Browsing by Subject "COAGULATION"

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  • Roininen, Saara; Laine, Outi; Kauppila, Marjut; Vesanen, Marko; Ramet, Maria; Sinisalo, Marjatta; Jantunen, Esa; Saily, Marjaana; Räty, Riikka; Elonen, Erkki; Wartiovaara-Kautto, Ulla (2017)
    Cerebral venous thrombosis (CVT) covers up to a third of all venous thromboses (VTs) detected in patients with acute lymphoblastic leukemia (ALL). It usually hampers patients' lives and may also endanger efficient leukemia treatment. Although many factors have been suggested to account for an elevated risk of VTs in patients with ALL, there still is a lack of studies focusing on CVTs and especially in the setting of adult ALL patients. We studied in our retrospective population-based cohort the occurrence, characteristics, as well as risk factors for VTs in 186 consecutively diagnosed Finnish adult ALL patients treated with a national pediatric-inspired treatment protocol ALL2000. In the risk factor analyses for VTs we found a distinction of the characteristics of the patients acquiring CVT from those with other kinds of VTs or without thrombosis. In contrast to previous studies we were also able to compare the effects of asparaginase in relation to CVT occurrence. Notably, more than half of the CVTs were diagnosed prior the administration of asparaginase which accentuates the role of other risk factors on the pathophysiology of CVT compared to truncal or central venous line (CVL) VTs in adult ALL patients.
  • Saraswat, Mayank; Joenvaara, Sakari; Seppanen, Hanna; Mustonen, Harri; Haglund, Caj; Renkonen, Risto (2017)
    Finland ranks sixth among the countries having highest incidence rate of pancreatic cancer with mortality roughly equaling incidence. The average age of diagnosis for pancreatic cancer is 69years in Nordic males, whereas the average age of diagnosis of chronic pancreatitis is 40-50years, however, many cases overlap in age. By radiology, the evaluation of a pancreatic mass, that is, the differential diagnosis between chronic pancreatitis and pancreatic cancer is often difficult. Preoperative needle biopsies are difficult to obtain and are demanding to interpret. New blood based biomarkers are needed. The accuracy of the only established biomarker for pancreatic cancer, CA 19-9 is rather poor in differentiating between benign and malignant mass of the pancreas. In this study, we have performed mass spectrometry analysis (High Definition MSE) of serum samples from patients with chronic pancreatitis (13) and pancreatic cancer (22). We have quantified 291 proteins and performed detailed statistical analysis such as principal component analysis, orthogonal partial least square discriminant analysis and receiver operating curve analysis. The proteomic signature of chronic pancreatitis versus pancreatic cancer samples was able to separate the two groups by multiple statistical techniques. Some of the enriched pathways in the proteomic dataset were LXR/RXR activation, complement and coagulation systems and inflammatory response. We propose that multiple high-confidence biomarker candidates in our pilot study including Inter-alpha-trypsin inhibitor heavy chain H2 (Area under the curve, AUC: 0.947), protein AMBP (AUC: 0.951) and prothrombin (AUC: 0.917), which should be further evaluated in larger patient series as potential new biomarkers for differential diagnosis.
  • Przybyla, Beata; Pinomäki, Anne; Petäjä, Jari; Joutsi-Korhonen, Lotta; Strandberg, Karin; Hillarp, Andreas; Öhlin, Ann-Kristin; Ruutu, Tapani; Volin, Liisa; Lassila, Riitta (2017)
    Background Allogeneic stem cell transplantation (SCT) enhances coagulation via endothelial perturbation and inflammation. Role of natural anticoagulants in interactions between coagulation and inflammation as well as in acute graft-versus-host disease (GVHD) are not well known. The purpose of this study was to define changes in natural anticoagulants over time in association with GVHD. Patients and methods This prospective study included 30 patients who received grafts from siblings (n = 19) or unrelated donors (n = 11). Eight patients developed GVHD. Standard clinical assays were applied to measure natural anticoagulants, represented by protein C (PC), antithrombin (AT), protein S (PS), complex of activated PC with its inhibitor (APC-PCI) and by markers of endothelial activation: Factor VIII coagulant activity (FVIII: C) and soluble thrombomodulin (s-TM) at 6-8 time points over three months. Results Overall, PC, AT and FVIII: C increased in parallel after engraftment. Significant correlations between PC and FVIII: C (r = 0.64-0.82, p Conclusion The coordinated activation of natural anticoagulants in our longitudinal study indicates the sustained ability of adaptation to endothelial and inflammatory activation during allogenic SCT treatment. The suboptimal control of coagulation by natural anticoagulants at early stage of SCT may contribute to onset of GVHD.
