Thrombosis Tendency After Splenectomy in a Danish Family With Hemoglobin Volga, and a Literature Review.

Hemoglobin (Hb) Volga is a rare, unstable ß-chain hemoglobin variant (ß27 Ala→Asp), causing chronic hemolytic anemia. This study presents two members of a Danish family, splenectomized due to Hb Volga at and with multiple thrombotic events. The proband was diagnosed with Hb Volga 9 years old and splenectomy was performed as a part of treatment. Throughout his life, he experienced multiple superficial thrombophlebitis, two episodes of distal deep venous thrombosis (DVT) on lower extremities (age 32 and 33) and a transient ischemic attack (TIA) presented as amaurosis fugax (age 51). Thrombophilia investigation was normal. The proband's son was diagnosed with Hb Volga and underwent splenectomy at the age of 6. Despite anticoagulation therapy, he suffered from multiple venous thromboembolic events in his youth and died of chronic pulmonary embolism (PE)/pulmonary hypertension combined with infection. Given the observed propensity for multiple thromboses in these two patients, a literature review was conducted investigating reported occurrence of thrombotic events in individuals with Hb Volga.Currently 25 cases of Hb Volga are reported worldwide. The clinical symptoms primarily described are related to hemolytic anemia. Splenectomy is reported in 15 patients. Thromboses have previously been reported in only three patients who were also splenectomized. These cases involved DVT and PE, myocardial infarction, and an unspecified thrombotic event. The proband represents the first reported Hb Volga case with both venous and arterial thrombotic disorders. The exact mechanism underlying thrombotic tendency in patients with Hb Volga remains unknown, but it is probably associated with splenectomy.

DANSPOT: A Multicenter Stepped-Wedge Cluster-Randomized Trial of the Reclassification of Acute Myocardial Infarction: Rationale and Study Design.

BACKGROUND: Cardiac troponins are the preferred biomarkers for the diagnosis of acute myocardial infarction. Although sex-specific 99th percentile thresholds of troponins are recommended in international guidelines, the clinical effect of their use is poorly investigated. The DANSPOT Study (The Danish Study of Sex- and Population-Specific 99th percentile upper reference limits of Troponin) aims to evaluate the clinical effect of a prospective implementation of population- and sex-specific diagnostic thresholds of troponins into clinical practice. METHODS: This study is a nationwide, multicenter, stepped-wedge cluster-randomized trial of the implementation of population- and sex-specific thresholds of troponins in 22 of 23 clinical centers in Denmark. We established sex-specific thresholds for 5 different troponin assays based on troponin levels in a healthy Danish reference population. Centers will sequentially cross over from current uniform manufacturer-derived thresholds to the new population- and sex-specific thresholds. The primary cohort is defined as patients with symptoms suggestive of acute coronary syndrome having at least 1 troponin measurement performed within 24 hours of arrival with a peak troponin value between the current uniform threshold and the new sex-specific female and male thresholds. The study will compare the occurrence of the primary outcome, defined as a composite of nonfatal myocardial infarction, unplanned revascularization, and all-cause mortality within 1 year, separately for men and women before and after the implementation of the new sex-specific thresholds. CONCLUSIONS: The DANSPOT Study is expected to show the clinical effects on diagnostics, treatment, and clinical outcomes in patients with myocardial infarction of implementing sex-specific diagnostic thresholds for troponin based on a national Danish reference population. REGISTRATION: URL: https://www.clinicaltrials.gov; Unique identifier: NCT05336435.

Congenital fibrinogen disorders.

Congenital fibrinogen disorders are rare pathologies of the haemostasis, comprising afibrinogenaemia, hypofibrinogenaemia, dysfibrinogenaemia and hypodysfibrinogenaemia. Phenotypic manifestations are variable, patients may be asymptomatic or suffer from bleeding or thrombosis. Most of congenital fibrinogen disorders are coincidentally discovered. Fibrinogen concentrate is used to treat bleeding, whereas low-molecular weight heparin is most often administered for the treatment of thrombotic complications. The aim of this review is to provide an update of the knowledge of congenital fibrinogen disorders for Danish physicians.

