ABSTRACT
Neddylation has been implicated in various cellular pathways and in the pathophysiology of numerous diseases. We identified four individuals with bi-allelic variants in NAE1, which encodes the neddylation E1 enzyme. Pathogenicity was supported by decreased NAE1 abundance and overlapping clinical and cellular phenotypes. To delineate how cellular consequences of NAE1 deficiency would lead to the clinical phenotype, we focused primarily on the rarest phenotypic features, based on the assumption that these would best reflect the pathophysiology at stake. Two of the rarest features, neuronal loss and lymphopenia worsening during infections, suggest that NAE1 is required during cellular stress caused by infections to protect against cell death. In support, we found that stressing the proteasome system with MG132-requiring upregulation of neddylation to restore proteasomal function and proteasomal stress-led to increased cell death in fibroblasts of individuals with NAE1 genetic variants. Additionally, we found decreased lymphocyte counts after CD3/CD28 stimulation and decreased NF-κB translocation in individuals with NAE1 variants. The rarest phenotypic feature-delayed closure of the ischiopubic rami-correlated with significant downregulation of RUN2X and SOX9 expression in transcriptomic data of fibroblasts. Both genes are involved in the pathophysiology of ischiopubic hypoplasia. Thus, we show that NAE1 plays a major role in (skeletal) development and cellular homeostasis during stress. Our approach suggests that a focus on rare phenotypic features is able to provide significant pathophysiological insights in diseases caused by mutations in genes with pleiotropic effects.
Subject(s)
Intellectual Disability , Lymphopenia , Humans , NEDD8 Protein/genetics , NEDD8 Protein/metabolism , Signal Transduction/genetics , Intellectual Disability/genetics , NF-kappa B/metabolism , Proteasome Endopeptidase Complex/metabolism , Lymphopenia/geneticsABSTRACT
INTRODUCTION: In patients with an increased bleeding tendency, extensive diagnostic blood testing is often performed. When results of tier 1 assays of primary haemostasis are normal, protocols recommend additional testing to rule out rare disorders including coagulation factor XIII (FXIII) and α2-antiplasmin (α2AP) deficiency. AIM: To evaluate the added diagnostic value of FXIII and α2AP levels in patients with a bleeding disorder of unknown cause (BDUC). METHODS: A retrospective monocentre cohort study between August 2011 and August 2023 was conducted. In all patients with bleeding tendencies and normal diagnostic tests for von Willebrand disease and platelet function, FXIII and α2AP were measured. RESULTS: We included 158 consecutive patients; mean ISTH-BAT scores were 8.2 (SD ± 3.7) in children, 6.2 (SD ± 2.1) in men and 10.6 (SD ± 3.3) in women. Median age was 37 (range 5-79) years, 88.6% of patients were female. Patients displayed median FXIII activity of 111% (IQR = 97-131) and median α2AP activity of 112% (IQR = 103-119). Three (1.9%) patients had FXIII levels < 50%, respectively 43%, 45% and 46%. Corresponding ISTH-BAT scores were 7, 12 and 14. No α2AP levels < 60% was observed. No significant association was found between FXIII levels and ISTH-BAT scores. CONCLUSION: In our cohort of BDUC patients, no clinical relevant FXIII deficiencies were detected; absolute values were well above the 30% cutoff considered adequate for normal haemostasis. No α2AP deficiencies were detected. These data suggest that in BDUC patients, measuring FXIII or AP activity is of limited value.
