Publications by authors named "Anne-Mette Hvas"

231 Publications

CORONARY FLOW VELOCITY RESERVE AND MYOCARDIAL DEFORMATION PREDICT LONG-TERM OUTCOME IN HEART TRANSPLANT RECIPIENTS.

J Am Soc Echocardiogr 2021 Jul 26. Epub 2021 Jul 26.

Department of Cardiology, Aarhus University Hospital, Palle Juul-Jensens Boulevard 99, 8200 Aarhus N, Denmark; Department of Clinical Medicine, Faculty of Health, Aarhus University, Incuba Skejby, building 2, Palle Juul-Jensens Boulevard 82, 8200 Aarhus N, Denmark.

Background: After heart transplantation (HTx), invasive coronary angiography is gold standard for surveillance of cardiac allograft vasculopathy (CAV). Non-invasive CAV surveillance is desirable.

Purpose: We examined left ventricular global longitudinal strain (LVGLS) and non-invasive coronary flow velocity reserve (CFVR) related to CAV and prognosis after heart transplantation (HTx).

Methods: Echocardiographic Doppler coronary flow velocity reserve (CFVR) and left ventricular global longitudinal strain (LVGLS) were evaluated in 98 HTx patients. All-cause mortality and major adverse cardiac events (MACE) including hospitalization due to heart failure, cardiovascular death and significant CAV progression, were recorded.

Results: Median follow-up was 3.3 (range 1.7-5.4) years. Patients with low CFVR (<2.0, n=20) showed reduced MACE free survival (hazard ratio (HR) 4.3 [2.2-8.4], p<0.0001) and increased all-cause mortality (HR 4.7 [2.0-11.3], p<0.0001) compared with patients with high CFVR (≥2.0, n=78). Worsened LVGLS (≥-15.5%) was also a strong independent predictor of MACE, cardiovascular- and all-cause mortality. Combined low CFVR and worsened LVGLS provided incremental prognostic value - even after adjustment for CAV and time since HTx. The prevalence of low CFVR increased significantly with CAV severity, and the prevalence of combined low CFVR and/or worsened LVGLS was high in CAV 2 (86 %) and CAV 3 (83 %) patients. The negative predictive value of combined high CFVR and improved LVGLS to rule out significant CAV was 94.5 [86.2-98.4] %, whereas the positive predictive value was 39.0 [25.3-54.3] %. The model had a sensitivity of 84.2 [63.6-95.3] % and a specificity of 67.5 [56.6-77.2] % for ≥ 1 abnormal parameter.

Conclusions: In HTx patients with severe CAV, a higher prevalence of low CFVR and worsened LVGLS was observed. Both measurements were strong independent predictors of MACE and all-cause mortality in HTx-patients. Combined CFVR and LVGLS provided incremental prognostic value and showed an excellent ability to rule out significant CAV and may be considered as part of routine CAV surveillance of HTx-patients.
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http://dx.doi.org/10.1016/j.echo.2021.07.012DOI Listing
July 2021

Hemostasis and Fibrinolysis following Aneurysmal Subarachnoid Hemorrhage: A Systematic Review on Additional Knowledge from Dynamic Assays and Potential Treatment Targets.

Semin Thromb Hemost 2021 Jul 14. Epub 2021 Jul 14.

Department of Clinical Medicine, Aarhus University, Aarhus, Denmark.

Mortality after aneurysmal subarachnoid hemorrhage (aSAH) is augmented by rebleeding and delayed cerebral ischemia (DCI). A range of assays evaluating the dynamic process of blood coagulation, from activation of clotting factors to fibrinolysis, has emerged and a comprehensive review of hemostasis and fibrinolysis following aSAH may reveal targets of treatment. We conducted a systematic review of existing literature assessing coagulation and fibrinolysis following aSAH, but prior to treatment. PubMed, Embase, and Web of Science were searched on November 18, 2020, without time boundaries. In total, 45 original studies were eventually incorporated into this systematic review, divided into studies presenting data only from conventional or quantitative assays ( = 22) and studies employing dynamic assays ( = 23). Data from conventional or quantitative assays indicated increased platelet activation, whereas dynamic assays detected platelet dysfunction possibly related to an increased risk of rebleeding. Secondary hemostasis was activated in conventional, quantitative, and dynamic assays and this was related to poor neurological outcome and mortality. Studies systematically investigating fibrinolysis were sparse. Measurements from conventional or quantitative assays, as well as dynamic fibrinolysis assays, revealed conflicting results with normal or increased lysis and changes were not associated with outcome. In conclusion, dynamic assays were able to detect reduced platelet function, not revealed by conventional or quantitative assays. Activation of secondary hemostasis was found in both dynamic and nondynamic assays, while changes in fibrinolysis were not convincingly demonstrable in either dynamic or conventional or quantitative assays. Hence, from a mechanistic point of view, desmopressin to prevent rebleeding and heparin to prevent DCI may hold potential as therapeutic options. As changes in fibrinolysis were not convincingly demonstrated and not related to outcome, the use of tranexamic acid prior to aneurysm closure is not supported by this review.
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http://dx.doi.org/10.1055/s-0041-1730346DOI Listing
July 2021

Lower Antiplatelet Effect of Aspirin in Essential Thrombocythemia than in Coronary Artery Disease.

TH Open 2021 Jul 4;5(3):e230-e238. Epub 2021 Jul 4.

Department of Cardiology, Aarhus University Hospital, Aarhus, Denmark.

