COVID-19 vaccination in patients with immune thrombocytopenia.

Immune thrombocytopenia (ITP) is an acquired autoimmune disorder that is characterized by low platelet count and increased bleeding risk. COVID-19 vaccination has been described as a risk factor for de novo ITP, but the effects of COVID-19 vaccination in patients with ITP are unknown. We aimed to investigate the effects of COVID-19 vaccination in patients with ITP on platelet count, bleeding complications, and ITP exacerbation (≥50% decline in platelet count, or nadir platelet count < 30 × 109/L with a >20% decrease from baseline, or use of rescue therapy). Platelet counts in patients with ITP and healthy controls were collected immediately before and 1 and 4 weeks after the first and second vaccinations. Linear mixed-effects modeling was applied to analyze platelet counts over time. We included 218 patients with ITP (50.9% female; mean age, 55 years; and median platelet count, 106 × 109/L) and 200 healthy controls (60.0% female; mean age, 58 years; median platelet count, 256 × 109/L). Platelet counts decreased by 6.3% after vaccination. We did not observe any difference in decrease between the groups. Thirty patients with ITP (13.8%; 95% confidence interval [CI], 9.5-19.1) had an exacerbation and 5 (2.2%; 95% CI, 0.7-5.3) suffered from a bleeding event. Risk factors for ITP exacerbation were platelet count < 50 × 109/L (odds ratio [OR], 5.3; 95% CI, 2.1-13.7), ITP treatment at time of vaccination (OR, 3.4; 95% CI, 1.5-8.0), and age (OR, 0.96 per year; 95% CI, 0.94-0.99). Our study highlights the safety of COVID-19 vaccination in patients with ITP and the importance of the close monitoring of platelet counts in a subgroup of patients with ITP. Patients with ITP with exacerbation responded well on therapy.

Therapeutic plasma exchange for anticoagulant-refractory antiphospholipid syndrome with severe ischemic and necrotic skin lesions: A case series.

Antiphospholipid syndrome (APS) is a systemic autoimmune disease characterized by clinical findings including thrombosis and/or obstetric complication and laboratory findings, e.g. ≥1 positive antiphospholipid antibodies (aPL) (lupus anticoagulant, anticardiolipin IgG/IgM and/or anti-ß2-glycoprotein IgG/IgM). A rare APS clinical entity is severe necrosis which is difficult to treat and often does not respond to anticoagulant therapy. Three consecutive patients with primary or secondary APS who presented with necrotic skin lesions secondary to APS were treated with therapeutic plasma exchange (TPE), glucocorticoids and low-molecular-weight heparin. All patients had a rapid-onset, either full or significant recovery of their APS-related necrotic lesions. Upon treatment, one patients showed resolution of lupus anticoagulant. Two patients had a decrease of at least 88 % in aPL titers after the initial treatment, and were kept on TPE maintenance every 5-6 weeks. None of the patients experienced significant side effects of the TPE. This is the first case series showing the clinical benefits of TPE in patients with ischemic and necrotic skin lesions due to severe anticoagulant-refractory vascular APS.

Effect of antithrombotic stewardship on the efficacy and safety of antithrombotic therapy during and after hospitalization.

BACKGROUND: Although the benefits of antithrombotic drugs are indisputable to reduce thrombotic events, they carry a high risk of compromising patient safety. No previous studies investigated the implementation and (cost-) effectiveness of a hospital-based multidisciplinary antithrombotic team on bleeding and thrombotic outcomes. The primary aim of this study was to compare the proportion of patients with a composite end point consisting of one or more bleeding episodes or one or more thrombotic event from hospitalization until three months after hospitalization. METHODS AND FINDINGS: A prospective, multicenter before-after intervention study was conducted in two Dutch hospitals. Adult patients hospitalized between October 2015 and December 2017 treated with anticoagulant therapy were included. The primary aim was to estimate the proportion of patients with a composite end point consisting of one or more bleeding episodes or one or more thrombotic event from hospitalization until three months after hospitalization. The intervention was the implementation of a multidisciplinary antithrombotic team focusing on education, medication reviews by pharmacists, implementing of local anticoagulant therapy guidelines based on national guidelines, patient counselling and medication reconciliation at admission and discharge. The primary endpoint was analysed using segmented linear regression. We obtained data for 1,886 patients: 941 patients were included in the usual care period and 945 patients in the intervention period. The S-team study showed that implementation of a multidisciplinary antithrombotic team over time significantly reduced the composite end point consisting of one or more bleeding episodes or one or more thrombotic event from hospitalization until three months after hospitalization in patients using anticoagulant drugs (-1.83% (-2.58% to -1.08%) per 2 month period). CONCLUSIONS: This study shows that implementation of a multidisciplinary antithrombotic team over time significantly reduces the composite end point consisting of one or more bleeding episodes or one or more thrombotic event from hospitalization until three months after hospitalization in patients using anticoagulant drugs. TRIAL REGISTRATION: Trialregister.nl NTR4887.

