Covid-19: Rewriting the rules

Since the beginning of 2020, COVID‑19 has spread aggressively throughout the world, imposing an immense strain on healthcare systems and turning peoples’ lives upside down as they come to terms with a new way of living. Over time, it has become increasingly clear that although COVID‑19 was originally considered to be a respiratory condition, it carries a considerable risk of thromboembolic complications.

Thrombosis may be present in over 30% of critically ill COVID-19 patients

By March 2020, COVID-19 was becoming a global problem, and doctors began to realise that the incidence of thrombosis in patients admitted to hospital was higher than expected. Moreover, doctors were seeing microthromboses in patients’ lungs and an increased rate of deep vein thrombosis (DVT), changes in the blood that result from severe lung inﬂammation. COVID-19 was also making their blood more ‘sticky’ than normal, which can lead to blood clots. Thrombosis expert Professor Beverley Hunt commented that in addition to blood clots, sticky blood may result in higher rates of stroke and heart attacks.

A precarious balance exists between treating thrombosis and provoking bleeding, and medical teams worldwide are working together to ﬁnd the most effective way of managing thrombosis in COVID-19 patients, while minimising the risk of bleeding.

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Current controversies in COVID-19

The impulse when a pandemic occurs is to act immediately, but inevitably there are many unknown factors. For example, we originally thought that COVID‑19 patients don’t bleed, but we now know that major bleeding can occur, particularly in ICU patients.

In the UK, we are set up to capture VTEs, but are less effective at capturing bleeding rates. Recent evidence from Europe from consecutive adult symptomatic patients who received thromboprophylaxis indicated that approximately half of patients with VTE were diagnosed in the ﬁrst 24 hours after admission,¹ suggesting that they had developed VTE beforehand.

Standard dosing for thromboprophylaxis in the UK is to give a ﬁxed dose; should it be based on weight? Accumulating evidence suggests that it should. Should extended prophylaxis be adopted in the UK? Large, randomised trials (>6000 patients) in high‑risk patients showed a decrease in symptomatic VTE or VTE deaths, but this was offset by a signiﬁcant increase in major or fatal bleeding.^2‑4 Which imaging technique should be used? Echo signs of pulmonary embolism are mimicked by COVID‑19; however, we can’t give every patient a CT scan.

Overall, the burden of evidence required for a change in practice should correlate with the nature of the intervention. The higher the risk: beneﬁt ratio, the higher the weight of evidence must be.

These are some of the issues raised during a webinar held by Thrombosis UK and attended by over 850 healthcare professionals from 54 countries. Chaired by Professor Beverley Hunt, the seminar was given by Dr Suzie Shapiro from Oxford and Professor Dan Horner from Salford.

References

Lodigiani C, et al. Thromb Res 2020; 191: 9-14.
Hull RD, et al. Ann Intern Med 2010; 153: 8-18.
Goldhaber SZ, et al. N Engl J Med 2011; 365: 2167-2177.
Cohen AT, et al. N Engl J Med 2013; 368: 513-523.

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COVID-19 guidance starts to ﬁll in the picture

Guidance on prophylaxis of VTE in COVID‑19 patients has now been issued by several authorities, although some of it is necessarily interim while we await the results of clinical trials.

The ICM Anaesthesia website was set up to act as a central source of information and guidance on COVID‑19 for intensivists and anaesthetists in the UK. In June, they published clinical guidance on the prophylaxis, detection, and management of VTE in hospital‑based patients. Prophylaxis with low molecular weight heparin is recommended for emergency/ambulatory, ward‑based, high‑dependency, and critical care patients, and for those requiring renal replacement therapy if concerns exist about ﬁlter clotting. Patients with conﬁrmed VTE should receive treatment doses of LMWH. They also recommend extended thromboprophylaxis with LMWH (14‑28 days) at discharge for high‑risk patients.

In early May, the British Thoracic Society issued updated guidance for respiratory and general medical doctors on VTE in COVID‑19. These guidelines discussed clinical issues in prevention and diagnosis, and approach to LMWH dosing in standard- and high‑risk patients, and those with proven or suspected VTE. They also made recommendations for extended prophylaxis.