  • Laine, Antti; Niemi, Tomi; Suojaranta-Ylinen, Raili; Raivio, Peter; Soininen, Leena; Lemstrom, Karl; Hammainen, Pekka; Schramko, Alexey (2016)
    Background: We aimed to characterize the coagulation disturbances which may increase the risk of bleeding, thrombosis or death shortly after implantation of an extracorporeal membrane oxygenation (ECMO) or ventricular assist (VAD) device. Methods: Antithrombotic treatment was started in 23 VAD and 24 ECMO patients according to the hospital protocol. Additionally, conventional laboratory testing, rotational thromboelastometry (ROTEM (R)) and platelet function analysis (Multiplate) were performed at predetermined intervals. Results: Four out of twenty-four (16.7%) of ECMO patients and 6/23 (26.1%) of VAD patients had severe bleeding after the procedure. When all the patients were analyzed together, low maximum clot firmness (MCF) in ExTEM and FibTEM analyses was associated with severe bleeding (p Conclusion: Hypocoagulation shown by ROTEM (R) was associated with bleeding complications in patients with mechanical circulatory support. In contrast, hypercoagulation did not correlate with clinical thrombosis.
  • Chen, Jason; Verni, Christopher C.; Jouppila, Annukka; Lassila, Riitta; Diamond, Scott L. (2018)
    Heparin proteoglycans (HEP-PGs) carry standard heparin-mediated anticoagulant properties as well as novel antiplatelet functions, a combination that may be significant for targeting multiple pathways in a single therapy. Recent work developing semisynthetic HEP-PG mimetics has shown promising results also in vivo, however flow conditions in vitro that replicate in vivo hemodynamics have not been reported. In this work, we present several assays (platelet calcium mobilization, aggregometry, microfluidic tests at venous and arterial hemodynamics) to characterize specific mechanistic effects of dual antiplatelet and anticoagulant (APAC) constructs as mimetics of HEP-PGs. Three APACs with different conjugation levels of heparin chains (CL10, CL18, HICL) were shown to decrease platelet deposition to collagen surfaces in PPACK-treated whole blood at venous shear rate (200 s(-1)). FXIIa-inhibited whole blood (CTI: corn trypsin inhibitor, 40 mu g/mL) perfused over collagen/tissue factor showed reduced both platelet and fibrin deposition when treated with APACs. IC50 values for platelet and fibrin inhibition were calculated for each molecule at venous shear rate. Increasing the shear rate to arterial flows (1000 s(-1)) and using APAC as the sole anticoagulant, resulted in a more potent antiplatelet effect of APAC, suggesting an added effect on von Willebrand Factor (vWF) function. Additionally, APAC caused an inhibition of calcium mobilization specific to thrombin and collagen stimulation and a dose-dependent reduction in collagen-mediated platelet aggregation. Understanding the sensitivity of APAC activity to shear rate, platelet signaling and procoagulant pathways is important for applications in which APAC administration may have beneficial therapeutic effects.
