Publications by authors named "Alex Gatt"

33 Publications

The effect of DOAC-Stop on several oral and parenteral anticoagulants.

Int J Lab Hematol 2021 Feb 17. Epub 2021 Feb 17.

Department of Pathology, Faculty of Medicine and Surgery, University of Malta, Msida, Malta.

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http://dx.doi.org/10.1111/ijlh.13487DOI Listing
February 2021

Effect of anticoagulants on fibrin clot structure: A comparison between vitamin K antagonists and factor Xa inhibitors.

Res Pract Thromb Haemost 2020 Nov 25;4(8):1269-1281. Epub 2020 Oct 25.

Discovery and Translational Science Department Institute of Cardiovascular and Metabolic Medicine University of Leeds Leeds UK.

Background: Abnormal clot structure has been identified in patients with thrombotic disorders. Anticoagulant therapy offers clear benefits for thrombosis prevention and treatment by reducing blood clot formation and size; nevertheless, there are limited data on the effects of different anticoagulants, where clotting is initiated with different triggers, on clot structure.

Objectives: Our aim was to investigate the effects of vitamin K antagonists and factor Xa inhibitors on clot structure.

Methods: Clots from pooled plasma spiked with rivaroxaban, apixaban, or enoxaparin, as well as plasma from patients on warfarin, were compared to plasma without anticoagulation. The kinetic profile of polymerizing clots was obtained by turbidity, fiber density was determined by confocal microscopy, clot pore size was investigated by permeation, and fiber size was analyzed using scanning electron microscopy. Clotting agonist was either tissue factor or thrombin.

Results: Following clotting with tissue factor, all anticoagulated clots had a significantly increased lag time, with the exception of enoxaparin. Rivaroxaban additionally led to significantly less dense and more permeable clots, with thicker fibers. In contrast, turbidity analysis following initiation with thrombin showed few effects of anticoagulation, with only enoxaparin leading to a prolonged lag time. Enoxaparin clots made with thrombin were less dense and more permeable.

Conclusion: Our results show that anticoagulants modulate clot structure particularly when induced by tissue factor, most likely due to reduction of thrombin generation. We propose that the effects of different anticoagulants could be assessed with a global clot structure measurement such as permeation or turbidity, providing information on clot phenotype.
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http://dx.doi.org/10.1002/rth2.12443DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7695561PMC
November 2020

Anticoagulation in splanchnic and cerebral vein thrombosis: An international vignette-based survey.

Res Pract Thromb Haemost 2020 Oct 11;4(7):1192-1202. Epub 2020 Sep 11.

Department of Medicine and Surgery University of Insubria Varese Italy.

Background: Anticoagulant treatment of splanchnic (SVT) and cerebral vein thrombosis (CVT) can be challenging due to the rarity of these conditions, the concomitantly high thrombotic and bleeding risks, and the available low-quality evidence.

Objectives: To explore the current therapeutic approaches to SVT and CVT, and the rationale behind the anticoagulant treatment choice.

Methods: A cross-sectional survey was conducted (October 2018-April 2019) among members of three thrombosis and hemostasis societies. The survey consisted of four vignette cases: (i) SVT secondary to transient risk factor; (ii) cirrhotic SVT with esophageal varices; (iii) CVT secondary to transient risk factor; and (iv) unprovoked CVT with intracranial hemorrhage.

Results: A total of 397 physicians responded to the survey. There was wide variability in anticoagulant treatment options, starting time, and duration. Vitamin K antagonists were the commonest choice across the four vignette cases (44.2%-63.0%). The direct oral anticoagulants (DOACs) were the second commonest choice in low-bleeding-risk scenarios (27.7% in case 1, 22.9% in case 3), while parenteral anticoagulation alone was the second commonest choice in high-bleeding-risk scenarios (39.9% in case 2, 39.8% in case 4). The most frequent reasons for selecting DOACs were oral route of administration (50.6%), lack of need for laboratory monitoring (48.1%), and favorable safety profile of these drugs (43.4%).

Conclusions: The results of our study showed that, despite being off-label, the DOACs were considered for the treatment of unusual-site venous thromboembolism. The wide variability among different physicians reflected the clinical difficulties and raised the need for more collaborative trials on these disorders.
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http://dx.doi.org/10.1002/rth2.12424DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7590282PMC
October 2020

Anticoagulation control with the point-of-care INR: A retrospective pre-/post-analysis.

Thromb Res 2020 12 1;196:21-24. Epub 2020 Aug 1.

Department of Pathology, Faculty of Medicine and Surgery, University of Malta, Msida, Malta; Coagulation Medicine Laboratory, Department of Pathology, Mater Dei Hospital, Msida, Malta. Electronic address:

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http://dx.doi.org/10.1016/j.thromres.2020.07.050DOI Listing
December 2020

Patients' satisfaction associated with portable coagulometers for warfarin monitoring: a cross-sectional study.

Blood Transfus 2020 09 4;18(5):386-395. Epub 2020 Jun 4.

Department of Pathology, Faculty of Medicine and Surgery, University of Malta, Msida, Malta, Italy.