Subject(s)
Factor XIII Deficiency , Factor XIII , alpha-2-Antiplasmin , Humans , Male , Female , Child , Adolescent , alpha-2-Antiplasmin/analysis , alpha-2-Antiplasmin/deficiency , alpha-2-Antiplasmin/metabolism , Retrospective Studies , Child, Preschool , Factor XIII Deficiency/diagnosis , Factor XIII Deficiency/complications , Factor XIII Deficiency/blood , Adult , Middle Aged , Young Adult , Aged , Factor XIII/analysis , Factor XIII/metabolism , Cohort StudiesABSTRACT
OBJECTIVE: A pre-operative marker for identification of patients at risk of peri-operative adverse events and 30 day mortality might be the percentage of young, reticulated platelets (pRP). This study aimed to determine the predictive value of pre-operative pRP on post-operative myocardial injury (PMI) and 30 day mortality, in patients aged ≥ 60 years undergoing moderate to high risk non-cardiac surgery. METHODS: The incidence of PMI (troponin I > 0.06 µg/L) and 30 day mortality was compared for patients with normal and high pRP (≥2.82%) obtained from The Utrecht Patient Orientated Database. The predictive pRP value was assessed using logistic regression. A prediction model for PMI or 30 day mortality with known risk factors was compared with a model including increased pRP using the area under the receiving operator characteristics curve (AUROC). RESULTS: In total, 26.5% (607/2289) patients showed pre-operative increased pRP. Increased pRP was associated with more PMI and 30 day mortality compared with normal pRP (36.1% vs. 28.3%, p < .001 and 8.6% vs. 3.6%, p < .001). The median pRP was higher in patients suffering PMI and 30 day mortality compared with not (2.21 [IQR: 1.57-3.11] vs. 2.07 [IQR: 1.52-1.78], p = .002, and 2.63 [IQR: 1.76-4.15] vs. 2.09 [IQR: 1.52-3.98], p < .001). pRP was independently related to PMI (OR: 1.28 [95% CI: 1.04-1.59], p = .02) and 30 day mortality (OR: 2.35 [95% CI: 1.56-3.55], p < .001). Adding increased pRP to the predictive model of PMI or 30 day mortality did not increase the AUROC 0.71 vs. 0.72, and 0.80 vs. 0.81. CONCLUSION: In patients undergoing major non-cardiac surgery, increased pre-operative pRP is related to 30 day mortality and PMI.
Subject(s)
Blood Platelets/physiology , Myocardial Infarction/epidemiology , Postoperative Complications/epidemiology , Surgical Procedures, Operative/adverse effects , Aged , Feasibility Studies , Female , Hospital Mortality , Humans , Incidence , Male , Middle Aged , Myocardial Infarction/blood , Myocardial Infarction/etiology , Platelet Count , Postoperative Complications/etiology , Predictive Value of Tests , Preoperative Period , ROC Curve , Risk Assessment/methods , Risk Factors , Troponin I/bloodABSTRACT
BACKGROUND: Vasoplegia after routine cardiac surgery is associated with severe postoperative complications and increased mortality. It is also prevalent in patients undergoing implantation of pulsatile flow left ventricular assist devices (LVAD). However, less is known regarding vasoplegia after implantation of newer generations of continuous flow LVADs (cfLVAD). We aim to report the incidence, impact on outcome and predictors of vasoplegia in these patients. METHODS: Adult patients scheduled for primary cfLVAD implantation were enrolled into a derivation cohort (n = 118, 2006-2013) and a temporal validation cohort (n = 73, 2014-2016). Vasoplegia was defined taking into consideration low mean arterial pressure and/or low systemic vascular resistance, preserved cardiac index and high vasopressor support. Vasoplegia was considered after bypass and the first 48 h of ICU stay lasting at least three consecutive hours. This concept of vasoplegia was compared to older definitions reported in the literature in terms of the incidence of postoperative vasoplegia and its association with adverse outcomes. Logistic regression was used to identify independent predictors. Their ability to discriminate patients with vasoplegia was quantified by the area under the receiver operating characteristic curve (AUC). RESULTS: The incidence of vasoplegia was 33.1% using the unified definition of vasoplegia. Vasoplegia was associated with increased ICU length-of-stay (10.5 [6.9-20.8] vs 6.1 [4.6-10.4] p = 0.002), increased ICU-mortality (OR 5.8, 95% CI 1.9-18.2) and one-year-mortality (OR 3.9, 95% CI 1.5-10.2), and a higher incidence of renal failure (OR 4.3, 95% CI 1.8-10.4). Multivariable analysis identified previous cardiothoracic surgery, preoperative dopamine administration, preoperative bilirubin levels and preoperative creatinine clearance as independent preoperative predictors of vasoplegia. The resultant prediction model exhibited a good discriminative ability (AUC 0.80, 95% CI 0.71-0.89, p < 0.01). Temporal validation resulted in an AUC of 0.74 (95% CI 0.61-0.87, p < 0.01). CONCLUSIONS: In the era of the new generation of cfLVADs, vasoplegia remains a prevalent (33%) and critical condition with worse short-term outcomes and survival. We identified previous cardiothoracic surgery, preoperative treatment with dopamine, preoperative bilirubin levels and preoperative creatinine clearance as independent predictors.
