Low Molecular Heparin Research Articles

COVID-19 Infection in Patients with Paroxysmal Nocturnal Hemoglobinuria in Italy

COVID-19 pandemic has raised several concerns regarding patients with hematologic and immune-mediated diseases. It can be assumed that Paroxysmal nocturnal hemoglobinuria (PNH), both classic hemolytic and associated with aplastic anemia, particularly on treatment with complement inhibitors, may be more susceptible and have higher morbidity and mortality rates from COVID-19 than the general population. Italy has been heavily affected from the COVID-19 outbreak with the peak of contagions at the end of March 2020. As of July, 23 2020 the cumulative incidence of COVID-19 in Italy was 0.4% (1 case every 246 residents) (ranging from 0.06% - 1/1621- in Calabria to 0.9% - 1/106 - in Lombardy). We conducted a survey on 126 patients with PNH (77 females/49 males, median age 48 years, range 19-86) among 7 reference Italian centers in order to evaluate the occurrence and clinical characteristics of COVID-19 infection from the outbreak until the time of writing. According to International PNH Interest Group (IPIG) classification, 95 patients suffered from classic hemolytic PNH, 24 had associated bone marrow failures (aplastic anemia or myelodysplastic syndrome), and 7 had subclinical PNH (clone size <10%). Sixty-nine cases were on complement fraction 5 (C5) inhibition (72 eculizumab and 19 ravulizumab). Comorbidities were present in 33 patients, including arterial hypertension (N=14), ischemic cardiomyopathy (N=3), atrial fibrillation (N=2), diabetes mellitus (N=2), breast cancer (N=3), colon cancer (N=1), prostate cancer (N=1), Crohn disease (N=1), and Hashimoto thyroiditis (N=1). During the observation period, only one patient (55 years female), from Milan, Lombardy, not on C5-inhibitor was diagnosed with COVID-19 infection (positive swab, ageusia, and mild fever for few days). No hemolytic flare occurred, nor hospital admission was required. She received azithromycin and low molecular heparin. Other 6 patients, all on C5-inhibitors, experienced fever (N=5) and cough (N=2), and/or dysgeusia (N=1), of whom 2 experienced breakthrough hemolysis (BTH), but swabs and CT scans (N=2) were negative. At variance, 6 patients (4 on eculizumab and 2 on ravulizumab) experienced BTH without COVID-19 symptoms. Interestingly, a young male patient on eculizumab, working as medical doctor in a COVID-19 ward, did not contract the infection. In conclusion, this survey suggests that PNH subjects, either on complement inhibition or not, are not at significantly higher risk of COVID-19 infection as compared with the general population. As a matter of fact, the basic protective measures against COVID-19 have always been advised to PNH patients particularly during treatment and were presumably carefully followed during the pandemic. On the other hand, immune activation and inflammation are thought to play an important role in the clinical severity of COVID-19 pneumonia. Complement inhibition, which is under investigation in COVID-19 disease, seems at least not disadvantageous in PNH.DisclosuresBarcellini:Agios: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Alexion: Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: invited speaker , Research Funding; Novartis: Honoraria, Other: invited speaker , Research Funding; Bioverativ: Membership on an entity's Board of Directors or advisory committees; Incyte: Membership on an entity's Board of Directors or advisory committees. Bianchi:Agios Pharmaceuticals: Other: Scientific Advisor. Notaro:Biocryst: Membership on an entity's Board of Directors or advisory committees; Alexion Pharmaceuticals: Honoraria.

HOW WE ACHIEVED 0% OF THROMBOTIC GRAFT LOSS -THE INITIAL 60 CASES OF PANCREAS TRANSPLANT

Background: One of the major surgical complications after pancreas transplant is early graft failure due to thrombosis. Unfor tunately, the early graft loss rate has not improved over the last 30 years. Even in recent reports, the technical failure rate due to thrombosis was 5%-10%. The low flow portal venous system must have the tendency of thrombosis, thus the graft pancreas in inherently thrombogenic. Therefore, wider and shorter anastomosis of the portal vein is better for maintaining blood flow. The size of the opening is more important than the length according to the equation above. Methods: We performed 60 cases of pancreas transplant (11 simultaneous pancreas-kidney, or simultaneous pancreas living-do nor kidney, 14 pancreas after kidney, 34 pancreas transplant alone, and one pancreas after liver transplant) in Pusan National University Yangsan Hospital, Korea, since 2015. There is no thrombotic graft loss in our cases. Results: Most of our cases were performed with venous drainage to vena cava and duodenal exocrine drainage. The venous anastomotic technique was evolved from the direct anastomosis (n=8). Then we did a diamond-shaped patch anastomosis (n=13). After that, the fence angioplasty with using vena cava graft was applied to 31 cases. And finally, we have been performing the ve nous anastomosis with aortic interpositional graft (n=8). The conventional or low molecular heparin was used for the prevention of thrombosis in the first 40 cases of transplant. However, we do not use any heparin anymore neither in the intraoperative nor postoperative periods. There was some partial thrombosis in graft splenic vein or superior mesenteric vein on computed tomog raphy scans. However, these partial thromboses did have any effect on graft loss. Conclusions: In conclusion, we need to understand the mechanism of thrombus in graft pancreas and should do the best effort to make the wide venous anastomosis and maintain the venous flow. We would like to share our know-how with members of transplant society.

The Abnormal Expression of miR-205-5p, miR-195-5p, and VEGF-A in Human Cervical Cancer Is Related to the Treatment of Venous Thromboembolism.