Background: The use of point-of-care (POC) coagulometers for monitoring patients on vitamin K antagonist (VKA) treatment makes international normalised ratio (INR) results immediately available. The aim of this study was to compare patients' satisfaction with VKA treatment in two settings characterised by distinct ways of monitoring: POC INR versus laboratory INR.

Materials And Methods: We recruited adult patients on long-term warfarin treatment (July 2017-February 2018) from the Anticoagulation Clinics at five district health centres (namely Cospicua, Floriana, Mosta, Qormi, Rabat-POC INR) and at Mater Dei Hospital (Msida - Laboratory INR) in Malta. We administered two psychometric questionnaires: the Duke Anticoagulation Satisfaction Scale (DASS) (range 25-175, lower scores corresponding to higher satisfaction) and the Perception of Anticoagulation Treatment Questionnaire (PACT-Q2) (range 0-100, higher scores corresponding to higher satisfaction).

Results: We analysed 313 questionnaires (POC INR n=159, laboratory INR n=154). In the POC INR cohort, median age was 72 years and 59.1% were males; in the laboratory INR cohort, median age was 70.5 years and 46.1% were males. The POC INR cohort obtained significantly lower overall DASS score (p<0.001) and significantly higher PACT-Q2 scores (p<0.001 for the subscale "convenience"; p=0.039 for the subscale "anticoagulant treatment satisfaction") than the laboratory INR cohort. In multiple regression analysis, the use of POC coagulometers was significantly associated with the overall DASS score (p=0.013) and the PACT-Q2 convenience score (p=0.012).

Discussion: Patients on warfarin treatment were generally satisfied. Patients monitored with the POC INR with a dedicated time slot reported less inconvenience and burdens and better psychological impact than patients monitored with the traditional laboratory INR.
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http://dx.doi.org/10.2450/2020.0005-20DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7592158PMC
September 2020

Impaired platelet-dependent thrombin generation associated with thrombocytopenia is improved by prothrombin complex concentrates in vitro.

Res Pract Thromb Haemost 2020 Feb 14;4(2):334-342. Epub 2020 Feb 14.

School of Biosciences & Medicine University of Surrey Guildford UK.

Background: Impaired thrombin generation (TG) in patients with acquired coagulopathy, is due to low coagulation factors and thrombocytopenia. The latter is typically treated with platelet transfusions and the former with plasma and occasionally with prothrombin complex concentrates (PCCs). We hypothesized that manipulating the concentrations of coagulation factors might result in restoration of platelet-dependent TG over and above that of simple replacement therapy.

Objective: To investigate the influence of PCCs on impaired TG secondary to thrombocytopenia.

Methods: TG was evaluated by thrombin generation assay using a thrombocytopenia model in which normal plasma samples with varying platelet counts (20-300 × 10/L) were spiked with PCCs (25%-150% increase in plasma PCC levels).

Results: PCCs and platelets significantly increased TG in a dose-dependent manner in vitro. Two-way repeated measures of analysis of variance showed variance in peak height, area under the curve, time to peak, and velocity. This variance explained, respectively, by levels of PCC was 47, 59, 25 and 53%; by platelet count was 45, 28, 44, and 14%; by the combination was 80, 67, 70, and 62% variance; and a combination with additional interaction was 91, 84, 76, and 68%. TG at a platelet count 40 × 10/L with an approximate 25% increase in PCC concentration was similar to TG at 150 × 10/L. Similarly, patient samples spiked ex vivo with PCCs also showed highly significant improvements in TG.

Conclusions: Impaired TG of thrombocytopenia is improved by PCCs, supporting the need for additional studies in complex coagulopathies characterized by mild to moderate thrombocytopenia and abnormal coagulation.
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http://dx.doi.org/10.1002/rth2.12310DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7040546PMC
February 2020

Validation and psychometric properties of the Maltese version of the Duke Anticoagulation Satisfaction Scale (DASS).

Psychol Res Behav Manag 2019 28;12:741-752. Epub 2019 Aug 28.

Department of Pathology, Faculty of Medicine and Surgery, University of Malta, Msida, Malta.

Purpose: Assessing treatment satisfaction can guide specific interventions to improve anticoagulation adherence and reduce adverse outcomes. We aimed to assess the psychometric properties (reliability and validity) of the Maltese translation of the Duke Anticoagulation Satisfaction Scale (DASS).

Patients And Methods: The DASS explores three dimensions (limitations, hassles/burdens, psychological impact). The translation process included forward and backward translations. Reliability was evaluated through internal consistency and reproducibility. Validity was evaluated through floor/ceiling effect, convergent/discriminant validity, construct validity, and known-group validity.

Results: The Maltese version of the DASS, administered to 174 patients on warfarin for different clinical indications, showed good reliability (Cronbach's alpha 0.87; intraclass correlation coefficient for test-retest 0.73). Floor effect was identified mainly in the limitations and hassles/burdens subscales. Significant positive correlations were found between the DASS total score and its subscales (limitations 0.80, hassles/burdens 0.85, psychological impact 0.68). Female sex, shorter warfarin treatment duration (≤5 years), previous hospitalization and history of bleeding were associated with lower satisfaction.

