Publications by authors named "David E Schmidt"

24 Publications

  • Page 1 of 1

Biological stratification of clinical disease courses in childhood immune thrombocytopenia.

J Thromb Haemost 2021 Apr 18;19(4):1071-1081. Epub 2021 Mar 18.

Department of Immunohematology Diagnostics, Sanquin Diagnostic Services, Amsterdam, The Netherlands.

Background: In childhood immune thrombocytopenia (ITP), an autoimmune bleeding disorder, there is a need for better prediction of individual disease courses and treatment outcomes.

Objective: To predict the response to intravenous immunoglobulins (IVIg) and ITP disease course using genetic and immune markers.

Methods: Children aged younger than 7 years with newly diagnosed ITP (N = 147) from the Treatment With or Without IVIG for Kids with ITP study were included, which randomized children to an IVIg or observation group. A total of 46 variables were available: clinical characteristics, targeted genotyping, lymphocyte immune phenotyping, and platelet autoantibodies.

Results: In the treatment arm, 48/80 children (60%) showed a complete response (platelets ≥100 × 10 /L) that lasted for at least 1 month (complete sustained response [CSR]) and 32 exhibited no or a temporary response (absence of a sustained response [ASR]). For a biological risk score, five variables were selected by regularized logistic regression that predicted ASR vs CSR: (1) hemoglobin; (2) platelet count; (3) genetic polymorphisms of Fc-receptor (FcγR) IIc; (4) the presence of immunoglobulin G (IgG) anti-platelet antibodies; and (5) preceding vaccination. The ASR sensitivity was 0.91 (95% confidence interval, 0.80-1.00) and specificity was 0.67 (95% confidence interval, 0.53-0.80). In the 67 patients of the observation arm, this biological score was also associated with recovery during 1 year of follow-up. The addition of the biological score to a predefined clinical score further improved the discrimination of favorable ITP disease courses.

Conclusions: The prediction of disease courses and IVIg treatment responses in ITP is improved by using both clinical and biological stratification.
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http://dx.doi.org/10.1111/jth.15232DOI Listing
April 2021

A clinical prediction score for transient versus persistent childhood immune thrombocytopenia.

J Thromb Haemost 2021 01 27;19(1):121-130. Epub 2020 Nov 27.

Department of Immunohematology Diagnostics, Sanquin Diagnostic Services, Amsterdam, the Netherlands.

Essentials There is a need for improved tools to predict persistent and chronic immune thrombocytopenia (ITP). We developed and validated a clinical prediction model for recovery from newly diagnosed ITP. The Childhood ITP Recovery Score predicts transient vs. persistent ITP and response to intravenous immunoglobulins. The score may serve as a useful tool for clinicians to individualize patient care. ABSTRACT: Background Childhood immune thrombocytopenia (ITP) is an autoimmune bleeding disorder. The prognosis (transient, persistent, or chronic ITP) remains difficult to predict. The morbidity is most pronounced in children with persistent and chronic ITP. Clinical characteristics are associated with ITP outcomes, but there are no validated multivariate prediction models. Objective Development and external validatation of the Childhood ITP Recovery Score to predict transient versus persistent ITP in children with newly diagnosed ITP. Methods Patients with a diagnosis platelet count ≤ 20 × 10 /L and age below 16 years were included from two prospective multicenter studies (NOPHO ITP study, N = 377 [development cohort]; TIKI trial, N = 194 [external validation]). The primary outcome was transient ITP (complete recovery with platelets ≥100 × 10 /L 3 months after diagnosis) versus persistent ITP. Age, sex, mucosal bleeding, preceding infection/vaccination, insidious onset, and diagnosis platelet count were used as predictors. Results In external validation, the score predicted transient versus persistent ITP at 3 months follow-up with an area under the receiver operating characteristic curve of 0.71. In patients predicted to have a high chance of recovery, we observed 85%, 90%, and 95% recovered 3, 6, and 12 months after the diagnosis. For patients predicted to have a low chance of recovery, this was 32%, 46%, and 71%. The score also predicted cessation of bleeding symptoms and the response to intravenous immunoglobulins (IVIg). Conclusion The Childhood ITP Recovery Score predicts prognosis and may be useful to individualize clinical management. In future research, the additional predictive value of biomarkers can be compared to this score. A risk calculator is available (http://www.itprecoveryscore.org).
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http://dx.doi.org/10.1111/jth.15125DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7839442PMC
January 2021

Evolution and Utility of Antiplatelet Autoantibody Testing in Patients with Immune Thrombocytopenia.

Transfus Med Rev 2020 10 16;34(4):258-269. Epub 2020 Sep 16.

Department of Immunohematology Diagnostics, Sanquin Diagnostic Services, Amsterdam, the Netherlands; Sanquin Research, Center for Clinical Transfusion Research, Leiden, the Netherlands; Department of Immunohematology and Blood Transfusion, Leiden University Medical Center, Leiden, the Netherlands.

