Publications by authors named "Riitta Lassila"

111 Publications

Treatment outcomes in persons with severe haemophilia B in the Nordic region: The B-NORD study.

Haemophilia 2021 Mar 29. Epub 2021 Mar 29.

Clinical Coagulation Research, Department of Translational Medicine, Lund University, Malmö, Sweden.

Introduction: Data on outcome in persons with haemophilia B (PwHB) are limited and mainly extrapolated from studies of haemophilia A (HA).

Aim: To characterize treatment outcomes in persons with severe HB in the Nordic region, with a focus on joint health, compared with matched controls with HA.

Methods: PwHB attending haemophilia centres in Denmark, Finland, Norway and Sweden were enrolled and matched with controls with HA. Joint assessment using Haemophilia Joint Health Score (HJHS) and ultrasound according to Haemophilia Early Arthropathy Detection protocol (HEAD-US) was conducted. Adherence was evaluated using the Validated Haemophilia Regimen Treatment Adherence Scale (VERITAS).

Results: Seventy-nine males with HB, with median age of 30 years (range 1-75), were enrolled. Eleven patients (14%) had a history of or current inhibitor. Twenty-nine PwHB (37%) reported joint bleeds during the prior year, and 35% had previously undergone joint surgery. Ninety-five per cent were on prophylaxis, and 70% used recombinant concentrates, with a median factor consumption of 3,900 IU/kg/year for standard half-life products. Only two patients had a VERITAS score corresponding to 'non-adherence'. Joint health, assessed with HJHS, showed a significant lower score among PwHB compared with HA controls, explained by a difference in the 18-49 age group, without observed differences in older or younger subgroups. The HEAD-US scores were overall low.

Conclusion: The Nordic cohort of PwHB is well treated by prophylaxis, but the goal of zero bleeds for all is not reached. Our findings suggest that patients with severe HB suffer from a milder arthropathy than patients with severe HA.
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http://dx.doi.org/10.1111/hae.14299DOI Listing
March 2021

Whole Blood Thromboelastometry by ROTEM and Thrombin Generation by Genesia According to the Genotype and Clinical Phenotype in Congenital Fibrinogen Disorders.

Int J Mol Sci 2021 Feb 25;22(5). Epub 2021 Feb 25.

Division of Angiology and Hemostasis, University Hospitals of Geneva, 1211 Geneva, Switzerland.

The outcome of congenital fibrinogen defects (CFD) is often unpredictable. Standard coagulation assays fail to predict the clinical phenotype. We aimed to assess the pheno- and genotypic associations of thrombin generation (TG) and ROTEM in CFD. We measured fibrinogen (Fg) activity and antigen, prothrombin fragments F1+2, and TG by ST Genesia with both Bleed- and ThromboScreen in 22 patients. ROTEM was available for 11 patients. All patients were genotyped for fibrinogen mutations. Ten patients were diagnosed with hypofibrinogenemia, nine with dysfibrinogenemia, and three with hypodysfibrinogenemia. Among the 17 mutations, eight were affecting the Fg γ chain, four the Fg Bβ chain, and five the Fg Aα chain. No statistical difference according to the clinical phenotypes was observed among and mutations. Median F1+2 and TG levels were normal among the different groups. Fg levels correlated negatively with F1+2 and peak height, and positively with lag time and time to peak. The pheno- and genotypes of the patients did not associate with TG. FIBTEM by ROTEM detected hypofibrinogenemia. Our study suggests an inverse link between low fibrinogen activity levels and enhanced TG, which could modify the structure-function relationship of fibrin to support hemostasis.
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http://dx.doi.org/10.3390/ijms22052286DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7956597PMC
February 2021

Characterisation of healthcare utilisation and cost of haemophilia care in real-life: A 4-year follow-up study in Finland.

Haemophilia 2021 Jan 20;27(1):e30-e39. Epub 2020 Nov 20.

Coagulation Disorders Unit, Department of Haematology, Comprehensive Cancer Centre, Helsinki University and Helsinki University Hospital, Helsinki, Finland.

Introduction: Characterisation of outcomes and costs of haemophilia care in common practice settings is essential for evaluation of new treatment options and for developing clinical practices. In Finland, haemophilia care is mostly centralised to University Hospitals, but treatment practices and costs in adult patients have not been systematically evaluated.

Aim: This study was designed to characterise healthcare resource utilisation and treatment costs of adult inhibitor-negative haemophilia patients managed in Finnish University Hospitals.

Methods: The study was based on a nationwide cohort, which consists of all adult haemophilia A (HA; n = 120) and B (HB; n = 35) patients treated in University Hospitals from 2012 to 2016. Patient characteristics and data on healthcare utilisation and factor replacement use were collected from medical records. Direct costs of care were evaluated based on wholesale drug prices and healthcare service utilisation with standard unit costs.

Results: Most of HA (79%, n = 96) and HB (84%, n = 31) patients received factor replacement therapy. The median annual bleeding rate (ABR) was low, at 0.8 for HA and 0.5 for HB, also among the patients with on-demand therapy. Over 94% (n = 149) of the patients had outpatient visits during the follow-up period. The mean total annual costs of treatment ranged from €2520 to €176,330. The highest individual cost was factor replacement therapy.

Conclusion: The outcomes of centralising the management of care to University Hospital Treatment Centres show low ABR and lower treatment costs compared with earlier reports from other high-income European populations. Management strategies, including choosing the right therapy between prophylaxis and on-demand, has been successful in Finland.
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http://dx.doi.org/10.1111/hae.14197DOI Listing
January 2021

Joint health and treatment modalities in Nordic patients with moderate haemophilia A and B - The MoHem study.

Haemophilia 2020 Sep 27;26(5):891-897. Epub 2020 Jul 27.

Department of Haematology, Oslo University Hospital, Oslo, Norway.

Introduction: The prevalence of arthropathy in moderate haemophilia A (MHA) and B (MHB) is not well known.