Subject(s)
Cardiac Surgical Procedures/methods , Heart-Assist Devices , Postoperative Complications/epidemiology , Vasoplegia/epidemiology , Adult , Cardiac Surgical Procedures/adverse effects , Cohort Studies , Female , Hospital Mortality , Humans , Incidence , Intensive Care Units , Length of Stay , Logistic Models , Male , Middle Aged , Retrospective Studies , Treatment Outcome , Vascular Resistance/physiology , Vasoplegia/etiologyABSTRACT
Background and purpose-Nonunion is common in femoral fractures. Previous studies suggested that the systemic immune response after trauma can interfere with fracture healing. Therefore, we investigated whether there is a relation between peripheral blood cell counts and healing of femur fractures. Patients and methods-62 multi-trauma patients with a femoral fracture presenting at the University Medical Centre Utrecht between 2007 and 2013 were retrospectively included. Peripheral blood cell counts from hematological analyzers were recorded from the 1st through the 14th day of the hospital stay. Generalized estimating equations were used to compare outcome groups. Results-12 of the 62 patients developed nonunion of the femoral fracture. The peripheral blood-count curves of total leukocytes, neutrophils, monocytes, lymphocytes, and platelets were all statistically significantly lower in patients with nonunion, coinciding with significantly higher CRP levels during the first 2 weeks after trauma in these patients. Interpretation-Patients who developed femoral nonunion after major trauma demonstrated lower numbers of myeloid cells in the peripheral blood than patients with normal fracture healing. This absent rise of myeloid cells seems to be related to a more severe post-traumatic immune response.
Subject(s)
Femoral Fractures/surgery , Fracture Healing/physiology , Fractures, Ununited/immunology , Myeloid Cells/pathology , Adolescent , Adult , Aged , Aged, 80 and over , C-Reactive Protein/metabolism , Erythrocyte Count , Female , Femoral Fractures/blood , Femoral Fractures/immunology , Fracture Fixation/methods , Fractures, Ununited/blood , Humans , Injury Severity Score , Leukocyte Count , Male , Middle Aged , Platelet Count , Retrospective Studies , Young AdultABSTRACT
BACKGROUND: Heparin fulfills its anticoagulant action through activation of antithrombin (AT), and thus thrombosis secondary to AT deficiency can be associated with heparin resistance. OBSERVATION: A 12-year-old girl with severe venous thrombosis was referred to us because of undetectable anti-Xa levels despite low-molecular-weight heparin therapy. Laboratory investigations revealed a homozygous AT mutation in the heparin binding site (AT Budapest III). She was subsequently treated with rivaroxaban successfully. CONCLUSIONS: Heparin resistance warrants evaluation for AT deficiency. Rivaroxaban may be considered a valid anticoagulant alternative to low-molecular-weight heparin in these patients.