To this day, immune thrombocytopenia (ITP) remains a clinical diagnosis made by exclusion of other causes for thrombocytopenia. Reliable detection of platelet autoantibodies would support the clinical diagnosis, but the lack of specificity and sensitivity of the available methods for platelet autoantibody testing limits their value in the diagnostic workup of thrombocytopenia. The introduction of methods for glycoprotein-specific autoantibody detection has improved the specificity of testing and is acceptable for ruling in ITP but not ruling it out as a diagnosis. The sensitivity of these assays varies widely, even between studies using comparable assays. A review of the relevant literature combined with our own laboratory's experience of testing large number of serum and platelet samples makes it clear that this variation can be explained by variations in the characteristics of the tests, including in the glycoprotein-specific monoclonal antibodies, the glycoproteins that are tested, the platelet numbers used in the assay and the cutoff levels for positive and negative results, as well as differences in the tested patient populations. In our opinion, further standardization and optimization of the direct autoantibody detection methods to increase sensitivity without compromising specificity seem possible but will still likely be insufficient to distinguish the often very weak specific autoantibody signals from background signals. Further developments of autoantibody detection methods will therefore be necessary to increase sensitivity to a level acceptable to provide laboratory confirmation of a diagnosis of ITP.
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http://dx.doi.org/10.1016/j.tmrv.2020.09.003DOI Listing
October 2020

Diagnostic Accuracy in Acute Venous Thromboembolism: Comparing D-Dimer, Thrombin Generation, Overall Hemostatic Potential, and Fibrin Monomers.

TH Open 2020 Jul 20;4(3):e178-e188. Epub 2020 Aug 20.

Department of Molecular Medicine and Surgery, Karolinska Institutet, Stockholm, Sweden.

 For acute venous thromboembolism (VTE), a biomarker with higher specificity than D-dimer would be of great clinical use. Thrombin generation and overall hemostatic potential (OHP) reflect the hemostatic balance by globally assessing multiple coagulation factors and inhibitors. These tests discriminate between healthy controls and patients with a prothrombotic tendency but have yet to be established as clinical biomarkers of VTE.  This study compares endogenous thrombin potential (ETP) and OHP to D-dimer and fibrin monomers (FM) in outpatients with suspected VTE.  A cross-sectional diagnostic study where 954 patients with suspected pulmonary embolism or deep venous thrombosis were recruited consecutively from the medical emergency department at Karolinska University Hospital. D-dimer, FM, OHP, and ETP were analyzed in a subpopulation of 60 patients with VTE and 98 matched controls without VTE. VTE was verified either by ultrasonography or computed tomography and clinical data were collected from medical records.  Compared with healthy controls, both VTE and non-VTE patients displayed prothrombotic profiles in OHP and ETP. D-dimer, FM, ETP area under the curve (AUC), and ETP T were significantly different between patients with VTE and non-VTE. The largest receiver-operating characteristic AUCs for discrimination between VTE and non-VTE, were found in D-dimer with 0.94, FM 0.77, and ETP AUC 0.65. No useful cutoff could be identified for the ETP or the OHP assay.  Compared with D-dimer, neither ETP nor OHP were clinically viable biomarkers of acute venous thrombosis. The data indicated that a large portion of the emergency patients with suspected VTE were in a prothrombotic state.
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http://dx.doi.org/10.1055/s-0040-1714210DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7440969PMC
July 2020

Anti-platelet antibody immunoassays in childhood immune thrombocytopenia: a systematic review.

Vox Sang 2020 May 20;115(4):323-333. Epub 2020 Feb 20.

Department of Immunohematology Diagnostics, Sanquin Diagnostic Services, Amsterdam, The Netherlands.

Background: In adult immune thrombocytopenia (ITP), an acquired autoimmune bleeding disorder, anti-platelet autoantibody testing may be useful as a rule-in test. Childhood ITP has different disease characteristics, and the diagnostic and prognostic value of anti-platelet antibody testing remains uncertain.

Objective: To systematically review the diagnostic accuracy of anti-platelet autoantibody testing in childhood ITP.

Methods: PubMed and EMBASE were searched for studies evaluating immunoassays in childhood ITP. Study quality was assessed (QUADAS2), and evidence was synthesized descriptively.

Results: In total, 40 studies (1606 patients) were identified. Nine studies reported sufficient data to determine diagnostic accuracy measures. Anti-platelet IgG antibody testing showed a moderate sensitivity (0·36-0·80 platelet-associated IgG [direct test]; 0·19-0·39 circulating IgG [indirect test]). In studies that reported control data, including patients with non-immune thrombocytopenia, specificity was very good (0·80-1·00). Glycoprotein-specific immunoassays showed comparable sensitivity (three studies) and predominantly identified IgG anti-GP IIb/IIIa antibodies, with few IgG anti-GP Ib/IX antibodies. Anti-platelet IgM antibodies were identified in a substantial proportion of children (sensitivity 0·62-0·64 for direct and indirect tests).

Conclusion: The diagnostic evaluation of IgG and IgM anti-platelet antibodies may be useful as a rule-in test for ITP. In children with insufficient platelets for a direct test, indirect tests may be performed instead. A negative test does not rule out the diagnosis of ITP. Future studies should evaluate the value of anti-platelet antibody tests in thrombocytopenic children with suspected ITP.
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http://dx.doi.org/10.1111/vox.12894DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7317748PMC
May 2020

IgG-Fc glycosylation before and after rituximab treatment in immune thrombocytopenia.

Sci Rep 2020 02 20;10(1):3051. Epub 2020 Feb 20.