Background Low molecular heparin (LWMH) therapy can prevent the occurrence of VTE in tumor patients and may have a direct antitumor effect. However, the expression pattern of VEGF-A and microRNAs was less reported in cervical cancer subjects who received concurrent chemoradiotherapy (CCRT) or received anticoagulant treatment with low molecular weight heparin (LWMH) after CCRT (CCRT+LWMH). Methods In this study, 30 cervical cancer subjects treated with CCRT and 30 cervical cancer patients treated with CCRT+LWMH were enrolled. We screened five miRNAs (miR-15a-5p, miR-16-5p, miR-29a-3p, miR-195-5p, and miR-205-5p), which have multiple binding sites with VEGF-A and are highly expressed in serum of patients with cervical cancer, by RT-qPCR. The expression level of VEGF-A was also detected by RT-qPCR and ELISA. Statistical methods were used for difference and correlation analyses. Results We observed the curative effect in the two treatment methods. In the CCRT group, the total effective rate was 60.00%, and in the CCRT+LWMT group, the total effective rate was 83.33% (P = 0.013, χ2 = 6.129). Additionally, the serum levels of VEGF-A in the CCRT+LWMH group were downregulated, relative to the CCRT group (P < 0.05), and VEGF-A in serum was significantly positively correlated with venous thromboembolism (VTE) (r = 2.134, P = 0.035). Only miR-205-5p and miR-195-5p were upregulated in CCRT+LWMH, relative to CCRT (P < 0.05). In serum of patients with cervical cancer after CCRT+LWMH treatment, there was no significant correlation between VEGF-A and miR-15a-5p (r = −0.132, P = 0.209), miR-16-5p (r = −0.205, P = 0.311), or miR-29a-3p (r = −0.029, P = 0.662), but VEGF-A was significantly negatively correlated with miR-195-5p (r = −0.396, P = 0.040) and miR-205-5p (r = −0.315, P = 0.032). Furthermore, VTE was also significantly negatively correlated with miR-195-5p (r = −0.412, P = 0.031) and miR-205-5p (r = −0.123, P = 0.044). Conclusion These data revealed roles for VEGF-A and these miRNAs as potential biomarkers in cervical cancer patients with VTE, which exhibited usage potential in the treatment of venous thromboembolism.

Prevention of COVID-19-associated Haemostasis Failure in Patient with Stented Coronary Arteries: a Clinical Case

Introduction.In patients with COVID-19, acute pulmonary lesion grows on inflammation and microvascular thrombosis. Thromboinflammation may develop outside alveolar endothelium and affect endothelium of the heart, kidneys, intestine and other vital organs leading to a multiple-organ insufficiency and possible lethal outcomes. Treatment and prevention of SARS-CoV-2 in the Russian Federation should comply with the Interim Methodological Guidelines of the Russian Ministry of Health that support the global mainstream of COVID-19 containment measures and are updated regularly with new evidence on drug effectiveness, including anticoagulants.Materials and methods.We review a clinical case of effective treatment of a COVID19 patient with prior coronary surgery from the perspective of the Interim Methodical Guidelines of different editions and international clinical experience in anticoagulant therapy.Results and discussion.A retrospective analysis of the patient’s treatment demonstrated the efficacy of thromboelastography in rapid assessment of blood hypercoagulation and parnaparin sodium as a drug of choice among low-molecular heparins in a combined setting with dual antiplatelet therapy. Etiotropic therapy rendered to this patient is currently considered less effective.Conclusion.Combination of anticoagulants with antiaggregants is shown effective under high risks of thrombosis and a background COVID-19 infection, if justified clinically. In cases of complicated diff erential diagnosis, selection of optimal management strategy, anticoagulant and/or antiplatelet therapy monitoring, a good practice is to rely on both the available domestic guidelines and latest meta-analyses combined with international clinical experience.

COVID-19-associated coagulopathy: review of current recommendations for diagnosis, treatment and prevention

The coronavirus infection COVID-19 is a highly contagious disease caused by the SARS-CoV-2 virus. Specific prothrombotic changes of the hemostasis system in COVID-19 are associated with increased incidence of venous thromboembolic complications. The article is a literature review on the diagnosis, treatment and prevention of coagulopathy and venous thromboembolic complications associated with COVID-19. 11 studies evaluating the frequency of registration of venous thromboembolic complications and 11 clinical recommendations on correction of coagulopathy published before May 22, 2020 have been studied. The frequency of venous thromboembolic complications was unexpectedly high: 8-13% in the general ward and 9-18% in the intensive care unit against the background of preventive measures. Preventive doses of anticoagulants, low-molecular weight heparins or unfractionated heparin are indicated to all hospitalized patients. Prolonged prophylaxis after discharge from hospital can be recommended for those at high risk of venous thromboembolic complications and low risk of bleeding. An increase in D-dimer may be considered as an indication for instrumental detection of venous thromboembolic complications. If there is a suspicion of venous thromboembolic complications, anticoagulant therapy at therapeutic doses can be started before the diagnosis is confirmed: during inpatient treatment preference should be given to low-molecular heparin or unfractionated heparin, after discharge from hospital it is recommended to transfer to direct oral anticoagulants for a period of at least 3 months. Routine prevention of venous thromboembolic complications in ambulatory patients is not recommended.