Management of Recurrent Venous Thromboembolism in Severe Immune Thrombocytopenia: A Case Report and a Review of the Literature.

We report a case of a 58-year-old man with recurrent unprovoked deep vein thrombosis (DVT) and severe immune thrombocytopenia (ITP) with a platelet count of 19 × 109/L. We further review studies reporting venous thromboembolism (VTE) in patients with severe ITP (≤ 35 × 109/L) and identified 14 patients highlighting VTE risk factors and management of these patients. The present case had several risk factors for VTE (previous DVT, obesity, heterozygosity for factor V Leiden mutation, and previous splenectomy). The patient was initially treated with low-molecular-weight heparin followed by long-term apixaban treatment. The literature review together with our case demonstrates that VTE in severe ITP (≤ 35 × 109/L) can occur in patients with VTE risk factors and antithrombotic management of these patients can be achieved without bleeding depending on severity of thrombocytopenia either by full or reduced dose of anticoagulation together with ITP therapy.

Vitamin D Deficiency is Associated With Increased Plasminogen Activator Inhibitor 1/Plasminogen Activator Inhibitor 2 Ratio in Pregnancy.

BACKGROUND: Vitamin D deficiency has recently been suggested as an independent risk factor for thrombosis. Notably, vitamin D deficiency is common in pregnant populations, whom already have an increased thrombotic risk. However, pregnant women are commonly excluded from studies investigating the hemostatic system, and knowledge on the impact of vitamin D on hemostasis in pregnancy is therefore limited. METHODS: A cross-sectional study comparing the hemostatic profile of pregnant women (gestational week 12.9 ± 0.7) with vitamin D deficiency (≤50 nmol/L) (n = 70) and high adequate vitamin D status (≥100 nmol/L) (n = 59). RESULTS: Vitamin D deficient women displayed increased plasminogen activator inhibitor 1 levels and an increased plasminogen activator inhibitor 1/plasminogen activator inhibitor 2 ratio, even after adjusting for factors with potential influence on hemostasis (body mass index, smoking and use of fish oil supplements). CONCLUSIONS: Vitamin D deficiency is associated with increased plasminogen activator inhibitor 1/plasminogen activator inhibitor 2 ratio in pregnant women. As an increased plasminogen activator inhibitor 1/plasminogen activator inhibitor 2 ratio with high plasminogen activator inhibitor 1 levels may increase thrombotic risk and is associated with the development of pregnancy complications, further research is needed to determine the optimal vitamin D supplementation in pregnancy.

Kinetics of cardiac troponin and other biomarkers in patients with ST elevation myocardial infarction.

Objective: To examine changes in concentration, time-to-peak and the ensuing half-life of cardiac biomarkers in patients with myocardial infarction. Methods: Blood sampling was performed every third hour within 24 h after percutaneous coronary intervention (PCI) on a cohort of patients with ST elevation myocardial infarction. Cardiac troponin (cTn) was measured by the Dimension Vista, Vitros, Atellica, and Alinity high-sensitivity (hs) cTnI assays, and the Elecsys hs-cTnT assay. Further, creatine kinase (CK), myoglobin, creatine kinase MB (CKMB) and other biomarkers were analyzed. Results: A total of 36 patients completed blood sampling (median age 60 years, IQR 56.4-66.5 years; seven women, 19.4%). Hs-cTnI measured by the Vitros assay was the first hs-cTn to peak at 9.1 h (95%-CI 6.2-10.1) after PCI and 11.7 h (95%-CI 10.4-14.8) after symptoms onset. There were no notable differences between hs-cTn assays in regard to time-to-peak. Also, Vitros hs-cTnI reached the highest median ratio of concentration to upper reference level of nearly 2,000. The median half-life from peak concentration ranged from 7.6 h for myoglobin (CI 6.8-8.6) to 17.8 h for CK (CI 6.8-8.6). For hs-cTn assays the median T½ ranged from 12.4 h for the Vista hs-cTnI assay (95%-CI 11.0-14.1 h) to 17.3 h for the Elecsys hs-cTnT (95%-CI 14.9-20.8 h). Conclusions: This study updates knowledge on the kinetics of cardiac biomarkers in current clinical use. There was no notable difference in trajectories, time-to-peak or half-life between hs-cTn assays.