Subject(s)
Antithrombin III Deficiency/complications , Heparin, Low-Molecular-Weight/pharmacology , Rivaroxaban/administration & dosage , Thrombosis/drug therapy , Antithrombin III/analysis , Binding Sites/genetics , Child , Drug Resistance/genetics , Factor Xa Inhibitors , Female , Heparin, Low-Molecular-Weight/therapeutic use , HumansABSTRACT
BACKGROUND: Neonatal encephalopathy (NE) is a serious condition, primarily seen following hypoxia-ischemia (HI). Two different patterns of brain injury can be recognized on magnetic resonance imaging (MRI): white matter/watershed (WM/WS) or basal ganglia/thalamus (BGT) injury. Whether these patterns of injury can be attributed to different associated risk factors still needs to be established. METHODS: In 118 infants with clinical signs of NE following perinatal HI, thrombophilic factors, such as factor V Leiden and prothrombin gene mutation, C677T and A1298C polymorphisms in the methylenetetrahydrofolate reductase (MTHFR) gene, and plasma levels of homocysteine and lipoprotein(a), were prospectively investigated. Antenatal and perinatal variables were studied. RESULTS: WM/WS injury was seen in 45 infants, BGT injury in 40, and normal neuroimaging in 33. Antenatal factors did not differ across these groups. The BGT pattern was associated with lower Apgar scores, whereas the WM/WS pattern was associated with hypoglycemia (<2.0 mmol/l), CT or TT 677 polymorphism in the MTHFR gene, and plasma homocysteine levels in the upper quartile. CONCLUSION: In infants with NE following perinatal HI, the WM/WS pattern of injury was associated with hypoglycemia, the MTHFR 677CT or TT genotype, and higher levels of plasma homocysteine. BGT injury showed an association with signs suggestive of acute HI.
Subject(s)
Basal Ganglia Diseases/pathology , Hypoglycemia/pathology , Hypoxia-Ischemia, Brain/pathology , Leukoencephalopathies/pathology , Apgar Score , Basal Ganglia Diseases/etiology , Factor V/genetics , Homocysteine/blood , Humans , Hypoglycemia/complications , Hypoxia-Ischemia, Brain/complications , Infant, Newborn , Leukoencephalopathies/etiology , Lipoprotein(a)/blood , Magnetic Resonance Imaging , Methylenetetrahydrofolate Reductase (NADPH2)/genetics , Polymorphism, Single Nucleotide/genetics , Prospective Studies , Prothrombin/genetics , Risk FactorsABSTRACT
This commentary discusses the prevalence and causes of anemia in primary care in the Netherlands and the role of laboratory diagnostics in determining the cause of anemia. There are indications that guidelines in primary care regarding anemia are insufficiently followed; there are also indications that the correct laboratory measurements are requested too limited (under-diagnosis). A possible solution lies in the introduction of reflective testing, in which the laboratory specialist has additional diagnostic laboratory tests performed on the basis of the laboratory results and specific characteristics of the patient. Reflective testing is in contrast to reflex testing; in reflex testing, laboratory measurements are added automatically using a simple flowchart. In the future, Artificial Intelligence solutions could play a role in determining the most optimal laboratory diagnostic strategy for the diagnosis of anemia in primary care.
Subject(s)
Anemia , Artificial Intelligence , Humans , Anemia/diagnosis , Anemia/etiology , Reflex , Algorithms , Primary Health CareABSTRACT
Even though routine screening of the general hospital population is discouraged, medical laboratories may use a "lupus sensitive" activated partial thromboplastin time test (aPTT) with phospholipid concentrations that are susceptible to inhibition by lupus anticoagulant (LA), to screen for the presence of LA. If deemed necessary, follow-up testing according to ISTH guidelines may be performed. However, LA testing is a laborious and time-consuming effort that is often not readily available due to a lack of automation and/or temporary unavailability of experienced staff. In contrast, the aPTT is a fully automated test that is available 24/7 in almost all medical laboratories and is easily interpreted with the use of reference ranges. In addition to clinical signs, the result of an LA sensitive aPTT may thus be used to lower the suspicion of the presence of LA and reduce costly follow-up testing. In this study, we show that a normal LA sensitive aPTT result may be safely used to refrain from LA testing in the absence of strong clinical suspicion.