Aim: We evaluated joint health in Nordic patients in relation to their treatment modality.

Methods: A cross-sectional, multicentre study covering MHA and MHB in Sweden, Finland and Norway. Arthropathy was evaluated by ultrasound (HEAD-US) and Haemophilia Joint Health Score (HJHS).

Results: We report on 145 patients: median age 28 years (IQR 13-52) and 61% MHA. Baseline factor VIII/factor IX activity (FVIII/FIX:C) was 2 IU/dL (median) (IQR 2-4): lower for MHB (2 IU/dL, IQR 1-2) than MHA (3 IU/dL, IQR 2-4) (P < .01). Eighty-five per cent of MHA and 73% MHB had a history of haemarthrosis (P = .07). Age at first joint bleed was lower for MHA (5 years [median], IQR 3-7) than MHB (7 years, IQR 5-12) (P = .01). Thirty-eight per cent received prophylaxis, started at median 10 years of age (IQR 4-24). Median joint bleeds and serious other bleeds during the last 12 months were both zero (IQR 0-1). Total HEAD-US captured 0/48 points (median) (IQR 0-2) and HJHS 4/120 points (IQR 1-10) with strong correlation between them (r = .72).

Fviii/fix: C ≤ 3 IU/dL was associated with higher HJHS (P = .04). Fifteen per cent had undergone orthopaedic surgery.

Conclusion: The current joint health in Nordic moderate haemophilia patients was rather good, but a subgroup had severe arthropathy.

Fviii/fix: C ≤ 3 IU/dL and MHA were associated with a more severe bleeding phenotype. We suggest primary prophylaxis to all patients with FVIII/FIX:C ≤ 3 IU/dL.
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http://dx.doi.org/10.1111/hae.14114DOI Listing
September 2020

Continuous intravenous infusion of enoxaparin controls thrombin formation more than standard subcutaneous administration in critically ill patients. A sub-study of the ENOKSI thromboprophylaxis RCT.

Acta Anaesthesiol Scand 2021 01 16;65(1):109-115. Epub 2020 Sep 16.

Department of Intensive Care Medicine, Tampere University Hospital, PO Box 2000, Tampere, 33521, Finland.

Introduction: Standard subcutaneous low-molecular-weight heparin (LMWH) thromboprophylaxis yields low anti-factor Xa activity in patients in the intensive care unit (ICU). The aim of the study was to assess coagulation status in ICU patients randomized to receive enoxaparin thromboprophylaxis either as a standard subcutaneous bolus (SCB) or continuous intravenous infusion (CII) for 3 consecutive days after the initiation of LMWH thromboprophylaxis.

Materials And Methods: Thirty-eight patients were studied by conventional coagulation variables: prothrombin fragment F 1+2 (F 1+2) representing FXa inhibition and antithrombin (AT). Additionally, 18 patients were analyzed by the thrombin generation assay-calibrated automated thrombogram (TGA-CAT). Blood samples were collected before the initiation of the LMWH thromboprophylaxis (ie, baseline), at 51 h, and at 72 h.

Results: At beginning, no differences in coagulation biomarkers were observed. The levels of F 1+2 were significantly lower at 51 and 72 h in the CII group than in the SCB group. AT levels increased during the follow-up in the CII group, unlike in the SCB group. TGA-CAT was poor in some patients overall. In a subset of patients at 51 h lag time (4.3 vs 7.5 min, respectively, P < 0.05) and time to peak (7.7 vs 14.3 min, respectively, P < 0.05) were prolonged in the SCB group. At 72 h, however, peak thrombin was lower in the CII than in the SCB group: 271 vs 356 nM, respectively (P < 0.05).

Conclusions: Enoxaparin thromboprophylaxis administered by CII inhibited more prominently FXa and preserved better the AT level, compared with standard subcutaneous care.
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http://dx.doi.org/10.1111/aas.13697DOI Listing
January 2021

COVID-19 and SIC (!).

J Vasc Surg 2020 09 1;72(3):1148-1150. Epub 2020 Jun 1.

Coagulation Disorders Unit, University of Helsinki, Departments of Haematology and Clinical Chemistry (HUSLAB Laboratory Services), Comprehensive Cancer Center, Helsinki University Hospital and Research Program in Systems Oncology, Faculty of Medicine, University of Helsinki and Helsinki University, Faculty of Medicine, Research Program in Oncology, Helsinki, Finland; Aplagon Oy, Helsinki, Finland.

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http://dx.doi.org/10.1016/j.jvs.2020.05.047DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7262520PMC
September 2020

Bleeding symptoms in patients diagnosed as type 3 von Willebrand disease: Results from 3WINTERS-IPS, an international and collaborative cross-sectional study.

J Thromb Haemost 2020 09 25;18(9):2145-2154. Epub 2020 Aug 25.

Hematology and Transfusion Medicine, Department of Oncology and Oncohematology, L. Sacco University Hospital, University of Milan, Milano, Italy.

Background: Type 3 von Willebrand's disease (VWD) patients present markedly reduced levels of von Willebrand factor and factor VIII. Because of its rarity, the bleeding phenotype of type 3 VWD is poorly described, as compared to type 1 VWD.

Aims: To evaluate the frequency and the severity of bleeding symptoms across age and sex groups in type 3 patients and to compare these with those observed in type 1 VWD patients to investigate any possible clustering of bleeding symptoms within type 3 patients.

Methods: We compared the bleeding phenotype and computed the bleeding score (BS) using the MCMDM-1VWD bleeding questionnaire in patients enrolled in the 3WINTERS-IPS and MCMDM-1VWD studies.

Results: In 223 unrelated type 3 VWD patients, both the BS and the number of clinically relevant bleeding symptoms were increased in type 3 as compared to type 1 VWD patients (15 versus 6 and 5 versus 3). Intracranial bleeding, oral cavity, hemarthroses, and deep hematomas were at least five-fold over-represented in type 3 VWD. A more severe bleeding phenotype was evident in patients having von Willebrand factor antigen levels < 20 IU/dL at diagnosis in the two merged cohorts. In type 3 patients, there was an apparent clustering of hemarthrosis with gastrointestinal bleeding and epistaxis, whereas bleeding after surgery or tooth extraction clusters with oral bleeding and menorrhagia.

