COVID: thrombi, inflammation, bradykinin, vitamin D...

 sorry, this blog is a bit long, but i wanted to bring in several different studies since it seems there is a large constellation of events triggered by the SARS-CoV-2 virus, and it seems important to look at a bigger picture than what is presented in individual studies with individual treatments.

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a small study documented diffuse immunothrombotic dysregulation and coagulopathy associated with Covid-19 pneumonia (see covid microthrombi immunodysregulation circ2020 in dropbox, or doi.org/10.1161/CIRCULATIONAHA.120.048488 )

 

Details: 

--38 patients with PCR-documented Covid-19, and 24 non-Covid controls 

    --Covid group: 18 severe cases, requiring intubation and ICU treatment; 20 had intermediate severity, requiring at most non-invasive supplemental oxygen 

--one patient died, age 91, declining intensive care treatment, and had an autopsy; 4 additional patients had lung specimens, and 5 died from cardiovascular causes without lung involvement 

--this was a complex study assessing many markers of thrombotic and immune function, as well as their combination. See the original article for the full analysis 

Results: 

--autopsied patient: developed progressive respiratory failure (decreasing oxygenation), cardiac injury without EKG changes (high-sensitive troponin T 0.798 pg/ml [normal <0.014]), kidney failure, dysregulated coagulation (D-dimer 3900 ng/ml) 

    --tissue eval: microvascular clots in the lung without pulmonary embolism (similar to findings in SARS cases in 2003) containing large numbers of neutrophils as well as platelets and fibrin (these findings were confirmed in 4 other fatal Covid-19 cases), and microthrombi were found in renal and cardiac microvessels as well.  overall, about 50% of the vessels in the Covid-19 patients (vs none in controls) had immunothromboses

--neutrophil dynamics:

    -- severe vs intermediate group of cases of Covid-19:  

        -- higher peripheral neutrophil counts, correlating with the degree of lung injury as assessed by oxygenation 

        -- higher CD177, a neutrophil activation marker, correlating significantly with pulmonary disease severity 

            -- peripheral neutrophils in those with severe Covid showed increased activation in the circulation as compared to controls, though there was a hyporeactive phenotype in those with intermediate disease

    -- there was a linear relationship between the formation of circulating platelet-neutrophil-aggregates (a key element in immunothrombosis) with pulmonary disease severity

-- platelet dynamics: Thrombocytopenia is more common in more severe cases (?platelet consumption), though thrombocytosis was present in the majority as the clinical condition deteriorated (likely as a response to IL-6 surges) 

    -- through assessment of antibody-based surface markers, they found that platelet activation patterns had a strong correlation was disease severity; there also was a generalized down-regulation of platelet adhesion receptors 

    -- all of this suggests that there was activation and sequestration of platelets within the microvasculature of the lungs, kidneys, and heart 

-- D-dimer: levels track with disease severity. 

    -- Other markers of DIC were not present; there was no evidence of macrovascular thrombosis such as MI/stroke/VTE (all severely affected patients had received heparin), suggesting that microvascular thrombosis was the result of this procoagulant state 

--they combined neutrophils from healthy donors with platelet-rich plasma from severe cases and controls, finding increased platelet adhesion to neutrophils and further confirming platelet activation leading to their complexing with neutrophils

 

Commentary: 

--studies of the current SARS-CoV-2 virus have revealed the complex interconnection between the innate immune system (including neutrophils), immunogenic platelets, and a dysregulated coagulation cascade, with its collateral tissue damage, referred to as "immunothrombosis" (eg see https://www.sciencedirect.com/science/article/abs/pii/S1044532316300318 

--it is evident from many studies that there are micro and macrothrombi (including increased risk of stroke), presumably related to this hypercoagulable state (thrombi track with d-dimer levels). and some evidence that anticoagulation may help (eg, see next) 

 

Observational data from New York found that use of either prophylactic or therapeutic anticoagulation was protective, in a preprint, pre-peer reviewed article (see covid anticoag dec mortality jacc2020 in dropbox, or doi.org/10.1016/j.jacc.2020.08.041 )

Details: 

-- a retrospective analysis of 4389 patients compared no anticoagulation (n= 1530, 35%), therapeutic anticoagulation (n=900, 21%), and prophylactic anticoagulation, (n= 1959, 45%) in patients> 18-year-old and admitted with PCR-confirmed SARS-CoV-2 to one of 5 New York City hospitals between March 1 and April 30 