Conclusion: Psychometric properties of the Maltese DASS were comparable to the original English version. The Maltese version of the DASS is a valid and reliable instrument that can be used by health care professionals to assess the level of satisfaction of Maltese-speaking anticoagulated patients.
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http://dx.doi.org/10.2147/PRBM.S216617DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6717846PMC
August 2019

Reliability and validity of the Maltese version of the Perception of Anticoagulant Treatment Questionnaire (PACT-Q).

Patient Prefer Adherence 2019 19;13:969-979. Epub 2019 Jun 19.

Department of Pathology, Faculty of Medicine and Surgery, University of Malta, Msida, Malta.

Anticoagulant therapy has an impact on the health-related quality of life, as it is a chronic treatment for most clinical indications and also requires some lifestyle changes. Since there was no validated questionnaire available in the Maltese language, the aim of our study was to translate and validate the Perception of Anticoagulant Treatment Questionnaire (PACT-Q2). The PACT-Q2 explores two dimensions (convenience and anticoagulant treatment satisfaction). Forward and backward translations were performed. The Maltese version of the PACT-Q2 was administered to 174 patients on warfarin treatment enrolled from different anticoagulation clinics in Malta. Reliability was assessed through internal consistency (Cronbach's alpha) and test-retest (intraclass correlation coefficient [ICC]). Validity was assessed through floor/ceiling effect, factor analysis (root mean square error of approximation [RMSEA], standardized root mean squared residual [SRMR], goodness-of-fit index [GFI], adjusted goodness-of-fit index [AGFI], comparative fit index [CFI]), subscales correlation and known-group validity. Reliability was very good for the convenience subscale (Cronbach's alpha 0.86, ICC 0.87), but less good for the satisfaction subscale (Cronbach's alpha 0.62, ICC 0.40). Floor effect was 0%; ceiling effect was low (6.3% convenience, 1.2% satisfaction). Fit parameters were close to acceptable cut-offs (RMSEA =0.09, SRMR =0.10, GFI =0.82, AGFI =0.78, CFI =0.79). There was no correlation between the two subscales (r=0.01, =0.83). Patients with history of bleeding showed lower convenience (r=-0.16, =0.08) and lower satisfaction (r=-0.21, =0.01). Our results support the finding that the Maltese translation of the PACT-Q2 is a valid and reliable instrument.
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http://dx.doi.org/10.2147/PPA.S207498DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6593733PMC
June 2019

Teaching an old dog new tricks?

Br J Haematol 2019 11 31;187(4):416-417. Epub 2019 Jul 31.

Haematology Laboratory, Department of Pathology, Mater Dei Hospital, Msida, Malta.

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http://dx.doi.org/10.1111/bjh.16110DOI Listing
November 2019

Fibrinogen measurement in liver disease: validation of the functional fibrinogen thromboelastography assay and a novel mathematical predictive model.

Blood Transfus 2019 05 9;17(3):237-246. Epub 2018 Nov 9.

Coagulation Laboratory, Department of Pathology, "Mater Dei" Hospital, Msida, Malta.

Background: Fibrinogen is produced in the liver and tends to be reduced in liver cirrhosis. Quantitative and qualitative tests exist to measure fibrinogen. We aimed to validate the functional fibrinogen thromboelastography assay (FF-TEG) and propose a new model to estimate fibrinogen levels via the Clauss method (Clauss) using data from a prothrombin time-derived fibrinogen assay (PT-Fg) in patients with liver cirrhosis.

Materials And Methods: Clauss, PT-Fg, fibrinogen antigen (Fib-Ag) and FF-TEG were studied in 55 patients with liver cirrhosis (26 with Child-Turcotte-Pugh [CTP]-A disease, 14 with CTP-B and 15 CTP-C) and 20 healthy individuals.

Results: The results of all four assays correlated strongly with each other, but gave significantly different mean levels in all cohorts. PT-Fg gave the highest levels whereas the Clauss gave the lowest levels. The FF-TEG performed well with results which were in between the Clauss and the PT-Fg. Significant differences were only observed between CTP-A and CTP-C for the Clauss, PT-Fg and Fib-Ag but not functional fibrinogen level. We devised a simple linear regression model in order to estimate Clauss from the PT-Fg.

Discussion: The results of the FF-TEG correlate well with those of routine fibrinogen assays in patients with liver cirrhosis. However, the FF-TEG assay does not discriminate between early and late stages of disease, pointing to a preserved fibrin clot strength in cirrhosis. Through linear regression models, fibrinogen levels can be accurately estimated using the Clauss method based on fibrinogen levels obtained in the cheaper PT-Fg.
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http://dx.doi.org/10.2450/2018.0105-18DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6596371PMC
May 2019

Biomarkers for the diagnosis of venous thromboembolism: D-dimer, thrombin generation, procoagulant phospholipid and soluble P-selectin.

J Clin Pathol 2018 Nov 9;71(11):1015-1022. Epub 2018 Aug 9.

Department of Pathology, Faculty of Medicine and Surgery, University of Malta, Msida, Malta

Background: The diagnostic algorithm for venous thromboembolism (VTE) currently involves a composite of pre-test probability, D-dimer and imaging. Other laboratory tests, however, may assist in the identification of patients with VTE.