Sanquin Research, Department of Experimental Immunohematology, Amsterdam, The Netherlands and Landsteiner Laboratory, Amsterdam UMC, University of Amsterdam, Amsterdam, The Netherlands.

The interactions of antibodies with myeloid Fcγ receptors and the complement system are regulated by an Asn297-linked glycan in the Fc portion of IgG. Alterations of serum IgG-Fc glycosylation have been reported in various autoimmune diseases, and correlate with treatment response and disease activity. We hypothesized that IgG-Fc glycosylation is altered in immune thrombocytopenia (ITP) and associates with response to anti-CD20 monoclonal antibody treatment (rituximab). IgG-Fc glycosylation was analyzed by liquid chromatography-mass spectrometry. We found that IgG-Fc glycosylation was identical between refractory ITP patients (HOVON64 trial; N = 108) and healthy controls (N = 120). Two months after rituximab treatment, we observed a shift in Fc glycosylation, with a mean 1.7% reduction in galactosylation for IgG1 and IgG4 and a mean 1.5% increase for bisection in IgG1, IgG2/3 and IgG4 (adjusted p < 1.7 × 10 and p < 2 × 10, respectively). Neither baseline nor longitudinal changes in IgG-Fc glycosylation after rituximab were associated with clinical treatment response. We conclude that IgG-Fc glycosylation in refractory ITP is similar to healthy controls and does not predict treatment responses to rituximab. The observed changes two months after treatment suggest that rituximab may influence total serum IgG-Fc glycosylation. Overall, our study suggests that the pathophysiology of refractory ITP may differ from other autoimmune diseases.
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http://dx.doi.org/10.1038/s41598-020-59651-7DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7033207PMC
February 2020

Anti-platelet antibodies in childhood immune thrombocytopenia: Prevalence and prognostic implications.

J Thromb Haemost 2020 05 12;18(5):1210-1220. Epub 2020 Apr 12.

Laboratory for Platelet and Leukocyte Serology, Department of Immunohematology Diagnostics, Sanquin Diagnostic Services, Amsterdam, the Netherlands.

Background: Anti-platelet antibody testing may be useful for the diagnosis and management of childhood immune thrombocytopenia (ITP).

Objectives: Here we aimed to assess the prevalence and prognostic significance of anti-platelet glycoprotein-specific IgM and IgG antibodies.

Methods: Children with newly diagnosed ITP were included at diagnosis and randomized to an intravenous immunoglobulins (IVIg) or careful observation group (TIKI trial). In this well-defined and longitudinally followed cohort (N = 179), anti-platelet glycoprotein-specific IgM and IgG antibodies were determined by monoclonal antibody-immobilization of platelet antigens.

Results: The dominant circulating anti-platelet antibody class in childhood ITP was IgM (62% of patients); but IgG antibodies were also found (10%). Children without IgM platelet antibodies were older and more often female. There was weak evidence for an association between IgM anti-GP IIb/IIIa antibodies and an increased bleeding severity (P = .03). The IgM and IgG anti-platelet responses partially overlapped, and reactivity was frequently directed against multiple glycoproteins. During 1-year follow-up, children with IgM antibodies in the observation group displayed a faster platelet recovery compared to children without, also after adjustment for age and preceding infections (P = 7.1 × 10 ). The small group of patients with detectable IgG anti-platelet antibodies exhibited an almost complete response to IVIg treatment (N = 12; P = .02), suggesting that IVIg was particularly efficacious in these children.

Conclusions: Testing for circulating anti-platelet antibodies may be helpful for the clinical prognostication and the guidance of treatment decisions in newly diagnosed childhood ITP. Our data suggest that the development of even more sensitive tests may further improve the clinical value of antibody testing.
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http://dx.doi.org/10.1111/jth.14762DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7318215PMC
May 2020

Genetic Variation in Low-To-Medium-Affinity Fcγ Receptors: Functional Consequences, Disease Associations, and Opportunities for Personalized Medicine.

Front Immunol 2019 3;10:2237. Epub 2019 Oct 3.

Sanquin Research and Landsteiner Laboratory, Department of Blood Cell Research, Amsterdam UMC, University of Amsterdam, Amsterdam, Netherlands.

Fc-gamma receptors (FcγR) are the cellular receptors for Immunoglobulin G (IgG). Upon binding of complexed IgG, FcγRs can trigger various cellular immune effector functions, thereby linking the adaptive and innate immune systems. In humans, six classic FcγRs are known: one high-affinity receptor (FcγRI) and five low-to-medium-affinity FcγRs (FcγRIIA, -B and -C, FcγRIIIA and -B). In this review we describe the five genes encoding the low-to-medium -affinity FcγRs (, and , including well-characterized functionally relevant single nucleotide polymorphisms (SNPs), haplotypes as well as copy number variants (CNVs), which occur in distinct copy number regions across the locus. The evolution of the locus is also discussed. Importantly, we recommend a consistent nomenclature of genetic variants in the locus. Next, we focus on the relevance of genetic variation in the locus in auto-immune and auto-inflammatory diseases, highlighting pathophysiological insights that are informed by genetic association studies. Finally, we illustrate how specific FcγR variants relate to variation in treatment responses and prognosis amongst autoimmune diseases, cancer and transplant immunology, suggesting novel opportunities for personalized medicine.
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http://dx.doi.org/10.3389/fimmu.2019.02237DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6786274PMC
October 2020

Anti-glycoprotein Ibα autoantibodies do not impair circulating thrombopoietin levels in immune thrombocytopenia patients.