Conclusions: In the largest cohort of type 3 VWD patients, we were able to describe a distinct clinical phenotype that is associated with the presence of a more severe hemostatic defect.
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http://dx.doi.org/10.1111/jth.14886DOI Listing
September 2020

Heparin Dose and Point-of-Care Measurements of Hemostasis in Cardiac Surgery-Results of a Randomized Controlled Trial.

J Cardiothorac Vasc Anesth 2020 Sep 7;34(9):2362-2368. Epub 2020 Jan 7.

Department of Cardiac Surgery, Heart, and Lung Center, University of Helsinki and Helsinki University Hospital, Helsinki, Finland.

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.
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http://dx.doi.org/10.1053/j.jvca.2019.12.050DOI Listing
September 2020

Fundamentals for a Systematic Approach to Mild and Moderate Inherited Bleeding Disorders: An EHA Consensus Report.

Hemasphere 2019 10 17;3(4):e286. Epub 2019 Sep 17.

Department of Medicine, Division of Heamtology-Oncology, University of North Carolina at Chapel Hill, NC, USA.

Healthy subjects frequently report minor bleedings that are frequently 'background noise' of normality rather than a true disorder. Nevertheless, unexpected or unusual bleeding may be alarming. Thus, the distinction between normal and pathologic bleeding is critical. Understanding the underlying pathologic mechanism in patients with an excessive bleeding is essential for their counseling and treatment. Most of these patients with significant bleeding will result affected by non-severe inherited bleeding disorders (BD), collectively denominated mild or moderate BD for their relatively benign course. Unfortunately, practical recommendations for the management of these disorders are still lacking due to the current state of fragmented knowledge of pathophysiology and lack of a systematic diagnostic approach. To address this gap, an International Working Group (IWG) was established by the European Hematology Association (EHA) to develop consensus-based guidelines on these disorders. The IWG agreed that grouping these disorders by their clinical phenotype under the single category of mild-to-moderate bleeding disorders (MBD) reflects current clinical practice and will facilitate a systematic diagnostic approach. Based on standardized and harmonized definitions a conceptual unified framework is proposed to distinguish normal subjects from affected patients. The IWG proposes a provisional comprehensive patient-centered initial diagnostic approach that will result in classification of MBD into distinct clinical-pathological entities under the overarching principle of clinical utility for the individual patient. While we will present here a general overview of the global management of patients with MBD, this conceptual framework will be adopted and validated in the evidence-based, disease-specific guidelines under development by the IWG.
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http://dx.doi.org/10.1097/HS9.0000000000000286DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6919472PMC
October 2019

Cellular Factor XIII, a Transglutaminase in Human Corneal Keratocytes.

Int J Mol Sci 2019 Nov 27;20(23). Epub 2019 Nov 27.

Division of Clinical Laboratory Science, Department of Laboratory Medicine, University of Debrecen, Faculty of General Medicine, 4032 Debrecen, Hungary.

Cellular factor XIII (cFXIII, FXIII-A), a transglutaminase, has been demonstrated in a few cell types. Its main function is to cross-link proteins by isopeptide bonds. Here, we investigated the presence of cFXIII in cells of human cornea. Tissue sections of the cornea were immunostained for FXIII-A in combination with staining for CD34 antigen or isopeptide cross-links. Isolated corneal keratocytes were also evaluated by immunofluorescent microscopy and flow cytometry. FXIII-A in the corneal stroma was quantified by Western blotting. FXIII-A mRNA was detected by RT-qPCR. The cornea of FXIII-A-deficient patients was evaluated by cornea topography. FXIII-A was detected in 68 ± 13% of CD34+ keratocytes. Their distribution in the corneal stroma was unequal; they were most abundant in the subepithelial tertile. cFXIII was of cytoplasmic localization. In the stroma, 3.64 ng cFXIII/mg protein was measured. The synthesis of cFXIII by keratocytes was confirmed by RT-qPCR. Isopeptide cross-links were detected above, but not within the corneal stroma. Slight abnormality of the cornea was detected in six out of nine FXIII-A-deficient patients. The presence of cFXIII in human keratocytes was established for the first time. cFXIII might be involved in maintaining the stability of the cornea and in the corneal wound healing process.
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http://dx.doi.org/10.3390/ijms20235963DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6928837PMC
November 2019

Novel Locally Acting Dual Antiplatelet and Anticoagulant (APAC) Targets Multiple Sites of Vascular Injury in an Experimental Porcine Model.

Eur J Vasc Endovasc Surg 2019 Dec 8;58(6):903-911. Epub 2019 Nov 8.

Coagulation Disorders Unit, University of Helsinki, Departments of Haematology and Clinical Chemistry (HUSLAB Laboratory Services), Comprehensive Cancer Center, Helsinki University Hospital and Research Program in Systems Oncology, Faculty of Medicine, University of Helsinki, Helsinki, Finland; Helsinki University, Faculty of Medicine, Research Program in Oncology, Helsinki, Finland; Aplagon Oy, Helsinki, Finland. Electronic address:

Objectives: Vascular binding of dual antiplatelet and anticoagulant (APAC) was assessed in surgically created femoral arteriovenous fistula (AVF) and iliac and carotid artery injury in porcine models.

Methods: Three models of collagen exposing injury were used: 1) femoral AVF, 2) in vivo iliac and carotid artery balloon angioplasty injury, and 3) in vitro femoral artery endothelial denudation injury. Biotinylated APAC (0.5 mg/mL) was incubated with the injury site before releasing blood flow. APAC, von Willebrand factor (vWF), laminin, platelet endothelial cell adhesion molecule 1 (PECAM-1), and podocalyxin were detected in histological sections using immunofluorescence and confocal microscopy and Manders' co-localisation coefficient (M1).