 Patients with essential thrombocythemia (ET) and coronary artery disease (CAD) have increased risk of thromboembolic complications. In addition, a reduced antiplatelet effect of aspirin has been demonstrated in both patient groups. As ET is a platelet disorder, platelets may be more important for the thromboembolic risk in ET than in CAD. We aimed to investigate the antiplatelet effect of aspirin and platelet turnover in ET versus CAD patients.  We included 48 ET patients and an age-matched group of 48 CAD patients. The effect of aspirin was evaluated by thromboxane B (TXB ) levels and platelet aggregation. Platelet turnover was assessed by immature platelet count (IPC) and immature platelet fraction (IPF).  ET patients had reduced effect of aspirin compared with CAD patients, demonstrated by significantly higher TXB levels (median of differences = 22.3 ng/mL,  < 0.0001) and platelet aggregation (median of differences = 131.0 AU*min,  = 0.0003). Furthermore, ET patients had significantly higher IPC (  < 0.0001) and IPF (  = 0.0004) than CAD patients.  ET patients have lower 24-hour antiplatelet effect of aspirin than CAD patients. This may be explained by an increased platelet production and turnover counteracting the antiplatelet effect of aspirin. These findings strengthen the rationale for exploring novel antiplatelet regimens in ET patients to reduce the risk of cardiovascular events.
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http://dx.doi.org/10.1055/s-0041-1731309DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8255105PMC
July 2021

Statistical and machine learning methods for analysis of multiplex protein data from a novel proximity extension assay in patients with ST-elevation myocardial infarction.

Sci Rep 2021 Jul 2;11(1):13787. Epub 2021 Jul 2.

Department of Clinical Medicine, Faculty of Health, Aarhus University, Palle Juul-Jensens Blvd 82, 8200, Aarhus N, Denmark.

Using data from patients with ST-elevation myocardial infarction (STEMI), we explored how machine learning methods can be used for analysing multiplex protein data obtained from proximity extension assays. Blood samples were obtained from 48 STEMI-patients at admission and after three months. A subset of patients also had blood samples obtained at four and 12 h after admission. Multiplex protein data were obtained using a proximity extension assay. A random forest model was used to assess the predictive power and importance of biomarkers to distinguish between the acute and the stable phase. The similarity of response profiles was investigated using K-means clustering. Out of 92 proteins, 26 proteins were found to significantly distinguish the acute and the stable phase following STEMI. The five proteins tissue factor pathway inhibitor, azurocidin, spondin-1, myeloperoxidase and myoglobin were found to be highly important for differentiating between the acute and the stable phase. Four of these proteins shared response profiles over the four time-points. Machine learning methods can be used to identify and assess novel predictive biomarkers as showcased in the present study population of patients with STEMI.
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http://dx.doi.org/10.1038/s41598-021-93162-3DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8253786PMC
July 2021

Efficacy and Safety of Antifibrinolytic Drugs in Pediatric Surgery: A Systematic Review.

Semin Thromb Hemost 2021 Jul 30;47(5):538-568. Epub 2021 Jun 30.

Thrombosis and Hemostasis Research Unit, Department of Clinical Biochemistry, Aarhus University Hospital, Aarhus, Denmark.

Antifibrinolytic drugs are used to reduce blood loss and subsequent transfusions during surgery and following trauma, but the optimal dosing regimen in the pediatric population is still unresolved. The aim of this systematic review was to evaluate efficacy and safety of antifibrinolytic drugs in pediatric surgery and trauma to determine the optimal dosing regimen. A literature search was performed in PubMed, Embase, Cochrane, and Web of Science on May 3, 2020. We included randomized controlled studies investigating the effect of tranexamic acid (TXA), aprotinin, and epsilon-aminocaproic acid, in terms of reducing blood loss, blood transfusions, reoperations, and rebleeds in pediatric patients aged 0 to 18 years undergoing cardiac surgery, noncardiac surgery, or trauma. Fifty randomized controlled trials (RCTs) were included; 28 RCTs investigated cardiac surgery and 22 investigated noncardiac surgery. No RCTs regarding trauma met the inclusion criteria. All antifibrinolytic drugs reduced postoperative blood loss and transfusions when used in pediatric surgery. The dosing regimen varied between studies, but similar effect sizes were found in terms of reduced blood loss regardless of the cumulative dose used. Few studies found adverse events, and no difference in incidence or type of adverse events was seen between the antifibrinolytic and the placebo group. In conclusion, use of antifibrinolytics is efficient and safe in children undergoing surgery. We propose TXA as the drug of choice based on its level of evidence and safety profile; we recommend a dosing regimen composed of a loading dose of 10 to 15 mg/kg prior to surgery followed by 1 to 5 mg/kg/h as continuous infusion throughout surgery.
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http://dx.doi.org/10.1055/s-0040-1721736DOI Listing
July 2021

Preface: Altered Fibrinolysis-Clinical Impact and Diagnostic Challenges.

Semin Thromb Hemost 2021 Jul 30;47(5):477-479. Epub 2021 Jun 30.

Thrombosis and Hemostasis Research Unit, Department of Clinical Biochemistry, Aarhus University Hospital, Aarhus, Denmark.

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http://dx.doi.org/10.1055/s-0041-1725100DOI Listing
July 2021

Thrombin: A Pivotal Player in Hemostasis and Beyond.

Semin Thromb Hemost 2021 Jun 21. Epub 2021 Jun 21.

Department of Clinical Biochemistry, Thrombosis and Hemostasis Research Unit, Aarhus University Hospital, Aarhus, Denmark.