Aim: To assess the accuracy of different coagulation tests (D-dimer, thrombin generation, phospholipid-dependent (PPL) clotting time, soluble P-selectin (sP-selectin)) as biomarkers of acute VTE.

Methods: Random samples arriving at the Coagulation Laboratory at Mater Dei Hospital (Msida, Malta) from the Accident and Emergency Department with a request for D-dimer measurement were collected between August 2015 and February 2016. The following tests were performed: Innovance D-dimer (Siemens Healthcare Diagnostics), HemosIL D-dimer HS (Instrumentation Laboratory), thrombin generation (using the calibrated automated thrombogram), STA Procoag PPL (Diagnostica Stago) and sP-selectin (Affymetrix; eBioscience). VTE was objectively confirmed by compression ultrasonography, CT pulmonary angiography or ventilation/perfusion lung scan.

Results: 100 samples were collected (33 with VTE). A strong positive linear correlation was found between the two D-dimer tests (r=0.97, p<0.001). Patients with VTE showed significantly higher sP-selectin concentrations compared with patients without VTE (75.7 ng/mL vs 53.0 ng/mL, p<0.001). In the random forest plot, the two D-dimer assays showed the highest variable importance, followed by sP-selectin. A sP-selectin cut-off of 74.8 ng/mL was associated with 72.7% sensitivity and 78.2% specificity for acute VTE in our cohort.

Conclusion: Our results confirmed D-dimer as the main biomarker of VTE and speculated a role for sP-selectin. The impact of thrombin generation was limited and no role emerged for the PPL clotting time. These observations need to be confirmed in large management studies.
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http://dx.doi.org/10.1136/jclinpath-2018-205293DOI Listing
November 2018

Estimating renal function in patients with atrial fibrillation: which dose of direct oral anticoagulants?

Intern Emerg Med 2018 10 24;13(7):1001-1004. Epub 2018 May 24.

Department of Pathology, Faculty of Medicine and Surgery, University of Malta, Msida, Malta.

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http://dx.doi.org/10.1007/s11739-018-1883-1DOI Listing
October 2018

Primary immune thrombocytopenia in adults: clinical practice versus management guidelines.

Postgrad Med J 2017 11 18;93(1105):645-646. Epub 2017 Jul 18.

CDHB Research Committee, Canterbury District Health Board, Christchurch, New Zealand.

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http://dx.doi.org/10.1136/postgradmedj-2017-135036DOI Listing
November 2017

Achieving a satisfactory clinical and biochemical response in antiphospholipid syndrome and severe thrombocytopenia with rituximab: two case reports.

Clin Case Rep 2017 06 18;5(6):845-848. Epub 2017 Apr 18.

Department of Haemato-Oncology Mater Dei Hospital Msida Malta.

In AP syndrome (APS) with severe thrombocytopenia, rituximab represents a unique drug which can balance the effect of bleeding and thrombosis. By reducing the production of autoantibodies, rituximab can simultaneously raise the platelets and reduce the chance of thrombosis by suppressing APL antibodies. Rituximab can supersede splenectomy as second-line therapy in similar patients.
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http://dx.doi.org/10.1002/ccr3.946DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5458029PMC
June 2017

A feasibility study on the effects of Triton X-100 for the in vitro inactivation of Ebola virus on haematological assays.

J Clin Pathol 2016 Jul 15;69(7):637-42. Epub 2015 Dec 15.

Department of Haematology, Mater Dei Hospital, Msida, Malta.

Aims: The aim of this study was to check the effect of Triton X-100 on various, commonly used haematology test parameters.

Methods: Anonymised blood samples were treated with 10 µL of 10% Triton X-100 per 1 mL of blood. Treated and untreated samples were tested in parallel for blood film morphology, complete blood counts (CBCs), flow cytometry, blood grouping and antibody screens. Samples were also taken in 3.2% citrate tubes for coagulation test analyses.

Results: Statistical differences were noted in all CBC parameters apart from the mean cell volume, eosinophil and basophil counts. Platelet counts were significantly different with an apparent rise after the addition of Triton X-100. Samples were noted to have a high red cell fragmentation index. Immunological platelet counting methods using flow cytometry and fluorescent methods showed no significant differences and gave reliable results. Neither flow cytometry for T-cell subsets nor blood grouping/antibody screens were affected by Triton X-100. However, coagulation samples were severely haemolysed prohibiting analysis.

Conclusions: We have demonstrated that the addition of Triton X-100 to haematology blood samples impacts mainly on platelet counts and coagulation studies due to haemolysis. The platelet count is spuriously raised probably due to the presence of red cell fragments. The latter can be circumvented by the use of immunological platelet counting technology.
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http://dx.doi.org/10.1136/jclinpath-2015-203331DOI Listing
July 2016

Inhibitor development in non-severe haemophilia across Europe.

Thromb Haemost 2015 Oct 13;114(4):670-5. Epub 2015 Aug 13.