Results: APAC bound to AVF at anastomosis and to both in vivo and in vitro injured arteries. APAC co-localised with matrix vWF (M1 ≥ 0.66) and laminin (M1 ≥ 0.60), but less so if endothelial PECAM-1 or podocalyxin was present (M1 ≤ 0.25). APAC targeted and penetrated the injured vessel wall, especially the AVF vein.

Conclusions: APAC, compatible with its high negative charge, rapidly targets injured vessels co-localizing with matrix vWF and laminin, but not with endothelial PECAM-1 and podocalyxin. This localising feature may have potential antithrombotic implications for vascular interventions.
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http://dx.doi.org/10.1016/j.ejvs.2019.05.019DOI Listing
December 2019

CA 19-9 doubling time in pancreatic cancer as a predictor of venous thromboembolism: a hospital database study.

Acta Oncol 2020 Feb 25;59(2):237-241. Epub 2019 Oct 25.

Institute of Biomedicine, Research Center for Cancer, Infections and Immunity, University of Turku, Turku, Finland.

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http://dx.doi.org/10.1080/0284186X.2019.1679881DOI Listing
February 2020

Management of coagulation factor VIII (FVIII) inhibitors.

Authors:
Riitta Lassila

Thromb Res 2019 Sep;181 Suppl 1:S60-S61

Helsinki University Hospital, Coagulation Disorders Unit, Hematology, Helsinki, Finland. Electronic address:

Acquired hemophilia is a rare but severe condition, which is unknown to medical specialties outside hematology. Sudden appearance of antibodies against coagulation FVIII is diagnosed by abnormal subcutaneous large and multiple hematomas with minor injuries only. APTT is prolonged, FVIII activity variably low and inhibitor titer varies, too. The antibodies are typically occurring in women after delivery and later in life at around 60 years of life due to immunological challenges, and in association with malignant diseases. Rapid recognition of the condition and support of hemostasis together with immunosuppressive therapy is important, since the diagnostic delay is a poor prognostic sign. Coagulation experts should be consulted to arrange the management and followup of the patients. Management of bleeds consists of so-called FVIII bypassing agents, activated prothrombin complex concentrate, aPCC, recombinant FVIIa or porcine FVIII. The immunotherapy should be continued for several weeks according to the timing of the remission. The relapse rate needs to be noted in the future under similar situations as the index event occurred. Register data collection is important to characterize this lifethreatening acquired bleeding disorder.
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http://dx.doi.org/10.1016/S0049-3848(19)30369-XDOI Listing
September 2019

Heparan sulfates are critical regulators of the inhibitory megakaryocyte-platelet receptor G6b-B.

Elife 2019 08 22;8. Epub 2019 Aug 22.

Institute of Cardiovascular Sciences, College of Medical and Dental Sciences, University of Birmingham, Birmingham, United Kingdom.

The immunoreceptor tyrosine-based inhibition motif (ITIM)-containing receptor G6b-B is critical for platelet production and activation. Loss of G6b-B results in severe macrothrombocytopenia, myelofibrosis and aberrant platelet function in mice and humans. Using a combination of immunohistochemistry, affinity chromatography and proteomics, we identified the extracellular matrix heparan sulfate (HS) proteoglycan perlecan as a G6b-B binding partner. Subsequent in vitro biochemical studies and a cell-based genetic screen demonstrated that the interaction is specifically mediated by the HS chains of perlecan. Biophysical analysis revealed that heparin forms a high-affinity complex with G6b-B and mediates dimerization. Using platelets from humans and genetically modified mice, we demonstrate that binding of G6b-B to HS and multivalent heparin inhibits platelet and megakaryocyte function by inducing downstream signaling via the tyrosine phosphatases Shp1 and Shp2. Our findings provide novel insights into how G6b-B is regulated and contribute to our understanding of the interaction of megakaryocytes and platelets with glycans.
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http://dx.doi.org/10.7554/eLife.46840DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6742478PMC
August 2019

Phenotypic characterization of haemophilia B - Understanding the underlying biology of coagulation factor IX.

Haemophilia 2019 Jul 10;25(4):567-574. Epub 2019 Jun 10.

Coagulation Disorders Unit, EHCCC, Hematology and Comprehensive Cancer Center and HUSLAB Helsinki University Hospital, University of Helsinki, Research Program Unit in Systems Oncology, Helsinki, Finland.

Haemophilia B is a recessive, X-linked bleeding disorder due to inherited deficiency in vitamin K-dependent coagulation factor IX (FIX). FIX activity levels, as a basis for the definition of disease severity, do not clearly correlate with bleeding phenotype, likely due to the multiple steps regulating coagulation. Timely, with the availability of extended half-life products and successful steps in gene therapy, haemophilia B therapy is in an active developmental phase. Therefore, increased knowledge of the factors contributing to the variation of haemostatic and clinical outcome and response to therapy is welcomed. FIX acts at the crossroads of both the extrinsic and intrinsic pathways, and on the platelet procoagulant membrane at the site of vascular injury, and therefore, FIX biology is targeted for multiple effectors and regulators. The synthesis, cellular and molecular interactions, and elimination routes of FIX are not as well studied as for FVIII. The specific roles of magnesium in both platelet adhesion and FIX activation, and of vascular collagen at the haemostatic site of platelet adhesion and FIX residence are of particular interest. Biochemical and translational research on these issues should improve our understanding of the mechanisms involved, leading to the development of relevant assays that measure both haemostasis and treatment response. The latter is becoming increasingly important in the new era of haemophilia management and ultimately may lead to improved treatment strategies individually tailored to a patient's needs and cost-efficiency.
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http://dx.doi.org/10.1111/hae.13804DOI Listing
July 2019

Warfarin dose requirement in patients having severe thrombosis or thrombophilia.

Br J Clin Pharmacol 2019 08 17;85(8):1684-1691. Epub 2019 Jun 17.