The serine protease thrombin, a naturally derived enzyme, plays a key role in hemostasis by converting fibrinogen to fibrin and activating coagulation factor XIII whereby the fibrin clot is stabilized. Furthermore, thrombin activates platelets through protease-activated receptors on the platelet surface. Conversely, thrombin also exerts anticoagulant effects, enhancing the protein C activity while complexed with thrombomodulin. During recent years, it has become evident that thrombin has significant effects beyond hemostasis, as it contributes also to modulation of the endothelium, promotes inflammation and angiogenesis, and plays a role in tumor progression. Yet, due to the very short half-life and almost immediate inhibition in fluid phase by antithrombin, thrombin itself remains elusive, and only indirect measurement of thrombin generation is possible. This review provides a description of structure and mechanisms of action of thrombin both in physiological and pathological processes. Furthermore, it summarizes laboratory tests that measure in vivo or ex vivo thrombin generation, and presents knowledge on the value of these biomarkers in bleeding disorders, cardiopulmonary bypass surgery, and thromboembolic risk assessment in different patient populations. Finally, this review outlines further perspectives on using thrombin generation biomarkers for research purposes and in clinical practice.
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http://dx.doi.org/10.1055/s-0041-1727116DOI Listing
June 2021

A case of thrombocytopenia and multiple thromboses after vaccination with ChAdOx1 nCoV-19 against SARS-CoV-2.

Blood Adv 2021 Jun;5(12):2569-2574

Section of Transfusion Medicine, Department of Clinical Immunology, Copenhagen University Hospital, Rigshospitalet, Copenhagen, Denmark.

Recently, reports of severe thromboses, thrombocytopenia, and hemorrhage in persons vaccinated with the chimpanzee adenovirus-vectored vaccine (ChAdOx1 nCoV-19, AZD1222, Vaxzevria; Oxford/AstraZeneca) against severe acute respiratory syndrome coronavirus 2 have emerged. We describe an otherwise healthy 30-year-old woman who developed thrombocytopenia, ecchymosis, portal vein thrombosis, and cerebral venous sinus thrombosis the second week after she received the ChAdOx1 nCoV-19 vaccine. Extensive diagnostic workup for thrombosis predispositions showed heterozygosity for the prothrombin mutation, but no evidence of myeloproliferative neoplasia or infectious or autoimmune diseases. Her only temporary risk factor was long-term use of oral contraceptive pills (OCPs). Although both the prothrombin mutation and use of OCPs predispose to portal and cerebral vein thrombosis, the occurrence of multiple thromboses within a short time and the associated pattern of thrombocytopenia and consumption coagulopathy are highly unusual. A maximum 4T heparin-induced thrombocytopenia (HIT) score and a positive immunoassay for anti-platelet factor 4/heparin antibodies identified autoimmune HIT as a potential pathogenic mechanism. Although causality has not been established, our case emphasizes the importance of clinical awareness. Further studies of this potentially new clinical entity have suggested that it should be regarded as a vaccine-induced immune thrombotic thrombocytopenia.
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http://dx.doi.org/10.1182/bloodadvances.2021004904DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8219289PMC
June 2021

Anti-Xa Monitoring of Low-Molecular-Weight Heparin during Pregnancy: A Systematic Review.

Semin Thromb Hemost 2021 Jun 15. Epub 2021 Jun 15.

Department of Clinical Biochemistry, Aarhus University Hospital, Aarhus, Denmark.

Low-molecular-weight heparin (LMWH) is commonly used for preventing or treating venous thromboembolic disease (VTE) during pregnancy. The physiological changes in maternal metabolism have led to discussions on optimal LMWH dosing strategy and possible need for monitoring. The aim of this systematic review is to summarize and discuss whether LMWH dose adjustment according to anti-Xa provides superior effectiveness and safety compared with weight adjusted or fixed dosed LMWH in pregnant women. A systematic literature search was performed in PubMed, Embase, and Scopus on September 26, 2020. The study is reported according to Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines. Effectiveness was defined as episodes of thrombosis and safety as bleeding episodes. In total, 33 studies were included: 4 randomized controlled studies and 29 cohort studies. Prophylactic dosing strategies employing weight dosed, fixed dosed, or anti-Xa adjusted LMWH dosing performed equal in effectiveness and safety. In pregnant women with VTE or high thromboembolic risk, therapeutic weight-adjusted LMWH and weight plus anti-Xa-adjusted LMWH provided equal results in terms of effectiveness and safety. Pregnant women with mechanical heart valves (MHVs) received therapeutic anti-Xa-adjusted LMWH with four out of seven studies presenting mean peak anti-Xa within target ranges. Still, pregnant women with MHV experienced both thrombosis and bleeding with anti-Xa in target. Based on the results of this systematic review, current evidence does not support the need for anti-Xa monitoring when using LMWH as thromboprophylaxis or treatment during pregnancy. Nonetheless, the need for anti-Xa monitoring in pregnant women with MHV may need further scrutiny.
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http://dx.doi.org/10.1055/s-0041-1726374DOI Listing
June 2021

Contemporary Clinical Use of Aspirin: Mechanisms of Action, Current Concepts, Unresolved Questions, and Future Perspectives.

Semin Thromb Hemost 2021 Jun 15. Epub 2021 Jun 15.

Department of Clinical Medicine, Faculty of Health, Aarhus University, Aarhus, Denmark.

The ability of aspirin to inhibit platelet aggregation has positioned this agent within the most frequently used drugs worldwide. The aim of this article is to review the contemporary clinical use of aspirin and also to discuss unresolved issues not yet translated into clinical practice. Results from several clinical trials have led to strong guideline recommendations for aspirin use in the acute management and secondary prevention of cardiovascular disease. On the contrary, guidelines regarding aspirin use as primary prevention of cardiovascular disease are almost conservative, supported by recent trials reporting that the bleeding risk outweighs the potential benefits in most patients. In pregnancy, aspirin has proved efficient in preventing preeclampsia and small-for-gestational-age births in women at high risk, and is hence widely recommended in clinical guidelines. Despite the vast amount of clinical data on aspirin, several unresolved questions remain. Randomized trials have reported that aspirin reduces the risk of recurrent venous thromboembolism, but the clinical relevance remains limited, because direct oral anticoagulants are more effective. Laboratory studies suggest that a twice-daily dosing regimen or evening intake may lead to more efficient platelet inhibition, and the potential clinical benefit of such strategies is currently being explored in ongoing clinical trials. Enteric-coated formulations of aspirin are frequently used, but it remains unclear if they are safer and as efficient as plain aspirin. In the future, aspirin use after percutaneous coronary interventions might not be mandatory in patients who also need anticoagulant therapy, as several trials support shorter aspirin duration strategies. On the other hand, new treatment indications for aspirin will likely arise, as there is growing evidence that aspirin may reduce the risk of colorectal cancer and other types of cancer.
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http://dx.doi.org/10.1055/s-0041-1726096DOI Listing
June 2021

MicroRNA as Biomarkers for Platelet Function and Maturity in Patients with Cardiovascular Disease.