Increased dose primary thromboprophylaxis in ambulatory patients with advanced pancreatic ductal adenocarcinoma, a single centre cohort study

BackgroundAdvanced pancreatic ductal adenocarcinoma (aPDAC) patients have a lifetime all type thromboembolic event (ATTE) rate of 25–35%. Efficacy and safety of increased dose primary thromboprophylaxis (IDPTP) with low molecular heparin (LMWH) given for 3 months has been shown in two prospective randomized trials.ObjectivesTo report on efficacy -reduction of all type thromboembolic events (ATTE)-, safety -incidence of Major Bleeding (MB)- and compliance in a single-centre cohort of aPDAC patients receiving first line chemotherapy and LMWH-IDPTP.MethodsFrom May 2009 to October 2016, 82 patients received IDPTP –LMWH with dalteparin. Schedule: 55 kg and below: 7500 IU, between 55 and 80 kg: 10,000 IU, above 80 kg: 12,500 IU. MB is reported using the International Society of Thrombosis and Haemostasis (ISTH) criteria. ATTE was defined as any arterial or venous event, incidental or clinically symptomatic, including visceral VTE.ResultsMean and median time on dalteparin was 10.2 (95%CI 8.1, 12.4) and 8.0 (95%CI 6.2, 9.7) months respectively. ATTE was observed in 7 (8.5%) of patients, with a median time on IDPTP of 6.2 months (95% CI 10.0, 13.2). MB was seen in 10 (12.2%) patients with a median time on IDPTP of 4.5 months (95% CI 1.6, 7.4). Six major bleeds (60%) were the direct or indirect result of aPDAC. Eighty-one patients had died at the time of data collection with a median overall survival time of 8.7 months (95%CI 6.4, 11.0). Thromboembolism and bleeding were late events. No impact of thromboembolism or bleeding on overall survival was observed.ConclusionsIDPTP-dalteparin was associated with lower ATTE occurrence rates than expected and comparable major bleeding rates. ATTE and MB were late events, the majority of MB was from direct or indirect result of locally progressing aPDAC. Since these conditions can frequently arise in aPDAC, IDPTP should be regularly reviewed beyond 3 months.

A real-world study of low molecular weight heparin sodium in the treatment of severe and critical bite by Trimeresurus stejnegeri

To investigate the clinical effect of low molecular weight heparin sodium combined with antivenin in the treatment of severe and critical bite by Trimeresurus stejnegeri. The clinical data of 48 patients with severe or critical bite by Trimeresurus stejnegeri admitted to emergency department of Southeast Hospital Affiliated to Xiamen University from March 2017 to May 2019 were retrospectively analyzed. On the basis of early treatment of antivenom serum, internal administration and external application of Jidesheng snake tablet, and wound incision and detoxification, the patients were divided into heparin treatment group and non-heparin treatment group according to whether the low molecular heparin sodium was used or not. The patients in the two groups were compared in terms of gender, age, clinical classification, swelling degree of injured limbs, change of coagulation function index, bleeding of skin, mucous membrane or digestive tract, blood transfusion, local symptoms of bite, length of hospital stay and prognosis. There was no significant difference in terms of gender, age, clinical classification or swelling degree of injured limbs between the two groups. On the 3rd day of treatment, the platelet count (PLT) in the heparin treatment group was significantly higher than that in the non-heparin treatment group [×109/L: 210.0 (160.0, 252.0) vs. 136.0 (104.0, 198.5), P < 0.05]. However, there was no significant difference in the four coagulation test results between the two groups. On the 6th day of treatment, the plasma thrombin time (TT) in the heparin treatment group was significantly shorter than that on the 3rd day of treatment [s: 30.3 (20.4, 37.0) vs. 34.7 (24.0, 73.4), P < 0.05], and the fibrinogen (FIB) in the heparin treatment group was significantly higher than that in the non-heparin treatment group [g/L: 0.60 (0.31, 1.07) vs. 0.20 (0.14, 0.60), P < 0.01]. The incidence of bleeding in the heparin treatment group was significantly lower than that in the non-heparin treatment group [21.7% (5/23) vs. 64.0% (16/25), P < 0.01]; 11 patients in the heparin treatment group and 18 patients in the non-heparin treatment group received blood transfusion and prothrombin complex supplement respectively. There was no significant difference in the length of hospital stay between the heparin group and non-heparin treatment group (days: 6.91±1.92 vs. 7.48±2.27, P > 0.05). The patients in both groups were followed up for 1 week to 1 month after treatment, and no death or local necrosis of skin and soft tissue was found. For the patients with severe and critical bite by Trimeresurus stejnegeri, on the basis of injection of antivenom serum, internal administration and external application of Jidesheng snake tablet, and wound incision and detoxification, early application of low molecular weight heparin sodium anticoagulation and other comprehensive treatment is helpful to improve limb swelling and inflammation, reduce blood transfusion, promote the recovery of coagulation function, and shorten the length of hospitalization.

Modulation of angiogenesis by topical application of leptin and high and low molecular heparin using the Japanese quail chorioallantoic membrane model.

Pathological angiogenesis characterized by uncontrollable vessel growth is an accompanying feature of many diseases. The avian embryo chorioallantoic membrane (CAM) is an excellent model for angiogenesis research. In our study we used a less common Japanese quail CAM model for the testing of angiogenic potential of leptin, high-molecular (heparin sodium) andlow-molecular (nadroparin calcium) heparins. Heparins play a significant role in vascular endothelial cell function, and they are able to modulate the activities of angiogenic growth factors. On embryonic day 7 leptin (5 μg per CAM), heparin sodium (75 IU per CAM) and nadroparin calcium (47.5 IU per CAM) in 500 μl PBS were applied on the CAM surface. After 24 h the fractal dimension (Df) of the vasculature was evaluated. Samples from each group were histologically analyzed and VEGF-A and Quek1 expression were detected by qPCR. Df was significantly increased in the leptin group. A moderate stimulatory effect of heparin sodium and an inhibitory effect of nadroparin calcium were observed. Both leptin and heparin sodium caused a noticeable increase in the CAM thickness compared to the control and nadroparin calcium groups. We observed an increased number of blood vessels and accumulation of fibroblasts. There was no significant impact on gene expression of VEGF-A and Quek1 24 h after treatment, however, trends similar to the changes in Df and CAM thickness were present. The resulting effect of nadroparin administration on Quek1 levels was exactly the opposite to that of leptin (p < 0.05).

