Risk of thrombosis with thrombocytopenia syndrome after COVID-19 vaccination prior to the recognition of vaccine-induced thrombocytopenia and thrombosis: A self-controlled case series study in England.

Background: Several studies have found increased risks of thrombosis with thrombocytopenia syndrome (TTS) following the ChAdOx1 vaccination. However, case ascertainment is often incomplete in large electronic health record (EHR)-based studies. Objectives: To assess for an association between clinically validated TTS and COVID-19 vaccination. Methods: We used the self-controlled case series method to assess the risks of clinically validated acute TTS after a first COVID-19 vaccine dose (BNT162b2 or ChAdOx1) or severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection. Case ascertainment was performed uninformed of vaccination status via a retrospective clinical review of hospital EHR systems, including active ascertainment of thrombocytopenia. Results: One hundred seventy individuals were admitted to the hospital for a TTS event at the study sites between January 1 and March 31, 2021. A significant increased risk (relative incidence [RI], 5.67; 95% confidence interval [CI], 1.02-31.38) of TTS 4 to 27 days after ChAdOx1 was observed in the youngest age group (18- to 39-year-olds). No other period had a significant increase, although for ChAdOx1 for all ages combined the RI was >1 in the 4- to 27- and 28- to 41-day periods (RI, 1.52; 95% CI, 0.88-2.63; and (RI, 1.70; 95% CI, 0.73-3.8, respectively). There was no significant increased risk of TTS after BNT162b2 in any period. Increased risks of TTS following a positive SARS-CoV-2 test occurred across all age groups and exposure periods. Conclusions: We demonstrate an increased risk of TTS in the 4 to 27 days following COVID-19 vaccination, particularly for ChAdOx1. These risks were lower than following SARS-CoV-2 infection. An alternative vaccine may be preferable in younger age groups in whom the risk of postvaccine TTS is greatest.

DOACs for stroke prevention in patients with AF and cancer.

Stroke prophylaxis in atrial fibrillation is an important consideration in patients with cancer. However, there is little consensus on the choice of anticoagulation, due to the numerous difficulties associated with active cancer. Direct oral anticoagulants (DOACs) have been shown to be a promising option. Here, we conduct a simple cross-sectional analysis of 29 cancer patients receiving DOACs for stroke prophylaxis in atrial fibrillation at a tertiary-care institution in London. Our study demonstrates an encouraging efficacy and safety profile of DOACs used in this setting. We conclude by suggesting that, while DOACs may be useful, anticoagulation in cancer patients should continue to be individualised.

Preventing strokes in people with atrial fibrillation by improving ABC.

Nationally, anticoagulation for atrial fibrillation (AF) is improving but remains characterised by marked provider variation. Uncontrolled blood pressure and coronary artery disease further increase cardiovascular risk. Redbridge Clinical Commissioning Group (CCG) and local National Health Service (NHS) hospital trusts supported a programme to improve anticoagulation, blood pressure and cholesterol management; the ABC of AF improvement. The programme was delivered by a clinical pharmacist in 43 general practices, who used Active Patient Link (APL-AF) software to identify and electronically review the records of AF patients potentially suitable for anticoagulation. These patients were invited for a general practitioner (GP)-pharmacist consultation with initiation of anticoagulation where appropriate. Blood pressure and lipid treatment were also optimised. The university-based Clinical Effectiveness Group (CEG) provided software support using standard data entry templates from which the APL-AF software was enabled. This identified suitable patients (eg, on aspirin monotherapy, no treatment or inappropriate dual treatments) for clinical and treatment review. It also reported real-time overall practice performance. Additionally, GP education on direct oral anticoagulant initiation in general practices, use of software and performance reviews, took place for all practices in Redbridge. A weekly multidisciplinary team (MDT) video conference discussed complex patients with a cardiologist, haematologist, GP with specialist interest in cardiology, GP coordinator and clinical pharmacist. This enabled sharing of patient records between GPs and hospital specialists with improved communication and learning. Over 1 year 2016-2017, anticoagulation in eligible AF patients (CHA2DS2-VASc≥2) increased significantly by 6.3% from 77.0% to 83.3% (p<0.0001), in comparison to 2.8% average improvement in England. Exception reporting was also significantly reduced from 10.0% to 5.8%; a reduction of 4.2% in comparison to a reduction in England of 1.5%. Use of antiplatelet monotherapy was approximately halved, from 12.3% to 6.4%. These methods are being scaled locally in other London CCGs and are potentially scalable nationally, specifically targeting the poorer performing CCGs.