Thromb Haemost 2021 Jun 6. Epub 2021 Jun 6.

Department of Clinical Biochemistry, Thrombosis and Haemostasis Research Unit, Aarhus University Hospital, Aarhus, Denmark.

Patients with cardiovascular disease (CVD) are at increased risk of suffering myocardial infarction. Platelets are key players in thrombus formation and, therefore, antiplatelet therapy is crucial in the treatment and prevention of CVD. MicroRNAs (miRs) may hold the potential as biomarkers for platelet function and maturity. This systematic review was conducted using the guidelines of Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA). To identify studies investigating the association between miRs and platelet function and maturity in patients with CVD, PubMed and Embase were searched on October 13 and December 13, 2020 without time boundaries. Risk of bias was evaluated using a standardized quality assessment tool. Of the 16 included studies, 6 studies were rated "good" and 10 studies were rated "fair." In total, 45 miRs correlated significantly with platelet function or maturity (rho ranging from -0.68 to 0.38, all  < 0.05) or differed significantly between patients with high platelet reactivity and patients with low platelet reactivity (-values ranging from 0.0001 to 0.05). Only four miRs were investigated in more than two studies, namely miR-223, miR-126, miR-21 and miR-150. Only one study reported on the association between miRs and platelet maturity. In conclusion, a total of 45 miRs were associated with platelet function or maturity in patients with CVD, with miR-223 and miR-126 being the most frequently investigated. However, the majority of the miRs were only investigated in one study. More data are needed on the potential use of miRs as biomarkers for platelet function and maturity in CVD patients.
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http://dx.doi.org/10.1055/s-0041-1730375DOI Listing
June 2021

Altered Fibrinolysis in Hematological Malignances.

Semin Thromb Hemost 2021 Jul 31;47(5):569-580. Epub 2021 May 31.

Department of Clinical Biochemistry, Aarhus University Hospital, Aarhus, Denmark.

Bleeding and thrombosis are well-known complications to hematological malignancies, and changes in fibrinolysis impact both these issues. In the present systematic review, we provide an overview and discussion of the current literature in regards to clinical manifestations, diagnosis, and treatment of altered fibrinolysis in patients suffering from hematological malignancies, beyond acute promyelocytic leukemia. We performed a systematic literature search employing the databases Pubmed, Embase, and Web of Science to identify original studies investigating fibrinolysis in hematological malignancies. Studies investigating fibrinolysis in acute promyelocytic leukemia or disseminated intravascular coagulation were excluded. We identified 32 studies fulfilling the inclusion criteria. A majority of the studies were published more than two decades ago, and none of the studies examined all available markers of fibrinolysis or used dynamic clot lysis assays. In acute leukemia L-asparaginase treatment induced a hypofibrinolytic state, and prior to chemotherapy there seemed to be little to no change in fibrinolysis. In studies examining fibrinolysis during chemotherapy results were ambiguous. Two studies examining multiple myeloma indicated hypofibrinolysis prior to chemotherapy, and in another plasma cell disease, amyloid light chain-amyloidosis, clear signs of hyperfibrinolysis were demonstrated. In myeloproliferative neoplasms, the studies reported signs of hypofibrinolysis, in line with the increased risk of thrombosis in this disease. Only one study regarding lymphoma was identified, which indicated no alterations in fibrinolysis. In conclusion, this systematic review demonstrated that only sparse, and mainly old, evidence exists on fibrinolysis in hematological malignancy. However, the published studies showed a tendency toward hypofibrinolysis in myeloproliferative disorders, an increased risk of hyperfibrinolysis, and bleeding in patients with AL-amyloidosis, whereas studies regarding acute leukemias were inconclusive except with regard to L-asparaginase treatment, which induced a hypofibrinolytic state.
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http://dx.doi.org/10.1055/s-0041-1725099DOI Listing
July 2021

[Work-up of thrombophilia].

Ugeskr Laeger 2021 04;183(15)

The number of thrombophilia investigations has been steadily increasing over the past decade. However, it is debatable to what extent treatment of thromboembolic events is further qualified by thrombophilia investigations. Based of the most recent literature as well as international and national expert opinions, this review provides a status on the frequency and severity of inherited and acquired thrombophilia, discusses indication for thrombophilia assessment, states the analyses to be included in the test panel, and the clinical implications that presence of thrombophilia may have.
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April 2021

Fibrinolytic Alterations in Sepsis: Biomarkers and Future Treatment Targets.

Semin Thromb Hemost 2021 Jul 20;47(5):589-600. Epub 2021 Apr 20.

Thrombosis and Haemostasis Research Unit, Department of Clinical Biochemistry, Aarhus University Hospital, Aarhus, Denmark.