Kathelijn Fischer, MD, PhD, Julius Center for Health Sciences and Primary Care and Van Creveldkliniek, University Medical Center Utrecht, Room C01.425, PO Box 85500, 3508 GA Utrecht, The Netherlands, Tel.: +31 88 755 8450, Fax: +31 88 755 5438, E-mail:

Evidence about inhibitor formation in non-severe haemophilia and the potential role for clotting factor concentrate type is scant. It was the aim of this study to report inhibitor development in non-severe haemophilia patients enrolled in the European Haemophilia Safety Surveillance (EUHASS) study. Inhibitors are reported quarterly and total treated patients annually. Incidence rates and 95% confidence intervals (95% CI) were calculated according to diagnosis and concentrate used. Between 1-10-2008 and 31-12-2012, 68 centres reported on 7,969 patients with non-severe haemophilia A and 1,863 patients with non-severe haemophilia B. For haemophilia A, 37 inhibitors occurred in 8,622 treatment years, resulting in an inhibitor rate of 0.43/100 treatment years (95% CI 0.30-0.59). Inhibitors occurred at a median age of 35 years, after a median of 38 exposure days (EDs; P25-P75: 20-80); with 72% occurring within the first 50 EDs. In haemophilia B, one inhibitor was detected in 2,149 treatment years, resulting in an inhibitor rate of 0.05/100 years (95% CI 0.001-0.26). This inhibitor developed at the age of six years, after six EDs. The rate of inhibitors appeared similar across recombinant and plasma derived factor VIII (FVIII) concentrates. Rates for individual concentrates could not be calculated at this stage due to low number of events. In conclusion, inhibitors in non-severe haemophilia occur three times more frequently than in previously treated patients with severe haemophilia at a rate of 0.43/100 patient years (haemophilia A) and 0.05/100 years (haemophilia B). Although the majority of inhibitors developed in the first 50 EDs, inhibitor development continued with increasing exposure to FVIII.
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http://dx.doi.org/10.1160/TH14-12-1044DOI Listing
October 2015

Thrombin generation assays for optimizing low molecular weight heparin dosing in pregnant women at risk of thrombosis--response to Ismail et al.

Br J Haematol 2016 Feb 3;172(4):643-4. Epub 2015 Jun 3.

Katharine Dormandy Haemophilia Centre and Thrombosis Unit, Royal Free Hospital, London, UK.

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http://dx.doi.org/10.1111/bjh.13523DOI Listing
February 2016

Inhibitor development in haemophilia according to concentrate. Four-year results from the European HAemophilia Safety Surveillance (EUHASS) project.

Thromb Haemost 2015 May 8;113(5):968-75. Epub 2015 Jan 8.

Kathelijn Fischer, MD, PhD, Julius Center for Health Sciences and, Primary Care and Van Creveldkliniek, University Medical Center Utrecht, Room C01.425, PO Box 85500, 3508 GA Utrecht, The Netherlands, Tel.: +31 88 755 8450, Fax: +31 88 755 5438, E-mail:

Inhibitor development represents the most serious side effect of haemophilia treatment. Any difference in risk of inhibitor formation depending on the product used might be of clinical relevance. It was this study's objective to assess inhibitor development according to clotting factor concentrate in severe haemophilia A and B. The European Haemophilia Safety Surveillance (EUHASS) was set up as a study monitoring adverse events overall and according to concentrate. Since October 2008, inhibitors were reported at least quarterly. Number of treated patients was reported annually, specifying the number of patients completing 50 exposure days (Previously Untreated Patients, PUPs) without inhibitor development. Cumulative incidence, incidence rates and 95 % confidence intervals (CI) were calculated. Data from October 1, 2008 to December 31, 2012 were analysed for 68 centres that validated their data. Inhibitors developed in 108/417 (26 %; CI 22-30 %) PUPs with severe haemophilia A and 5/72 (7 %; CI 2-16%) PUPs with severe haemophilia B. For Previously Treated Patients (PTPs), 26 inhibitors developed in 17,667 treatment years [0.15/100 treatment years; CI 0.10-0.22) for severe haemophilia A and 1/2836 (0.04/100; (CI 0.00-0.20) for severe haemophilia B. Differences between plasma-derived and recombinant concentrates, or among the different recombinant FVIII concentrates were investigated. In conclusion, while confirming the expected rates of inhibitors in PUPs and PTPs, no class or brand related differences were observed.
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http://dx.doi.org/10.1160/TH14-10-0826DOI Listing
May 2015

Thrombin generation assay identifies individual variability in responses to low molecular weight heparin in pregnancy: implications for anticoagulant monitoring.

Br J Haematol 2015 Mar 29;168(5):719-27. Epub 2014 Oct 29.

Katharine Dormandy Haemophilia Centre and Thrombosis Unit, Royal Free Hospital, London, UK.