Patient safety and estimation of renal function in patients prescribed new oral anticoagulants for stroke prevention in atrial fibrillation: a cross-sectional study.

OBJECTIVE: In clinical trials of dabigatran and rivaroxaban for stroke prevention in atrial fibrillation (AF), drug eligibility and dosing were determined using the Cockcroft-Gault equation to estimate creatine clearance as a measure of renal function. This cross-sectional study aimed to compare whether using estimated glomerular filtration rate (eGFR) by the widely available and widely used Modified Diet in Renal Disease (MDRD) equation would alter prescribing or dosing of the renally excreted new oral anticoagulants. PARTICIPANTS: Of 4712 patients with known AF within a general practitioner-registered population of 930 079 in east London, data were available enabling renal function to be calculated by both Cockcroft-Gault and MDRD methods in 4120 (87.4%). RESULTS: Of 4120 patients, 2706 were <80 years and 1414 were ≥80 years of age. Among those ≥80 years, 14.9% were ineligible for dabigatran according to Cockcroft-Gault equation but would have been judged eligible applying MDRD method. For those <80 years, 0.8% would have been incorrectly judged eligible for dabigatran and 5.3% would have received too high a dose. For rivaroxaban, 0.3% would have been incorrectly judged eligible for treatment and 13.5% would have received too high a dose. CONCLUSIONS: Were the MDRD-derived eGFR to be used instead of Cockcroft-Gault in prescribing these new agents, many elderly patients with AF would either incorrectly become eligible for them or would receive too high a dose. Safety has not been established using the MDRD equation, a concern since the risk of major bleeding would be increased in patients with unsuspected renal impairment. Given the potentially widespread use of these agents, particularly in primary care, regulatory authorities and drug companies should alert UK doctors of the need to use the Cockcroft-Gault formula to calculate eligibility for and dosing of the new oral anticoagulants in elderly patients with AF and not rely on the MDRD-derived eGFR.

Cumulative flying time and risk of venous thromboembolism.

The risk of venous thromboembolism (VTE) associated with cumulative flying time remains uncertain. In a case-control study in general practices throughout the UK, participants comprised 550 VTE cases identified from practice records and 1971 age- and gender-matched controls. Participants returned identical questionnaires asking for information including air travel details. Compared to not flying, cumulative flying time >12 h within the previous 4 weeks was associated with a threefold increase in the risk of VTE [odds ratio (OR) 2·75, 95% confidence interval (CI), 1·44-5·28]. Those who had flown >4 h in a single leg in the previous 4 weeks had twice the risk of VTE (OR 2·20, 95% CI, 1·29-3·73). These risks were no longer evident by 12 weeks and were similar to those of day-case or minor surgery (OR 5·35, 95% CI, 2·15-13·33). Equivalent risks for moderate and high-risk surgery were over 30-fold (OR 36·57, 95% CI, 13·05-102·52) and 140-fold (OR 141·71, 95% CI, 19·38-1036·01) respectively. The temporary nature of the association of cumulative and long-haul air travel with VTE suggests a causal relationship. The risks of VTE in those with a higher baseline risk due to surgery, previous VTE or obesity are further increased by air travel.

Airway and systemic inflammation and decline in lung function in patients with COPD.

STUDY OBJECTIVES: Patients with COPD experience lower airway and systemic inflammation, and an accelerated decline in FEV1. There is no evidence on whether this inflammation changes over time, or if it is associated with a faster decline in FEV1. PATIENTS AND DESIGN: A cohort of 148 COPD patients (100 men) was monitored daily for a median of 2.91 years (interquartile range [IQR], 2.1 to 4.8). At recruitment, median age was 68.5 years (IQR, 62.5 to 73.6) and FEV1 as percentage of predicted (FEV1%Pred) was 38.5% (IQR, 27.7 to 50.3). RESULTS: During the study, the patients experienced 1,389 exacerbations, a median of 2.52/yr (IQR, 1.48 to 3.96) and FEV1 declined by 40.2 mL/yr or as FEV1%Pred by 1.5%/yr. Concerning inflammatory markers, sputum interleukin (IL)-6 rose by 9 pg/mL/yr, sputum neutrophil count rose by 1.64 x 10(6) cells per gram sputum per year, an plasma fibrinogen rose by 0.10 g/L/yr (all p < 0.05). Patients with frequent exacerbations (> or = 2.52/yr) had a faster rise over time in plasma fibrinogen and sputum IL-6 of 0.063 g/L/yr (p = 0.046, n = 130) and 29.5 pg/mL/yr (p < 0.001, n = 98), respectively, compared to patients with infrequent exacerbations (< 2.52/yr). Using the earliest stable (nonexacerbation) measured marker, patients whose IL-6 exceeded the group median had a faster FEV1%Pred decline of 0.42%/yr (p = 0.018). Similarly, a high neutrophil count or fibrinogen were associated with a faster FEV1%Pred decline of 0.97%/yr (p = 0.001) and 0.40%/yr (p = 0.014), respectively. CONCLUSIONS: In COPD, airway and systemic inflammatory markers increase over time; high levels of these markers are associated with a faster decline in lung function.