Subject(s)
Antiphospholipid Syndrome , Lupus Coagulation Inhibitor , Humans , Partial Thromboplastin Time , Blood Coagulation Tests , Reference ValuesABSTRACT
INTRODUCTION: Hemoglobin-based oxygen carriers, for example HBOC-201 (Hemopure), are aimed to bridge acute anemia when blood transfusion is not available or refused by the patient. However, since HBOC-201 appears free in plasma, it interferes with laboratory tests. This study presents an overview of HBOC-201 interference on four commonly used hematology analyzers and suggests treatment monitoring possibilities. METHODS: Blood samples were spiked with therapeutic doses of HBOC-201 and nine hematology parameters were measured with the Sysmex XN-20, Siemens Advia 2120i, Abbott Alinity Hq and Abbot Cell Dyn Sapphire hematology analyzers. The results were compared to control samples and the bias was determined. RESULTS: Most parameters, including all cell counts, hematocrit and MCV, showed a non-significant bias compared to control. However, the standard, total hemoglobin (Hb) measurement as well as MCH and MCHC showed poor agreement with control, as HBOC-201 was included in this measurement. Yet, the flow cytometry-based Hb method quantified intracellular Hb in spiked samples, excluding HBOC-201. CONCLUSION: Of all included hematology parameters, only total Hb and the associated MCH and MCHC suffered from interference. In contrast, the flow cytometry-based Hb measurement provided an accurate measure of intracellular Hb. The difference between total Hb and cellular Hb represents the HBOC-201 concentration and can be used to monitor HBOC-201 treatment.
Subject(s)
Hematology , Hemoglobins , Humans , Hemoglobins/analysis , Hematologic Tests , Blood Transfusion , OxygenABSTRACT
INTRODUCTION: This study assessed the comparability of complete blood count (CBC) parameters between capillary and venous samples, and extended previous research by examining the influence of different storage temperatures on CBC stability up to 7 days after sample collection. METHODS: Venous and capillary blood samples were collected from 93 adult patients. Hemoglobin (Hb), hematocrit (Ht), mean corpuscular volume (MCV), mean corpuscular hemoglobin (MCH), mean corpuscular hemoglobin concentration (MCHC), mean platelet volume (MPV), leukocytes, lymphocytes, basophils, eosinophils, erythrocytes, red cell distribution width (RDW), immature granulocytes (IG), immature reticulocyte fraction (IRF), monocytes, neutrophils, platelets, and reticulocytes were measured. Deming regression and mean relative differences between venous and capillary measurements were contrasted with desirable total allowable error (TEa). Stability was assessed in 20-27 venous blood samples stored at 4, 21-22, or 30°C, and analyzed at 0, 24, 48, 72, 96, 120, 144, and 168 h. Mean relative change with respect to baseline measurements was compared to the desirable TEa to determine acceptable stability. RESULTS: Deming regression demonstrated strong linear correlations and acceptable variation between venous and capillary measurements. Erythrocytes, Hb, Ht, MCH, MCV, RDW, reticulocytes, and platelets showed acceptable stability for at least 96 h at 4°C. Mean relative change exceeded desirable TEa after 24 h at 30°C for all parameters, except erythrocytes, Hb, leukocytes, and MCH. CONCLUSION: Clinical laboratory specialists and clinicians should be aware of potential differences between venous and capillary measurements, and the influence of storage conditions. Clinical validity of delayed CBC analysis depends on the clinical situation and required precision of the result.