Haematologica 2020 04 11;105(4):e172-e174. Epub 2019 Jul 11.

Sanquin Research, Department of Experimental Immunohematology and Landsteiner Laboratory, Amsterdam UMC, University of Amsterdam, Amsterdam

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http://dx.doi.org/10.3324/haematol.2019.228908DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7109722PMC
April 2020

Transient and chronic childhood immune thrombocytopenia are distinctly affected by Fc-γ receptor polymorphisms.

Blood Adv 2019 07;3(13):2003-2012

Department of Immunohematology Diagnostics, Sanquin Diagnostic Services, Amsterdam, The Netherlands.

In childhood immune thrombocytopenia (ITP), anti-platelet autoantibodies mediate platelet clearance through Fc-γ receptor (FcγR)-bearing phagocytes. In 75% to 90% of patients, the disease has a transient, self-limiting character. Here we characterized how polymorphisms of FcγR genes affect disease susceptibility, response to intravenous immunoglobulin (IVIg) treatment, and long-term recovery from childhood ITP. Genotyping of the locus was performed in 180 children with newly diagnosed ITP, 22 children with chronic ITP, and 180 healthy control children by multiplex ligation-dependent probe amplification. Children with newly diagnosed ITP were randomly assigned to a single administration of IVIg or observation, and followed for 1 year (Treatment With or Without IVIg for Kids With ITP [TIKI] trial). We defined transient ITP as a complete recovery (≥100 × 10/L) 3 months after diagnosis, including both self-limiting disease/IVIg responders and chronic ITP as absence of a complete recovery at 12 months. ITP susceptibility, as well as spontaneous recovery and response to IVIg, was associated with the genetic variants *ORF and *27W and the promoter variant 2B.4. These variants were overrepresented in patients with transient (N = 131), but not chronic (N = 43), disease. The presence of *ORF predisposed to transient ITP with an odds ratio of 4.7 (95% confidence interval, 1.9-14.3). Chronic ITP was associated with a deletion of (copy number region 1) with an odds ratio of 6.2 (95% confidence interval, 1.8-24.7). Taken together, susceptibility to transient and chronic ITP is distinctly affected by polymorphic variants of genes. Our data suggest that genotyping of the locus may be useful for prognosis and guidance of treatment decisions in newly diagnosed childhood ITP.
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http://dx.doi.org/10.1182/bloodadvances.2019000068DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6616256PMC
July 2019

Correlation of thromboelastography and thrombin generation assays in warfarin-treated patients.

Thromb Res 2019 Jun 1;178:34-40. Epub 2019 Apr 1.

Department of Medicine, Division of Haematology, Coagulation Unit, Karolinska University Hospital and Karolinska Institutet, Stockholm, Sweden; Department of Clinical Sciences, Danderyds Hospital, Division of Cardiovascular Medicine, Karolinska Institutet, Stockholm, Sweden. Electronic address:

Venous thromboembolism (VTE) affects approximately 1 per 1000 persons annually. Although patients are increasingly treated with direct oral anticoagulants, many patients continue to be anticoagulated with vitamin K antagonists (VKA). The most important adverse events during VKA treatment, bleeding and the risk of recurrent VTE, are difficult to predict. Global haemostatic assays, such as thrombin generation assays and the viscoelastic whole blood tests thromboelastography (TEG) and thromboelastometry (ROTEM), allow a comprehensive assessment of haemostasis and could potentially predict such side effects. In the present study we compared results from thrombin generation (Calibrated Automated Thrombogram and Innovance ETP assays) and TEG and ROTEM in 84 warfarin-treated patients with primary or recurrent VTE and 87 healthy controls. VKA treatment lead to lagtime prolongation and a lower overall thrombin production, which correlated strongly with INR (Pearson r = 0.89 and r = -0.85, respectively). The reduced thrombin generation of VKA-treated patients was accurately reflected by tissue-factor activated ROTEM (EXTEM) clotting time prolongation (vs. CAT lagtime, r = 0.87). Clot strength or clot formation kinetics were only weakly affected by thrombin generation. Intrinsic pathway activated TEG or ROTEM (INTEM) were not sensitive to the reduced thrombin generation. In conclusion, patients anticoagulated with VKA after VTE showed a reduced plasma thrombin generation that was accurately reflected by tissue factor activated ROTEM. ROTEM provided additional information to thrombin generation, including clot formation kinetics and strength.
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http://dx.doi.org/10.1016/j.thromres.2019.03.022DOI Listing
June 2019

Whole blood ristocetin-activated platelet impedance aggregometry (Multiplate) for the rapid detection of Von Willebrand disease.

Thromb Haemost 2017 07 6;117(8):1528-1533. Epub 2017 Jul 6.