Sepsis is a life-threatening condition which develops as a dysregulated immune response in the face of infection and which is associated with profound hemostatic disturbances and in the most extreme cases disseminated intravascular coagulation (DIC). In addition, the fibrinolytic system is subject to alterations during infection and sepsis, and impaired fibrinolysis is currently considered a key player in sepsis-related microthrombus formation and DIC. However, we still lack reliable biomarkers to assess fibrinolysis in the clinical setting. Furthermore, drugs targeting the fibrinolytic system have potential value in sepsis patients with severe fibrinolytic disturbances, but these are still being tested in the preclinical stage. The present review provides an overview of key fibrinolytic changes in sepsis, reviews the current literature on potential laboratory markers of altered fibrinolysis in adult sepsis patients, and discusses future perspectives for diagnosis and treatment of fibrinolytic disturbances in sepsis patients.
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http://dx.doi.org/10.1055/s-0041-1725096DOI Listing
July 2021

Thrombocytopenia with acute ischemic stroke and bleeding in a patient newly vaccinated with an adenoviral vector-based COVID-19 vaccine.

J Thromb Haemost 2021 07 5;19(7):1771-1775. Epub 2021 May 5.

Department of Clinical Biochemistry, Aarhus University Hospital, Aarhus, Denmark.

We describe the first Danish case of presumed inflammatory and thrombotic response to vaccination with an adenoviral (ChAdOx1) vector-based COVID-19 vaccine (AZD1222). The case describes a 60-year-old woman who was admitted with intractable abdominal pain 7 days after receiving the vaccine. Computed tomography of the abdomen revealed bilateral adrenal hemorrhages. On the following day, she developed a massive right-sided ischemic stroke and magnetic resonance imaging angiography showed occlusion of the right internal carotid artery. The ischemic area was deemed too large to offer reperfusion therapy. During admission, blood tests showed a remarkable drop in platelet counts from 118,000 to 5000 per μl and a substantial increase in D-dimer. The patient died on the sixth day of hospitalization. Blood tests revealed platelet factor 4 reactive antibodies, imitating what is seen in heparin-induced thrombocytopenia. This may be a novel immune-mediated response to the vaccine.
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http://dx.doi.org/10.1111/jth.15347DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8250306PMC
July 2021

Histone-DNA Complexes and Coagulation after Intracerebral and Subarachnoid Hemorrhage.

TH Open 2021 Apr 14;5(2):e139-e142. Epub 2021 Apr 14.

Department of Anesthesiology and Intensive Care, Aarhus University Hospital, Aarhus, Denmark.

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http://dx.doi.org/10.1055/s-0041-1728672DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8046511PMC
April 2021

Heparin-induced thrombocytopenia: pathophysiology, diagnosis and treatment.

Expert Rev Hematol 2021 Apr 30;14(4):335-346. Epub 2021 Mar 30.

Department of Cardiology, Herning Regional Hospital, Herning, Denmark.

: Immune-mediated heparin-induced thrombocytopenia (HIT) is an infrequent complication following heparin exposure but with potentially fatal outcome due to thrombotic complications. Prompt suspension of heparin is necessary if HIT is suspected, followed by initiation of non-heparin anticoagulant therapy.: In this review, the pathophysiology and challenges in diagnosing HIT are elucidated. Current and emerging treatment options are discussed with special focus on parenteral thrombin inhibitors (argatroban, bivalirudin), parenteral factor Xa inhibitors (danaparoid, fondaparinux) and direct oral anticoagulants (DOACs [rivaroxaban, apixaban, dabigatran]) including dosing strategies for DOACs. The database PubMed was employed without time boundaries.: Only argatroban holds regulatory approval for HIT treatment in both U.S. and Europe. This treatment is, however, challenged by the need for close monitoring and high costs. Fondaparinux has been increasingly used for off-label treatment and during recent years, evidence for the use of DOACs has emerged. Preliminary results from observational studies hold promise for future use of DOACs in the acute and subacute phase of HIT. However, so far, the use of DOACs in acute HIT should be reserved for clinically stable patients without severe thrombotic complications. Importantly, both fondaparinux and DOAC use is contraindicated in severe renal insufficiency.
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http://dx.doi.org/10.1080/17474086.2021.1905512DOI Listing
April 2021

[Diagnostic approach and evaluation of hospitalized patients with COVID-19].

Ugeskr Laeger 2021 03;183(9)

COVID-19 is the infectious disease caused by coronavirus SARS-CoV-2. The most common symptoms of COVID-19 are dry cough, tiredness and fever. Most patients recover from COVID-19 within a few weeks, but some patients have symptoms lasting for weeks or even months after recovery from acute illness, such as fatigue, shortness of breath and cough. This is a review of what we currently know about the clinical disease and its severity as well as which diagnostic strategies are recommended during and after hospital admission.
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March 2021

[Clinical management of hospitalised patients with COVID-19].

Ugeskr Laeger 2021 03;183(9)

COVID-19 is the infectious disease caused by SARS-CoV-2. This is a review of the current treatment strategies available for patients with COVID-19 during hospital admission. Patients requiring hospitalisation frequently suffer from respiratory failure and may require oxygen therapy. Insufficient response to oxygen may be an indication, that other modalities such as high-flow nasal cannula, continuous positive airway pressure or mechanical ventilation are needed. The only medical treatments currently being used are remdesivir and dexamethasone.
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March 2021

Current Treatment Regimens for Transfeminine Individuals in the Nordic Countries.

J Sex Med 2021 03 10;18(3):656-663. Epub 2021 Feb 10.

Sexological Centre, Aalborg University Hospital, Aalborg, Denmark.

Background: The demand for gender-affirming hormone therapy is increasing worldwide prompting a growing requirement for solid evidence for efficacy and safety.

Aim: We aimed to report on the organization of transgender care and the current clinical practice of feminizing hormone therapy in specialized clinics in the Nordic countries.

