Smaller nadroparin dose reductions required for patients with renal impairment: A multicenter cohort study.

BACKGROUND: Guidelines advise 50 % and 25 % dose reduction of the therapeutic nadroparin dose (86 IU/kg) in patients with eGFR 15-29 and 30-60 ml/min respectively. For monitoring, peak anti-Xa levels are suggested. Data lack whether this results in therapeutic anti-Xa levels or in anti-Xa levels that are comparable to those of patients without renal impairment. AIMS: To determine dose ranges in patients with renal impairment that result in therapeutic anti-Xa levels and to determine the percentage of the 86 IU/kg dose that results in anti-Xa levels normally occurring in patients without renal impairment. METHODS: A retrospective cohort study was conducted in five hospitals. Patients ≥18 years of age, with an eGFR ≥ 15 ml/min were included. The first correctly sampled peak (i.e. 3-5 h after ≥ third administration, regardless of dose per patient) was included. Simulated prediction models were developed using multiple linear regression. RESULTS: 770 patients were included. eGFR and hospital affected the association between dose and anti-Xa level. The doses for peak anti-Xa levels of 0.75 IU/ml differed substantially between hospitals and ranged from 55 to 91, 65-359 and 68-168 IU/kg in eGFR 15-29, 30-60 and > 60 ml/min/1.73m2, respectively. In eGFR 15-29 and 30-60 ml/min/1.73m2, doses of 75 % and 91 % of 86 IU/kg respectively, were needed for anti-Xa levels normally occurring in patients with eGFR > 60 ml/min. CONCLUSION: We advise against anti-Xa based dose-adjustments as long as anti-Xa assays between laboratories are not harmonized and an anti-Xa target range is not validated. A better approach might be to target levels similar to eGFR > 60 ml/min/1.73m2, which are achieved by smaller dose reductions.

Occurrence of FVIII Inhibitors in Hemophilia A Patients Following an Institutional Switch to a Third Generation B-Domain-Deleted FVIII.

In 2018, Refacto AFR, a B-domain-deleted third-generation FVIII concentrate, became our preferential product. After the introduction, the development of inhibitors was prospectively monitored; retrospectively, we sought for risk factors in the patients who developed a de-novo inhibitor. Over a period of 15 months, 4/19 adult patients with non-severe haemophilia who were treated on demand for surgery, developed high titer antibodies to FVIII after administration of Refacto AFR; 5/52 mostly severe patients on prophylaxis, developed an inhibitor (3 ≥ 0.1 BU; 1 > 0.6 BU, 1 high titre) after they switched to Refacto AFR; all were children <14 years of age and with >100 exposure days, none related to surgery or intensive treatment; all received KovaltryR before. In conclusion: inhibitors were encountered in on demand patients and previously treated prophylaxis patients; this observation might be a coincidental finding, but also risk factors like genotype and surgery and/or that Refacto AFR is more immunogenic should be considered. For the patients on prophylaxis we hypothesize that loss of tolerance by preceding KovaltryR might have contributed to inhibitor development.

Fluctuations in Thyroid Hormone Levels During Initial Treatment for Differentiated Thyroid Carcinoma are Associated with Changes in Hemostasis: A Prospective Cohort Study.