Anna Ågren, MD, PhD, Coagulation Unit, Hematology Center, Karolinska University Hospital, 171 76 Stockholm, Sweden, Tel.: +46 8 51773373, Fax: +46 8 51775084, E-mail:

Von Willebrand disease (VWD) is the most common bleeding disorder, but no bedside tests specific for Von Willebrand factor are available. The objective of this study was to evaluate the diagnostic accuracy of whole blood ristocetin-induced platelet aggregometry (WB-RIPA) in VWD. WB-RIPA was performed in VWD patients (n=100) and healthy controls (n=17) using the Multiplate® platelet impedance aggregometry platform. The diagnostic properties of the test were described as sensitivity/specificity, positive and negative predictive value, and ROC area under the curve (AUC). Patients with VWD had impaired platelet aggregation by WB-RIPA. At a cut-off of 98 U, the test sensitivity and specificity of WB-RIPA for VWD was 0.95 and 0.53. A cut-off of 60 U provided a specificity of 1.00 with reduced sensitivity of 0.76. All patients with type 3 VWD and >90 % of patients with type 2 VWD were accurately distinguished from the controls. Incorrect classifications were attributable to patients with type 1 VWD, showing partly overlapping WB-RIPA results with healthy controls. Remarkably, these patients had lower bleeding scores and higher VWF activity than other type 1 VWD patients. Overall, WB-RIPA discriminated VWD patients from healthy controls accurately with a ROC AUC of 0.94. These results show that WB-RIPA is a promising diagnostic test for VWD, especially when timely results are required. Depending on the chosen test threshold, WB-RIPA could be clinically used as a rule out test, or to suggest patients in whom further testing for VWD is warranted.
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http://dx.doi.org/10.1160/TH17-02-0129DOI Listing
July 2017

Relative effects of plasma, fibrinogen concentrate, and factor XIII on ROTEM coagulation profiles in an in vitro model of massive transfusion in trauma.

Scand J Clin Lab Invest 2017 Oct 20;77(6):397-405. Epub 2017 Jun 20.

a Department of Medicine, Division of Haematology, Coagulation Unit , Karolinska University Hospital and Karolinska Institutet , Stockholm , Sweden.

Massive traumatic haemorrhage is aggravated through the development of trauma-induced coagulopathy, which is managed by plasma transfusion and/or fibrinogen concentrate administration. It is yet unclear whether these treatments are equally potent in ensuring adequate haemostasis, and whether additional factor XIII (FXIII) administration provides further benefits. In this study, we compared ROTEM whole blood coagulation profiles after experimental massive transfusion with different transfusion regimens in an in vitro model of dilution- and transfusion-related coagulopathy. Healthy donor blood was mixed 1 + 1 with six different transfusion regimens. Each regimen contained RBC, platelet concentrate, and either fresh frozen plasma (FFP) or Ringer's acetate (RA). The regimens were further augmented through addition of a low- or medium-dose fibrinogen concentrate and FXIII. Transfusion with FFP alone was insufficient to maintain tissue-factor activated clot strength, coincidental with a deficiency in fibrin-based clot strength. Fibrinogen concentrate conserved, but did not improve coagulation kinetics and overall clot strength. Only combination therapy with FFP and low-dose fibrinogen concentrate improved both coagulation kinetics and fibrin-based clot strength. Administration of FXIII did not result in an improvement of clot strength. In conclusion, combination therapy with both FFP and low-dose fibrinogen concentrate improved clotting time and produced firm clots, representing a possible preferred first-line regimen to manage trauma-induced coagulopathy when RBC and platelets are also transfused. Further research is required to identify optimal first-line transfusion fluids for massive traumatic haemorrhage.
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http://dx.doi.org/10.1080/00365513.2017.1334128DOI Listing
October 2017

Monitoring of coagulation factor therapy in patients with von Willebrand disease type 3 using a microchip flow chamber system.

Thromb Haemost 2017 01 20;117(1):75-85. Epub 2016 Oct 20.

Anna Ågren, MD, PhD, Coagulation Unit, Hematology Center, Karolinska University Hospital, 171 76 Stockholm, Sweden, Tel.: +46 8 517 73373, Fax: +46 8 51775084, E-mail:

Patients with type 3 von Willebrand disease (VWD-3) have no measurable levels of VW factor (VWF) and usually require treatment with VWF-FVIII concentrate to prevent and/or stop bleeding. Even though the patients are treated prophylactically, they may experience bleeding symptoms. The aim of this study was to evaluate the effect of VWF-FVIII concentrate treatment in VWD-3 patients with the Total Thrombus Analysis System (T-TAS), which measures thrombus formation under flow conditions. Coagulation profiles of 10 VWD-3 patients were analysed using T-TAS before and 30 minutes after VWF-FVIII concentrate (Haemate) injection. Results were compared to VWF- and FVIII activity in plasma, and results with thromboelastometry and ristocetin-activated platelet impedance aggregometry (Multiplate) in whole blood. For comparison, 10 healthy controls were also analysed with T-TAS. A median dose of 27 (range 15-35) IU/kg of VWF-FVIII concentrate increased VWF- and FVIII activity as expected. T-TAS thrombus formation was enhanced when a tissue factor/collagen-coated flow chamber was used at low shear, but treatment effects at high shear using a collagen-coated flow chamber were minimal. Whole blood coagulation assessed by thromboelastometry was normal and did not change (p > 0.05) but ristocetin-induced platelet aggregation improved (p < 0.001). In conclusion, T-TAS detects effects of VWF-FVIII concentrate treatment on coagulation-dependent thrombus formation at low shear, but minor effects are observed on platelet-dependent thrombus formation at high shear. The poor prediction of bleeding by conventional laboratory monitoring in VWD-3 patients might be related to insufficient restoration of platelet-dependent thrombus formation.
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http://dx.doi.org/10.1160/TH16-06-0430DOI Listing
January 2017

Circulating endothelial cells in coronary artery disease and acute coronary syndrome.