Risk of bleeding in hospitalized patients on anticoagulant therapy: Prevalence and potential risk factors.

INTRODUCTION: Bleeding is the most important complication of treatment with anticoagulant therapy. Although several studies have identified risk factors of bleeding in outpatients, no studies have been performed that evaluated prevalence and potential risk factors of bleeding in hospitalized patients treated with anticoagulant therapy. METHODS: The primary objective of this study was to determine the prevalence of bleeding in anticoagulant users during hospitalization. The secondary objective was to identify potential risk factors of bleeding in hospitalized patients on anticoagulant therapy. A prospective, observational cohort study was conducted in two Dutch hospitals. Adult patients hospitalized between October 2015 and October 2016 treated with anticoagulant therapy were included. Bleeding was defined as a composite endpoint of major bleeding and non-major bleeding according to the International Society on Thrombosis and Heamostasis (ISTH) criteria. Data analysis was performed by multivariate logistic regression. RESULTS: The prevalence of in-hospital bleeding in patients using anticoagulant therapy was 7.2%; 95% confidence interval [95% CI] 5.5-9.1 (65 out of 906 patients). Multivariate logistic regression analysis indicated that female gender (adjusted odds ratio [ORadj] 2.1; 95% CI 1.2-3.7), high-bleeding-risk surgical procedure (ORadj 5.3; 95% CI 2.7-10.2), low-bleeding-risk surgical procedure (ORadj 4.9; 95% CI 1.9-12.6), and non-surgical interventions (ORadj 6.2; 95% CI 3.0-12.6) were associated with bleeding events in hospitalized patients treated with anticoagulants. CONCLUSIONS: The prevalence of bleeding in anticoagulant users during hospitalization was 7.2%. This study detected potential risk factors that can help to identify patients on anticoagulants who have an increased risk of bleeding during hospitalization.

Risk of Venous Thrombosis in Antithrombin Deficiency: A Systematic Review and Bayesian Meta-analysis.

Antithrombin deficiency is a strong risk factor for venous thromboembolism (VTE), but the absolute risk of the first and recurrent VTE is unclear. The objective of this paper is to establish the absolute risks of the first and recurrent VTE and mortality in individuals with antithrombin deficiency. The databases Embase, Medline Ovid, Web of Science, the Cochrane Library, and Google Scholar were systematically searched for case-control and cohort studies. Bayesian random-effects meta-analysis was used to calculate odds ratios (ORs), absolute risks, and probabilities of ORs being above thresholds. Thirty-five publications were included in the systematic review and meta-analysis. Based on 19 studies, OR estimates for the first VTE showed a strongly increased risk for antithrombin deficient individuals, OR 14.0; 95% credible interval (CrI), 5.5 to 29.0. Based on 10 studies, meta-analysis showed that the annual VTE risk was significantly higher in antithrombin-deficient than in non-antithrombin-deficient individuals: 1.2% (95% CrI, 0.8-1.7) versus 0.07% (95% CrI, 0.01-0.14). In prospective studies, the annual VTE risk in antithrombin deficient individuals was as high as 2.3%; 95% CrI, 0.2-6.5%. Data on antithrombin deficiency subtypes are very limited for reliable risk-differentiation. The OR for recurrent VTE based on 10 studies was 2.1; 95% CrI, 0.2 to 4.0. The annual recurrence risk without long-term anticoagulant therapy based on 4 studies was 8.8% (95% CrI, 4.6-14.1) for antithrombin-deficient and 4.3% (95% CrI, 1.5-7.9) for non-antithrombin-deficient VTE patients. The probability of the recurrence risk being higher in antithrombin-deficient patients was 95%. The authors conclude that antithrombin deficient individuals have a high annual VTE risk, and a high annual recurrence risk. Antithrombin deficient patients with VTE require long-term anticoagulant therapy.

Antithrombin levels are associated with the risk of first and recurrent arterial thromboembolism at a young age.