New aspects on autoantibodies for classification, diagnosis and therapy within rheumatology

Recent advances in rheumatology indicate increased relevance of autoantibodies. In this regard, positive ANA are now required as entrance criterium for the first EULAR/ACR classification criteria of SLE. Importantly, ANA diagnostic with detection of isolated anti-dense fine speckled antibodies (DSF-70) need consideration since their unique detection has been identified to exclude largely an autoimmune disease. Thus, highly qualified ANA diagnostic preferably on Hep-2 cell lines is a prerequisite of reliable diagnostics.Recent recommendations for the management of antiphospholipid syndrome define high versus low risk seroprofiles which also guide primary and secondary prophylaxis. Importantly triple positive APS patients (positive for anticradiolipin, anti-ß2 GP I positive and carrying lupus anticoagulant) should be treated with vitamin K antagonists while direct oral anticoagulants have been shown to be inferior in terms of risk/benefit. Treatment of obstetric APS is mainly based on low dose aspirin and low molecular heparin. Notably, this treatment should be maintained for 6 weeks after delivery. Thus, serologic findings provide the basis for certain key clinical decisions and require their reliable detection.

PROPHYLAXIS OF VENOUS THROMBOEMBOLIC COMPLICATIONS IN PATIENTS WITH ACTIVE ONCOLOGICAL DISEASE, RECEIVING MEDICAL ANTI-CANCER CHEMOTHERAPY IN OUTPATIENT CONDITIONS. ROLE OF APIXABAN

Oncological disease is one of the most important risk factors for venous thromboembolic complications (VTEC). The treatment of an already confirmed VTEC in an oncological patient is always associated with additional difficulties, which are related to drug interactions, which may affect the efficacy of chemotherapy or the efficacy and safety of anticoagulant therapy. VTEC prophylaxis for oncological patients could take the lead. However, it remains unclear whether medication-based thromboprophylaxis should be given to patients with oncological diseases, as thrombotic risks and risks of hemorrhagic complications vary widely and depend on the type of cancer, the stage of the process and the anticancer treatment provided. The criteria for thromboprophylaxis are clearly defined for hospitalized patients and patients undergoing surgical treatment. However, long-term cancer therapy is mainly carried out in outpatient conditions. Chemotherapy increases the risk of developing VTEC. The new targeted therapy, which is performed independently or in combination with traditional chemotherapy, does not reduce the risk of developing VTEC. Low-molecular heparins are the «gold standard» for the treatment and prevention of VTEC in cancer patients. When using LMWH, especially in groups of oncological patients with high thrombotic risk, a reliable decrease in thrombotic events was shown, but bleeding remains the main adverse effect, leveling out the benefit of medical thromboprophylaxis. Another attempt to increase the safety of thromboprophylaxis is the use of direct oral anticoagulants (DOACs). The article deals with modern provisions of medical thromboprophylaxis in patients with cancer, as well as the possibility of using DOACs, in particular apixaban, for the prevention of cancer-associated VTEC.

Effectiveness of the use of Low Molecular Heparin in patients with repetition abortion history: Systematic review and meta-analysis.

Objective:To evaluate the efficacy and safety of using low molecular weight heparin (LMWH) in women with a history of recurrent abortion without an identified cause.Methods:To develop a systematic review to select the studies. Total found 437 papers. Seven studies were completed or requested. The following variables were analyzed: clinical pregnancy, implantation rate, live births, abortion, premature birth, pregnancy, continuous pregnancy, beyond the 20th gestational week, congenital abnormality, hemorrhage, preeclampsia, placental premature detachment.Results:The LMWH group had a higher incidence of continuous pregnancy after the 20th week of gestation and there was no significant difference between the LMWH group and the expectant management group in the analysis of other variables.Conclusions:There was no data showing risk and/or less use of LMWH compared to expectant management; on the contrary, LMWH use increased the incidence of evolutionary pregnancy after the 20th gestational week. LMWH has some influence on prophylactic treatment of repeat abortion for unknown cause.

Effect of age on the functioning of hemostasis system during hip joint endoprosthesis

The study was performed on 109 osteoarthritis patients who underwent hip joint endoprosthetics; the effect of age on changes in hemostasis system, blood loss level and deep veins thrombosis development in the background of standard prevention with low-molecular heparins were studied. Before the surgery, it was determined that 56 elderly patients (60.3 ± 6.4 years) compared to 53 middle-aged patients (41.8 ± 6.8 years) had a significantly higher initial and postoperative endothelial dysfunction, higher fibrin formation and lower anticoagulant potential; however, it was found that on the background of pharmacological anticoagulant therapy the changes in the hemostasis functioning in elderly patients did not lead to an increase of either blood loss or the number of thromboses.

Role of Heparin Sodium Salt in the Modulation of Human Umbilical Cord-Derived Mesenchymal Stem Cell Differentiation

Introduction: The present study aims to investigate the role of low molecular weight compound heparin sodium salt (HSS) to control the differentiation of the human umbilical cord (UC) derived mesenchymal stem cells (MSCs) through possible interaction with WWTR1 protein. Materials and Methods: In order to carry out this study, the human UC-derived stem cells were isolated and characterized by stem cell specific markers and the effect of HSS was studied by altering the phenotypes of MSCs. An Insilco approach was employed to reveal the structural determination of the ligand, the WWTR1 protein binding site and to predict the strength of the interaction. After HSS treatment, WWTR1, Oct4, nanog, SOX9 gene expressions were studied using real-time polymerase chain reaction (PCR). Cell staining was performed using alizarin red to confirm the formation of osteocytes. Results: Mineralization indicated by osteocytes was confirmed using alizarin red after the treatment of HSS. Post, HSS treatment, OCT4, Nanog, RUNX2, COL1A1 and WWTR1 gene expressions were positively modulated. Heparin treatment of MSCs lead to the up regulation of WWTR1 along with the down regulation of stemness markers Oct4 and Nanog expression. In silico studies also predicted the possible interaction of WWTR1 with HS. Results indicated that Amino acid residues ASP57, GLN83, GLN109, THR135, and TYR141 came up as a prominent interaction centre; ASP57, GLN83 and THR135 recorded the highest interaction energy – while ASP57 mostly participated in an electrostatic interaction. Conclusions: To conclude, it can be stated that heparin can possibly interact with WWTR1 along with having the capability to direct cells towards osteogenic lineages.