Trends Cardiovasc Med 2015 Oct 7;25(7):578-87. Epub 2015 Feb 7.

Department of Experimental Cardiology, University Medical Center Utrecht, Utrecht, The Netherlands; Laboratory of Clinical Chemistry and Hematology, University Medical Center Utrecht, The Netherlands. Electronic address:

Circulating endothelial cells (CECs) have been put forward as a promising biomarker for diagnosis and prognosis of coronary artery disease and acute coronary syndromes. This review entails current insights into the physiology and pathobiology of CECs, including their relationship with circulating endothelial progenitor cells and endothelial microparticles. Additionally, we present a comprehensive overview of the diagnostic and prognostic value of CEC quantification, as well as possibilities for improvement, for example, by inclusion of CEC morphology, transcriptomics, and proteomics. The current stand of knowledge calls out for improved counting methods and consensus on a validated cell definition. Finally, our review accentuates the importance of large, well-designed, population-based prospective studies that will have to show the clinical value of CEC as a cardiovascular biomarker.
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http://dx.doi.org/10.1016/j.tcm.2015.01.013DOI Listing
October 2015

Detection of elevated INR by thromboelastometry and thromboelastography in warfarin treated patients and healthy controls.

Thromb Res 2015 May 26;135(5):1007-11. Epub 2015 Feb 26.

Department of Medicine, Division of Hematology, Coagulation Unit, Karolinska Institutet and Karolinska University Hospital, Stockholm, Sweden. Electronic address:

Introduction: The diagnostic potential of whole blood viscoelastic tests thromboelastography (TEG®) and thromboelastometry (ROTEM®) to detect warfarin-induced INR elevation remains elusive.

Methods: Viscoelastic tests were performed in 107 patients on warfarin and 89 healthy controls. Tests were activated by kaolin for TEG, and ellagic acid (INTEM) or tissue factor (EXTEM) for ROTEM.

Results: Viscoelastic tests revealed significant differences in clotting profiles between controls and warfarin-treated patients. Compared with healthy controls, patients treated with warfarin had prolonged EXTEM clotting and TEG reaction time (p<0.001), both of which were also increased beyond the reference range. Increased INR values correlated with EXTEM CT (Spearman rho=0.87) and TEG R-time (rho=0.73). EXTEM CT had a sensitivity and specificity of 0.89 and 1.00, respectively, to detect elevated INR above 1.2 units, with a positive and negative predictive values (PPV and NPV) of 1.00 and 0.88, respectively. Similarly, TEG R-time had a sensitivity and specificity of 0.86 and 0.87, respectively, with a PPV of 0.89 and a NPV of 0.83. The corresponding receiver operator characteristic area under the curve was 0.99 (95% confidence interval [CI], 0.99 - 1.00) for EXTEM CT and 0.94 (95% CI, 0.91 - 0.97) for TEG R-time.

Conclusions: Tissue factor-activated viscoelastic testing (EXTEM) revealed individuals with warfarin-induced INR elevation accurately, while TEG - activated through the intrinsic pathway - still was of acceptable diagnostic value. Further studies are required to evaluate the diagnostic potential of viscoelastic tests in relation to standard laboratory tests in other mixed patient populations, where the PPV and NPV may be inferior.
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http://dx.doi.org/10.1016/j.thromres.2015.02.022DOI Listing
May 2015

Thrombin generation in a patient with an acquired high-titre factor V inhibitor.

Blood Coagul Fibrinolysis 2015 Jan;26(1):81-7

aUtrecht University Medical Center, Utrecht, The Netherlands bII. Medizinische Klinik und Poliklinik cInstitut für Klinische Chemie, Universitätsklinikum Eppendorf, Hamburg, Germany dDepartment for Molecular Medicine and Surgery, Karolinska Institute, Stockholm, Sweden *David E. Schmidt and Friederike Steinhagen contributed equally to this work.

The management of patients with acquired factor V inhibitors is challenging, because their bleeding risk is highly variable and only poorly correlated with routine coagulation tests. Furthermore, there is no standardized treatment for bleeding control or inhibitor eradication. An 84-year-old white man underwent uneventful surgery for a ruptured intracerebral haemangioma. There were no perioperative coagulation abnormalities. Eight weeks after surgery, however, the prothrombin and the activated partial thromboplastin times were found to be maximally prolonged without signs of acute haemorrhage. A factor V inhibitor of 212 Bethesda units was diagnosed. We used a fluorogenic real-time thrombin generation assay with low concentrations of tissue factor (TF) to analyse the factor V inhibitor for interference with coagulation in platelet-poor plasma. Compared with three bleeding patients with acquired haemophilia A and severely deficient thrombin generation, total thrombin generation capacity was similar in the patient and healthy controls. However, the lag phase was significantly prolonged, suggesting a defect in the initiation/amplification, but not in the propagation phase of TF-triggered thrombin generation. This defect could be fully reproduced by purified patient IgG and largely corrected by ex-vivo addition of activated prothrombin complex concentrate, but not recombinant human FVIIa. Addition of normal platelets to the patient's plasma resulted in a pronounced shortening of the lag phase, suggesting that platelet-derived factor V can escape the inhibitor. Our findings offer an explanation for the absence of spontaneous bleeding in this patient and support the concept of platelet transfusions for the management of acute haemorrhages in patients with acquired factor V inhibitors.
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http://dx.doi.org/10.1097/MBC.0000000000000181DOI Listing
January 2015

Output control of da Vinci surgical system's surgical graspers.