-- median age 65, 44% female, BMI 28, current smokers 5%, 23% diabetes/35% hypertension/12% CAD/11% CKD 

-- blood pressure 138/80, oxygen sat 94%, d-dimer 1700 ng/mL, ferritin 706 ng per mL, CRP 108 mg/L, procalcitonin 0.2, PT 13.7, INR 1.1, platelet count 211 

-- primary endpoint: in-hospital mortality; secondary endpoints were intubation and major bleeding 

-- results below were adjusted for age, sex, race/ethnicity, BMI, history of hypertension, atrial fibrillation, heart failure, CKD, use of anticoagulants or antiplatelet agents prior to hospitalization, month of admission, intubation, time of implementation of anticoagulation guidelines, respiratory rate, O2 sat, and d-dimer 

-- autopsies were performed in 26 people 

 

Results: 

-- d-dimer: 2300 ng/mL in the therapeutic anticoagulation group, 1500 ng/mL in prophylactic anticoagulation group, and 1700 ng/mL in those not on anticoagulation 

-- inflammatory markers (ferritin, LDH, CRP) increased progressively from those with no anticoagulation to prophylactic coagulation to therapeutic anticoagulation [ie, those patients where the clinicians decided to anticoagulate also had more inflammation going on, and were presumably judged to be sicker]

-- overall mortality: 24% died  

    -- no anticoagulation 26%, prophylactic anticoagulation 22%, therapeutic anticoagulation 29% [again, as confirmed below, those who were anticoagulated were likely sicker]

-- compared to no anticoagulation: 

    -- decreased in-hospital mortality: 

        -- therapeutic anticoagulation: 47% decrease, adjusted HR 0.53 (0.45-0.62), p<0.001 

        -- prophylactic anticoagulation: 50% decrease, aHR 0.50 (0.45-0.57), p<0.001 

    -- decreased intubation: 

        -- therapeutic anticoagulation: 31% decrease, aHR 0.69 (0.51-0.94), p=0.02 

        -- prophylactic anticoagulation: 28% decrease, aHR 0.72 (0.58-0.89), p=0.003 

-- when initiated less than 48 hours from admission, no statistically significant difference between those on therapeutic vs prophylactic anticoagulation, HR 0.86 (0.73-1.02), p=0.08  [note that this is still a pretty strong trend favoring therapeutic anticoagulation] 

-- bleeding: 

    -- 89 patients: 2% had major bleeding; 3% on therapeutic anticoagulation , 1.7% on prophylactic anticoagulation , and 1.9% on no anticoagulation 

    -- bleeding rates tended to be higher in those on low molecular weight heparin vs NOACs in the therapeutic anticoagulation group, and higher in unfractionated heparin vs low molecular weight heparin in the prophylactic group 

    -- site of bleeding was most commonly GI (51%), followed by mucocutaneous (19%), bronchopulmonary (15%), and intracranial (6%) 

-- 26 autopsies were done in the 1^st sequential cases, 4 were on anticoagulation prior to admission for atrial fibrillation or DVT 

    -- 11 (42%) had thromboembolic disease not clinically suspected, including 4 pulmonary emboli, 2 cerebral infarctions, and 5 with microthrombi in multiple organs including the heart (4), liver (1), kidneys (2) and lymph nodes (2)

    -- 3 of these 11 patients (27%) with thromboemboli were on therapeutic anticoagulation, and 8 (73%) were not

 

Commentary: 

 --a preliminary analysis of 2773 patients admitted to Mount Sinai Health System in New York found an association between in-hospital anticoagulation and lower mortality vs those on no or just prophylactic anticoagulation (see covid anticoag dose dec mortal jacc2020 in dropbox or doi.org/10.1016/j.jacc.2020.05.001 ). 