  • Lillemäe, Kadri; Luostarinen, Teemu; Reinikainen, Matti; Bendel, Stepani; Laitio, Ruut; Hoppu, Sanna; Ala-Kokko, Tero; Niemi, Tomi; Skrifvars, Markus B.; Raj, Rahul (2022)
    Background Coagulopathy after traumatic brain injury (TBI) is associated with poor prognosis. Purpose To assess the prevalence and association with outcomes of early thrombocytopenia in patients with TBI treated in the intensive care unit (ICU). Methods This is a retrospective multicenter study of adult TBI patients admitted to ICUs during 2003-2019. Thrombocytopenia was defined as a platelet count < 100 x 10(9)/L during the first day. The association between thrombocytopenia and hospital and 12-month mortality was tested using multivariable logistic regression, adjusting for markers of injury severity. Results Of 4419 patients, 530 (12%) had early thrombocytopenia. In patients with thrombocytopenia, hospital and 12-month mortality were 26% and 48%, respectively; in patients with a platelet count > 100 x 10(9)/L, they were 9% and 22%, respectively. After adjusting for injury severity, a higher platelet count was associated with decreased odds of hospital mortality (OR 0.998 per unit, 95% CI 0.996-0.999) and 12-month mortality (OR 0.998 per unit, 95% CI 0.997-0.999) in patients with moderate-to-severe TBI. Compared to patients with a normal platelet count, patients with thrombocytopenia not receiving platelet transfusion had an increased risk of 12-month mortality (OR 2.2, 95% CI 1.6-3.0), whereas patients with thrombocytopenia receiving platelet transfusion did not (OR 1.0, 95% CI 0.6-1.7). Conclusion Early thrombocytopenia occurs in approximately one-tenth of patients with TBI treated in the ICU, and it is an independent risk factor for mortality in patients with moderate-to-severe TBI. Further research is necessary to determine whether this is modifiable by platelet transfusion.
  • Borges, Alvaro H.; O'Connor, Jemma L.; Phillips, Andrew N.; Baker, Jason V.; Vjecha, Michael J.; Losso, Marcelo H.; Klinker, Hartwig; Lopardo, Gustavo; Williams, Ian; Lundgren, Jens D.; INSIGHT SMART Study Grp; ESPRIT Study Grp; SILCAAT Sci Comm; Ristola, Matti A (2014)
  • Ilmakunnas, M.; Turunen, A. J.; Lindgren, L.; Salmela, K. T.; Kyllönen, L. E.; Andersson, S.; Petäjä, J.; Pesonen, E. J. (2019)
    Background. Inflammation, coagulation, and fibrinolysis are tightly linked together. Reperfusion after transient ischemia activates both neutrophils, coagulation, and fibrinolysis. Experimental data suggest that tissue plasminogen activator (tPA) regulates renal neutrophil influx in kidney ischemia and reperfusion injury. Methods. In 30 patients undergoing kidney transplantation, we measured renal neutrophil sequestration and tPA release from blood samples drawn from the supplying artery and renal vein early after reperfusion. tPA antigen levels were measured using a commercial enzyme-linked immunosorbent assay kit. For each parameter, transrenal difference (Delta) was calculated by subtracting the value of the arterial sample (ingoing blood) from the value of the venous sample (outgoing blood). Results. Positive transrenal gradients of tPA antigen occurred at 1 minute [Delta = 14 (3-46) ng/mL, P <.01] and 5 minutes [Delta = 5 (-3 to 27) ng/mL, P <.01] after reperfusion. At 5 minutes after reperfusion, a negative transrenal gradient of neutrophils was observed [Delta = -0.17 (-1.45 to 0.24) x 10E9 cells/L, P <.001]. At 1 minute after reperfusion, neutrophil sequestration into the kidney (ie, negative transrenal neutrophil count) correlated significantly with tPA release from the kidney (ie, positive transrenal tPA concentration), (R = -0.513 and P = .006). Conclusions. The findings suggest a proinflammatory role for tPA in ischemia and reperfusion injury in human kidney transplantation.