Subject(s)
Erythrocyte Indices , Erythrocytes , Adult , Humans , Blood Cell Count/methods , Hematocrit , Erythrocytes/chemistry , Hemoglobins/analysis , EosinophilsABSTRACT
Background: Patients with antiphospholipid syndrome (APS) receive anticoagulant therapy with vitamin K antagonists (VKAs) to prevent recurrent thrombosis. VKA treatment requires strict monitoring with an international normalized ratio (INR). It is known that lupus anticoagulants (LAs) can lead to elevated INR results with point-of-care-testing (POCT) devices, which could result in inadequate adaptation of anticoagulant therapy. Objective: To determine discrepancies between POCT-INR and laboratory-INR in patients who are LA-positive on VKA therapy. Methods: Paired INR testing was performed with 1 POCT device (CoaguChek XS) and 2 laboratory assays (Owren and Quick method) in 33 patients with LA-positive APS on VKA in a single-center cross-sectional study. Patients were tested for anti-ß2-glycoprotein I, anticardiolipin, and antiphosphatidylserine/prothrombin immunoglobulin (Ig) G and IgM antibodies. Agreement between assays was evaluated with Spearman's correlation, Lin's correlation coefficient, and Bland-Altman plots. Agreement limits were considered satisfactory if differences were ≤20% as determined by the Clinical and Laboratory Standards Institute. Results: We found poor agreement between POCT-INR and laboratory-INR based on Lin's concordance correlation coefficient (ρc) of 0.42 (95% CI, 0.26-0.55) between POCT-INR and Owren-INR, a ρc of 0.64 (95% CI, 0.47-0.76) between POCT-INR and Quick-INR, and a ρc of 0.77 (95% CI, 0.64-0.85) between Quick-INR and Owren-INR. High anti-ß2-glycoprotein I IgG antibody titers correlated with INR disagreement between POCT-INR and laboratory-INR. Conclusion: There is a disagreement between INR values measured with the CoaguChek XS and laboratory-INR in a proportion of patients with LA. Consequently, laboratory-INR monitoring should be preferred over POCT-INR monitoring in patients with LA-positive APS, especially in patients with high anti-ß2-glycoprotein IgG antibody titers.
ABSTRACT
BACKGROUND: Thrombopoietin receptor agonists are frequently used in treating immune thrombocytopenia (ITP) owing to high response rates and good tolerability. ITP is associated with an increased risk of thrombosis. Whether treatment with eltrombopag further increases this risk is controversial. The mechanisms behind the thrombotic risk in ITP are unclear. OBJECTIVES: To assess platelet function and hypercoagulability in patients with ITP and the effect of eltrombopag thereon. METHODS: This prospective multicenter study assessed adult primary patients with ITP who were starting eltrombopag treatment. Platelet (re)activity and hypercoagulability were measured in whole blood or plasma before start and after 2 to 3 weeks of eltrombopag treatment and compared with those of controls. Change over time was assessed by mixed-effects models, and the results were corrected for multiple testing. RESULTS: We included 16 patients and 33 controls. At baseline, patients with ITP exhibited lower expression of glycoprotein VI, more activated platelets, and lower reactivity toward agonists compared with controls. ß-Thromboglobulin levels reduced and thrombin generation peak height increased compared with those of controls. In line with this finding, patients with ITP showed high factor VIII (median, 217%; IQR, 174%-272%) and von Willebrand factor levels (median, 167%; IQR, 109%-198%). Eltrombopag treatment increased thrombin generation potential: lag time decreased and peak height and endogeneous thrombin potential increased. The latter changes were not significant after correction for multiple testing. CONCLUSION: Patients with ITP in this study were in a hypercoagulable state, with preactivated platelets, increased thrombin generation potential, and increased levels of factor VIII and von Willebrand factor. Eltrombopag treatment further increased plasma thrombin generation potential but no other hemostatic parameters.
Subject(s)
Purpura, Thrombocytopenic, Idiopathic , Thrombocytopenia , Thrombophilia , Adult , Humans , Purpura, Thrombocytopenic, Idiopathic/diagnosis , Purpura, Thrombocytopenic, Idiopathic/drug therapy , Purpura, Thrombocytopenic, Idiopathic/chemically induced , Prospective Studies , Factor VIII , Thrombin , von Willebrand Factor , Hydrazines/adverse effects , Thrombophilia/chemically inducedABSTRACT
Red blood cell distribution width (RDW) is a biomarker associated with a variety of clinical outcomes. While anemia and subclinical inflammation have been posed as underlying pathophysiology, it is unclear what mechanisms underlie these assocations. Hence, we aimed to unravel the mechanisms in silico using a large clinical dataset and validate our findings in vitro. We retrieved complete blood counts (CBC) from 1,403,663 measurements from the Utrecht Patient Oriented Database, to model RDW using gradient boosting regression. We performed (sex-stratified) analyses in patients with anemia, patients younger/older than 50 and validation across platforms and care settings. We then validated our hypothesis regarding oxidative stress using an in vitro approach. Only percentage microcytic (pMIC) and macrocytic (pMAC) erythrocytes and mean corpuscular volume were most important in modelling RDW (RMSE = 0.40, R2 = 0.96). Subgroup analyses and validation confirmed our findings. In vitro induction of oxidative stress underscored our results, namely increased RDW and decreased erythrocyte volume, yet no vesiculation was observed. We found that erythrocyte size, especially pMIC, is most informative in predicting RDW, but no role for anemia or inflammation. Oxidative stress affecting the size of the erythrocytes may play a role in the association between RDW and clinical outcomes.