Background: During treatment for differentiated thyroid carcinoma (DTC), patients go from euthyroidism to severe hypothyroidism to subclinical hyperthyroidism induced by thyroid hormone suppression therapy (THST). Severe hypothyroidism may induce a tendency toward bleeding, whereas hyperthyroidism is thrombogenic. Therefore, treatment for DTC may increase the risk of bleeding during thyroid hormone withdrawal, and thrombosis during THST. This study aims to provide prospective analysis of changes in the hemostatic system from euthyroidism to hypothyroidism, and during THST, in patients treated for DTC. Methods: This is a secondary study in a larger Dutch prospective cohort. Consecutive samples were obtained from 20 patients (18 female [90%]; median age 48 [interquartile range 35.8-56.5] years) throughout their treatment for DTC during euthyroidism (n = 5), severe hypothyroidism (n = 20), and THST (n = 20). We measured selected hemostatic proteins and C-reactive protein (CRP), performed functional tests of hemostasis (a thrombin generation test and a plasma-based clot lysis test), and assessed markers of in vivo activation of hemostasis (thrombin-antithrombin complexes, plasmin-antiplasmin [PAP] complexes, and D-dimer levels). Results: During hypothyroidism, the majority of measured parameters did not change. During THST, plasma levels of nearly all measured hemostatic proteins were higher than during hypothyroidism. Additionally, CRP significantly increased from 1.3 (0.5-3.3) to 3.2 (1.3-5.1) mg/L during THST (p < 0.01). Ex vivo thrombin generation increased from 626.0 (477.0-836.3) to 876.0 (699.0-1052.0) nM × min (p = 0.02), and ex vivo clot lysis time increased from 60.6 (55.6-67.4) to 76.0 (69.7-95.0) minutes during THST (p < 0.01). PAP levels reduced from 266.5 (211.8-312.0) to 192.0 (161.0-230.0) µg/L during THST (p < 0.01); other markers of in vivo activation of coagulation remained unaffected. Conclusions: During THST-induced hyperthyroidism, a shift toward a more hypercoagulable and hypofibrinolytic state occurred. However, in vivo activation of hemostasis did not increase. The rise in CRP levels suggests the presence of a low-grade inflammation in patients during THST. Both a hypercoagulable and hypofibrinolytic state and a low-grade inflammation are associated with an increased risk of cardiovascular diseases (CVD). Therefore, the subtle changes found during THST could potentially play a role in the pathogenesis of CVD as observed in DTC patients. Clinical Trial Registration: This study is part of a larger clinical trial registered at the Netherlands Trial Register (NTR ID 7228).

TEMPORARY REMOVAL: Direct oral anticoagulants in antithrombin deficiency: initial experience in a single center.

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Optimising the Nadroparin Dose for Thromboprophylaxis During Hemodialysis by Developing a Population Pharmacodynamic Model Using Anti-Xa Levels.

INTRODUCTION: The optimal nadroparin dose in patients undergoing hemodialysis is difficult to determine in clinical practice. Anti-Xa levels ≥ 0.4 IU/mL and < 2.0 IU/mL are suggested to prevent thrombus formation within the extracorporeal circuit whilst minimizing bleeding risk. We aimed to characterize the variability in the association between dose and anti-Xa levels, identify patient and dialysis characteristics that explained this variability, and optimize nadroparin dosing based on the identified characteristics. METHODS: Anti-Xa samples were collected in patients who received intravenous nadroparin as thromboprophylaxis during routine dialysis sessions. A population pharmacodynamic model was developed using non-linear mixed-effects modelling. The percentage of patients ≥ 0.4 IU/mL (efficacy) and < 2.0 IU/mL (safety) was simulated for different doses, patient and dialysis characteristics. RESULTS: Patients (n = 137) were predominantly receiving standard hemodialysis (84.7% vs. hemodiafiltration 15.3%) and had a mean bodyweight of 76.3 kg (± 16.9). Lean body mass (LBM), mode of dialysis, and dialyzer partially explained between-subject variability in anti-Xa levels. Patients on hemodiafiltration and those receiving hemodialysis with a high LBM (≥ 80 kg) had a low probability (< 29%) of anti-Xa levels ≥ 0.4 IU/mL during the entire dialysis session. All patients, except hemodialysis patients with a low LBM (< 50 kg), had a high probability (> 70%) of peak anti-Xa levels < 2.0 IU/mL. CONCLUSION: Mainly patients receiving hemodiafiltration and those receiving hemodialysis with a high LBM can benefit from a higher nadroparin dose than currently used in clinical practice, while having anti-Xa levels < 2.0 IU/mL.

Impact of COVID-19 pandemic on the quality of test output in haemostasis laboratories.

