Experimental Validation of Methods for Prophylaxis against Deep Venous Thrombosis: A Review and Proposal

The experimental procedure by which the valve cusp hypoxia (VCH) hypothesis of the etiology of deep venous thrombosis (DVT) was confirmed lends itself to testing of methods of prophylaxis. Similar animal experiments could end the present exclusive reliance on statistical analysis of data from large patient cohorts to evaluate prophylactic regimes. The reduction of need for such (usually retrospective) analyses could enable rationally-based clinical trials of prophylactic methods to be conducted more rapidly, and the success of such trials would lead to decreased incidences of DVT-related mortality and morbidity. This paper reviews the VCH hypothesis (“VCH thesis”, following its corroboration) and its implications for understanding DVT and its sequelae, and outlines the experimental protocol for testing prophylactic methods. The advantages and limitations of the protocol are briefly discussed

Diet as prophylaxis and treatment for venous thromboembolism?

<p>Abstract</p> <p>Background</p> <p>Both prophylaxis and treatment of venous thromboembolism (VTE: deep venous thrombosis (DVT) and pulmonary emboli (PE)) with anticoagulants are associated with significant risks of major and fatal hemorrhage. Anticoagulation treatment of VTE has been the standard of care in the USA since before 1962 when the U.S. Food and Drug Administration began requiring randomized controlled clinical trials (RCTs) showing efficacy, so efficacy trials were never required for FDA approval. In clinical trials of 'high VTE risk' surgical patients before the 1980s, anticoagulant prophylaxis was clearly beneficial (fatal pulmonary emboli (FPE) without anticoagulants = 0.99%, FPE with anticoagulants = 0.31%). However, observational studies and RCTs of 'high VTE risk' surgical patients from the 1980s until 2010 show that FPE deaths without anticoagulants are about one-fourth the rate that occurs during prophylaxis with anticoagulants (FPE without anticoagulants = 0.023%, FPE while receiving anticoagulant prophylaxis = 0.10%). Additionally, an FPE rate of about 0.012% (35/28,400) in patients receiving prophylactic anticoagulants can be attributed to 'rebound hypercoagulation' in the two months after stopping anticoagulants. Alternatives to anticoagulant prophylaxis should be explored.</p> <p>Methods and Findings</p> <p>The literature concerning dietary influences on VTE incidence was reviewed. Hypotheses concerning the etiology of VTE were critiqued in relationship to the rationale for dietary versus anticoagulant approaches to prophylaxis and treatment.</p> <p>Epidemiological evidence suggests that a diet with ample fruits and vegetables and little meat may substantially reduce the risk of VTE; vegetarian, vegan, or Mediterranean diets favorably affect serum markers of hemostasis and inflammation. The valve cusp hypoxia hypothesis of DVT/VTE etiology is consistent with the development of VTE being affected directly or indirectly by diet. However, it is less consistent with the rationale of using anticoagulants as VTE prophylaxis. For both prophylaxis and treatment of VTE, we propose RCTs comparing standard anticoagulation with low VTE risk diets, and we discuss the statistical considerations for an example of such a trial.</p> <p>Conclusions</p> <p>Because of (a) the risks of biochemical anticoagulation as anti-VTE prophylaxis or treatment, (b) the lack of placebo-controlled efficacy data supporting anticoagulant treatment of VTE, (c) dramatically reduced hospital-acquired FPE incidence in surgical patients without anticoagulant prophylaxis from 1980 - 2010 relative to the 1960s and 1970s, and (d) evidence that VTE incidence and outcomes may be influenced by diet, randomized controlled non-inferiority clinical trials are proposed to compare standard anticoagulant treatment with potentially low VTE risk diets. We call upon the U. S. National Institutes of Health and the U.K. National Institute for Health and Clinical Excellence to design and fund those trials.</p

Immunological assessment of SARS-CoV-2 infection in pregnancy from diagnosis to delivery: a multicentre prospective study

Background: Background Population-based data on SARS-CoV-2 infection in pregnancy and assessment of passive immunity to the neonate, is lacking. We profiled the maternal and fetal response using a combination of viral RNA from naso-pharyngeal swabs and serological assessment of antibodies against SARS-CoV-2.Methods: This multicentre prospective observational study was conducted between March 24th and August 31st 2020. Two independent cohorts were established, a symptomatic SARS-CoV-2 cohort and a cohort of asymptomatic pregnant women attending two of the largest maternity hospitals in Europe. Symptomatic women were invited to provide a serum sample to assess antibody responses. Asymptomatic pregnant women provided a nasopharyngeal swab and serum sample. RT-PCR for viral RNA was performed using the Cobas SARS-CoV-2 6800 platform (Roche). Umbilical cord bloods were obtained at delivery. Maternal and fetal serological response was measured using both the Elecsys® Anti-SARS-CoV-2 immunoassay (Roche), Abbott SARS-CoV-2 IgG Assay and the IgM Architect assay. Informed written consent was obtained from all participants.Results: Ten of twenty three symptomatic women had SARS-CoV-2 RNA detected on nasopharyngeal swabs. Five (5/23, 21.7%) demonstrated serological evidence of anti-SARS-CoV-2 IgG antibodies and seven (30.4%, 7/23) were positive for IgM antibodies. In the asymptomatic cohort, the prevalence of SARS-CoV-2 infection in RNA was 0.16% (1/608). IgG SARS-CoV-2 antibodies were detected in 1·67% (10/598, 95% CI 0·8%-3·1%) and IgM in 3·51% (21/598, 95% CI 2·3-5·5%). Nine women had repeat testing post the baseline test. Four (4/9, 44%) remained IgM positive and one remained IgG positive. 3 IgG anti-SARS-CoV-2 antibodies were detectable in cord bloods from babies born to five seropositive women who delivered during the study. The mean gestation at serological test was 34 weeks. The mean time between maternal serologic positivity and detection in umbilical cord samples was 28 days.Conclusion: Using two independent serological assays, we present a comprehensive illustration of the antibody response to SARS-CoV-2 in pregnancy, and show a low prevalence of asymptomatic SARS-CoV2. Transplacental migration of anti-SARS-CoV-2 antibodies was identified in cord blood of women who demonstrated antenatal anti-SARS-CoV-2 antibodies, raising the possibility of passive immunity.</p