Predictors for Chronic Thromboembolic Pulmonary Hypertension

Introduction - The most dangerous complication of acute venous thrombosis is pulmonary embolism (PE), which results directly in mortality in most cases. In non-fatal cases of massive pulmonary embolism, when thrombolytic therapy or embolectomy is not possible or ineffective, there is severe chronic thromboembolic pulmonary hypertension (CTEPH). The purpose of our study was to develop clinical, laboratory and instrumental criteria to characterize the development of varying CTEPH intensity after the earlier is PE. Methods - The study is based on a retrospective material comprising 26 patients with the pulmonary embolism arteries and survived it. At different times (1-5 years) after the event and discharge from the hospital, the patients were summoned and examined. All patients were performed to an ultrasonography of the lower limbs, echocardiography, and some patients had pulmonary perfusion scintigraphy and CT angiography. In case of high pulmonary hypertension, which was detected with echocardiography, the right heart catheterization was used for the immediate detection of pulmonary pressure. In the course of our study, we compared the patients' findings received in the initial hospital admissions with the findings of clinical and instrumental methods we had received in the long term after the pulmonary embolism (PE). Results - According to our study, there is a certain trend towards the development of severe CTEPH forms, depending on the following primary clinical and instrumental characteristics. The following factors have been recognized as favorable factors resulting in the incidence of milder CTEPH forms or its total absence in the long term: effective thrombolytic therapy, relative “freshness” of thrombotic masses, distal lesion level of the lower extremity veins (up to the popliteal veins inclusive), young age of patients. It is worth mentioning separately the adequate anticoagulant therapy, which is prescribed following the thrombolysis or in automedication. As a rule, patients followed two regimens of anticoagulant therapy after the thrombolytic therapy: unfractionated heparin during the first 24 hours, with the subsequent transition to warfarin, rivaroxaban immediately at the end of the thrombolysis. Two regimens of anticoagulant therapy: low molecular heparins followed by the transition to warfarin and rivaroxaban from the first days of treatment were also present when the thrombolytic therapy was not possible or not necessary. In the long term, we observed the best pulmonary artery recanalization by combination of the thrombolytic therapy and rivaroxaban, although there were patients who were not treated with the thrombolysis due to the developed allergic reaction in the massive PE, but on the top of administered rivaroxaban there was detected a full pulmonary channel permeability one year after the treatment onset. The effect of the pulmonary artery recanalization in the warfarin treatment was much weaker. Negative factors in the CTEPH development could include the proximal level of deep vein lesions, the elderly age of patients, not "fresh" thrombotic masses. After 10 days of their formation, each consecutive day affected negatively the efficiency forecast of the thrombolytic and anticoagulant therapy in terms of pulmonary artery recanalization. Conclusion - There are certain clinical and instrumental parameters that allow for a certain degree of prediction of the CTEPH development following the earlier PE, but further studies are required to have more reliable statistics.

Tromboza splanhničkih vena kao rijedak uzrok akutnog abdominalnog bola

Cilj: Prikazati slučaj pacijenta s akutnim abdominalnim bolom kojemu je dijagnosticirana tromboza splanhničkog venskog sustava, a uzrok je naknadno dokazana mijeloproliferativna bolest uz JAK2 V617F varijantu sekvence. Prikaz slučaja: 44-godišnji pacijent primljen je u hitnu medicinsku službu zbog akutizacije paraumbilikalnog bola koji je trajao 10-ak dana. U laboratorijskim nalazima bile su povišene vrijednosti alfa amilaze i upalnih parametara, zbog čega je pacijent hospitaliziran. Nativna snimka abdomena i ultrazvuk abdomena pokazivali su meteorizam tankog i debelog crijeva. Zbog nejasne dijagnoze učinjena je i kompjutorizirana tomografija (CT) abdomena koja je pokazala samo zamućeno mezenterijalno masno tkivo u korijenu mezenterija. Trećeg dana hospitalizacije zbog intenzivnijih bolova, koji nisu popustili ni na opiodne analgetike, učinjen je kontrolni CT abdomena koji je pokazivao trombozu v. portae, v. mesentericae superior i v. lienalis. Navedene promjene bile su praćene zadebljanjem stijenke tankog crijeva u smislu kongestije i raslojavanja stijenke, ali bez znakova jasne ishemije, te parcijalnim poremećajima perfuzije jetre uz prisutnost ascitesa. U terapiju je uveden niskomolekularni heparin u punoj dozi uz acetilsalicilnu kiselinu, a zbog dodatnog pogoršanja stanja sa znakovima paralitičkog ileusa i progresijom ishemijskih promjena tankog crijeva učinjena je hitna laparotomija. Za vrijeme hospitalizacije, hematološkom obradom dokazana je JAK2 V617F varijanta sekvence i mijeloproliferativna bolest koja je etiološki čimbenik tromboze portalnog sustava i ishemije crijeva. Zaključak: Uzrok akutnog bola u trbuhu može rijetko biti i tromboza splahničkog sustava, koja u kratkom vremenskom periodu može dovesti do životno ugrožavajućeg stanja. Akutno nastalu trombozu splanhničkog venskog sustava nužno je liječiti antikoagulantnom terapijom, a ako taj način liječenja ne pokaže zadovoljavajuće rezultate, nužan je kirurški zahvat. Dokazana mijeloproliferativna bolest uz JAK2 V617F varijantu sekvence mogući je etiološki čimbenik splanhničke venske tromboze kod mlađih pacijenata.