J Surg Res 2014 Jan 8;186(1):56-62. Epub 2013 Aug 8.

University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania. Electronic address:

Introduction: The number of robot-assisted surgeries performed with the da Vinci surgical system has increased significantly over the past decade. The articulating movements of the robotic surgical grasper are controlled by grip controls at the master console. The user interface has been implicated as one contributing factor in surgical grasping errors. The goal of our study was to characterize and evaluate the user interface of the da Vinci surgical system in controlling surgical graspers.

Materials And Methods: An angular manipulator with force sensors was used to increment the grip control angle as grasper output angles were measured. Input force at the grip control was simultaneously measured throughout the range of motion. Pressure film was used to assess the maximum grasping force achievable with the endoscopic grasping tool.

Results: The da Vinci robot's grip control angular input has a nonproportional relationship with the grasper instrument output. The grip control mechanism presents an intrinsic resistant force to the surgeon's fingertips and provides no haptic feedback. The da Vinci Maryland graspers are capable of applying up to 5.1 MPa of local pressure.

Conclusions: The angular and force input at the grip control of the da Vinci robot's surgical graspers is nonproportional to the grasper instrument's output. Understanding the true relationship of the grip control input to grasper instrument output may help surgeons understand how to better control the surgical graspers and promote fewer grasping errors.
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http://dx.doi.org/10.1016/j.jss.2013.07.032DOI Listing
January 2014

Oscillatory shear stress created by fluid pulsatility versus flexed specimen configurations.

Comput Methods Biomech Biomed Engin 2014 May 24;17(7):728-39. Epub 2012 Aug 24.

a Tissue Engineered Mechanics, Imaging and Materials (TEMIM) Laboratory, Department of Biomedical Engineering , Florida International University , Miami , FL , USA.

Oscillatory shear stress (OSS), caused by time-varying flow environments, may play a critical role in the production of engineered tissue by bone marrow-derived stem cells. This is particularly relevant in heart valve tissue engineering (HVTE), owing to the intense haemodynamic environments that surround native valves. In this study, we examined and quantified the role that (i) physiologically relevant scales of pulsatility and (ii) changes in geometry as a function of specimen flexure have in creating OSS conditions. A U-shaped bioreactor capable of producing flow, stretch and flexure was modelled with housed specimens, and computational fluid dynamic simulations were performed. We found that physiologically relevant OSS can be maximised by the application of pulsatile flow to straight, non-moving specimens in a uniform manner. This finding reduces a substantial layer of complexity in dynamic HVTE protocols in which traditionally, time-varying flow has been promoted through specimen movement in custom-made bioreactors.
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http://dx.doi.org/10.1080/10255842.2012.715157DOI Listing
May 2014

The role of organ level conditioning on the promotion of engineered heart valve tissue development in-vitro using mesenchymal stem cells.

Biomaterials 2010 Feb 26;31(6):1114-25. Epub 2009 Nov 26.

Cardiovascular Biomechanics Laboratory, Department of Bioengineering, Swanson School of Engineering, The McGowan Institute, School of Medicine, University of Pittsburgh, Pittsburgh, PA 15219, USA.

We have previously shown that combined flexure and flow (CFF) augment engineered heart valve tissue formation using bone marrow-derived mesenchymal stem cells (MSC) seeded on polyglycolic acid (PGA)/poly-L-lactic acid (PLLA) blend nonwoven fibrous scaffolds (Engelmayr, et al., Biomaterials 2006; vol. 27 pp. 6083-95). In the present study, we sought to determine if these phenomena were reproducible at the organ level in a functional tri-leaflet valve. Tissue engineered valve constructs (TEVC) were fabricated using PGA/PLLA nonwoven fibrous scaffolds then seeded with MSCs. Tissue formation rates using both standard and augmented (using basic fibroblast growth factor [bFGF] and ascorbic acid-2-phosphate [AA2P]) media to enhance the overall production of collagen were evaluated, along with their relation to the local fluid flow fields. The resulting TEVCs were statically cultured for 3 weeks, followed by a 3 week dynamic culture period using our organ level bioreactor (Hildebrand et al., ABME, Vol. 32, pp. 1039-49, 2004) under approximated pulmonary artery conditions. Results indicated that supplemented media accelerated collagen formation (approximately 185% increase in collagen mass/MSC compared to standard media), as well as increasing collagen mass production from 3.90 to 4.43 pg/cell/week from 3 to 6 weeks. Using augmented media, dynamic conditioning increased collagen mass production rate from 7.23 to 13.65 pg/cell/week (88.8%) during the dynamic culture period, along with greater preservation of net DNA. Moreover, when compared to our previous CFF study, organ level conditioning increased the collagen production rate from 4.76 to 6.42 pg/cell/week (35%). Newly conducted CFD studies of the CFF specimen flow patterns suggested that oscillatory surface shear stresses were surprisingly similar to a tri-leaflet valve. Overall, we found that the use of simulated pulmonary artery conditions resulted in substantially larger collagen mass production levels and rates found in our earlier CFF study. Moreover, given the fact that the scaffolds underwent modest strains (approximately 7% max) during either CFF or physiological conditioning, the oscillatory surface shear stresses estimated in both studies may play a substantial role in eliciting MSC collagen production in the highly dynamic engineered heart valve fluid mechanical environment.
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http://dx.doi.org/10.1016/j.biomaterials.2009.10.019DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2813971PMC
February 2010

On the mechanical role of de novo synthesized elastin in the urinary bladder wall.