Subject(s)
Anemia , Erythrocytes , Humans , Erythrocyte Indices , Inflammation , Oxidative StressABSTRACT
Thrombus formation is a common complication during left ventricular assist device (LVAD) therapy, despite anticoagulation with vitamin K antagonists (VKA) and a platelet inhibitor. Plasma levels of markers for primary and secondary hemostasis and contact activation were determined before LVAD implantation and 6 and 12 months thereafter in 37 adults with end-stage heart failure. Twelve patients received a HeartMate 3, 7 patients received a HeartWare, and 18 patients received a HeartMate II. At baseline, patients had elevated plasma levels of the platelet protein upon activation, ß-thromboglobulin, and active von Willebrand factor in thrombogenic state (VWFa), which remained high after LVAD implantation. Von Willebrand factor levels and VWF activity were elevated at baseline but normalized 12 months after LVAD implantation. High D -dimer plasma levels, at baseline, remained elevated after 12 months. This was associated with an increase in plasma thrombin-antithrombin-complex levels and plasma levels of contact activation marker-cleaved H-kininogen after LVAD implantation. Considering these results it could be concluded that LVAD patients show significant coagulation activation despite antithrombotic therapy, which could explain why patients are at high risk for LVAD-induced thrombosis. Continuous low-grade systemic platelet activation and contact activation may contribute to prothrombotic effects of LVAD.
Subject(s)
Heart Failure , Heart-Assist Devices , Thrombosis , Adult , Humans , von Willebrand Factor/metabolism , Heart-Assist Devices/adverse effects , Hemostasis , Blood Coagulation , Thrombosis/etiology , Heart Failure/therapyABSTRACT
Background: Heavy menstrual bleeding (HMB), self-reported by 37% of adolescents, can be the first sign of a bleeding disorder (BD) during adolescence. The Dutch general practitioner (GP) guideline demands laboratory diagnostics and referral for patients at risk for a BD. How often adolescents consult the GP for HMB and which diagnostic and management strategies are used are unknown. Objectives: This study aims to estimate the incidence of HMB in adolescents in primary care and to identify diagnostic and management practices for HMB, considering the HMB GP guideline. Methods: Retrospective analyses of a GP network database containing over 200 Dutch GPs were performed. Adolescents aged 10 to 21 years, with a new diagnosis of HMB between 2010 and 2020, and a 6-month follow-up were eligible. The incidence rate and diagnostic and therapeutic strategy data were extracted. Results: We identified 1879 new diagnoses of HMB in adolescents. The average incidence rate was 7.91 per 1000 person-years. No diagnostic studies were performed in 67%. Laboratory studies were mainly restricted to hemoglobin levels (31%). Full coagulation screening occurred in 1.3%, and ferritin levels in 10%. Medication was prescribed in 65%; mostly hormonal treatment (56%) and/or nonsteroidal antiinflammatory drugs (NSAIDs) (18%). The referral rate was higher after >2 follow-up visits (6.7%) vs after 1 GP visit for HMB (1.6%; Odds ratio: 8.8; 95% CI: 5.1-15), mostly to gynecologists (>85%). Conclusion: According to this GP database study, few adolescents visit their GP with HMB despite its high self-reported incidence. Most adolescents were prescribed hormonal contraception without further diagnostics. Referral was rare and mostly occurred after multiple follow-up visits.