INTRODUCTION: The high incidence of thrombotic events in patients with COVID-19 affects health care worldwide and results in an increased workload in haemostasis laboratories due to more frequent testing of D-dimer, haemostatic parameters and anti-Xa tests. However, the impact of this increase in assay requests on the quality of performance in haemostasis laboratories remains unclear. In this study, the impact of the COVID-19 pandemic on the quality of performance and management of haemostasis laboratories was evaluated. METHODS: The impact on the quality of performance was studied using external quality assessment data from 2019 to 2020 derived from ECAT surveys. A questionnaire was sent to Dutch haemostasis laboratories to identify challenges and management strategies. Furthermore, the number of assays performed in 2019 and 2020 was supplied by four Dutch hospitals, located in regions with different disease incidence. RESULTS: No differences in response rate nor the quality of the measurements were observed between the EQA surveys in 2019 and 2020. The questionnaire results showed a large increase of >25% in the number of test requests for anti-Xa, D-dimer and fibrinogen assays in 2020 compared to 2019. Extreme peaks in test requests were also observed in the four evaluated hospitals. Additionally, 84% of the respondents indicated that they had experienced increased work pressure, and increased sick leave was observed in 71% of the participating laboratories. CONCLUSIONS: The enormous increase in test requests, especially for D-dimer assays and anti-Xa activity, did not affect the quality of performance within haemostatic laboratories during the COVID-19 pandemic.

Hepatocyte-specific glucose-6-phosphatase deficiency disturbs platelet aggregation and decreases blood monocytes upon fasting-induced hypoglycemia.

OBJECTIVE: Glycogen storage disease type 1a (GSD Ia) is a rare inherited metabolic disorder caused by mutations in the glucose-6-phosphatase (G6PC1) gene. When untreated, GSD Ia leads to severe fasting-induced hypoglycemia. Although current intensive dietary management aims to prevent hypoglycemia, patients still experience hypoglycemic events. Poor glycemic control in GSD Ia is associated with hypertriglyceridemia, hepatocellular adenoma and carcinoma, and also with an increased bleeding tendency of unknown origin. METHODS: To evaluate the effect of glycemic control on leukocyte levels and coagulation in GSD Ia, we employed hepatocyte-specific G6pc1 deficient (L-G6pc-/-) mice under fed or fasted conditions, to match good or poor glycemic control in GSD Ia, respectively. RESULTS: We found that fasting-induced hypoglycemia in L-G6pc-/- mice decreased blood leukocytes, specifically proinflammatory Ly6Chi monocytes, compared to controls. Refeeding reversed this decrease. The decrease in Ly6Chi monocytes was accompanied by an increase in plasma corticosterone levels and was prevented by the glucocorticoid receptor antagonist mifepristone. Further, fasting-induced hypoglycemia in L-G6pc-/- mice prolonged bleeding time in the tail vein bleeding assay, with reversal by refeeding. This could not be explained by changes in coagulation factors V, VII, or VIII, or von Willebrand factor. While the prothrombin and activated partial thromboplastin time as well as total platelet counts were not affected by fasting-induced hypoglycemia in L-G6pc-/- mice, ADP-induced platelet aggregation was disturbed. CONCLUSIONS: These studies reveal a relationship between fasting-induced hypoglycemia, decreased blood monocytes, and disturbed platelet aggregation in L-G6pc-/- mice. While disturbed platelet aggregation likely accounts for the bleeding phenotype in GSD Ia, elevated plasma corticosterone decreases the levels of proinflammatory monocytes. These studies highlight the necessity of maintaining good glycemic control in GSD Ia.

Reduction of anti-K-mediated hemolytic disease of newborns after the introduction of a matched transfusion policy: A nation-wide policy change evaluation study in the Netherlands.