Fatal deep venous thrombosis and pulmonary embolism secondary to melioidosis in China: case report and literature review

BackgroundBurkholderia pseudomallei is a gram-negative bacterium and the causative pathogen of melioidosis, which manifests a variety ranges of infection symptoms. However, deep venous thrombosis (DVT) and pulmonary embolism (PE) secondary to bacteremic melioidosis are rarely documented in the literature. Herein, we reported a fatal case of melioidosis combined with DVT and PE.Case presentationA 54-year-old male construction worker and farmer with a history of diabetes was febrile, painful in left thigh, swelling in left lower limb, with chest tightness and shortness of breath for 4 days. He was later diagnosed as DVT of left lower extremity and PE. The culture of his blood, sputum and bone marrow samples grew B. pseudomallei. The subject was administrated with antibiotics (levofloxacin, cefoperazone/tazobactam, and imipenem) according to antimicrobial susceptibility testing and low molecular heparin for venous thrombosis. However, even after appropriate treatment, the patient deteriorated rapidly, and died 2 weeks after admission.ConclusionsThis study enhanced awareness of the risk of B. pseudomallei bloodstream infection in those with diabetes. If a patient has predisposing factors of melioidosis, when DVT is suspected, active investigation and multiple therapeutic interventions should be implemented immediately to reduce mortality rate.

VTE Incidence in RRMM Patients Treated with NOVEL Agents: A Monocentric Real Life Experience

INTRODUCTION: Venous thromboembolism (VTE) is very common in patients with malignancies. Compared to the general population, patients with multiple myeloma (MM) have a 9-fold increased risk of developing VTE. In patients treated with thalidomide or lenalidomide, current guidelines recommend systematic VTE prophylaxis with ASA in low risk patients while vitamin K antagonists (VKA) or low weight molecular heparin (LWMH) or unfractionated heparin (UFH) in high-risk patients, based on the type of anti-MM treatment that patients receive and patient-related individual risk factors (e. g. history of VTE). However, little is known on VTE prophylaxis in patients treated with next generation anti-myeloma drugs, such as pomalidomide, carfilzomib and monoclonal antibodies daratumumab and elotuzumab. Here, we describe the incidence of VTE in MM patients treated with third generation novel agents in real life. In addition, we stratify patients on drugs category-based regimens to evaluate strategy of VTE prophylaxis between different groups of patients. MATERIALS AND METHODS: A retrospective cohort of 137 patients affected by relapsed and/ or refractory multiple myeloma treated with novel agents was analyzed. Patients were followed at the Division of Hematology of Catania from April 2013 to June2019. Our series includes 75 patients exposed to Pomalidomide and Dexametasone (PomaD), 46 patients receiving Carfilzomib, Lenalidomide and desamethasone regimen (KRd), 14 patients exposed to Daratumumab(Dara), 27 patients to Daratumumab, Bortezomib and desamethasone (DaraVD), 4 patients to Daratumumab lenalidomide and desamethasone (DaraRd), and12 patients exposed to Elotuzumab and Lenalidomide (EloRd). Several patients were exposed to multiple lines of treatment with novel agents: the total number of analyzed treatments are 178. Patients were stratified to high or low risk for VTE: risk factors taken into account were obesity, history of VTE, central venous catheter, inhered thrombophilia, surgical procedures and comorbidities such as infections, immobilization, cardiac disease, chronic renal disease. Low risk patients had no or one risk factor; in case of two or more risk factors, the patients were classified as high risk. Low-dose aspirin (ASA 100 mg per os once daily) or equivalent was prescribed in low risk patients, low-molecular-weight heparin (LMWH) or equivalent was given to high risk patients. Only Dara treatment did not include standard prophylaxis in patients without risk factors. RESULTS: Real life observation revealed a low incidence of VTE (6 VTE-4,3%) in patients exposed to novel agents together with a standard prophylaxis in case of risk of thromboembolic complications. Forty patients were at high risk of VTE, while 97 patients were classified as low risk; VTE/PE occurred in 2 high risk patients who refused to make correct LMWH prophylaxis due to the discomfort of the subcutaneous administration, developing distal DVT respectively after cycle 1 and 2 of KRd. Two low risk patients treated with PomaD developed DVT of lower extremities during cycle 2 and 4; 2 low risk patients had pulmonary embolism during PomaD cycle 8. CONCLUSIONS: Low incidence of VTE in patients with RRMM receiving PomaD, KRd, EloRd, DaraVD, DaraRd, Dara or EloRd treatment is probably due to a correct risk assessment and subsequent prophylaxis in case of therapies including immunomodulators or in case of patients with high risk for thromboembolic complications. These data support the use of VTE risk stratification-based prophylactic strategies in myeloma patients treated with new drugs. Disclosures Conticello: Celgene: Consultancy, Honoraria, Research Funding; Amgen: Consultancy, Honoraria, Research Funding. Di Raimondo:Takeda: Consultancy; Amgen: Consultancy, Honoraria, Research Funding.