Coagulation Disorders Unit, Clinical Chemistry, University of Helsinki and HUSLAB, Helsinki University Hospital, Helsinki, Finland.

Aims: Warfarin dose requirement varies significantly. We compared the clinically established doses based on international normalized ratio (INR) among patients with severe thrombosis and/or thrombophilia with estimates from genetic dosing algorithms.

Methods: Fifty patients with severe thrombosis and/or thrombophilia requiring permanent anticoagulation, referred to the Helsinki University Hospital Coagulation Center, were screened for thrombophilias and genotyped for CYP2C9*2 (c.430C>T, rs1799853), CYP2C9*3 (c.1075A>C, rs1057910) and VKORC1 c.-1639G>A (rs9923231) variants. The warfarin maintenance doses (target INR 2.0-3.0 in 94%, 2.5-3.5 in 6%) were estimated by the Gage and the International Warfarin Pharmacogenetics Consortium (IWPC) algorithms. The individual warfarin maintenance dose was tailored, supplementing estimates with comprehensive clinical evaluation and INR data.

Results: Mean patient age was 47 years (range 20-76), and BMI 27 (SD 6), 68% being women. Forty-six (92%) had previous venous or arterial thrombosis, and 26 (52%) had a thrombophilia, with 22% having concurrent aspirin. A total of 40% carried the CYP2C9*2 or *3 allele and 54% carried the VKORC1-1639A allele. The daily mean maintenance dose of warfarin estimated by the Gage algorithm was 5.4 mg (95% CI 4.9-5.9 mg), and by the IWPC algorithm was 5.2 mg (95% CI 4.7-5.7 mg). The daily warfarin maintenance dose after clinical visits and follow-up was higher than the estimates, mean 6.9 mg (95% CI 5.6-8.2 mg, P < 0.006), with highest dose in patients having multiple thrombophilic factors (P < 0.03).

Conclusions: In severe thrombosis and/or thrombophilia, variation in thrombin generation and pharmacodynamics influences warfarin response. Pharmacogenetic dosing algorithms seem to underestimate dose requirement.
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http://dx.doi.org/10.1111/bcp.13948DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6624394PMC
August 2019

Platelets compensate for poor thrombin generation in type 3 von Willebrand disease.

Platelets 2020 5;31(1):103-111. Epub 2019 Mar 5.

Faculty of Medicine, University of Helsinki, Helsinki, Finland.

In type 3 von Willebrand disease (VWD3), the most severe form with absent von Willebrand factor (VWF), the bleeding phenotype is variable. Platelet contribution to the hemostatic defect in VWD3 calls upon further studies. We investigated the contribution of platelets to thrombin generation (TG) and platelet procoagulant activity in VWD3. TG was assessed by calibrated automated thrombogram (CAT) in platelet-poor (PPP) and -rich plasma (PRP) from 9 patients before and in 6 patients also 30 min after receiving their regular VWF therapy. Responsiveness of PPP to FVIII and protein S was also investigated. TG data were compared with routine laboratory variables, rotational thromboelastometry (ROTEM) and platelet expression of P-selectin and phosphatidylserine in flow cytometry. Compared with healthy controls, TG was markedly decreased in VWD3 PPP (peak thrombin was 16% of normal median), but not in PRP (77% of normal median) (p = 0.002). Six out of nine patients (67%) were high responders in their platelet P-selectin, and 5/9 (56%) in phosphatidylserine expression. Replacement therapy improved TG in PPP, while in PRP TG only modestly increased or was unaffected. In PPP, FVIII levels associated with TG and FVIII-supplemented TG inclined up to threefold. Conversely, a FVIII inhibitory antibody reduced plasma TG in all, but especially in patients with remnant FVIII levels. Inhibition of protein S improved plasma TG, particularly at low FVIII levels. ROTEM failed to detect VWD3.In VWD3, TG is reduced in PPP and regulated by FVIII and protein S, but TG is close to normal in PRP. VWD3 platelets seem to compensate for the FVIII-associated reduction in TG by their exposure of P-selectin and phosphatidylserine.
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http://dx.doi.org/10.1080/09537104.2019.1581922DOI Listing
April 2020

Evaluation of a standardized protocol for thrombin generation using the calibrated automated thrombogram: A Nordic study.

Haemophilia 2019 Mar 4;25(2):334-342. Epub 2019 Feb 4.

Department of Translational Medicine & Centre for Thrombosis and Haemostasis, Lund University, Malmö, Sweden.

Introduction: The thrombin generation assay-calibrated automated thrombogram (TGA-CAT) method is used to measure the overall coagulation capacity in plasma. However, the method is still considered to be a research tool, mainly because of its' lack of standardization.

Aim: Our study aimed to further raise the standardization level for the TGA-CAT method by evaluating a detailed standardization protocol and three reference plasmas' (RP)s ability to normalize results.

Methods: Six Nordic centres participated in the study, and with input from all centres a detailed laboratory standardization protocol based on the TGA-CAT manual of the manufacturer was established. Three types of plasma, hypo-,normal and hypercoagulable plasma were assessed. Three commercial lyophilized RPs were used for normalization of data. All samples were aliquoted at the Malmö centre and sent frozen at -20˚C to participating centres.

Results: Before normalization, all results under all testing conditions showed inter-laboratory coefficient of variability of 10% or lower except for endogenous thrombin potential (12%) and peak (14%) in hypo-plasma with 1 pmol/L tissue factor as starting agent. Successful normalization, improving variability in results, was obtained with two of the three evaluated RPs (HemosIL RP and Affinity RP).

Conclusion: With our standardization concept, we were able to produce TGA-CAT results as robust as standard coagulation assays used in the routine laboratories. Normalization with HemosIL RP may be considered in populations with low or unknown coagulability, while when analysing plasma samples from populations where hypercoagulability is known or suspected, normalization with Affinity RP may be preferred.
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http://dx.doi.org/10.1111/hae.13640DOI Listing
March 2019

Hemostatic profile under fluid resuscitation during rivaroxaban anticoagulation: an in vitro survey.