Low molecular weight heparin (LMWH) given to inhibit coagulation and reduce the risk of thrombosis, is typically monitored by anti-Xa assay. However, anti-Xa levels may not necessarily provide an accurate measure of coagulation inhibition. Moreover, pregnancy is associated with hypercoagulability, which may compromise the efficacy of LMWH. We looked at the association between anti-Xa levels and parameters of thrombin generation assay [TGA; area under the curve (AUC), peak height (PH) and time to peak (ttP)] using samples from 41 pregnant women receiving LMWH and 40 normal pregnant women controls. TGA results confirmed the physiological hypercoagulability of normal pregnancy (mean normalised values: AUC 119%; PH 157%; ttP 72%). Although anti-Xa measures correlated with all three TGA parameters, this group correlation masked significant inter-individual variability, demonstrated by the R(2) value or coefficient of determination. Anti-Xa levels contributed to 74% of variation in AUC values, 63% of variation in PH values and only 53% of variation in ttP values. The remainder reflects the contribution of patients' intrinsic coagulation status. Hence, some patients with 'safe' anti-Xa levels may potentially be under-anticoagulated, particularly in pregnancy. Measuring coagulability directly with TGA may lower the risk of adverse events due to under-anticoagulation in selected patients.
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http://dx.doi.org/10.1111/bjh.13193DOI Listing
March 2015

Flow cytometry and thromboelastography to assess platelet counts and coagulation in patients with haematological malignancies.

Blood Transfus 2014 Oct 5;12(4):479-84. Epub 2014 Jun 5.

Haematology-Oncology Department, Mater Dei Hospital, Msida, Malta Blood Transfusion Department, Mater Dei Hospital, Msida, Malta.

Background: Accurate platelet counts (PC) are necessary in order to follow recommendations for prophylactic platelet transfusion. We carried out a study comparing the standard way of counting platelets using a routine analyser and compared it with PC determined by flow cytometry (FC) and haemostatic data obtained with thromboelastography (TEG).

Materials And Methods: The study was carried out on 24 patients with haematological malignancies, all given one adult dose of platelets. The PC was determined before and after transfusion using an automated blood cell counter and FC. Citrated, "native" whole blood TEG was carried out before and after platelet transfusion to assess global haemostasis.

Results: No bleeding was observed in any of the subjects. Thirty-one assessments were performed in the 24 patients. The mean pre-transfusion PC were 9.8 and 13×10(9)/L with the automated counter and FC, respectively with a difference of 3.7 (p=0.0011). Excellent correlation was observed between the two counts (r=0.89; p<0.0001). Mean post-transfusion increments were 23 and 29×10(9)/L for the routine counter and FC, respectively. Using the immunological PC, patients would not have qualified for transfusion in 18.2% of cases since their PC was >20×10(9)/L. TEG showed a shortened reaction time in 69.6% of cases and a normal mean K time of 6.7 min. Only 9% had a low α angle signifying hypocoagulability. The maximum amplitude was reduced in the majority of cases but normal in 25% despite PC<20×10(9)/L. Mean activated partial thromboplastin time, prothrombin time and fibrinogen were normal prior to transfusion.

Discussion: Although higher PC as assessed by FC could potentially have an impact on platelet transfusion practices, TEG was sensitive enough to detect PC<10×10(9)/L and some between 10-20×10(9)/L. Whether patients with the latter PC are more prone to bleeding remains to be verified in larger studies.
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http://dx.doi.org/10.2450/2014.0259-13DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4212027PMC
October 2014

Does balanced haemostasis equate to normal coagulation in patients with acute liver failure?

Liver Int 2014 May;34(5):652-4

Department of Pathology, Faculty of Medicine and Surgery, University of Malta, Msdia, Malta.

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http://dx.doi.org/10.1111/liv.12477DOI Listing
May 2014

The Owren INR in liver disease: a way towards standardisation?

Thromb Res 2013 Sep 22;132(3):327-8. Epub 2013 Jun 22.

Haematology Unit, Department of Haemato-Oncology, Mater Dei Hospital, Tal-Qroqq, Malta. Electronic address:

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http://dx.doi.org/10.1016/j.thromres.2013.05.030DOI Listing
September 2013

Hemostasis in patients with acute kidney injury secondary to acute liver failure.

Kidney Int 2013 Jul 20;84(1):158-63. Epub 2013 Mar 20.

Intensive Care Unit, Royal Free Hospital, London, UK.

Acute kidney injury (AKI) occurs in over half of patients with acute liver failure. Despite prolonged prothrombin times and thrombocytopenia, continuous renal replacement therapy circuits frequently develop clots during patient treatment. Here we assessed factors contributing to this by measuring coagulation parameters (standard coagulation tests, pro- and anticoagulant factors, thromboelastography, and thrombin generation) in 20 consecutive patients with acute liver failure; mean age 42 years. Within 48 h, 10 had developed stage 3 AKI and 9 required continuous renal replacement therapy, of whom 2 had frequent circuit clots. The patients with stage 3 AKI were found to have significantly lower platelet counts and levels of factor V and the natural anticoagulants antithrombin, Protein C and Protein S, but increased extrinsic pathway activation and von Willebrand factor levels. Tissue factor levels were greater in those with stage 3 AKI, as was microparticle activity. Although patients with acute liver failure and advanced AKI requiring continuous renal replacement therapy have an even more marked thrombocytopenia and more prolonged extrinsic pathway activation, this was not associated with increased bleeding. Thus, more frequent circuit clots during continuous renal replacement therapy appear to be due to a combination of increased tissue factor and microparticle release, endothelial activation, and reduction in natural anticoagulants.
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http://dx.doi.org/10.1038/ki.2013.92DOI Listing
July 2013

Evaluation of coagulation abnormalities in acute liver failure.

