Journal of Thrombosis and Haemostasis最新文献

Ischemic stroke is a common cause of morbidity and mortality worldwide. The majority of affected individuals are older, with clear cardiovascular or embolic risk factors; however, up to a fifth of cases may occur in patients under the age of 50 years. In this review, we discuss some common hematological causes of ischemic stroke in this age range, with a focus on antiphospholipid syndrome, myeloproliferative neoplasms, immune thrombocytopenic purpura, and sickle cell disease. We review the etiology of stroke associated with these conditions and explore important management considerations that may be unique to these settings. These include the choice of antithrombotic agents, cytoreduction in myeloproliferative neoplasms, management of thrombocytopenia in immune thrombocytopenic purpura, and treatment of sickle cell disease.

Background: Although P5 (preventive, personalized, predictive, participatory, psychocognitive) medicine and patient-focused healthcare are gaining ground in various healthcare areas, the diagnosis of antithrombin deficiency (ATD) is still based on crude diagnostic tests, clustering patients into clinically heterogeneous subgroups whereby relevant thrombophilia phenotypes may go unnoticed. Clinical pathways and the majority of evidence are based on these tests; therefore, generic treatment is still the norm.

Objectives: To unravel the heterogeneity of ATD, a mass spectrometry (liquid chromatography coupled to multiple-reaction-monitoring mass spectrometry [LC-MRM-MS])-based test for antithrombin was developed allowing molecular characterization of the antithrombin proteoforms in patient plasma. This study provides the first insight into the tests' clinical performance.

Methods: Plasma from 91 unrelated ATD patients and 41 patients with a congenital disorder of glycosylation affecting antithrombin glycosylation were characterized functionally, genetically, and analyzed by LC-MRM-MS. An established data analysis strategy was applied for quantitation and molecular characterization of antithrombin proteoforms.

Results: The test recognized patients with a quantitative defect, discriminated between type I and type II ATD, and identified variant proteoforms. Overall, the diagnostic sensitivity for ATD was 100% for LC-MRM-MS compared with 81.1% by the functional test. Type II ATD, a subtype prone to misdiagnosis, revealed an even larger difference of 100% identification by LC-MRM-MS vs 56.8% by functional test.

Conclusion: The qualitative and quantitative mass spectrometry-based AT-test can serve as a platform for investigating the molecular basis of the clinical heterogeneity of ATD. This "precision diagnostics" approach for ATD can lower diagnostic uncertainty and modernize the ATD diagnostic and clinical pathways.

Background: Therapeutic plasma exchange (TPE) is the primary intervention for treating symptomatic hyperviscosity from hypergammaglobulinemia, yet its efficacy for treating hyperviscosity related to hyperfibrinogenemia is unclear.

Objective: Define the safety and efficacy of TPE for critically ill COVID-19 patients with elevated blood viscosity from hyperfibrinogenemia.

Method: A prospective, randomized controlled trial in critically ill COVID-19 patients at a single US healthcare system. Patients with hyperfibrinogenemia (>800 mg/dL) or elevated plasma viscosity (2.3-3.5 cP) were randomized to receive TPE on two consecutive days or continued standard of care (SOC).

Results: Twenty participants were enrolled, with 10 receiving TPE and 10 receiving SOC alone. Mean (± SEM) plasma viscosity decreased significantly from 2.35cP (±0.12) to 1.61cP (±0.03) in the TPE group and was unchanged in the SOC group (2.47cP (±0.11) to 2.47cP (±0.15). Mean fibrinogen decreased from 934.0mg/dL (±25.1) to 359.1mg/dL (±22.5) after TPE, versus from 859.6mg/dL (±57.6) to 807.3mg/dL (±63.1) in SOC. There was no significant difference in 28-day all-cause mortality between groups, with 2 deaths in the TPE cohort and 5 deaths in the SOC cohort (p=0.13). No serious safety events related to TPE were reported. TPE significantly decreased biomarkers of inflammation (ESR, CRP) and endothelial activation (vWF, FVIII), but not hemostatic activation (PF1.2, TAT, FM) or immunoglobulin (IgG, IgM) levels.

Conclusion: TPE is safe and effective for normalizing elevated blood viscosity from hyperfibrinogenemia in COVID-19 patients. Additional studies are needed to determine the impact of TPE on overall patient outcomes, including in those with non-COVID conditions associated with hyperfibrinogenemia.