Transfusion 2018 12 21;58(12):3014-3026. Epub 2018 Oct 21.

Department of Molecular and Cellular Hemostasis, Sanquin Research, Amsterdam, The Netherlands.

Background: Uncontrollable bleeding is the leading cause of death in traumatically injured patients. The extent to which direct factor Xa inhibitors interfere with the applied resuscitation measures is presently unknown.

Study Design And Methods: In this study, we investigated the effect of the resuscitation fluids saline, albumin, fresh frozen plasma (FFP) and solvent/detergent (S/D)-treated plasma, fibrinogen concentrate, prothrombin complex concentrate (PCC), and combinations thereof on the hemostatic profile of rivaroxaban-anticoagulated whole blood and plasma. We used rivaroxaban-spiked whole blood and plasma from healthy donors, as well as plasma from patients on rivaroxaban, and mimicked a resuscitation approach in a 50% plasma dilution setting. Thromboelastography, thrombin generation, and fibrin generation clot lysis test were assessed using tissue factor to initiate coagulation and tissue plasminogen activator to induce clot lysis.

Results: Rivaroxaban resulted in a hypocoagulant state that remained largely unaltered upon subsequent 50% dilution with S/D-treated plasma or FFP. Using S/D-treated plasma as a diluent, clot stability decreased due to its low α -antiplasmin. Dilution with saline and albumin induced a profibrinolytic state and further deteriorated the impaired hemostatic potential of rivaroxaban-anticoagulated blood, even after PCC and fibrinogen support. Combined use of plasma (either FFP or S/D treated) and PCC, however, considerably improved both coagulation and clot stability.

Conclusion: In the setting of rivaroxaban anticoagulation and major blood loss, transfusing plasma together with PCC may provide the most effective resuscitation approach with the notion that additional antifibrinolytic drug support (e.g., tranexamic acid) is likely required.
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http://dx.doi.org/10.1111/trf.14933DOI Listing
December 2018

Real-world features associated with cancer-related venous thromboembolic events.

ESMO Open 2018 23;3(5):e000363. Epub 2018 Jul 23.

Genome Scale Biology Research Program and Department of Pathology, University of Helsinki and Helsinki University Hospital, Helsinki, Finland. Electronic address:

Background: The incidence of venous thromboembolism (VTE) is 1-2/1000 individuals. Patients with cancer, especially during chemotherapy, are at enhanced risk, but real-world data on factors associated with VTE events are still scarce.

Aim: The aim of this retrospective study was to survey the incidence of VTE based on a large hospital database, and to identify comorbidities and features associated with VTE events. We focused on cancer-related VTE events and on factors indicating increased VTE risk during chemotherapy.

Methods: The cohort included patients treated at Turku University Hospital during years 2005-2013. Health information was derived and analysed from multiple electronic databases. The diagnoses of VTE and all comorbidities, including type of cancer, were based on International Classification of Diseases 10th Revision coding. For further analysis, we focused on 16 common types of cancers treated with chemotherapy. Age, gender, surgery, radiotherapy, distant metastasis, available laboratory values and platinum-based chemotherapy were evaluated for VTE group, and associations were estimated by Cox regression analyses.

Results: The entire database contained information from 495 089 patients, of whom 5452 (1.1%) had a VTE diagnosis. Among individuals with VTE, 1437 (26.4%) had diagnosis of coronary heart disease and 1467 (26.9%) had cancer diagnosis. Among 7778 patients with cancer treated with chemotherapy, 282 (3.6%) had a VTE, platinum-based chemotherapy being a major risk factor (HR 1.77, 95% CI 1.40 to 2.24, p<0.001). In multivariate analysis, elevated blood neutrophil counts (>3.25×10 cells/L, HR 1.96, 95% CI 1.33 to 2.89, p<0.001) and plasma creatinine (>62.5 μmol/L; HR 1.60, 95% CI 1.21 to 2.13, p=0.001) values were independent indicators of increased VTE risk during chemotherapy.

Conclusions: Longitudinal electronic health record analysis provides a powerful tool to gather meaningful real-world information to study clinical associations, like comorbidities, and to identify markers associated with VTE. The combination of various clinical and laboratory variables could be used for VTE risk evaluation and targeted prevention.
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http://dx.doi.org/10.1136/esmoopen-2018-000363DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6069925PMC
July 2018

Dual antiplatelet and anticoagulant (APAC) heparin proteoglycan mimetic with shear-dependent effects on platelet-collagen binding and thrombin generation.

Thromb Res 2018 09 25;169:143-151. Epub 2018 Jul 25.

Department of Chemical and Biomolecular Engineering, Institute for Medicine and Engineering, University of Pennsylvania, Philadelphia, PA, USA. Electronic address:

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). FXIIa-inhibited whole blood (CTI: corn trypsin inhibitor, 40 μg/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) 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.
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http://dx.doi.org/10.1016/j.thromres.2018.07.026DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6179373PMC
September 2018

Differences in the risk of stroke, bleeding events, and mortality between female and male patients with atrial fibrillation during warfarin therapy.

Eur Heart J Cardiovasc Pharmacother 2019 01;5(1):29-36

Department of Cardiology, Heart and Lung Center, Helsinki University Hospital, Haartmaninkatu 4, Helsinki, Finland.

Aims: Females with atrial fibrillation (AF) have been suggested to carry a higher risk for thromboembolic events than males. We compared the residual risk of stroke, bleeding events, and cardiovascular and all-cause mortality among female and male AF patients taking warfarin.