-- The current study supported and extended this finding, noting that anticoagulation was effective especially in these likely sicker patients overall (those on therapeutic anticoagulant coagulation were older, had higher blood pressures, faster heart rate and respiratory rates, lower oxygen saturation, and high d-dimer concentrations, as well as elevated inflammatory markers) 

-- overall, when the analysis was restricted to those receiving anticoagulation within 48 hours of admission, there was no statistically significant difference between therapeutic and prophylactic anticoagulation (though, again, a strong trend favoring therapeutic anticoagulation)

--another New York study, this one from NYU Langone Health of 4 New York City hospitals between March 1 and April 17 of (see https://jamanetwork.com/journals/jama/fullarticle/2768715 ): 

    -- median age 64, 40% female 

    -- thrombotic events occurred in 533 (16%) patients: 207 (6%) were venous (3% PE, 4% DVT), 11% were arterial (2% ischemic stroke, 9% MI, 1% systemic thromboembolism)

    -- d-dimer levels had strong association, in a linear fashion, with events: 

        -- 500-1999: overall HR 1.92, venous HR 2.63, arterial HR 1.52 

        -- 2000-4999: overall HR 2.82, venous 4.71, arterial 1.98 

        -- 5000-9999: overall HR 5.55, venous 14.25, arterial 2.95 

        -- >10,000 overall HR 7.09, venous 32.63, arterial 2.3 

-- though screening for thrombotic events was not standard at that time, and these diagnoses were made during routine clinical care 

-- Overall the studies confirm a very high incidence of macro and micro thrombi, as suggested in several earlier studies

 

limitations of study: 

-- institutional guidelines for anticoagulation were implemented at Mount Sinai, which might have affected which of patients received anticoagulation (though likely bias was to the sicker patients)

-- as an observational study there may have been inherent biases in the decision to use no anticoagulation, vs prophylactic or therapeutic anticoagulation 

-- no information of other medications used, such as remdesivir or IL-1 antagonists or steroids...

-- autopsy analysis was involved few patients,l and the results may not be generalizable 

 

--other factors that might be involved in the web of clinically-adverse interactions triggered by SARS-CoV-2:

--studies have suggested potential roles for steroids in decreasing mortality in patients with severe covid-19: a meta-analysis of 1703 patients found that there was a 36% decreased mortality with dexamethasone in particular, suggesting a role for anti-inflammatory therapy (see covid steroids dec mortality jama2020 in dropbox, or JAMA. doi:10.1001/jama.2020.17023) 

--there is an interesting argument that there may be an important bradykinin role (see https://elemental.medium.com/a-supercomputer-analyzed-covid-19-and-an-interesting-new-theory-has-emerged-31cb8eba9d63 and https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7267506/ )

    --a recent small study from the Netherlands found benefit from the FDA-approved bradykinin receptor blocker icatibant in Covid-19 cases (see https://jamanetwork.com/journals/jamanetworkopen/fullarticle/2769237 ). the issue here is that the SARS-CoV-2 virus binds to the ACE2 receptors, ACE degrades bradykinin, but the virus effectively interferes with the cells ability to regulate bradykinin. and high bradykinin levels, among other things, lead to hypotension and increased vascular permeability

--and, by the way, vitamin D is involved in the renin-angiotensin system, and there is some evidence that vitamin D might be helpful for Covid-19 patients who have deficient levels (observational study: https://jamanetwork.com/journals/jamanetworkopen/fullarticle/2770157 ).

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So, pretty complex stuff. Is it useful?? 

--it is pretty clear that Covid-19 is associated with a high incidence of micro and macrothrombi, especially in more severe cases.

--it seems that several interventions may be useful, though this conclusion is largely based on observational studies (eg the data on steroids or anticoagulaton are promising, but there really needs to be RCTs to try to get a more rigorous answer on their efficacy )

--but, maybe there should be a combined approach??

    --should we measure some of the markers of these effects and contour therapy to the specifics of the individual (also verified by RCTs)?? 

        --eg, should we have a cutpoint for d-dimer levels to initiate the anticoagulant component? What should the cutoff be? The same as for thromboembolism? (see http://gmodestmedblogs.blogspot.com/2020/01/new-d-dimer-threshhold-for-pe.html ) 

        --what should be the actionable cutpoint for bradykinin level?  

        --which of the inflammatory cytokines for inflammation or other inflammatory markers are predictive, and  what cutpoint, should be used to consider dexamethasone treatment?

        --and maybe we should throw in a little vitamin D into the cocktail????

        --and, do other therapies we are using (eg remdesivir) add anything further??

--it certainly seems that we need studies looking at more than one intervention at a time, since the virus leads to so much internal disruption in inter-related  but disparate arenas....

geoff

 

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