Objectives: Study aims were to assess the impact of co-incident lower extremity (LE) deep vein thrombosis (DVT) on clinical outcomes of pulmonary embolism (PE) including venous thromboembolism (VTE) recurrence and mortality.

Methods: Consecutive patients with confirmed acute symptomatic or incidental PE (March 1, 2013 - June 30, 2021) who underwent ultrasound imaging were divided into two groups depending on the presence or absence of LE DVT. Patients were followed prospectively for VTE recurrence, bleeding, and all-cause mortality.

Results: Over the study period, 1,907 patients with PE were stratified into groups based on the presence (n=920) or absence (n=987) of LE DVT. Patients with co-incident LE DVT were older, heavier, and had a significantly greater frequency of trauma, confinement, thrombophilia, and VTE. Those without LE DVT had a higher prevalence of active cancer, metastatic disease, and active systemic therapy use. All-cause mortality rates (per 100 person-years) were significantly higher for patients without vs. with co-incident LE DVT (42.4/100 person-years vs 29.6/100 person- years; p<0.001) with no differences in VTE recurrence or bleeding outcomes. After stratification by cancer status, mortality in those without vs. with co-incident DVT only remained significant among noncancer patients (15.2/100 person-years vs 12.1/100 person-years, p=0.046).

Conclusions: Among patients with acute PE and within the limitations introduced by known variability in the sub-population of asymptomatic PE, the absence of co-incident lower extremity DVT is associated with significantly higher mortality rates. Mortality rate differences were only observed for those without cancer. No differences in VTE recurrence or bleeding were observed.

Background: Atrial fibrillation (AF) is a major risk factor for ischemic stroke. Whether prothrombotic single nucleotide polymorphisms (SNPs) impact stroke risk in AF is not well known.

Objectives: To investigate the joint effects of five prothrombotic SNPs and AF on ischemic stroke risk.

Methods: A sub-cohort (n=14,583) was randomly sampled from the Tromsø (1994-2012) and the Trøndelag Health (HUNT) (1995-2008) studies. DNA was genotyped for rs8176719 (ABO blood type), rs6025 (Factor V Leiden; FVL), rs1799963 (prothrombin G20210A), rs2066865 (fibrinogen-γ; FGG) and rs2036914 (Factor 11; F11). Hazard ratios (HR) with 95% confidence intervals (CI) for incident ischemic stroke were estimated by AF status for individual SNPs and by categories of a genetic risk score (GRS).

Results: 1091 participants developed AF during follow-up, of whom 169 (15.5%) subsequently had a stroke. Having ≥ 1 risk allele in prothrombin, FVL, F11 or FGG was not associated with excess stroke risk in AF. In the absence of AF, ≥ 1 risk allele(s) in ABO was not associated with stroke (HR 1.03, 95% CI 0.85-1.25), whereas those with AF and ≥ 1 risk allele(s) in ABO had a 1.4-fold increased stroke risk compared to those with AF and no risk allele (HR 1.42, 95% CI 0.99-2.04). There was no linear increase in stroke risk across categories of the GRS in participants either with or without AF.

Conclusions: Most prothrombotic SNPs were not associated with ischemic stroke risk, regardless of AF status. The ABO SNP was associated with ischemic stroke risk in those with AF only.

Background: A unique form of Hemophilia B (HB) is HB Leyden. We evaluated the International PedNet Registry database to explore the natural history of HB Leyden, investigate genotype-phenotype associations and guide clinical decision-making.

Objectives: To assess the association between genetic variants, endogenous factor (FIX) levels over time, treatment and bleeding phenotype in children with HB Leyden.

Patients and methods: Data on genetic variants, FIX levels at diagnosis and over time, bleeding and treatment details, were extracted from the PedNet Registry in children with hemophilia born since 2000.

Results: Of 457 individuals with HB, 24 showed a HB Leyden genotype. The most frequent F9 variant was c.-35G>A affecting 14 individuals, followed by c.-35G>C (n=4), c.-49T>A (n=2), and c.-52C>T, c.-34A>G and c.-22delT (n=1 each). Major clinical differences in bleeding and treatment modality were observed comparing c.-35G>A to non-c.-35G>A genotypes: For all children with a c.-35G>A genotype, FIX levels increased before the age of 4 years , but did not normalize over time, irrespective of initial severity. In children with non-c.-35G>A genotypes, increase in FIX was less common (4/9) and occurred later.