Direct Oral Anticoagulant Use and Outcomes in Patients with High and Intermediate Risk BCR-ABL-Negative Myeloproliferative Neoplasms

Background: Patients with BCR-ABL-negative myeloproliferative neoplasms (MPNs) are prone to thrombohemorrhagic complications. Vitamin K antagonists (VKA) or low weight molecular heparin (LWMH) are considered standard treatments for venous or arterial thromboses in BCR-ABL-negative MPN patients. However, there is little information regarding the safety and efficacy of direct oral anticoagulants (DOACs) in this population. Our primary aim was to determine the prevalence and outcomes of DOAC use in BCR-ABL-negative MPN patients at our institution. Methods: We performed a single-center, retrospective cohort study of all active BCR-ABL-negative MPN patients in the UCSF Hematology Clinic between January 2017 and March 2019. Patients were identified by ICD-10 codes and chart abstraction. Problem and medication lists were reviewed for appropriate diagnoses and medications. Provider notes were reviewed for anticoagulation indication, treatment course, and hemorrhagic or thrombotic complications. Descriptive statistics were used to summarize the data. Results: Of 299 patients with BCR-ABL-negative MPNs, 42 were treated with anticoagulation during our abstraction period. Of the 42 patients, 22 (52%) were treated with DOACs, 17 (41%) with warfarin, and 3 (7%) with LWMH. Of the 22 patients on DOACs, the median age was 74 (range 39-94) with a female to male ratio of 1.2:1. Of those on DOACs, the most common diagnosis was essential thrombocythemia (ET) (n=9; 41%), followed by primary myelofibrosis (MF) and post-ET or post-PV myelofibrosis (n=7; 32%), polycythemia vera (PV) (n=5; 22%), and MPN-Unclassifiable (n=1; 5%). All ET and PV patients (except 1 ET) were high-risk by IPSET-thrombosis and clinical criteria, and all primary myelofibrosis and post-ET or post-PV myelofibrosis patients were intermediate-2 by DIPSS-plus. Most patients were JAK2 V617F positive (n=19; 86%), with the remainder positive for CALR type 2 (n=2; 9%) and type 1 (n=1; 5%). Almost all ET and PV patients were concurrently treated with hydroxyurea (12/14; 86%) and 1 out of 5 PV patients was also treated with phlebotomy. Roughly one-third of patients (n=8; 36%) remained on aspirin while on a DOAC. Of the 22 patients, 15 (68%) were prescribed DOACs for thrombosis treatment and prophylaxis. The primary indications were pulmonary embolus (PE) (n=5), deep venous thrombosis (DVT) (n=4), splanchnic thrombosis (SVT) (n=3), organ ischemia (n=2), and cerebral sinus thrombosis (CVT) (n=1). The remaining 7 patients were on DOACs for atrial fibrillation, although two had histories of prior thrombotic events (PE and stroke). Nine (41%) of the patients on DOACs had a history of more than one significant venous or arterial thrombotic event. Most were on long-term anticoagulation with a median DOAC prescription of 26 months (range 4 to 62). Nineteen patients (86%) remained on a DOAC at their last provider visit, with two having completed treatments for provoked PEs and one discontinued for thrombocytopenia. DOACs prescribed for thrombosis indications included apixaban (n=8), rivaroxaban (n=5), and dabigatran (n=2). Of the 22 patients on DOACs, none experienced significant thrombotic events and one patient had a hemorrhagic event shortly before establishing care at our institution; a post-PV MF patient on dabigatran for a splanchnic thrombosis had an upper gastrointestinal bleed and required reversal with idarucizumab. Of the patients on warfarin and LWMH, there were 4 significant thrombohemorrhagic events: 1 bleeding and 3 clotting. The bleeding event happened in a high risk ET patient on warfarin plus aspirin for a splanchnic vein thrombosis (INR 2.2). Three clotting events occurred in high risk ET and PV patients on warfarin. One was concurrently diagnosed with a DVT, PE, and arterial thrombus (INR 2.1), and the other two were diagnosed with portal vein thromboses (INRs of 1.8 and 2.2). None were taking hydroxyurea or aspirin at time of their recurrent thrombosis. Conclusions: DOACs were used more frequently than warfarin or LWMH in our high and intermediate risk BCR-ABL-negative MPN patients with no clotting events but one notable hemorrhagic event. Future research regarding the safety and efficacy of DOAC use in BCR-ABL-negative MPNs, including randomized controlled trials, should be considered. Disclosures Damon: Jazz Pharmaceuticals: Membership on an entity's Board of Directors or advisory committees. Logan:Incyte: Membership on an entity's Board of Directors or advisory committees; Novartis: Consultancy; TeneoBio: Consultancy; Kadmon: Research Funding; Pharmacyclics: Research Funding; Abbvie: Consultancy; Astellas: Research Funding; Amgen: Consultancy, Membership on an entity's Board of Directors or advisory committees; Kiadis: Consultancy; Kite: Research Funding; Agios: Consultancy, Membership on an entity's Board of Directors or advisory committees; Jazz: Research Funding. Olin:MedImmune: Research Funding; Ignyta: Research Funding; Clovis: Research Funding; Mirati Therapeutics: Research Funding; AstraZeneca: Research Funding; Genentech: Consultancy, Research Funding; Pfizer: Research Funding; Spectrum: Research Funding; Jazz Pharmaceuticals: Consultancy, Honoraria; Novartis: Research Funding; Revolution Medicine: Consultancy; Daiichi Sankyo: Research Funding; Astellas: Research Funding. Smith:Revolution Medicines: Research Funding; Astellas Pharma: Research Funding; fujiFilm: Research Funding; Abbvie: Research Funding.