The International Society for Thrombosis and Haemostasis (ISTH) published interim guidance and a management algorithm for COVID‑19 patients in March this year. Coagulopathy is a signiﬁcant sign of poor prognosis in COVID‑19, and an increase in D‑dimer, a marker of coagulopathy, is one of the most common ﬁndings in COVID‑19 patients who require hospitalisation. Based on current evidence that markedly increased D‑dimer is associated with high mortality in COVID‑19 patients, they advised that prophylactic LMWH should be considered for all patients who require hospital admission, assuming that there are no contraindications.

In 2018, the Health Service Executive in Ireland published a report and toolkit covering the prevention of blood clots in hospital, following a year‑long collaboration with multidisciplinary teams from 27 hospitals. The toolkit included patient alert cards and posters, and a VTE prophylaxis protocol template for risk assessment and suggested prophylaxis with low molecular weight heparin (LMWH)/heparin. In April this year, they issued an updated protocol which gives recommendations for prophylaxis with LMWH/heparin for COVID‑19 patients.

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New guidance issued for COVID-19-associated thrombosis in pregnancy

Many people, especially those who are pregnant or have loved ones who are pregnant, will have questions regarding COVID-19 and speciﬁc risks associated with pregnancy, such as:

Are pregnant women more likely to be infected with COVID-19?
Are pregnant women with COVID-19 infection more likely to become unwell, or become severely affected?
What are the maternal and foetal implications of COVID-19 infection?
Is COVID-19 a risk factor for thrombosis in pregnancy?

Answers to some of these questions can be found in a paper published in June,¹ a large cohort study using the UK Obstetric Surveillance System (UKOSS) involving all 194 obstetric units in the UK. A total of 427 pregnant women were admitted to hospital with conﬁrmed COVID-19 during this 6-week period – an estimated 4.9 per 1000 maternities,¹ a similar incidence to that for women who are not pregnant. Most women were admitted during the third trimester suffering with ﬂu-like symptoms,¹ but they were not more likely to become unwell than non-pregnant women. Risk factors for presenting to hospital with COVID-19 while pregnant were also identiﬁed and, reassuringly, no infants died as a direct result of COVID-19. Moreover, 93% of mothers went home well, and only 6% were still in hospital at the end of the study. Unfortunately, 3 women (1.2%) died as a result of COVID-19.¹

Some people may have concerns regarding vertical transmission of COVID-19 from the mother to the infant in utero. The UKOSS and other studies suggest that while it cannot be ruled out, it does not appear to be a problem since infected infants do not show symptoms and do well.^1-3

Pregnant women are prone to the same risk factors for venous thromboembolism (VTE) as women who are not pregnant, but with additional pregnancy-speciﬁc risk factors such as pregnancy itself, pre-eclampsia, and multiple pregnancy.⁴ It is therefore essential that all pregnant women are assessed for VTE risk so that any appropriate thromboprophylaxis can be given. There is always a risk of bleeding with VTE prophylaxis, so as with non-pregnant women, the aim is to get the risk/beneﬁt balance right when making these clinical decisions.⁴

To help clinicians manage cases of pregnancy with COVID-19 infection, the Royal College of Obstetricians and Gynaecologists (RCOG) have this month produced speciﬁc guidance on COVID-19 infection in pregnancy.⁵ This guidance is based on literature review and expert consensus. COVID-19 should be regarded as a transient risk factor for VTE in pregnancy, and so pregnant women may need a period of thromboprophylactic treatment.⁵ The new RCOG guidelines cover self-isolation while pregnant; those admitted to hospital with conﬁrmed or suspected COVID-19; those with severe complications of COVID-19; and women admitted postpartum with conﬁrmed or suspected COVID-19.⁵

These and related issues were discussed in some depth in a recent webinar held by Thrombosis UK, chaired by Professor Beverley Hunt with presentations by Dr Claire McLintock from Auckland, New Zealand; Professor Saskia Middledorp from Amsterdam, The Netherlands; and Dr Jahnavi Daru from London, UK.

Watch the webinar at: https://us02web.zoom.us/webinar/register/WN_NY44AdLHQbGR9mUTAbgnJA

Access the RCOG guidelines on COVID-19 in pregnancy here: https://www.rcog.org.uk/globalassets/documents/guidelines/2020-06-04-coronavirus-covid-19-infection-in-pregnancy.pdf