosed HD and 8 control subjects. All subjects received escalating doses of Enoxaparin 0.25, 0.50 and 1.0 mg/kg subcutaneously during this study. Blood samples were obtained four hours post-dose to capture the peak effect of Enoxaparin on antifactor Xa activity, TGT, PCF and CEM. Pearson’s correlation was used to determine the relationships between antifactor Xa activity and TGT, PCF and CEM at each dose, respectively. Repeated measures analysis of covariance was used to assess for intergroup differences in the slopes of each regression line using the group status and antifactor Xa concentration as the covariates. The correlation coefficient (r), coefficient of determination (r2) and p-value for each parameter in each group are listed in the Tables. The figure illustrates the relationship between antifactor Xa and TGT in both controls and ESRD patients. These findings suggest that TGT, PCF and CEM are highly correlated to antifactor Xa activity in patients with and without renal dysfunction. There were no differences in the slopes of the regression lines between groups. Further studies are needed to determine if TGT, PCF and CEM provide more useful clinical information regarding the level of anticoagulation in high-risk patients receiving low-molecular weight heparin therapy.
TGT vs. Antifactor Xa Activity TGT vs. Antifactor Xa Activity
Correlation Parameters for Antifactor Xa and TGT, PCF and CEM for Control Subjects Model r r2 P-value Antifactor Xa vs. TGT 0.88 0.77 0.001 Antifactor Xa vs.PCF 0.85 0.73 0.0003 Antifactor Xa vs. CEM 0.80 0.63 0.02 Correlation Parameters for Antifactor Xa and TGT, PCF and CEM for HD subjects Model r r2 P-value Antifactor Xa vs. TGT 0.91 0.82 0.0002 Antifactor Xa vs. PCF 0.90 0.80 0.0004 Antifactor Xa vs. CEM 0.90 0.80 0.0005
Comparative Study on the Anticoagulant Effects of Low Molecular Weight Heparins as Measured by Whole Blood Act, Anti-Xa and a Newly Developed Prothrombinase Induced Clotting Time (PiCT) Assay.
Authors: Hoppensteadt D. , Tobu M. , Wahi R. , Iqbal O. , Walenga J. M. , Demir M. , Baltasar F. , Fareed J. 
Published: April 2020

Abstract
Low Molecular Weight Heparins (LMWHs) are currently developed for anticoagulation in various intravenous indications such as DVT treatment and percutaneous interventions (PCI). Traditionally, these drugs are administered in anti-Xa units. The purpose of this study was to compare the relative levels of anticoagulation produced by different LMWHs in whole blood ACT (Hemochron), an amidolytic anti-Xa method and a plasma-based global anticoagulant assay, the PiCT test (Pentapharm, Basel, Switzerland). Various LMWHs such as dalteparin, enoxaparin, reviparin and a synthetic pentasaccharide were supplemented to freshly drawn native blood samples to simulate patient samples containing 1 U/ml anti-Xa levels. Three generic versions of enoxaparin were also included in this study. In addition to the ACT measurement in whole blood, citrated plasma samples were also tested for APTT, Heptest, PiCT, amidolytic anti-Xa and IIa activities, and protease generation assays. All agents produced assay-based effects on different tests, which were not proportional to the adjusted anti-Xa activity. Correlation of the ACT data resulted in a good relationship with PiCT for the commercially available branded products(r2=0.97). ACT and Heptest (r2=0.51), ACT and anti-Xa (r2&lt;0.3), ACT and anti-IIa (r2= 0.93). The correlation of PiCT and Heptest was (r2=0.73) better than ACT and Heptest. However, the generic versions of enoxaparin did not provide similar results. PiCT and Heptest also gave the good correlation. These results clearly suggest that for the global anticoagulant actions of LMWHs, anti-Xa measurements are of limited value and should not be used to asses the anticoagulant efficacy of LMWHs in PCI and other surgical conditions. These differences may be more obvious in the generic versions of LMWHs, which are apparently produced using pharmacopeial specifications. Thus, it is important to include a clot-based method in the cross referencing and standardization of LMWHs.
“M-AAA-Thrombin”, a New Thrombin Mutant with Potent Anticoagulant and Antiplatelet Properties.
Authors: Hosokawa Kazuya , Ohnishi Tomoko , Matsuda Hiroyuki , Kashima Kousuke , Koide Takehiko 
Published: April 2020

Abstract
Thrombosis is a major cause of morbidity and mortality, and thrombin is a major inducer of thrombus formation. Thus several antithrombotic agents targeting thrombin have been developed. We previously reported an anticoagulant and antiplatelet thrombin derivative, ‘M-anhydrothrombin’ prepared by chemical modifications. In this study, we prepared a new thrombin mutant, specificity of which was highly modulated with substantially improved antithrombotic efficacy. The thrombin mutant designated “AAA-Thrombin” in which Lys65, His43 and Ser205 in B-chain have been replaced by Ala revealed higher affinity and specificity for factor VIII with no enzymatic activity. AAA-Thrombin prolonged APTT much more than anhydrothrombin in a dose dependent manner without affecting PT and TT. Platelet aggregation induced by activation of PAR-1 was also effectively suppressed by AAA-Thrombin. “M-AAA-Thrombin” prepared by further chemical modification of carboxyl groups in AAA-Thrombin enhanced its antithrombotic efficacy. M-AAA-Thrombin (250nM) prolonged APTT approx. two times, and suppressed platelet aggregation by PAR-1 activation, while AAA-Thrombin did not at the same concentration. M-AAA-Thrombin also suppressed ristocetin-induced platelet aggregation. In vivo experiments, M-AAA-Thrombin demonstrated significant antithrombotic property in the arterio-venous shunt thrombosis model and the FeCl3-induced carotid artery thrombosis model in guinea pigs. These results indicate that M-AAA-Thrombin would be a candidate for quite an innovative anticoagulant and antiplatelet agent for both arterial and venous thromboses. Further optimization of mutagenesis and modification, in terms of efficacy and safety is in progress in our laboratory.