BACKGROUND: During pregnancy, maternal red blood cell (RBC) antibodies can lead to life-threatening fetal hemolysis and anemia. Women can become immunized by a pregnancy or an unmatched transfusion. Our aim was to quantify the effect of a nationwide K-matched transfusion policy for women of childbearing age potential to prevent K-immunization in pregnancy. STUDY DESIGN AND METHODS: In this nation-wide policy change evaluation study we determined the occurrence of RBC antibodies before and after introduction of a K-matched transfusion policy and evaluated the cause K alloimmunization 10 years after introduction of this measure. K-matched transfusion for females under 45 years of age is advised in the Dutch transfusion guideline since 2004. We used laboratory data from pregnancies with RBC antibodies identified in the period 1999-2018 obtained as part of a population-based screening program in the Netherlands. RESULTS: Tests of 36 286 pregnancies produced a positive antibody screening result which concerned anti-K in 1550 pregnancies. The occurrence of anti-K decreased from 67.9 to 20.2 per 100 000 pregnancies. The relative risk reduction was 0.70 which largely exceeded the relative risk reduction of 0.27 for antibodies against RBC antigens for which no preventive matching is required. The number of pregnancies at risk for anti-K-mediated disease decreased from 9.7 to 4.2 per 100 000 pregnancies. CONCLUSIONS: A K-matched transfusion policy is associated with a major decrease in a number of pregnant women with anti-K and pregnancies at risk for anti-K-mediated disease. A relatively simple measure is now shown to impact prevention of hemolytic disease in the fetus and newborn.

Comparison of different immunoassays for the detection of antibodies against Intrinsic Factor and Parietal Cells.

OBJECTIVES: In the diagnostic work up of autoimmune gastritis several immunological methods are available for the detection of antibodies against Intrinsic Factor (IF) and Parietal Cells (PC). However, there are no recent reports directly comparing all the available assays and methods. The objective of this study was to compare the performance of several commercially available anti-IF and anti-PC antibody assays from different manufacturers in a multi-center multi-cohort setting. METHODS: Sera were used from 5 different cohorts consisting of samples from 25 healthy elderly, 20 HCV or HIV positive patients and 150 patients positive for anti-IF or anti-PC antibodies or in whom these antibodies were requested. These cohorts were tested for anti-IF antibodies with 6 different assays (IIF, ELISA, DIA and EliA) and for anti-PC antibodies with 7 different assays (IIF, ELISA, DIA and EliA). Performance was evaluated by calculating the concordance and relative sensitivity and specificity. RESULTS: Good concordance was found between the assays for both antibody specificities, ranging from 81 to 100% and 91-100% for anti-IF and anti-PC antibodies, respectively. Highest relative sensitivity was found with the (automated) ELISA based methods. However, all assays had a relative sensitivity between 85 and 100% for anti-IF antibodies and between 95 and 100% for anti-PC antibodies. The relative specificity ranged between 76 and 100% for anti-IF antibodies and between 96 and 100% for anti-PC antibodies. CONCLUSIONS: We conclude that most assays perform well and are concordant to each other, despite the methodological differences and the different sources of antigen used. However, the method used affects the sensitivity and specificity. The (automated) ELISA based assays have the highest relative sensitivity and relative specificity. Care should be taken in the interpretation of positive results by IIF and negative results by the Blue Diver when testing for anti-IF antibodies.

Monitoring of heparins in antithrombin-deficient patients.

INTRODUCTION: Heparins exert their anticoagulant effect through activation of antithrombin. Whether antithrombin deficiency leads to clinically relevantly reduced anti-Xa activity of heparins is unknown. We investigated the relation between antithrombin deficiency and anti-Xa activity measurements of plasma samples spiked with unfractionated heparin (UFH) or low-molecular-weight heparin (LMWH). MATERIALS AND METHODS: Plasma samples from 34 antithrombin-deficient subjects and 17 family controls were spiked with UFH and LMWH (nadroparin) aimed to correspond with an anti-Xa activity of 0.8 IU/mL. Antithrombin, ß-antithrombin and anti-Xa activities were measured. RESULTS: Mean anti-Xa activity with LWMH was 0.55 IU/mL (0.30-0.74) (recovery 69%, 38-93%) in antithrombin-deficient subjects and 0.82 (0.71-0.89) IU/mL in controls (recovery 103%, 89-111%). Expected anti-Xa measurements after LMWH spiking were found in 17/17 non-deficient subjects and in 8/34 antithrombin-deficient subjects. Anti-Xa measurements in the expected range (0.6-1.0 IU/mL) after UFH spiking were found in 17/17 non-deficient subjects and in 1/22 antithrombin-deficient subjects. Antithrombin activity correlated with anti-Xa activity of UFH (R = 0.77) and LMWH (R = 0.66). Mixing studies of pooled normal plasma and antithrombin-deficient plasma showed that anti-Xa recovery was linearly reduced with antithrombin activity decreasing below 100%. CONCLUSIONS: Reduced antithrombin activity causes significantly reduced anti-Xa levels. Standard LWMH- or UFH-doses are likely to lead to under treatment in antithrombin-deficient individuals.