Airway and systemic inflammation and decline in lung function in patients with COPD

Study objective: Patients with COPD experience lower airway and systemic inflammation, and an accelerated decline in FEV. There is no evidence on whether this inflammation changes over time, or if it is associated with a faster decline FEV. Patient and design: a cohort of 148 COPD patients (100 men) was monitored daily for a median 2.9 years (interquartile range [IQR], 2.1 to 4.8). At recruitment median age was 68.5 years (IQR, 62.5 to 73.6) and FEV as percentage of predicted (FEV percent Pred) was 38.5 percent (IQR, 27.7 to 50.3). Results: During the study, the patients experienced 1,389 exacerbations, a median of 2.52/yr (IQR 1.48 to 3.96) and FEV declined by 40.2 mL/yr or as FEV percent Pred by 1.5 percent/yr. Concerning inflammatory markers, sputum interlukin (IL)-6 rose by 9 pg/mL, sputum neutrophil count rose by 1.64 x 10,000,000 cells per gram sputum per year, and plasma fibrinogen rose by 0.10 g/L/yr (all p, 0.05). Patients with frequent exacerbations (less than or equal to 2.52/yr) had a faster rise over time in plasma fibrinogen and sputum IL-6 of 0.063 g/L/yr (p= 0.046, n= 130) and 29.5 pg/mL/yr (p< 0.001, n=98), respectively, compared to patients with infrequent exacerbations (<2.52/yr). Using the earliest stable (nonexacerbation) measured marker, patients whose IL-6 exceeded the group median had a faster FEV percentPred decline of 0.97 percent/yr (p=0.001 and .40 percent/yr (p=0.014). respectively. Conclusions: In COPD, airway and systemic inflammatory markers increase over time; high levels of these markers are associated with a faster decline in lung function (AU)

Markers of hemostasis and systemic inflammation in heart disease and atherosclerosis in smokers.

Smoking is a major cause of both chronic obstructive pulmonary disease (COPD) and coronary heart disease, the latter being more common in individuals with COPD. Acute coronary events are usually caused by the development of a platelet-rich thrombus associated with atheromatous plaque rupture or erosion. Levels of systemic biomarkers of inflammation and hemostasis may reflect the presence of atherosclerosis and predisposition to thrombosis, and may allow identification of "vulnerable plaque" and "vulnerable blood" in "vulnerable patients." Hemostasis and inflammation, often viewed as separate processes, are integrated closely, and their response to smoking likely has contributed to the current coronary heart disease epidemic. Coagulation is initiated after exposure of blood to tissue factor present in atheromatous plaques. Fibrinogen and other hemostatic factors important in thrombus formation are influenced by inflammatory stimuli, possibly reflecting both vascular and systemic inflammation. Smokers who develop COPD may have higher basal levels of inflammatory markers, such as fibrinogen, due to lung damage, and respiratory infections to which they are prone may further increase levels, predisposing smokers to coronary events. In summary, smoking predisposes to coronary heart disease and the mechanisms may involve proinflammatory and procoagulant changes. These changes may be more marked in smokers with COPD.

Low-intensity warfarin reduces thrombin generation and fibrin turnover, but not low-grade inflammation, in men at risk of myocardial infarction.