J Hepatol 2012 Oct 23;57(4):780-6. Epub 2012 Jun 23.

Department of Intensive Care Medicine, Royal Free Hospital, London, United Kingdom.

Background & Aims: In acute liver failure (ALF), prothrombin time (PT) and its derivative prothrombin time ratio (PTR) are elevated, and are considered predictors of increased bleeding risk. We aimed at determining whether increased PT/PTR reflects the haemostatic potential and bleeding risk in ALF patients.

Methods: Twenty consecutive ALF patients were recruited. Samples were analysed on admission for standard laboratory clotting tests (e.g. PT), thromboelastography (TEG), individual pro and anticoagulant factors and thrombin generation (TG) kinetics with and without Protac, a snake venom protein C activator, and microparticle assay. TG was also measured in 20 age and sex matched healthy volunteers.

Results: PT was significantly raised (50.7s ± 7.2, p=0.0001) but did not correlate with TEG parameters. TEG tracings were consistent with a hypocoagulable state in 20%, normal in 45%, and hypercoagulable in 35% of the patients. There was a concomitant and proportional reduction in plasma levels of both procoagulants and natural anticoagulant proteins, in conjunction with a significant elevation in plasma levels of factors-VIII (FVIII) and Von Willebrand factor, and microparticles, culminating in an overall efficient, albeit reduced, thrombin generation capacity in comparison with healthy individuals. A heparin-like effect (HLE) was also noted in most patients. No significant clinical bleeding complications occurred and no blood transfusions were required.

Conclusions: In ALF, despite grossly deranged PT in all patients, estimation of bleeding risk suggests that the coagulation disturbance in ALF patients is complex and heterogeneous for which an individualised approach is required.
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http://dx.doi.org/10.1016/j.jhep.2012.06.020DOI Listing
October 2012

Anaphylactic reaction with prothrombin complex concentrate in a patient with IgA deficiency and anti-IgA antibodies.

Blood Coagul Fibrinolysis 2010 Dec;21(8):764-5

KD Haemophilia Centre and Thrombosis Unit, UK.

Immunoglobulin A (IgA) deficiency with anti-IgA antibodies is not listed as an absolute or relative contraindication for the use of prothrombin complex concentrates (PCCs). We discuss a patient who developed an anaphylactic reaction to PCC on a background of selective IgA deficiency with anti-IgA antibodies and with a history of anaphylactic reaction to other blood products. Further analysis of PCCs revealed the presence of variable quantities of immunoglobulins of all classes, including IgA. Although the summary of product characteristics for PCCs from various manufacturers does not list IgA deficiency with anti-IgA antibodies as an absolute or relative contraindication, our findings suggest that PCCs are not devoid of IgA and great caution must be exercised with their use in patients with IgA deficiency with anti-IgA antibodies and with previously documented reactions.
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http://dx.doi.org/10.1097/MBC.0b013e3283401465DOI Listing
December 2010

Alternatives to warfarin--the next generation of anticoagulants.

Cardiovasc Ther 2011 Dec 9;29(6):e80-8. Epub 2010 Jul 9.

Haemophilia Centre and Thrombosis Unit, Royal Free Hospital, Pond Street, London, UK.

Anticoagulation therapy plays an important role in the management of cardiovascular disease. Currently, oral anticoagulation therapy is reliant on vitamin K antagonists (VKA). In clinical practice, VKA present several limitations including a narrow therapeutic window and frequent drug and food interactions. Despite the clear clinical need for alternative anticoagulants it is only within the last decade that significant progress has been made. These new anticoagulants target specific factors in the hemostatic network and appear to overcome some of the difficulties seen with VKA. Many have now progressed to phase III clinical trials including patients with cardiovascular disease. This review aims to highlight the exciting progress that has been made in the development of these new anticoagulants. It will focus on the key agents that have demonstrated the most promise in clinical trials to date. This will include data on cardiovascular indications for anticoagulant therapy. Finally, the review aims to analyze the future prospects for these new agents. Several issues remain to be addressed for these agents to finally replace vitamin K antagonists as the mainstay of anticoagulant therapy.
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http://dx.doi.org/10.1111/j.1755-5922.2010.00197.xDOI Listing
December 2011

Calibrated automated thrombin generation and modified thromboelastometry in haemophilia A.

Thromb Res 2009 Apr 13;123(6):895-901. Epub 2008 Nov 13.

Sheffield Haemophilia and Thrombosis Centre, Royal Hallamshire Hospital, Glossop Road, Sheffield S10 2JF, United Kingdom.

Introduction: Global coagulation tests may have a better relation with phenotype in haemophilia than traditional coagulation tests. These include the Calibrated Automated Thrombin generation assay (CAT) and modified thromboelastometry using low tissue factor triggering. Both have shown marked variability in thrombin generation and clot formation profiles respectively despite similar FVIII:C levels and have been suggested as means to monitor treatment. Data with modified thromboelastometry are largely limited to severe and moderate haemophiliacs. CAT measurements in haemophilia are generally performed at low TF concentrations (1 pM) because of a higher sensitivity for the intrinsic pathway at this concentration but is also sensitive for FVIII at higher concentrations (5 pM) and this has the advantage that inhibition of contact factor activation can be avoided. No formal comparison of both TF concentrations has been reported and the data on modified thromboelastometry in mild haemophilia are limited.