ß-Antithrombin, subtype of antithrombin deficiency and the risk of venous thromboembolism in hereditary antithrombin deficiency: A family cohort study.

Hereditary antithrombin deficiency is associated with a high incidence of venous thromboembolism (VTE), but VTE risk differs between families. Beta-antithrombin is reported to be the most active isoform of antithrombin in vivo. Whether ß-antithrombin activity and subtypes in antithrombin deficiency have impact on VTE risk has not been investigated outside the proband setting. We performed a retrospective family cohort study to investigate whether subtypes of antithrombin deficiency or ß-antithrombin levels are associated with the risk of first or recurrent VTE. Eighty-one subjects from 21 families were included, of which 52 were antithrombin deficient. Βeta-antithrombin levels were decreased in most type I and type IIPE subjects, but normal levels were found in all subtypes of antithrombin deficiency. The annual incidence of VTE in antithrombin-deficient family members was 1.24%, 95%CI: 0.72-1.99%, in low ß-antithrombin 1.36% (95%CI: 0.76-2.25%) and in normal ß-antithrombin 0.79% (95%CI: 0.10-2.77). The annual incidence of recurrence in family members was 3.1% (95%CI: 0.9-7.1%). Duration of anticoagulation had an impact on recurrence risk: In family members annual recurrence with fixed duration was 10% (95%CI: 2.1-29.2%), with indefinite duration 1.5% (95%CI: 0.2-5.4%), p < 0.05. Beta-antithrombin levels were not associated with the risk for first or recurrent VTE in antithrombin deficient subjects. CONCLUSIONS: In this high-risk antithrombin-deficient population, both subjects with low and normal plasma ß-antithrombin activity had high risks of first and recurrent VTE. This puts the importance of ß-antithrombin into question. Long-term anticoagulation is warranted in antithrombin-deficient VTE patients.

High protein S activity due to C4b-binding protein deficiency in a 34-year-old Surinamese female with ischemic retinopathy.

In this study, we present the first case of a 34-year-old Surinamese female with ischemic retinopathy and increased free protein S due to C4BP deficiency. Possibly, the low PS/C4BP complex level has increased the risk of arterial thrombosis in our patient.

SERPINC1 gene mutations in antithrombin deficiency.

Existing evidence suggests that in most cases antithrombin deficiency can be explained by mutations in its gene, SERPINC1. We investigated the molecular background of antithrombin deficiency in a single centre family cohort study. We included a total of 21 families comprising 15 original probands and sixty-six relatives, 6 of who were surrogate probands for the genetic analysis. Antithrombin activity and antigen levels were measured. The heparin-antithrombin binding ratio assay was used to distinguish between the different subtypes of type II antithrombin deficiency. SERPINC1 mutations were detected by direct sequencing of all 7 exons and regulatory regions, and multiplex ligation-dependent probe amplification. Eighty-six per cent of the families had a detrimental SERPINC1 gene mutation that segregated in the family. We detected 13 different SERPINC1 gene mutations of which 5 were novel. Among all these mutations, 44% was associated with type I deficiency, whereas the remainder was associated with type II heparin binding site (11%), type II pleiotropic effect (33%), type II reactive site (6%) or had the antithrombin Cambridge II mutation (6%). The current study reports several novel SERPINC1 mutations, thereby adding to our knowledge of the molecular background of antithrombin deficiency. Finally, our results point out the importance of future research outside the conventional SERPINC1 gene approach.