COVID: coagulopathy, ?increasing the mortality

 

An interesting small study found that more than ½ of patients dying from Covid-12 had autopsy evidence of venous thromboembolism (see https://annals.org/aim/fullarticle/2765934/autopsy-findings-venous-thromboembolism-patients-covid-19-prospective-cohort-study or DOI: 10.7326/M20-2003)

 

Details:

-- 12 consecutive Covid-10 positive deaths in a single academic medical center in Hamburg, Germany

    -- autopsies are mandated there for all patients dying with a PCR-confirmed diagnoses of Covid-19

    -- complete autopsies were done, as well as postmortem CT, and histopathologic and virologic studies

-- median age 73, 75% male, 10 deaths in hospital/2 outpatient

-- comorbidities: CAD 50%, COPD  25%

-- D-dimer was available for only 5 people: median 495, CRP median 189 mg/L, LDH was 470 U/L (normal up to 280)

 

Results:

-- DVT: in 7 of the 12 (58%), none had suspected DVT

    -- massive pulmonary embolism was direct cause of death in 4, from deep lower extremity veins

    -- D-dimer was available for only one of the 4 patients who died from a PE; that person had D-dimer of 23,100.

    -- the other 3 cases had fresh deep venous thrombosis but no PE

    -- in all 7 cases, both legs had DVTs

    -- in 6 of 9 men, fresh thromboses were found in the prostatic venous plexus

-- 3 other patients had very high D-dimers:  one with 28,800 but was on edoxaban; the other two were >200,000  and 5700

 

-- PCR for SARS-CoV-2 was high in the lungs of all: from 1.2x10⁴ to 9x10⁹

    -- also found in the pharynx of 9

    -- viremia in 6, though lower titer: <4x10⁴

    -- 5 patients were PCR-positive in the heart, liver or kidney, at higher concentrations

    -- 4 patients were PCR-positive in the brain and saphenous vein

    -- those without viremia had no or low levels of viremia in other tissues

-- in all 12 cases, the cause of death was found in the lungs or the pulmonary vascular system

    -- lungs were typically congested, heavy, and firm in those dying from a lung-involved cause

-- histologically, a few important findings:

    -- one had lymphocytic myocarditis (see case at  http://gmodestmedblogs.blogspot.com/2020/03/covid-myocarditis.html )

    -- 6 had chronic pharyngitis with lymphocytic infiltrates

    -- 4 had microthrombi in lungs, and these were found regularly in the lung arteries

    -- 4 had extensive granulocytic infiltrates in alveoli and bronchi suggestive of bacterial focal bronchopneumonia

 

-- postmortem CT: reticular infiltration of the lungs with severe bilateral, dense consolicdatin

    -- histomorphologically diffuse alveolar damage was seen in 8 patients

-- all patients had SARS-CoV-2 RNA in the lung at high concentrations

  

Commentary:

-- this is a small study, but there have been very few known autopsies done on patients with Covid-19: only 3 in the literature. And this current study was the only systematic one

-- coagulopathy has been a common complication of those with severe Covid-19: 50% of 119 patients who died had coagulopathy (defined as 3-second extension of protime or 5-second extension of aPTT) and 81% had D-dimer >2000, though in this study they did not comment on the co-occurrence of these 2 findings: see covid mortality risk factors lancet2020 in dropbox, or doi.org/10.1016/ S0140-6736(20)30566-3

-- in this autopsy study, though 4 people died from large PEs, it was clear that there was a profound predilection to thrombosis more generally: bilateral leg thromboses (vs the usually observed unilateral ones), thromboses elsewhere (prostatic venous plexus), and microthrombi.

    --would have been useful to have autopsies at the same time on non-Covid patients, to compare the apparently high incidence of these microthrombi and prostatic venous plexus thromboses found in these Covid ones (my cursory reading suggested that these were uncommon, but...)

-- purported mechanisms: coronavirus infections have been association with endothelial dysfunction (and increased von Willebrand factor levels),  systemic inflammation , and tissue factor activation; and the cytokine storm might activate the coagulation cascade. Hypoxemia might also facilitate coagulation. And there might be  immune-mediated damage by antiphosphlipid antibodies

 

Limitations of the autopsy study:

--small sample size, so may be significant errors in generalizing their conclusions

--viral cultures were not done, just PCR (which might have picked up nonviable viral particles)

--they did not have consistent data on D-dimer levels, raising the question of whether this was in fact a good discriminator for those who subsequently had major thrombotic events

 

So,

-- this study does reinforce a substantial contribution for thromboembolic disease in fatal outcomes, and one mioght speculate that there may well be an additive contribution to those with intrinsic severe pulmonary disease who survive

-- and there were clearly lots of other, nonfatal thromboses

-- it raises the potential benefit from anticoagulation in those with severe Covid-19 infections. studies are now being done. maybe answers soon....

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-- a pre-print, pre-peer-reviewed literature review by an international panel (see covid thrombosis review jacc2020 in dropbox, or doi.org/10.1016/j.jacc.2020.04.031 ), noted:

    -- Covid-19 predisposes people to both venous and arterial thrombotic disease, felt to be from excessive inflammation, platelet activation , endothelial dysfunction, and stasis

    -- IL-6, an inflammatory cytokine marker, seems to correlate with disease severity, and also has procoagulant activity

    -- studies have also found that there is increased fibrin degradation products; and in a study of 183 patients 71% of the 21 who died fulfilled the International Society on Thrombosis and Haemostasis criteria for DIC (vs 0.6% of survivors)

    -- a study of 184 patients from 3 centers in the Netherlands found 31% developed incident VTE (all patients had pharmacologic prophylaxis, though was under-dosed in 2 of the centers). and this study should be validated

    -- they comment on the PT prolongation but note that the aPTT has had variable effects associated with Covid-19

    -- there are a few cases of Covid-19 associated cerebral infarction or limb ischemia in the setting of elevated anitphospholipid antibodies (which may suggest a potential benefit from hydroxychloroquine....)

    -- the WHO in their 13 March interim guidance on managing severe Covid-19 acute respiratory infection recommends prophylactic daily low-molecular weight heparins or twice daily regular heparin; if contraindicated, consider mechanical VTE prophylaxis (intermittent pneumatic compression devices)

    -- pregnancy is another concern, given the increased VTE risk, but limited data with Covid-19

    -- no info on post-discharge continuation of anticoagulation, though it is reasonable to consider up to 45 days for those with elevated VTE risk (reduced mobility, active cancer, and maybe elevated D-dimer >2x ULN if low bleeding risk)

    -- and then there is the issue of finding out if a DVT/PE exists: the index of suspicion should be high, but we are limiting studies of Covid patients: to decrease risk of transmission of virus to staff/other patients, these patients may be unstable or in prone position. echocardiography may help for some, finding right ventricular dysfunction with larger PEs

    -- the role of using empiric full-dose anticoagulation (done by some) more routinely is unclear; the panel in this report consider using only the prophylactic dosing

    -- one concern is that adding anticoagulants to the mix of meds severe Covid patients are getting may lead to significant drug-drug interactions. unfractionated heparin may be best since it can be reversed easily and does not have drug-drug interactions with the therapies now being used (but there are more freqeunt blood draws and potential exposures to the blood drawers)

    -- the paper also covers interventional therapies for VTE, acute coronary syndromes (basically the usual therapy if not contraindicated), DIC, and managing bleeding. see the manuscript for details

and, there are the reports of young healthy people with Covid-19 having strokes (eg see https://www.washingtonpost.com/health/2020/04/24/strokes-coronavirus-young-patients/ )

geoff

 

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