Methods And Results: Data from several nationwide registries and laboratory databases were linked with the civil registration number of the patients. A total of 54 568 patients with data on the quality of warfarin treatment (time in therapeutic range) 60 days prior to the events were included (TTR60). Gender differences in the endpoints were reported for the whole population, pre-specified age groups, and different TTR60 groups. During the 3.2 ± 1.6 years follow-up, there were no differences in the adjusted risk of stroke [hazard ratio (HR) 0.97, 95% confidence interval (CI) 0.91-1.03, P = 0.304] between the genders. Cardiovascular mortality (HR 0.82, 95% CI 0.78-0.88, P < 0.001) and all-cause mortality (HR 0.79, 95% CI 0.75-0.83, P < 0.001) were lower in women when compared with men. There were no differences in the risk of stroke, cardiovascular mortality, and all-cause mortality between the genders in the TTR60 categories except for those with TTR60 <50%. Bleeding events were less frequent in females (HR 0.52, 95% CI 0.49-0.56, P < 0.001).

Conclusion: There were no differences in the risk of stroke between female and male AF patients taking warfarin. Cardiovascular mortality, all-cause mortality, and risk of bleeding events were lower in females. Hence, female gender was not a risk marker for adverse outcomes in AF patients with proper warfarin therapy.
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http://dx.doi.org/10.1093/ehjcvp/pvy026DOI Listing
January 2019

Haematopoietic Stem Cell Transplantation in Children Shifts the Coagulation System towards a Pro-Coagulant State.

Thromb Haemost 2018 Aug 30;118(8):1390-1396. Epub 2018 Jun 30.

Unit for Coagulation Disorders, Department of Haematology, Comprehensive Care Center and Cancer Center, Helsinki University Central Hospital, University of Helsinki, Helsinki, Finland.

Coagulation system is disturbed by several mechanisms after allogeneic haematopoietic stem cell transplantation (HSCT). We evaluated the effect of HSCT on coagulation system by various conventional and investigational methods in 30 children and adolescents who received HSCT due to haematological malignancies. Pro-thrombin fragment 1 + 2, a specific measure of thrombin generation, and von Willebrand factor, a measure of endothelial activation, increased after conditioning treatment, and remained elevated until 3 months after HSCT ( < 0.05 for all comparisons to pre-conditioning treatment). D-dimer, a measure of fibrin turnover, was elevated from the second week onwards until 4 weeks after HSCT ( < 0.05). Endogenous thrombin potential was increased after conditioning, and at 2 weeks after HSCT ( < 0.05). Furthermore, the activities of acute phase reactants fibrinogen and coagulation factor VIII were increased ( < 0.05 for all comparisons to pre-conditioning treatment) from the first week onwards up to 3 weeks and 3 months after HSCT, respectively. Taken together, paediatric patients receiving HSCT demonstrate distinct and prolonged variations in the coagulation system towards a pro-coagulant state. This shift is of importance when estimating the risk of haemostatic and thrombotic complications in these children.
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http://dx.doi.org/10.1055/s-0038-1661394DOI Listing
August 2018

Preoperative Biomarker Panel, Including Fibrinogen and FVIII, Improves Diagnostic Accuracy for Pancreatic Ductal Adenocarcinoma.

Clin Appl Thromb Hemost 2018 Nov 4;24(8):1267-1275. Epub 2018 Jun 4.

1 Department of Hematology, Coagulation Disorders Unit, Comprehensive Cancer Center, University of Helsinki and Helsinki University Hospital, Helsinki, Finland.

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.
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http://dx.doi.org/10.1177/1076029618779133DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6714782PMC
November 2018

The quality of warfarin therapy and CHA2DS2-VASc score associate with the incidence of myocardial infarction and cardiovascular outcome in patients with atrial fibrillation: data from the nationwide FinWAF Registry.

Eur Heart J Cardiovasc Pharmacother 2018 10;4(4):211-219

Department of Cardiology, Heart and Lung Center, Helsinki University Hospital, Haartmaninkatu 4, Helsinki, Finland.

Aims: The impact of the quality of warfarin therapy on cardiovascular outcomes excluding stroke is largely unknown. The aims of this study were to evaluate the association between the warfarin control and the incidence and outcome of myocardial infarction (MI) and to validate the predictive value of the CHA2DS2-VASc score for MI in atrial fibrillation (AF) patients taking warfarin.

Methods And Results: The nationwide FinWAF Registry consists of 54 568 AF patients (mean age 73.31 ± 10.7 years, 52% men) taking warfarin. The quality of warfarin therapy was assessed continuously by calculating the time in therapeutic range within a 60-day window using the Rosendaal method (TTR60). Adjusted Cox proportional hazards models were prepared for the incidence of MI and cardiovascular mortality in six different TTR60 categories. During the 3.2 ± 1.6 years of follow-up, the annual incidence of MI (95% confidence interval) was 3.3% (3.0-3.5%), 2.9% (2.6-3.3%), 2.4% (2.1-2.7%), 1.9% (1.7-2.2%), 1.7% (1.5-2.0%), and 1.2% (1.1-1.3%) among patients with TTR60 <40%, 40-50%, 50-60%, 60-70%, 70-80%, and >80%, respectively. Well-managed warfarin therapy (TTR60 > 80%) was associated also with a lower cardiovascular mortality, whereas a high CHA2DS2-VASc score correlated with poor outcome.

Conclusion: Cardiovascular outcome was superior among AF patients with good warfarin control and in those with a low CHA2DS2-VASc score. The inverse association between the TTR60 and incidence of MI and cardiovascular mortality indicate that in AF patients the quality of warfarin therapy is critical not only for prevention of stroke but also with regard to cardiovascular outcome.
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http://dx.doi.org/10.1093/ehjcvp/pvy009DOI Listing
October 2018

Recombinant FXIII (rFXIII-A2) Prophylaxis Prevents Bleeding and Allows for Surgery in Patients with Congenital FXIII A-Subunit Deficiency.

Thromb Haemost 2018 03 15;118(3):451-460. Epub 2018 Feb 15.

Sackler Faculty of Medicine, Tel Aviv University, Tel Aviv, Israel.