Methods: In this study we compared thrombin generation at 1 and 5 pM in 57 haemophilia patients without exposure to treatment and 41 patients after treatment. We also assessed the sensitivity of thromboelastometry for haemophilia A in 29 patients.

Results And Conclusion: We found that CAT discriminates well between normal individuals and haemophilia patients; also FVIII:C correlates well with the ETP/peak. We found no clear advantages of measurements at 1 compared to 5 pM but found increased variation over time at 1 pM. The sensitivity of modified thromboelastometry for haemophilia A was less than CAT with abnormal measurements largely limited to severe and moderate patients. Larger studies correlating both methods with clinical outcome are required.
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http://dx.doi.org/10.1016/j.thromres.2008.09.011DOI Listing
April 2009

Thrombin generation assays are superior to traditional tests in assessing anticoagulation reversal in vitro.

Thromb Haemost 2008 Aug;100(2):350-5

Sheffield Haemophilia and Thrombosis Centre, Royal Hallamshire Hospital, Sheffield, UK.

Even though new anticoagulants are being devised with the notion that they do not require regular monitoring, when bleeding occurs, it is important to have an antidote and a reliable test to confirm whether the anticoagulant effects are persisting. We examined the effects of five heparinoids, unfractionated heparin (UFH), tinzaparin, enoxaparin, danaparoid and fondaparinux on the traditional APTT and anti-Xa assays as well as on the calibrated automated thrombogram (CAT). We also studied the ability of protamine sulphate (PS), NovoSeven, FEIBA and FFP to reverse maximum anticoagulation induced by the different heparinoids. The CAT was the only test to detect the coagulopathy of all the anticoagulants. PS produced complete reversal of UFH, and this could be monitored with all three tests. Tinzaparin can also be completely neutralised in vitro with high doses of PS, but the maximum enoxaparin reversal achieved with PS is only approximately 60%. Fondaparinux does not significantly affect the APTT and PS has no significant effect on its reversal. Only NovoSeven was able to correct the fondaparinux induced CAT abnormalities whilst having no effect on the anti-Xa level. None of the reversal agents was very effective in danaparoid spiked plasma but NovoSeven, at high dose, increased the ETP by 40% and reduced the anti-Xa level from 0.93 to 0.78 IU/ml. We conclude that the CAT is superior to the traditional coagulation tests in that it not only detects the coagulopathy of all the heparinoids but can be also be used to monitor their reversal.
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August 2008

Corn trypsin inhibitor in fluorogenic thrombin-generation measurements is only necessary at low tissue factor concentrations and influences the relationship between factor VIII coagulant activity and thrombogram parameters.

Blood Coagul Fibrinolysis 2008 Apr;19(3):183-9

Sheffield Haemophilia and Thrombosis Centre, Royal Hallamshire Hospital, Sheffield, UK.

The fluorogenic calibrated automated thrombin-generation assay is influenced by contact pathway activation in platelet-rich and platelet-poor plasma. This influence lessens with increasing tissue factor (TF) concentrations and is inhibited by corn trypsin inhibitor (CTI). CTI is expensive and at what TF concentration its influence becomes irrelevant is unclear. Spiking of factor VIII (FVIII)-depleted plasma with FVIII, in samples without CTI, shows a plateau of thrombin generation at low normal FVIII levels. Given the association with thrombosis at high levels, a continuing increase in thrombin generation would be expected. We studied the effect of CTI on this relation by spiking experiments up to 4.8 IU/ml at 1 pmol/l TF and compared the influence of CTI at 1 and 5 pmol/l in platelet-poor plasma. CTI significantly influences thrombin generation in platelet-poor plasma at 1 pmol/l TF (difference of means for endogenous thrombin potential of 232.5 nmol/l per min, P<0.0001) and peak of 48 nmol/l (P<0.0001)) but not at 5 pmol/l. Spiking experiments without CTI confirm the hyperbolic relation between FVIII coagulant activity (FVIII:C) and endogenous thrombin potential with a plateau at 0.70-1.40 IU/ml. With CTI, a near-linear response up to 1.0 IU/ml was found with a plateau at 2.4-4.8 IU/ml. For peak thrombin, no plateau was reached with CTI. The present study confirms and extends previous data on CTI and the relationship between FVIII:C and thrombin generation. CTI is not necessary at 5 pmol/l TF, and thrombin generation remains dependent on FVIII:C up to 4.8 IU/ml at 1 pmol/l with CTI. Higher levels than previously thought may be needed to normalize thrombin generation.
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http://dx.doi.org/10.1097/MBC.0b013e3282f4bb47DOI Listing
April 2008

Protein C deficiency screening using a thrombin generation assay - an upgrade.

Thromb Haemost 2007 Sep;98(3):691-2

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September 2007