Conclusions: HB Leyden is caused by the variant c.-35G>A in >50% of cases, in whom a FIX increase occurs at very young ages, associated with low bleeding rates. This contrasts to the phenotype of individuals with HB Leyden due to a non-c.-35G>A variant. Our study may thus help guide clinical decision-making in this rare HB entity.

Platelets have important roles in hemostasis, but also actively participate in cancer metastasis and inflammatory processes. They are produced by large precursor cells, the megakaryocytes, residing mainly in the bone marrow. Clinically, elevated platelet counts and/or increased platelet to lymphocyte ratio are being explored as biomarkers of metastatic disease, and to predict survival or response to therapy in certain cancers. Multiple mechanisms have been put forward on how platelets promote hematogenous metastasis stemming mainly from murine experimental models. Research is now beginning to explore potential roles of megakaryocytes in solid cancer, myeloma, and lymphoma. Here, we review mechanisms on how platelets and megakaryocytes contribute to cancer progression and metastasis, but also discuss potential cancer suppressing functions mainly related to the regulation of vascular intratumor integrity. Recent developments in cancer immune checkpoint therapy are reviewed with a focus on potential roles of platelets. Moreover, we review studies exploring platelets for targeted drug delivery systems in cancer therapy.

Background: Immunoglobulin G antibodies (Abs) to platelet factor 4 (PF4) complexed to heparin (PF4/H) commonly occur after H exposure but cause life-threatening complications of H-induced thrombocytopenia (HIT) in only a few patients. Presently, only platelet activation assays reliably distinguish anti-PF4/H Abs that cause disease (HIT Abs) from those likely to be asymptomatic (AAbs).

Objectives: Recent studies indicate that complement activation is an important serologic property of HIT Abs and is essential for IgG Fc receptor IIA-mediated cellular activation. As platelet activation by HIT Abs also relies on IgG Fc receptor IIA activation, we correlated the complement- and platelet-activating properties of anti-PF4/H Abs in a clinically annotated patient cohort.

Methods: Clinical and laboratory features of patients with HIT (n = 8) and AAbs+ (n = 14) were correlated with properties of complement, platelet, and monocyte/neutrophil activation.

Results: Expected clinical and laboratory differences were seen between HIT and AAb+ patients, with HIT patients having lower mean platelet counts, greater percentage drop in platelet counts, higher 4T and HIT expert probability scores, higher anti-PF4 polyclonal and immunoglobulin G Ab levels, and serotonin release assay positivity. Ex vivo assays revealed significant differences in complement activation by HIT vs AAb+ patients, with the extent of complement activation closely correlated with percent serotonin release by anti-PF4/H Abs and matrix metalloproteinase-9 and interleukin-8 release in whole blood.

Conclusion: These findings suggest that complement activation strongly correlates with cellular activation endpoints, including platelet and monocyte/neutrophil activation, and if confirmed in a larger prospective study, may serve as a "functional" biomarker for pathogenic HIT Abs.

Background: Arterial thrombosis is increasingly recognized in children and is most commonly related to the presence of an arterial catheter. Diagnosis and treatment of arterial thrombosis in children varies widely and consists of commonly available anticoagulants and antiplatelet drugs. No evidence-based guidelines exist for management strategies of catheter related arterial thrombosis (CAT).

Objectives: To understand pediatric hematologist's current practices and opinions in the management of CAT in children and neonates.

Methods: A multinational survey on diagnostic and management practices from experts and practitioners in the field was conducted by means of a questionnaire with general questions and specific clinical CAT scenarios in regard to umbilical arterial catheters, extremity indwelling arterial catheters and cardiac catheterization.

Results: Of 54 complete survey responses, there was agreement that doppler ultrasound is the preferred diagnostic modality to identify CAT, unfractionated heparin and low molecular weight heparin are the preferred antithrombotic treatments while thrombolysis/thrombectomy is used in life-/limb-threatening CAT, long-term follow-up is necessary to detect adverse outcomes, and generally no thrombophilia testing is indicated. There was considerable heterogeneity in treatment indications on when to start antithrombotic treatment, treatment duration, timepoint of catheter removal, and length of follow-up.

Conclusion: These results highlight some congruency, but also considerable heterogeneity, in management practices of CAT. Based on these findings, an international guidance document is necessary to harmonize management practices and to further clinical investigations in CAT.