J Biomech Eng 2009 Oct;131(10):101018

Department of Bioengineering, McGowan Institute, University of Pittsburgh, PA 15219, USA.

The urinary bladder wall (UBW), which is composed of smooth muscle, collagen, and elastin, undergoes profound remodeling in response to changes in mechanical loading resulting from various pathologies. In our laboratory, we have observed the production of fibrillar elastin in the extracellular matrix (ECM), which makes the UBW a particularly attractive tissue to investigate smooth muscle tissue remodeling. In the present study, we explored the mechanical role that de novo elastin fibers play in altering UBW ECM mechanical behavior using a structural constitutive modeling approach. The mechanical behavior of the collagen fiber component of the UBW ECM was determined from the biaxial stress-stretch response of normal UBW ECM, based on bimodal fiber recruitment that was motivated by the UBW's unique collagen fiber structure. The resulting fiber ensemble model was then combined with an experimentally derived fiber angular distribution to predict the biaxial mechanical behavior of normal and the elastin-rich UBW ECM to elucidate the underlying mechanisms of elastin production. Results indicated that UBW ECM exhibited a distinct structure with highly coiled collagen fiber bundles and visible elastic fibers in the pathological situation. Elastin-rich UBW ECM had a distinct mechanical behavior with higher compliance, attributable to the indirect effect of elastin fibers contracting the collagen fiber network, resulting in a retracted unloaded reference state of the tissue. In conclusion, our results suggest that the urinary bladder responds to prolonged periods of high strain by increasing its effective compliance through the interaction between collagen and de novo synthesized elastic fibers.
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http://dx.doi.org/10.1115/1.4000182DOI Listing
October 2009

On the biomechanics of heart valve function.

J Biomech 2009 Aug 21;42(12):1804-24. Epub 2009 Jun 21.

Department of Bioengineering, Engineered Tissue Mechanics and Mechanobiology Laboratory, The McGowan Institute, University of Pittsburgh, Pittsburgh, PA, United States.

Heart valves (HVs) are fluidic control components of the heart that ensure unidirectional blood flow during the cardiac cycle. However, this description does not adequately describe the biomechanical ramifications of their function in that their mechanics are multi-modal. Moreover, they must replicate their cyclic function over an entire lifetime, with an estimated total functional demand of least 3x10(9) cycles. The focus of the present review is on the functional biomechanics of heart valves. Thus, the focus of the present review is on functional biomechanics, referring primarily to biosolid as well as several key biofluid mechanical aspects underlying heart valve physiological function. Specifically, we refer to the mechanical behaviors of the extracellular matrix structural proteins, underlying cellular function, and their integrated relation to the major aspects of valvular hemodynamic function. While we focus on the work from the author's laboratories, relevant works of other investigators have been included whenever appropriate. We conclude with a summary of important future trends.
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http://dx.doi.org/10.1016/j.jbiomech.2009.05.015DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2746960PMC
August 2009

The effects of anisotropy on the stress analyses of patient-specific abdominal aortic aneurysms.

Ann Biomed Eng 2008 Jun 9;36(6):921-32. Epub 2008 Apr 9.

Department of Aerospace and Mechanical Engineering, University of Arizona, Tucson, AZ 85721, USA.

The local dilation of the infrarenal abdominal aorta, termed an abdominal aortic aneurysm (AAA), is often times asymptomatic and may eventually result in rupture-an event associated with a significant mortality rate. The estimation of in-vivo stresses within AAAs has been proposed as a useful tool to predict the likelihood of rupture. For the current work, a previously-derived anisotropic relation for the AAA wall was implemented into patient-specific finite element simulations of AAA. There were 35 AAAs simulated in the current work which were broken up into three groups: elective repairs (n = 21), non-ruptured repairs (n = 5), and ruptured repairs (n = 9). Peak stresses and strains were compared using the anisotropic and isotropic constitutive relations. There were significant increases in peak stress when using the anisotropic relationship (p < 0.001), even in the absence of the ILT (p = 0.014). Ruptured AAAs resulted in elevated peak stresses as compared to non-ruptured AAAs when using both the isotropic and anisotropic simulations, however these comparisons did not reach significance (p(ani) = 0.55, p(iso) = 0.73). While neither the isotropic or anisotropic simulations were able to significantly discriminate ruptured vs. non-ruptured AAAs, the lower p-value when using the anisotropic model suggests including it into patient-specific AAAs may help better identify AAAs at high risk.
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http://dx.doi.org/10.1007/s10439-008-9490-3DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2674610PMC
June 2008