  • Lax, Mikko; Pesonen, Eero; Hiippala, Seppo; Schramko, Alexey; Lassila, Riitta; Raivio, Peter (2020)
    Objective: High heparin doses during cardiopulmonary bypass (CPB) have been suggested to reduce thrombin activation and consumption coagulopathy and consequently bleeding complications. The authors investigated the effect of a high heparin dose during CPB on point-of-care measurements of coagulation. The authors hypothesized that during CPB a high heparin dose compared with a lower heparin dose would reduce thrombin generation and platelet activation and tested whether this would be reflected in the results of rotational thromboelastometry (TEM) and platelet aggregation, measured with multiple electrode aggregometry (MEA). Design: Prospective, randomized, controlled, open single-center study. Setting: University teaching hospital. Participants: Sixty-three consecutive patients undergoing elective coronary artery bypass grafting with CPB were enrolled. Interventions: Patients were randomly assigned to receive either a high (600 IU/kg, n = 32) or a low (300 IU/kg, n = 31) initial dose of heparin. Target levels of activated clotting time during CPB were >600 seconds in the high heparin dose group and >400 seconds in the low heparin dose group. Measurements and Main Results: Blood samples were collected (1) preoperatively after induction of anesthesia, (2) 10 minutes after aortic declamping, (3) 30 minutes after protamine administration, and (4) 3 hours after protamine administration. TEM and MEA were then measured. There was no difference in blood loss up to 18 hours postoperatively (median 735 mL for high dose v 610 mL for low dose; p <0.056) or transfusions between the groups. Total median heparin dose (54,300 IU v 27,000 IU; p = 0.001) and median antifactor Xa levels during CPB (9.38 U/mL v 5.04 U/mL; p = 0.001) were greater in the high than in the low heparin dose group. However, neither TEM nor MEA results differed significantly between the groups. Conclusions: Compared with a lower dose of heparin during CPB, a high dose of heparin had little effect on the point-of-care measurements of hemostasis, TEM, and MEA. Based on the similarity of platelet and coagulation activity assessments, the higher heparin dose does not appear to offer benefit during CPB. (C) 2020 Elsevier Inc. All rights reserved.
  • Mattila, N.; Hisada, Y.; Przybyla, B.; Posma, J.; Jouppila, A.; Haglund, C.; Seppänen, H.; Mackman, N.; Lassila, R. (2021)
    Background: Pancreatic ductal adenocarcinoma (PDAC) is associated with a hypercoagulable state and high mortality. Increases in the plasma levels of tumor marker carbohydrate antigen (CA) 19-9 are used in diagnosis and follow-up but have also been reported to precede venous thromboembolism (VTE). Aims: We examined the association between CA 19-9 and thrombin generation (TG) in plasma from PDAC patients, as well as their association with coagulation biomarkers prior to pancreatic surgery. In addition, we determined the effect of commercial sources of CA 19-9 on TG. Methods: We collected plasma from 58 treatment-naive PDAC patients without any signs of VTE. We measured levels of CA 19-9, FVIII, fibrinogen, D-dimer, antithrombin and extracellular vesicle (EV) tissue factor (TF) activity and TG using a Calibrated Automated Thrombogram (CAT). The effect of different commercial sources of CA 19-9 on TG in Standard Human Plasma (SHP) was also studied. Results: Patient plasma samples were divided into 4 preoperative groups based on the level of CA 19-9: none <2, low = 3200, high = 201-1000, and very high > 1000 U/mL. CA 19-9 levels were associated with several of the TG parameters, including endogenous thrombin potential, peak, and time to peak. CA 19-9 did not associate with any of the coagulation biomarkers. Spiking of SHP with CA 19-9 increased TG but this was decreased by an antiTF antibody. Conclusions: CA 19-9 was associated with TG in patients prior to any pancreatic cancer treatments or signs of VTE. Some commercial sources of CA 19-9 enhanced TG in SHP seemingly due to contaminating TF.
  • Asgharzadeh, Fereshteh; Barneh, Farnaz; Fakhraie, Maryam; Barkhordar, Seyede Leili Adel; Shabani, Mohammad; Soleimani, Atena; Rahmani, Farzad; Ariakia, Fatemeh; Mehraban, Saeedeh; Avan, Amir; Hashemzehi, Milad; Arjmand, Mohammad-Hassan; Behnam-Rassouli, Reyhaneh; Jaberi, Najmeh; Sayyed-Hosseinian, Sayyed-Hadi; Ferns, Gordon A.; Ryzhikov, Mikhail; Jafari, Mohieddin; Khazaei, Majid; Hassanian, Seyed Mahdi (2021)
    Circulating inflammatory factor inorganic polyphosphate (polyP) released from activated platelets could enhance factor XII and bradykinin resulted in increased capillary leakage and vascular permeability. PolyP induce inflammatory responses through mTOR pathway in endothelial cells, which is being reported in several diseases including atherosclerosis, thrombosis, sepsis, and cancer. Systems and molecular biology approaches were used to explore the regulatory role of the AMPK activator, metformin, on polyP-induced hyper-permeability in different organs in three different models of polyP-induced hyper-permeability including local, systemic shortand systemic long-term approaches in murine models. Our results showed that polyP disrupts endothelial barrier integrity in skin, liver, kidney, brain, heart, and lung in all three study models and metformin abrogates the disruptive effect of polyP. We also showed that activation of AMPK signaling pathway, regulation of oxidant/ anti-oxidant balance, as well as decrease in inflammatory cell infiltration constitute a set of molecular mechanisms through which metformin elicits it's protective responses against polyP-induced hyper-permeability. These results support the clinical values of AMPK activators including the FDA-approved metformin in attenuating vascular damage in polyP-associated inflammatory diseases.