BACKGROUND AND AIMS: It is as yet unknown whether antithrombin levels are associated with arterial thromboembolism (ATE) at a young age. To investigate the association between antithrombin levels and premature and recurrent ATE, we performed a case-control study and a subsequent nested cohort study of premature coronary heart disease (CHD) patients. METHODS: In the case-control study, we included 571 patients who had a recent premature ATE, including CHD and ischemic stroke (IS), and 461 healthy controls. The association between antithrombin levels (dichotomized: ≤median vs. >median) and ATE was investigated. Subsequently we studied the association between antithrombin levels and recurrent cardiac events, ATE or death in a nested cohort of 323 CHD patients. RESULTS: Low antithrombin levels (≤median, 1.04 IU/mL) are associated with an increased risk of ATE (OR 1.46; 95% CI:1.09-1.96), after adjustment for classical cardiovascular risk factors. This was observed in the subgroups of CHD patients (1.43; 1.01-2.02) and IS patients (1.48; 1.01-2.19). CHD patients with low antithrombin levels had a higher risk of recurrent cardiac events (HR 2.16, 95% CI:1.07-4.38). Especially in women with low antithrombin levels, the risk of recurrent cardiac events was high (HR 5.97, 95% CI 1.31-27.13) as was the risk of recurrent ATE or death (HR 4.22, 95% CI 1.19-15.00). CONCLUSIONS: Individuals with relatively low antithrombin levels have an increased risk for ATE at a younger age. CHD patients with low antithrombin levels, especially women, have a higher risk of recurrent cardiac events.

Pregnancy, thrombophilia, and the risk of a first venous thrombosis: systematic review and bayesian meta-analysis.

Objective To provide evidence to support updated guidelines for the management of pregnant women with hereditary thrombophilia in order to reduce the risk of a first venous thromboembolism (VTE) in pregnancy.Design Systematic review and bayesian meta-analysis.Data sources Embase, Medline, Web of Science, Cochrane Library, and Google Scholar from inception through 14 November 2016.Review methods Observational studies that reported on pregnancies without the use of anticoagulants and the outcome of first VTE for women with thrombophilia were eligible for inclusion. VTE was considered established if it was confirmed by objective means, or when the patient had received a full course of a full dose anticoagulant treatment without objective testing. Results 36 studies were included in the meta-analysis. All thrombophilias increased the risk for pregnancy associated VTE (probabilities ≥91%). Regarding absolute risks of pregnancy associated VTE, high risk thrombophilias were antithrombin deficiency (antepartum: 7.3%, 95% credible interval 1.8% to 15.6%; post partum: 11.1%, 3.7% to 21.0%), protein C deficiency (antepartum: 3.2%, 0.6% to 8.2%; post partum: 5.4%, 0.9% to 13.8%), protein S deficiency (antepartum: 0.9%, 0.0% to 3.7%; post partum: 4.2%; 0.7% to 9.4%), and homozygous factor V Leiden (antepartum: 2.8%, 0.0% to 8.6%; post partum: 2.8%, 0.0% to 8.8%). Absolute combined antepartum and postpartum risks for women with heterozygous factor V Leiden, heterozygous prothrombin G20210A mutations, or compound heterozygous factor V Leiden and prothrombin G20210A mutations were all below 3%. Conclusions Women with antithrombin, protein C, or protein S deficiency or with homozygous factor V Leiden should be considered for antepartum or postpartum thrombosis prophylaxis, or both. Women with heterozygous factor V Leiden, heterozygous prothrombin G20210A mutation, or compound heterozygous factor V Leiden and prothrombin G20210A mutation should generally not be prescribed thrombosis prophylaxis on the basis of thrombophilia and family history alone. These data should be considered in future guidelines on pregnancy associated VTE risk.

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.

[AL amyloidosis-associated factor X deficiency]. / Factor X-deficiëntie bij AL-amyloïdose.

BACKGROUND: An acquired bleeding tendency is a specific symptom that can indicate an underlying disease. CASE DESCRIPTION: Here we describe a 69-year-old patient with an acquired bleeding tendency resulting from a factor X deficiency due to an underlying amyloid light-chain (AL) amyloidosis. Factor X deficiency in AL amyloidosis arises from a quantitative and qualitative deficiency of factor X because it binds to amyloid fibrils exposed to circulating blood. CONCLUSION: Bleeding tendency is a rare complication of AL amyloidosis, often resulting from a factor X deficiency.