Methods: This study was a cross-sectional study performed as a questionnaire survey. A quantitative questionnaire was sent to 15 specialized clinics prescribing feminizing hormone therapy in the Nordic countries.

Outcomes: Twelve clinics responded to the inquiry.

Results: The answers showed great variance in both number of clinics in each country as well as number of doctors responsible for prescribing gender-affirming hormone therapy. There was great difference in the width of the target ranges for estrogen plasma concentrations and in preferred route of administration for estrogens. Likewise, the risk assessment and monitoring of side effects were diverse.

Clinical Implications: To gather solid data on efficacy and safety of feminizing hormone therapy, the treatment regimens and the recording of side effects need to be consistent across the clinics responsible for the treatment of transfeminine patients. Strenghts & Limitations: This is to our knowledge the first report on treatment regimens for feminizing hormone treatment in the Nordic countries. The response rate was 80%; however, the included clinics only cover approximately 30% of the expected numbers of transfeminine individuals.

Conclusion: Despite the great diversity across clinics as regard to organization of clinics and to treatment regimens, the vast majority of clinics operated within the guidelines defined by The Endocrine Society. Hojbjerg JA, Saini SL, Hvas A-M, et al. Current Treatment Regimens for Transfeminine Individuals in the Nordic Countries. J Sex Med 2021;18:656-663.
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http://dx.doi.org/10.1016/j.jsxm.2020.12.018DOI Listing
March 2021

Disseminated intravascular coagulation: epidemiology, biomarkers, and management.

Br J Haematol 2021 03 8;192(5):803-818. Epub 2021 Feb 8.

Department of Clinical Biochemistry, Aarhus University Hospital, Aarhus, Denmark.

Disseminated intravascular coagulation (DIC) is a systemic activation of the coagulation system, which results in microvascular thrombosis and, simultaneously, potentially life-threatening haemorrhage attributed to consumption of platelets and coagulation factors. Underlying conditions, e.g. infection, cancer, or obstetrical complications are responsible for the initiation and propagation of the DIC process. This review provides insights into the epidemiology of DIC and the current understanding of its pathophysiology. It details the use of diagnostic biomarkers, current diagnostic recommendations from international medical societies, and it provides an overview of emerging diagnostic and prognostic biomarkers. Last, it provides guidance on management. It is concluded that timely and accurate diagnosis of DIC and its underlying condition is essential for the prognosis. Treatment should primarily focus on the underlying cause of DIC and supportive treatment should be individualised according to the underlying aetiology, patient's symptoms and laboratory records.
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http://dx.doi.org/10.1111/bjh.17172DOI Listing
March 2021

The activated partial thromboplastin time may not reveal even severe fibrinogen deficiency.

Clin Chem Lab Med 2021 Jun 28;59(7):e297-e300. Epub 2021 Jan 28.

Department of Clinical Biochemistry, Aarhus University Hospital, Aarhus N, Denmark.

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http://dx.doi.org/10.1515/cclm-2020-1626DOI Listing
June 2021

Platelet Function and Turnover in Essential Thrombocythemia: A Systematic Review.

Semin Thromb Hemost 2021 Feb 1;47(1):90-101. Epub 2021 Feb 1.

Department of Clinical Biochemistry, Aarhus University Hospital, Aarhus, Denmark.

Essential thrombocythemia (ET) is a myeloproliferative neoplasm characterized by increased platelet counts. ET has an incidence of 0.6 to 2.5 per 100,000 per year in Europe and North America. The disease is characterized by an increased thromboembolic risk, possibly caused by increased platelet counts. Furthermore, increased platelet function and/or increased platelet turnover may play a role. We aimed to explore: (1) whether platelet function and platelet turnover are increased in ET patients compared with healthy controls, and (2) whether these parameters are associated with increased thromboembolic risk and, therefore, may support decision-making on treatment in ET patients. We performed a systematic literature search on March 20, 2020 in Embase and PubMed following the Preferred Reporting Items for Systematic and Meta-Analysis (PRISMA) guidelines. In total, 1,923 articles were identified, 38 of which were included according to prespecified inclusion and exclusion criteria. Among the 38 studies, platelet activation (CD36 and CD62P) was investigated in 18 studies and was found to be increased in 12 of these. Platelet aggregation was investigated in 21 studies and was reported to be reduced in 20 of them. Platelet turnover (immature platelet count and mean platelet volume) was investigated in five studies with inconclusive results. No parameters were reported to predict the risk of thromboembolic events. In conclusion, platelet activation was increased in ET patients, but platelet aggregation was reduced. Future studies exploring markers of thromboembolic risk in ET patients are warranted.
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http://dx.doi.org/10.1055/s-0040-1718873DOI Listing
February 2021

Dosage of Anticoagulants in Obesity: Recommendations Based on a Systematic Review.

Semin Thromb Hemost 2020 Nov 23;46(8):932-969. Epub 2020 Dec 23.

Department of Clinical Biochemistry, Thrombosis and Hemostasis Research Unit, Aarhus University Hospital, Aarhus, Denmark.