  • Helenius-Hietala, Jaana; Åberg, Fredrik; Meurman, Jukka H.; Nordin, Arno; Isoniemi, Helena (2016)
    Objective. Untreated dental infections pose a threat for immunocompromised liver transplant (LT) recipients. Therefore, pretransplant dental evaluations are recommended. However, risk of bleeding should be considered among patients with end-stage liver disease, and prophylactic blood transfusions may be used to prevent bleeding. We performed a retrospective study of the incidence of and risk factors for oral surgery-related bleeding in candidates for LT and hypothesized that complications may occur despite preoperative and perioperative hemostatic actions. Study Design. One hundred thirty-four patients who had tooth extractions performed by oral and maxillofacial surgeons before LT were studied. The primary endpoint was bleeding between 24 hours and 2 weeks after extraction. Bleeding risk was analyzed by preoperative platelet (PLT) count and international normalized ratio (INR). Invasiveness of procedures, severity of liver disease, PLT, INR, prophylactic transfusions of PLT, fresh frozen plasma, and tranexamic acid (TA) were included in univariate and multivariate logistic regression analyses to further assess risk. Results. Twelve patients exhibited minor bleeding; four despite PLT > 100 x 10(9)/L and INR <1.5. Increased bleeding associated with INR and prophylactic transfusions by univariate analysis; by multivariate analyses, prophylactic TA (odds ratio [OR] = 8.0; 95% confidence interval [CI] 1.7-37.0), and PLT (OR = 8.3; 95% CI 1.1-62.7) remained significant. Conclusions. Most extractions were safe, but prophylactic transfusions did not ensure adequate hemostasis. Local hemostatic measures and close follow-up are warranted.
  • Mattila, Nora; Seppänen, Hanna; Mustonen, Harri; Przybyla, Beata; Haglund, Caj; Lassila, Riitta (2018)
    Pancreatic ductal adenocarcinoma (PDAC) is a deadly cancer often diagnosed late. Earlier detection is urgently needed. Pancreatic ductal adenocarcinoma is known to associate with increased coagulation activity. We studied whether preoperative coagulation biomarkers are useful in distinguishing PDAC from a benign tumor, intraductal papillary mucinous neoplasm (IPMN) in this observational study. We analyzed standard clinical and coagulation variables in patients operated during 2010 and 2015 at Helsinki University Hospital. Pancreatic ductal adenocarcinoma with preoperative coagulation variables available and no neoadjuvant treatment or other active cancer was observed in 80 patients (stage I-III in 67 and IV in 13) and IPMN in 18 patients. Fibrinogen, factor VIII (FVIII), carbohydrate antigen (CA) 19-9, albumin, alkaline phosphatase, and conjugated bilirubin were higher in both stages I to III and IV PDAC compared to IPMN (P <.05). Factor VIII was highest in stage IV (P <.05). Combining these variables in a panel increased sensitivity and specificity for PDAC. In receiver operating characteristic analysis, the area under the curve (95% confidence interval) was 0.95 (0.90-1.00) for the panel, compared to 0.80 (0.71-0.88) for CA 19-9 alone (P <.01). In conclusion, PDAC was associated with increased fibrinogen and FVIII. Combining these coagulation biomarkers with CA 19-9, albumin, and alkaline phosphatase improves diagnostic accuracy.