Antiphospholipid antibodies in pulmonary embolism treated with direct oral anticoagulants: Prevalence data from unselected consecutive patients.

Background: Direct oral anticoagulants (DOACs) are the first-choice treatment option for the prevention of the recurrence of venous thrombosis in patients with pulmonary embolism (PE); however, their effect in patients with antiphospholipid syndrome (APS) is challenged. Therefore, the prevalence of antiphospholipid autoantibodies in patients with PE is noteworthy. Objectives: To determine the prevalence of unselected patients presenting with PE who meet the criteria for APS based on elevated levels of anticardiolipin (aCL) and anti-ß2-glycoprotein I (aß2GPI) antibodies. Methods: Consecutive patients with PE, in whom DOACs were primarily initiated, were tested for aCL and aß2GPI. If the levels were elevated, the tests were repeated after 12 weeks for APS diagnosis. Laboratory results and patient characteristics were retrospectively collected from a laboratory information system and electronic patient journal entries over a 2-year period. Results: The prevalence of APS based on consistently elevated levels of aCL or aß2GPI was 3.7% (10 of 267 patients). Three patients were double positive. In 11 out of 21 patients (52%) with initially elevated values, the levels of the antibodies normalized after 12 weeks. The patient characteristics were largely similar in those with APS and those without APS; however, patients with APS tended to be older and more likely to receive antithrombotic treatment at the time of PE. Conclusion: We found a relatively low prevalence of APS based on aCL or aß2GPI. The high rate of normalized levels of the antibodies after 12 weeks reaffirms the need for repeated tests for APS diagnosis. Older patients more frequently met the criteria for APS. Determining the effectiveness of DOACs in non-triple-positive patients with APS following venous thromboembolism is important to further determine the feasibility of unselected tests in patients with PE.

Is Vitamin D Deficiency Prothrombotic? A Systematic Review.

Observational studies indicate a relationship between vitamin D deficiency and an increased risk of venous and arterial thrombotic events, but the underlying mechanisms behind this association are uncertain. This systematic review explores if there is an association between decreased vitamin D levels and a prothrombotic profile. The systematic literature search initially identified 3,214 studies (published until December 21, 2021) investigating the relationship between vitamin D and numerous hemostatic parameters. After the screening process, 18 observational and intervention studies fulfilled the inclusion criteria and were included in this systematic review. Parameters of primary hemostasis, secondary hemostasis, and fibrinolysis were investigated in six, thirteen, and fifteen of these studies, respectively. Most of the eligible studies did not identify significant associations between decreased vitamin D levels and hemostatic parameters. Some conflicting results were found between decreased vitamin D levels and thrombin generation parameters and the tissue factor pathway inhibitor. Conflicting results were also found between decreased vitamin D levels and fibrinolytic parameters, although the evidence may point toward weak associations with some regulators of fibrinolysis, mostly decreased tissue type plasminogen activator. Overall, our systematic review did not identify any definitive link between vitamin D deficiency and a prothrombotic profile, which might otherwise help explain the observed association between vitamin D deficiency and increased risk of thrombotic events. Moreover, there is no clinical evidence to confirm or refute a possible antithrombotic effect of vitamin D. Larger high-quality randomized controlled trials are needed to better elucidate the link between vitamin D deficiency and a prothrombotic risk profile.