Anticoagulants are frequently used as thromboprophylaxis and in patients with atrial fibrillation (AF) or venous thromboembolism (VTE). While obesity rates are reaching epidemic proportions worldwide, the optimal dosage for obese patients has not been established for most anticoagulants, including low-molecular-weight heparin (LMWH), non-vitamin K antagonist oral anticoagulants (NOAC), and pentasaccharides (fondaparinux). The aim of the present systematic review was to summarize the current knowledge and provide recommendations on dosage of LMWH, NOAC, and fondaparinux in obese patients (body mass index [BMI] ≥ 30 kg/m or body weight ≥ 100 kg). Based on a systematic search in PubMed and Embase, a total of 72 studies were identified. For thromboprophylaxis with LMWH in bariatric surgery ( = 20 studies), enoxaparin 40 mg twice daily, dalteparin 5,000 IE twice daily, or tinzaparin 75 IU/kg once daily should be considered for patients with BMI ≥ 40 kg/m. For thromboprophylaxis with LMWH in nonbariatric surgery and in medical inpatients ( = 8 studies), enoxaparin 0.5 mg/kg once or twice daily or tinzaparin 75 IU/kg once daily may be considered in obese patients. For treatment with LMWH ( = 18 studies), a reduced weight-based dose of enoxaparin 0.8 mg/kg twice daily should be considered in patients with BMI ≥ 40 kg/m, and no dose capping of dalteparin and tinzaparin should be applied for body weight < 140 kg. As regards NOAC, rivaroxaban, apixaban, or dabigatran may be used as thromboprophylaxis in patients with BMI < 40 kg/m ( = 4 studies), whereas rivaroxaban and apixaban may be administered to obese patients with VTE or AF, including BMI > 40 kg/m, at standard fixed-dose ( = 20 studies). The limited available evidence on fondaparinux ( = 3 studies) indicated that the treatment dose should be increased to 10 mg once daily in patients weighing > 100 kg.
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http://dx.doi.org/10.1055/s-0040-1718405DOI Listing
November 2020

Immature Platelets and Risk of Cardiovascular Events among Patients with Ischemic Heart Disease: A Systematic Review.

Thromb Haemost 2021 May 10;121(5):659-675. Epub 2020 Dec 10.

Department of Clinical Medicine, Faculty of Health, Aarhus University, Aarhus, Denmark.

Background:  Immature platelets are larger and may be more thrombogenic than mature platelets. This systematic review included studies on the association between mean platelet volume (MPV), immature platelet count (IPC), and immature platelet fraction (IPF) and the risk of major cardiovascular events (MACEs) in patients with acute coronary syndrome (ACS) or stable coronary artery disease (CAD).

Methods:  The literature search included studies in PubMed, Embase, Web of Science, and Cochrane Library. The review was performed according to the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) statement. Effect estimates that included multivariate adjusted odds ratios, relative risks, or hazard ratios were extracted.

Results:  Forty-two studies were identified. High MPV was positively associated with MACE in 20 of 26 studies of patients with ACS, four of five studies in patients with stable CAD, and in all six studies comprising a combined population with ACS and stable CAD. Using continuous models of MPV in patients with ACS, effect estimates varied from 0.90 (95% confidence interval [CI]: 0.95-1.03) to 1.66 (95% CI: 1.32-2.09). The strength of these associations was broadly similar among patients with stable CAD and in combined populations. Five studies investigated IPC or IPF as exposures and all reported positive associations with MACE among patients with ACS, stable CAD, or in combined populations.

Conclusion:  This review demonstrated clear evidence for positive associations between measures of immature platelets and subsequent risk of MACE in acute and stable ischemic heart disease patients.
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http://dx.doi.org/10.1055/s-0040-1721386DOI Listing
May 2021

[Menorrhagia during oral anticoagulant therapy].

Ugeskr Laeger 2020 11;182(49)

Menorrhagia is a common complication to oral anticoagulant therapy in premenopausal women. Clinical management of menorrhagia poses a clinical dilemma with the need of weighting bleeding risk against the risk of recurrent thrombosis. In this review, we describe the risk of menorrhagia during oral anticoagulant therapy, with emphasis on the differences between the specific anticoagulant drugs. We critically assess the treatment options for anticoagulant-associated menorrhagia, and we provide a treatment algorithm for the management of anticoagulant-associated menorrhagia.
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November 2020

Efficacy and Safety of Oral Anticoagulants in Patients with Systolic Heart Failure in Sinus Rhythm: A Systematic Review and Meta-analysis of Randomized Controlled Trials and Cohort Studies.

TH Open 2020 Oct 30;4(4):e383-e392. Epub 2020 Nov 30.

Department of Cardiology, Aarhus University Hospital, Aarhus, Denmark.

 There is conflicting evidence on the risk-benefit ratio of oral anticoagulants (OAC) in heart failure (HF) patients without atrial fibrillation. We aimed to evaluate the efficacy and safety of OAC in HF patients in sinus rhythm.  A systematic literature search was conducted using PubMed and Embase. We included randomized controlled trials (RCT) and cohort studies, comparing OAC with antiplatelet or no treatment/placebo in patients with HF. Outcomes evaluated were stroke, myocardial infarction (MI), all-cause mortality, and major bleeding.  Five RCTs and three cohort studies were included. OAC was associated with a reduced risk of ischemic stroke when compared with no treatment/placebo (odds ratio [OR] = 0.67, 95% confidence interval [CI]: [0.47, 0.94]) and antiplatelet therapy (OR = 0.55, 95% CI: [0.37, 0.81]). No significant reduction was found in MI, when OAC was compared with no treatment/placebo (OR = 0.82, 95% CI: [0.63, 1.07]) or antiplatelet therapy (OR = 1.04, 95% CI: [0.60, 1.81]). The all-cause mortality analysis showed no significant reduction when comparing OAC with no treatment/placebo (OR = 0.99, 95% CI: [0.87, 1.12]) or antiplatelet therapy (OR = 1.00, 95% CI: [0.86, 1.16]). The nonsignificant effect of OAC on all-cause mortality was supported by a meta-analysis of the three cohort studies (OR = 1.02, 95% CI: [0.75, 1.38]). Patients treated with OAC had a significantly higher risk of major bleeding than patients receiving antiplatelet therapy (OR = 2.16, 95% CI: [1.55, 3.00]) and a numerically higher risk when compared with no treatment/placebo (OR = 2.38, 95% CI: [0.87, 6.49]).  The present study does not support the routine use of OAC in patients with HF in sinus rhythm.
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http://dx.doi.org/10.1055/s-0040-1720961DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7704246PMC
October 2020

Real-world experience with reversal of dabigatran by idarucizumab.