Recombinant factor XIII-A (rFXIII-A) was developed for prophylaxis and treatment of bleeds in patients with congenital FXIII A-subunit deficiency. mentor™2 (NCT00978380), a multinational, open-label, single-arm, multiple-dosing extension to the pivotal mentor™1 trial, assessed long-term safety and efficacy of rFXIII-A prophylaxis in eligible patients (patients with severe [<0.05 IU/mL] congenital FXIII subunit A deficiency) aged ≥6 years. Patients received 35 IU/kg rFXIII-A (exact dosing) every 28 ± 2 days for ≥52 weeks. Primary endpoint was safety (adverse events including immunogenicity); secondary endpoints were rate of bleeds requiring FXIII treatment, haemostatic response after one 35 IU/kg rFXIII-A dose for breakthrough bleeds and withdrawals due to lack of rFXIII-A efficacy. Steady-state pharmacokinetic variables were also summarized. Elective surgery was permitted during the treatment period. Sixty patients were exposed to rFXIII-A; their median age was 26.0 years (range: 7.0-77.0). rFXIII-A was well tolerated without any safety concerns. No non-neutralizing or neutralizing antibodies (inhibitors) against FXIII were detected. Mean annualized bleeding rate (ABR) was 0.043/patient-year. Mean spontaneous ABR was 0.011/patient-year. No patients withdrew due to lack of efficacy. Geometric mean FXIII trough level was 0.17 IU/mL. Geometric terminal half-life was 13.7 days. rFXIII-A prophylaxis provided sufficient haemostatic coverage for 12 minor surgeries without the need for additional FXIII therapy; eight procedures were performed within 7 days of the patient's last scheduled rFXIII-A dose, and four were performed 10 to 21 days after the last dose.
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http://dx.doi.org/10.1055/s-0038-1624581DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6260112PMC
March 2018

Coordinated responses of natural anticoagulants to allogeneic stem cell transplantation and acute GVHD - A longitudinal study.

PLoS One 2017 22;12(12):e0190007. Epub 2017 Dec 22.

Coagulation Disorders Unit, Helsinki University Hospital and University of Helsinki, Helsinki, Finland.

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<0.001) and between PC and AT (r = 0.62-0.81, p<0.05) were observed at each time point. Patients with GVHD had 21% lower PC during conditioning therapy and 55% lower APC-PCI early after transplantation, as well as 37% higher values of s-TM after engraftment. The GVHD group had also increases of PC (24%), FVIII: C (28%) and AT (16%) three months after transplantation.

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.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0190007PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5741247PMC
January 2018

Total joint replacement in inhibitor-positive haemophilia: Long-term outcome analysis in fifteen patients.

World J Orthop 2017 Oct 18;8(10):777-784. Epub 2017 Oct 18.

Orton Orthopaedic Hospital, Invalid Foundation, Helsinki 00280, Finland.

Aim: To collect data from joint replacement in inhibitor patients, evaluate haemostatic and patient outcomes, and analyse the costs.

Methods: We report our 21-year, single-centre cumulative experience of 15 joint arthroplasties in six inhibitor patients.

Results: Two low responder inhibitor patients were in the early days treated with FVIII, whereas bypassing agents were used in the rest of the high responder patients. The primary haemostatic outcome was good in 8/15, fair in 4/15 and poor in 3/15 operations. The overall patient outcome, including joint health and patient satisfaction, was good in 10/15, fair 4/15 and poor in 1/15. No deep infections were observed. Cost analysis was most beneficial in low responders and in two immune-tolerized, high responder patients. In all cases, factor replacement comprised the main treatment costs.

Conclusion: Our experience supports the initial use of bypassing agents as well as preoperative immune-tolerance induction when possible. Despite the challenges of haemostasis and severe joint disease, total joint arthroplasty can reach a good outcome, even in inhibitor patients. The risk for deep infection might be smaller than previously reported. Individual planning, intense multidisciplinary teamwork and execution of operations should be centralised in a professional unit.
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http://dx.doi.org/10.5312/wjo.v8.i10.777DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5656493PMC
October 2017

The evolution of the Helsinki frostbite management protocol.

Burns 2017 Nov 1;43(7):1455-1463. Epub 2017 Aug 1.

Helsinki Burn Centre, Department of Plastic Surgery, Töölö Hospital, Helsinki University Hospital, University of Helsinki, Finland.

Background: Severe frostbite can result in devastating injuries leading to significant morbidity and loss of function from distal extremity amputation. The modern day management approach to frostbite injuries is evolving from a historically very conservative approach to the increasingly reported use of early interventional angiography and fibrinolysis with tPA. The aim of this study was to evaluate the results of our frostbite treatment protocol introduced 3 years ago.

Methods: All frostbite patients underwent first clinical and then Doppler ultrasound examination. Angiography was conducted if certain clinical criteria indicated a severe frostbite injury and if there were no contraindications to fibrinolysis. Intra-arterial tissue plasminogen activator (tPA) was then administered at 0.5-1mg/h proximal to the antecubital fossa (brachial artery) or popliteal fossa (femoral artery) if angiography confirmed thrombosis, as well as unfractionated intravenous heparin at 500 units/h. The vasodilator iloprost was administered intravenously (0.5-2.0ng/kg/min) in selected cases.

Results: 20 patients with frostbite were diagnosed between 2013-2016. Fourteen patients had a severe injury and angiography was performed in 10 cases. The total number of digits at risk was 111. Nine patients underwent fibrinolytic treatment with tPA (including one patient who received iloprost after initial non response to tPA), 3 patients were treated with iloprost alone and 2 patients received neither treatment modality (due to contraindications). The overall digital salvage rate was 74.8% and the Hennepin tissue salvage rate was 81.1%. One patient developed a catheter-site pseudoaneurysm that resolved after conservative treatment.

Conclusions: Prompt referral to a facility where interventional radiology and 24/7 laboratory services are available, and the combined use of tPA and iloprost, may improve outcome after severe frostbite.
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http://dx.doi.org/10.1016/j.burns.2017.04.016DOI Listing
November 2017