Risk of Thrombosis in Adult Philadelphia-Positive ALL Treated with an Asparaginase-Free Pediatric-Inspired ALL Regimen with Imatinib

Background: Venous thromboembolism (VTE) is a well-known complication in adults with acute lymphoblastic leukemia (ALL) receiving asparaginase (ASNase) based therapy. The MD Anderson Cancer Centre reported an overall VTE incidence of 29% (14/49) in patients with Philadelphia positive ALL (Ph+ ALL) treated with Hyper-CVAD and in the absence of ASNase (Vu et al. Cancer Medicine. 2015;4(1):27-35. doi:10.1002/cam4.332). The VTE incidence in adult Ph+ ALL patients treated with tyrosine kinase inhibitor plus the pediatric-inspired regimen modified from the Dana Farber Cancer Institute (DFCI) ALL protocol remains unclear. We have previously compared the incidence of VTE in adults with Ph+ ALL treated with or without ASNase during the intensification phase of the modified DFCI treatment. This study suggested that patients with Ph+ve ALL experience high incidence of VTE, even in the absence of ASNase, and that this risk is not restricted to the intensification phase. As ASNase was omitted from the protocol due to toxicity since 2008, in this report, we provide further insight into the risk of VTE in adults with Ph+ ALL during the entire ASNase-free DFCI treatment course. Methods: A single-institution retrospective review of sequential Ph+ ALL patients treated at Princess Margaret Cancer Center (PMCC) from 2008-2018 with an imatinib-containing DFCI protocol-based regimen that omitted ASNase. VTE events were recorded from the time of diagnosis to the end of modified DFCI treatment, including at the time of allogenic bone marrow transplantation. Co-variants of age, sex, weight, BMI, Padua score, white blood cell count, and platelet count were also collected. Statistical analyses were performed using the 2-tailed t test. Results: Overall, 130 patients were included for analysis; none received prophylactic anticoagulation. Among the 130 Ph+ ALL patients treated with the modified DFCI protocol, 28 (21.5%) patients had at least 1 VTE events from diagnosis to the end of treatment. The mean age of patients with and without VTE were 56.8 and 49.0 years, respectively (p=0.014) (Table 1). The majority of the VTE events occurred during active treatment, with 9 (7.0%), 11 (8.5%), and 4 (3.1%) occurring during induction, intensification, and maintenance, respectively (Figure 1). Only four patients (3.1%) presented with VTE at the time of diagnosis. Of all VTE events, 14 (50%) were DVT and/or PE, 12 (43%) were line-related, and 2 (7%) involved a cardiac thrombus (Table 2). The average Padua score for these patients was 5.4 with a range of 3-10. All VTE events were treated with low weight molecular heparin (LMWH), with 2 patients experiencing a recurrent episode within a year while on LMWH treatment. Bleeding following anticoagulation was rare. One patient experienced a major bleeding into the psoas muscle while on LMWH plus platelet transfusion for a right atrial clot during the induction phase in ICU. No other significant bleeding event was observed. Conclusion: VTE was observed in more than 20% of adults with Ph+ ALL patients treated with imatinib plus a modified DFCI pediatric ALL protocol. The majority of VTE events occurred during active treatment (induction and intensification), and DVT/PE incidence was similar to that of line-related thrombosis. The high observed VTE incidence suggests that prophylactic anticoagulation should be considered for adult patients with Ph+ ALL even in ASNase-free regimens, especially if additional thromboembolic risk factors are present. Disclosures Maze: Pfizer Inc: Consultancy; Novartis: Honoraria, Membership on an entity's Board of Directors or advisory committees. Chan:Celgene: Honoraria, Research Funding; Agios: Honoraria; AbbVie Pharmaceuticals: Research Funding. Gupta:Sierra Oncology: Honoraria, Membership on an entity's Board of Directors or advisory committees; Novartis: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Celgene: Honoraria, Membership on an entity's Board of Directors or advisory committees; Incyte: Honoraria, Research Funding. Yee:Novartis, Pfizer: Honoraria, Membership on an entity's Board of Directors or advisory committees; Astellas, Celgene, Otsuka, Shire, Takeda: Membership on an entity's Board of Directors or advisory committees; Agensys, Astex, Hoffman La Roche, MedImmune, Merck, Millenium, Roche/Genentech: Research Funding. Minden:Trillium Therapetuics: Other: licensing agreement. Schimmer:Novartis Pharmaceuticals: Consultancy; Otsuka Pharmaceuticals: Consultancy; Medivir Pharmaceuticals: Research Funding; Jazz Pharmaceuticals: Consultancy. Schuh:Jazz: Honoraria, Membership on an entity's Board of Directors or advisory committees; Pfizer: Honoraria, Membership on an entity's Board of Directors or advisory committees; Amgen: Honoraria, Membership on an entity's Board of Directors or advisory committees; AbbVie: Honoraria, Membership on an entity's Board of Directors or advisory committees; Agios: Honoraria; Celgene: Honoraria, Membership on an entity's Board of Directors or advisory committees; Astellas: Honoraria, Membership on an entity's Board of Directors or advisory committees; Teva Canada Innovation: Honoraria, Membership on an entity's Board of Directors or advisory committees. McNamara:Novartis Pharmaceutical Canada Inc.: Consultancy.

Lost in (Clinical) Translation: Recent Advances in Heparin Neutralization and Monitoring.

The heparin family, which includes unfractionated heparin, low-molecular heparin, and fondaparinux, is a class of drugs clinically used as intravenous blood thinners. To date, issues related to both the reversal of anticoagulation and the blood level determination of the anticoagulant at the point-of-care remain: while the only U.S. Food and Drug Administration (FDA) approved antidote for heparin displays serious efficacy and safety drawbacks, the current assays for heparin monitoring are indirect measurements subject to their own limitations and variations. Herein, we provide an update on the numerous recent chemical approaches to tackle these issues, from which it is clear that some new antidotes and sensors for heparin certainly have the potential to exceed current clinical standards. This review aims to review a field that requires close collaborations between physicians, biologists, and chemists in order to foster advances toward clinical translation.