Managing antithrombotic treatment in a patient with atrial fibrillation and coronary stent with transient neurological symptoms in cerebral amyloid angiopathy.

We present the antithrombotic dilemma in a case with atrial fibrillation and a coronary stent and suspected transient ischemic attacks after diagnosed as a probable cerebral amyloid angiopathy and discuss plausible treatment options for the patient based on the available evidence.

Does vitamin K supplementation improve vitamin K antagonist therapy? A case report and update of the literature.

We report a multi-morbid patient with mechanical aortic valve and unstable and sub-therapeutic levels of international normalized ratio (INR), initially in phenprocoumon and later in warfarin therapy. All efforts, including self-testing using Point of Care Testing with telemedicine support to stabilize the patient's INR within the therapeutic range, were unsuccessful. Since INR fluctuations can occur due to poor or varied dietary vitamin K, 180 µg/day vitamin K was added to the patient's warfarin treatment in an attempt to stabilize INR fluctuations. Three weeks later INR was in therapeutic range and remained within range for two consecutive months suggesting beneficial effect of vitamin K. Our updated literature review demonstrates that vitamin K supplementation can improve the stability of INR without improvement of time therapeutic range. .

Dysfibrinogenemia-Potential Impact of Genotype on Thrombosis or Bleeding.

The congenital dysfibrinogenemias, most often associated with bleeding disorders, encompass mutations in the amino-terminal end of fibrinogen α-chain consisting of Gly17-Pro18-Arg19-Val20, known as knob A, which is a critical site for fibrin polymerization. Here we review the studies reporting dysfibrinogenemia due to mutations affecting fibrinogen knob A and identified 29 papers. The number of reports on dysfibrinogenemias related to residues Gly17, Pro18, Arg19, and Val20 is 5, 4, 18, and 2, respectively. Dysfibrinogenemias related to residues Gly17, Pro18, and Val20 are exclusively associated with bleeding tendency. However, the clinical picture associated with dysfibrinogenemia related to residue Arg19 varies, with most patients suffering from bleeding tendencies, but also transitory ischemic attacks and retinal thrombosis may occur. The reason for this variation is unclear. To elaborate the genotype-phenotype associations further, we studied a Danish family with knob A-related dysfibrinogenemia caused by the Aα Arg19Gly (p.Arg19Gly) mutation using whole-exome sequencing and fibrin structure analysis. Our family is the first reported carrying the p.Arg19Gly mutation combined with one or more single nucleotide polymorphisms (SNP)s in FGA, FGB, and/or FGG and increased fibrin fiber thickness and fibrin mass-to-length ratio suffering from pulmonary emboli, suggesting that compound genotypes may contribute to the thrombogenic phenotype of these patients. Our review, accordingly, focuses on significance of SNPs, compound genotypes, and fibrin structure measures affecting the genotype-phenotype associations in fibrinogen knob A mutations.

Daily intake of 4 to 7 microg dietary vitamin B-12 is associated with steady concentrations of vitamin B-12-related biomarkers in a healthy young population.

BACKGROUND: Studies have questioned whether the current Recommended Dietary Allowance (RDA) of 2.4 microg vitamin B-12/d is adequate. OBJECTIVE: We examined the association between dietary vitamin B-12 intake and biomarkers of vitamin B-12 status. DESIGN: Dietary vitamin B-12 intake was estimated, and biomarkers of vitamin B-12 status were measured, in healthy men and women (n = 299; age range: 18-50 y) who were recruited from a Florida community. The National Cancer Institute Diet History Questionnaire was used. Plasma cobalamin, total transcobalamin, holo-transcobalamin, methylmalonic acid (MMA), total homocysteine (tHcy), and autoantibodies against intrinsic factor (IF) and Helicobacter pylori were analyzed in blood samples. RESULTS: Antibodies to H. pylori were detected in 12% of subjects (35/299), and negative results for IF antibodies were obtained for all subjects. The intake of vitamin B-12 correlated significantly with cobalamin, holo-transcobalamin, MMA, and tHcy. Subjects were divided into quintiles on the basis of their dietary vitamin B-12 intake (range: 0.42-22.7 microg/d), and biomarkers of vitamin B-12 status were plotted against estimated dietary vitamin B-12 intake. All biomarkers appeared to level off at a daily dietary vitamin B-12 intake between 4.2 and 7.0 microg. CONCLUSION: In persons with normal absorption, our data indicate that an intake of 4-7 microg vitamin B-12/d is associated with an adequate vitamin B-12 status, which suggests that the current RDA of 2.4 microg vitamin B-12/d might be inadequate for optimal biomarker status even in a healthy population between 18 and 50 y of age.