  • Jokinen, Ville; Kankuri, Esko; Hoshian, Sasha; Franssila, Sami; Ras, Robin H. A. (2018)
    Superhydrophobic surfaces repel water and, in some cases, other liquids as well. The repellency is caused by topographical features at the nano-/microscale and low surface energy. Blood is a challenging liquid to repel due to its high propensity for activation of intrinsic hemostatic mechanisms, induction of coagulation, and platelet activation upon contact with foreign surfaces. Imbalanced activation of coagulation drives thrombogenesis or formation of blood clots that can occlude the blood flow either on-site or further downstream as emboli, exposing tissues to ischemia and infarction. Blood-repellent superhydrophobic surfaces aim toward reducing the thrombogenicity of surfaces of blood-contacting devices and implants. Several mechanisms that lead to blood repellency are proposed, focusing mainly on platelet antiadhesion. Structured surfaces can: (i) reduce the effective area exposed to platelets, (ii) reduce the adhesion area available to individual platelets, (iii) cause hydrodynamic effects that reduce platelet adhesion, and (iv) reduce or alter protein adsorption in a way that is not conducive to thrombus formation. These mechanisms benefit from the superhydrophobic Cassie state, in which a thin layer of air is trapped between the solid surface and the liquid. The connections between water-and blood repellency are discussed and several recent examples of blood-repellent superhydrophobic surfaces are highlighted.
  • Niinikoski-Fusswinkel, Paula; Purkamo, Lotta; Karhu, Juha (2020)
    This study examines the effect of poly-aluminium chloride (PACl) pre-treatment on the biological purification process taking place during managed aquifer recharge (MAR). PACl treatment is used in waste and surface water treatment to remove organic material. PACl can decrease the organic carbon contents of water significantly. However, aluminium is toxic to microbes, which may be detrimental when the PACl treatment is followed by infiltration into an aquifer (MAR). In this study the effect of pre-treatment with PACl on the water purification process in MAR was examined, by using sediment from a MAR site in four test columns. Two columns were filled with PACl-treated water, and the remaining ones with river water without PACl. The residence time of water in the columns was raised from direct sampling gradually to 64 days. Among the parameters monitored were the pH of the water, microbial activity and the decomposition of dissolved organic carbon (DOC). The results showed active decomposition in all columns. Decomposition of organic matter, and the amount of living/active microbial cells, was marginally higher in the untreated water, which could imply a better functioning MAR system. However, this may also be due to higher DOC starting concentration.
  • Forsblom, E.; Tielinen, I.; Ruotsalainen, E.; Jarvinen, A. (2017)
    The prognostic impact of thrombocytopaenia in Staphylococcus aureus bacteraemia (SAB) has previously been determined at bacteraemia onset only and relevant pre-bacteraemic thrombocytopaenia predisposing parameters have not been accounted for. We evaluated the prognostic impact of low thrombocyte count in SAB excluding pre-bacteraemic factors potentially causing thrombocytopaenia. This was a multicentre retrospective analysis of methicillin-sensitive SAB (MS-SAB) patients. Thrombocyte count was determined at blood culture collection and at days 3 and 7. Thrombocytopae nia was defined as a thrombocyte count less than 150 x 10(9)/L. Patients with chronic alcoholism, liver diseases and haematologic malignancies were excluded. Altogether, 495 patients were identified. Thrombocytopaenia at blood culture and at day 3 associated to endocarditis (p <0.05 and p <0.01) and defervescence (p <0.001 and p <0.01). Mortality at 90 days was higher for patients with thrombocytopaenia at blood culture collection (26 vs. 16%, p <0.05), at day 3 (32 vs. 13%, p <0.01) and at day 7 (50 vs. 14%, p <0.001). In receiver operating characteristic analyses, thrombocytopaenia predicted a poor outcome at blood culture collection (p <0.05), at day 3 (p <0.001) and at day 7 (p <0.001). When accounting for all prognostic parameters, thrombocytopaenia at day 3 [hazard ratio (HR), 1.83; p = 0.05] demonstrated a trend towards poor outcome, whereas thrombocytopaenia at day 7 (HR, 3.64; p <0.001) associated to poor outcome. Thrombocytopaenia at blood culture collection was not a prognostic parameter when all prognostic factors were taken into account. However, thrombocytopaenia at day 3 indicated a poor outcome and thrombocytopaenia at day 7 was a significant independent negative prognostic marker that has not been previously reported in SAB.