In the Thrombosis Prevention Trial (TPT), low-intensity warfarin reduced the risk of first coronary events only when the achieved international normalized ratio (INR) was > or =1.4. To validate the likely mechanism of action of low-intensity warfarin we measured its effects on plasma markers of thrombin generation, fibrin turnover and low-grade inflammation in TPT participants. D-dimer and prothrombin fragment F1.2 levels were lower at INRs > or =1.4 (P = 0.02 and 0.03 respectively); levels fell as INR increased (P for trend 0.04 and 0.002 respectively). C-reactive protein did not vary with INR. The efficacy of warfarin is related to reductions in thrombin generation and fibrin turnover.

Associations of haemostatic variables with body mass index: a community-based study.

Obesity is a risk factor for venous and arterial thrombosis. We examined relationships between body mass index (BMI) and a number of haemostatic and inflammatory variables in a community-based study of 150 adults (73 male, 77 female; age range, 23-80 years). Associations with BMI were sought after adjustment for age, smoking and diurnal variation. There were significant interactions of gender on the associations of BMI with fibrinogen (P = 0.002) and C-reactive protein (P = 0.02). In women, there were strong positive associations of BMI with fibrinogen (r = 0.57, P < 0.0001) and C-reactive protein (r = 0.40, P = 0.001). In men, these associations were non-significantly inverse. For all other variables there were no sex differences, so results for men and women were combined. Significant positive associations with BMI were seen for factor VIIc, activated factor XII, antithrombin activity, protein C activity and plasminogen activator inhibitor-1 activity. Inverse associations with BMI were seen for tissue plasminogen activator activity and activated protein C ratio. Increasing BMI is associated with elevation of certain coagulation factors, inhibitors of fibrinolysis, and inhibitors of coagulation, the latter potentially reflecting a compensatory response. Gender influences the association of certain inflammatory variables with BMI so the sexes should be considered separately in studies of inflammation and obesity.

Molecular cloning of a constitutional t(7;22) translocation associated with risk of hematological malignancy.

We report the molecular characterization of a reciprocal constitutional translocation t(7;22)(p13;q11.2) carried by three family members who have each developed a hematological malignancy. The chromosome 7 breakpoint was localized to a single BAC clone, RP11-571N3, by sequential fluorescence in situ hybridization analysis of clones selected from the NCBI chromosome 7 map. This was further refined to a 739-bp region by Southern blot analysis of DNA from the two cell lines 1193 and 1194 digested with EcoRI, HindIII, PstI, and PvuII. A 2.8-kb fragment spanning the der(22) breakpoint was amplified by long-range inverse PCR. The sequence of this fragment was used to predict the composition of the der(7) breakpoint, and a 1.3-kb fragment was amplified by use of primers from both chromosomes 7 and 22 based on this prediction. The breakpoint on chromosome 22 is located between the 3rd and 4th V regions of the immunoglobulin lambda (IGL) locus, and the breakpoint on chromosome 7 is located 122 kb proximal to the insulin-like growth factor binding protein (IGFBP) 3 gene. Examination of both reciprocal junctions showed that four bases were lost from chromosome 22, whereas 75 bases were lost from chromosome 7. Small insertions of 46 bases and 13 bases were found at the der(22) and the der(7) junctions, respectively. As a consequence of this event, the entire IGL locus, less the first three Vlambda elements, is translocated to chromosome 7, whereas the three remaining Vlambda elements on the der(22) are juxtaposed with IGFBP3 and IGFBP1.

Size at birth and carotid atherosclerosis in later life.

Several studies have shown that low birthweight is associated with a higher risk of stroke and coronary heart disease in later life. Increased atherogenesis may be one underlying mechanism, but few studies have examined this directly. We used duplex ultrasonography to assess the extra-cranial carotid arteries of 389 elderly men and women born and still living in Sheffield, UK, whose recorded birth measurements were available. Men and women who had weighed 6.5 lbs or less at birth had a higher risk of having carotid stenosis >30% than those who weighed over 7.5 lbs, but this trend was not statistically significant (OR 1.8, 95% CI 1.0-3.3). Women who had been lighter or who had a smaller head circumference at birth tended to have an increased intima-media thickness, but these relations ceased to be statistically significant after adjustment for gestational age and cardiovascular risk factors. In men, by contrast, an increased intima-media thickness was associated with having been heavier at birth (P=0.049) or having had a larger abdominal circumference at birth (P=0.040), after adjustment for gestational age and cardiovascular risk factors. These results provide little evidence that impaired fetal growth increases susceptibility to atherogenesis.