Assessment of vitamin B(12) absorption based on the accumulation of orally administered cyanocobalamin on transcobalamin.

BACKGROUND: Vitamin B(12), or cobalamin (Cbl), is absorbed in the intestine and transported to the cells bound to transcobalamin (TC). We hypothesize that cyanocobalamin (CNCbl) is absorbed unchanged, thereby allowing measurement of the complex of CNCbl bound to TC (TC-CNCbl) to be used for studying the absorption of the vitamin. METHODS: TC was immunoprecipitated from serum samples obtained from healthy donors at baseline and at 24 h after oral administration of three 9-microg CNCbl doses over 1 day. Cbl was released by treatment with subtilisin Carlsberg. The different forms of Cbl were isolated by HPLC and subsequently quantified with an ELISA-based Cbl assay. RESULTS: At baseline, the median TC-CNCbl concentration was 1 pmol/L (range, 0-10 pmol/L); the intraindividual variation (SD) was 1.6 pmol/L (n = 31). After CNCbl administration, the TC-CNCbl concentration increased significantly (P = 0.0003, paired t-test), whereas no major changes were observed in any of the other Cbl forms bound to TC (n = 10). Only a moderate additional increase in TC-CNCbl was observed with prolonged (5 days) CNCbl administration (n = 10). We designed an absorption test based on measuring TC-CNCbl at baseline and 24 h after CNCbl intake and established a reference interval for the increase in TC-CNCbl (n = 78). The median absolute increase was 23 pmol/L (range, 6-64 pmol/L), and the relative increase was >3-fold. CONCLUSIONS: Our data demonstrate that CNCbl is absorbed unchanged and accumulates on circulating TC. We suggest that measuring TC-CNCbl will improve the assessment of vitamin B(12) absorption.

Infrequency of low red blood cell (RBC) folate levels despite no folate fortification program: a study based on results from routine requests for RBC folate.

BACKGROUND: We investigated the prevalence of a low level of red blood cell (RBC) folate in individuals suspected to be deficient and further evaluated the clinical consequence of identifying an individual with a low folate level in a population where no fortification with folate has been introduced. METHODS: We conducted a retrospective review of all RBC folate analyses requested in one of the university hospitals in Denmark and identified patients with abnormally low (<350 nmol/L) and high (>1700nmol/L) folate levels. For requests from the hospital, we evaluated the clinicians' response to a decreased level of folate. RESULTS: A total of 12,932 RBC folates requested from the hospital (26%) or from general practitioners (GPs) (74%) were investigated. RBC folate levels were low in a comparable fraction of those requested from the hospital (1.7%) and from the GPs (1.3%). A high level of RBC folate was observed more often than a low RBC folate and occurred considerably more frequently (p<0.0001) in patients referred from the hospital (4.9%) than amongst those referred from GPs (1.2%). The clinicians' response rate to a low folate was around 60% and occurred more often for patients with a low level of cobalamins than in other patients. CONCLUSIONS: Low RBC folate values are rare in Danish patients despite no folate fortification program. Further, the clinical reaction to a low folate value is unexpectedly low.