Thromb Res 2021 01 10;197:179-184. Epub 2020 Nov 10.

Department of Clinical Medicine, Faculty of Health, Aarhus University, Aarhus, Denmark; Department of Cardiology, Aarhus University Hospital, Aarhus, Denmark. Electronic address:

Aims: Idarucizumab reverses the anticoagulant effect of dabigatran. We aimed to investigate real-world experience with idarucizumab and associated clinical outcomes.

Methods: We conducted a retrospective observational case series on dabigatran users treated with idarucizumab. Using electronic patient records, we identified patients from December 2015 (market introduction) to 31 December 2019 from the Central Denmark Region, covering approximately 1.3 million inhabitants. Treatment indications included need of acute surgery, major bleeding, dabigatran intoxication and need of thrombolysis. Outcomes were defined according to treatment indication, and adverse events were defined as bleeding, thrombosis or death within 30 days of infusion.

Results: A total of 46 dabigatran users were treated with idarucizumab. All patients except one received dabigatran due to atrial fibrillation. Indications for idarucizumab use were need of acute surgery in 22 (48%), severe bleeding in 20 (43%), dabigatran intoxication in three (7%), and prior to thrombolysis in acute stroke in one (2%) patient. There were no reports of excessive bleeding during surgery in patients reversed just prior to surgery. For patients presenting with severe bleeding, all but one achieved effective haemostasis. Among all patients receiving idarucizumab, six (13%) experienced bleeding within 30 days after infusion. None experienced thromboembolic complications. At 30 days follow-up, 38 (83%) patients were alive of whom 35 (92%) had restarted anticoagulant treatment.

Conclusion: This study of real-world application of idarucizumab demonstrated effectiveness in terms of surgery performed without excessive bleeding and cessation of severe bleeding in dabigatran-treated patients. Safety appeared high as no patients experienced thromboembolic complications within 30 days.
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http://dx.doi.org/10.1016/j.thromres.2020.11.010DOI Listing
January 2021

Micro- and macrovascular cardiac allograft vasculopathy in relation to 91 cardiovascular biomarkers in heart transplant recipients-An exploratory study.

Clin Transplant 2021 01 20;35(1):e14133. Epub 2020 Nov 20.

Department of Cardiology, Aarhus University Hospital, Aarhus, Denmark.

Background: Cardiac allograft vasculopathy (CAV) limits survival after heart transplantation (HTx), and the pathogenesis is not fully clarified. We aimed to investigate a wide range of biomarkers and their correlation with micro- and macrovascular CAV and major adverse cardiac events in HTx patients.

Methods: We evaluated 91 cardiovascular disease-related proteins in 48 HTx patients using a novel proteomic panel. Patients were dichotomized according to micro- and macrovascular CAV burden determined by coronary angiography, optical coherence tomography, and O-H O positron emission tomography imaging. Major adverse cardiac events included significant CAV progression, heart failure, treated rejection, and cardiovascular death.

Results: We found consistent differences in two proteins involved in cholesterol homeostasis: significantly increased proprotein convertase subtilisin/kexin type 9 (PCSK9) (p < .05) and significantly decreased paraoxonase 3 (PON3) (p < .05). N-terminal pro-brain natriuretic peptide (NT-proBNP) was significantly increased in patients with microvascular CAV (p < .05) and borderline significantly increased in patients experiencing major adverse cardiac events (p = .10) and patients with macrovascular CAV (p = .05).

Conclusions: We identified consistent changes in two proteins involved in cholesterol homeostasis which may be important players in the pathogenesis of CAV: PON3 and PCSK9. NT-proBNP also showed consistent changes across all groups but only reached statistical significance in patients with microvascular CAV. Our results warrant further validation in future studies.
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http://dx.doi.org/10.1111/ctr.14133DOI Listing
January 2021

Thrombophilia testing in patients with portal vein thrombosis.

Scand J Clin Lab Invest 2020 Dec 7;80(8):694-698. Epub 2020 Oct 7.

Department of Clinical Medicine, Aarhus University, Aarhus, Denmark.

Portal vein thrombosis (PVT) is a rare but severe condition. Several risk factors predispose to PVT. However, it remains unclear to which degree thrombophilia contributes to the risk of PVT and whether PVT patients should be routinely referred for thrombophilia testing. The aim of the present study was to investigate the prevalence of thrombophilia in PVT patients to clarify the relevance of thrombophilia testing in PVT patients. Clinical data and results from thrombophilia investigations were systematically obtained from all PVT patients referred to Centre for Hemophilia and Thrombosis, Aarhus University Hospital, Denmark for thrombophilia testing between 1 of January 2010 and 31 of December 2018 ( = 93). The investigated thrombophilias included factor V Leiden and prothrombin G20210A mutations, deficiency of protein S, protein C and antithrombin, antiphospholipid syndrome, and increased levels of factor VIII. The prevalence of thrombophilia was compared to healthy controls obtained from previously published data on thrombophilia distribution in cohorts of the Western European adult general population. Comparing PVT patients with healthy controls, significantly increased odds of presence of lupus anticoagulant (crude odds ratio (OR) 6.2, 95% confidence interval (CI) 1.8-20.6) were found, whereas no significantly increased odds of inherited thrombophilia were demonstrated. In conclusion, routine testing for inherited thrombophilia in PVT patients does not seem indicated. However, PVT patients should still be tested for antiphospholipid antibodies because patients meeting the criteria for antiphospholipid syndrome preferentially should receive vitamin K antagonists as anticoagulant therapy.
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http://dx.doi.org/10.1080/00365513.2020.1827289DOI Listing
December 2020
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