Coronavirus Disease 2019 (COVID-19), caused by a novel coronavirus (SARS-CoV-2), is a highly contagious disease that appeared in Wuhan, Hubei province of China in December 2019. It has now spread to multiple countries through infected persons travelling mainly by air. Most of the infected patients have mild symptoms including fever, fatigue and cough. But in severe cases, patients can progress rapidly and develop the acute respiratory distress syndrome, septic shock, metabolic acidosis and coagulopathy including a disseminated intravascular coagulation (DIC).
There is little international guidance on how to manage thrombotic risk, coagulopathy, and DIC in patients with COVID-19 This brief paper provides concise pragmatic guidance on management of both thrombotic risk and DIC. This is living guidance document that will be updated weekly.
Managing risk of hospital-associated venous thromboembolism
COVID-19 infected patients are likely to be at increased risk of HA-VTE, especially if they become immobilised on critical care. At the moment it is unclear if hospitalized patients with COVID-19 have a greater risk of VTE than other medical patients who have chest infections and elevated D-dimer values (Darzi). Some have used an elevated D-dimer in a scoring system to identify those at increased risk of VTE (Spyropoulos).
Critically ill patients fulfil two out of three criteria of Virchows triad which states that reduced venous flow from immobility, prothrombotic changes and vessel wall changes increase the risk of VTE. Patients with severe COVID-19 are immobile, have an acute inflammatory state leading to a hypercoagulable state. There is also the possibility of endothelial cell activation/damage due to binding of the virus to ACE2 receptor. The optimal thromboprophylaxis in COVID patients is unknown. Drug-drug interactions between antiviral treatments and direct oral anticoagulants, and the difficulty in maintaining stable INRs in patients taking vitamin K antagonists while unwell, mean that patients on these drugs should be switched/bridged to low molecular weight heparins (LMWHs) or unfractionated heparins (UFH) with or without mechanical prophylaxis while unwell.
The risk of venous thromboembolism (VTE) must be assessed in all patients admitted to hospital, and prevention should be given to all high-risk patients according to international guidance on thromboprophylaxis in medical patients(NICE/ASH).
i.e. Pharmacological thromboprophylaxis should be given to all immobilised and severely ill patients with COVID-19 patients unless otherwise contraindicated
For CrCl > 30: Give LMWH or fondaparinux s.c. according to license
For CrCl < 30 or AKI: Unfractionated heparin 5000 units SC BD or TDS or dose-reduced LMWH
All completely immobilised patients would benefit from intermittent pneumatic compression in addition to pharmacological thromboprophylaxis.
Mechanical thromboprophylaxis should be used alone if platelets <30,000 or bleeding
Consider the possibility of pulmonary thromboembolism (PTE) in patients with sudden onset of oxygenation deterioration, respiratory distress, reduced blood pressure.
Consider switching to LMWH in patients taking direct oral anticoagulants (DOACs) or vitamin K antagonist (e.g warfarin) for stroke prevention in atrial fibrillation or previous VTE.
Management of COVID-associated coagulopathy
Descriptions of infection with Covid-19 from Wuhan, China described a coagulopathy in patients who were critically ill with Covid-19. It has long been recognised that activation of coagulation and/or fibrinolysis occur as part of the acute inflammatory response. Zhou et al performed a retrospective multicentre cohort study of 191 adults with laboratory confirmed COVID-19 from Wuhan Hospitals. Coagulopathy, defined as a 3 second extension of prothrombin time (PT) or a 5 second extension of activated partial thromboplastin time (APTT), was present in 50% of the non-survivors but only 7% of the survivors (p< 0.0001). Thrombocytopenia was a poor prognostic factor as in other groups of patients admitted to intensive care (Hunt). Platelet counts < 1009 /l were noted in 20% non-survivors compared to 1% of survivors (<0.0001)
Multivariable regression showed increased odds of in-hospital death associated with very high D-dimer values (odds ratio 18.42, CI -2.6-128; p=0.0033). Higher values of D-dimers have been reported to be associated with 28-day mortality in patients with infection or sepsis in the emergency department (Rodelo et al)
Tang et al looked at coagulation screens, D-dimer & FDPs and antithrombin levels in 183 consecutive patients in Wuhan with an overall mortality of 11.5%5. Non-survivors had marked derangements in haemostatic defects at the time of admission in comparison to survivors with prolongation of APTT, PT, elevated D-dimers and fibrin degradation products (FDP). Progressive elevation of D-dimer and FDP was seen in non-survivors. Fibrinogen levels remained elevated in keeping with an acute phase response initially as opposed to a reduction that is commonly seen in DIC, mainly after day 7. In this cohort 71% of non-survivors met the International Society of Thrombosis and Haemostasis criteria of DIC compared to 0.4% of survivors. Higher D-dimer and FDP levels track with multi-organ dysfunction syndrome and poorer prognosis. (Wang et al, JAMA 2020). Median time to onset of DIC was 4 days into hospital admission but it is unclear at what stage of the illness patients were admitted.
Histological similarities have been shown to the Severe Acute Respiratory Syndrome-Coronavirus (SARS-CoV), the cause of a previous endemic between 2002-3, similarly causing ARDS. Localised pulmonary haemorrhage, pulmonary oedema, desquamation with hyaline membrane formation and an interstitial mononuclear inflammatory infiltrate have been seen. Localised pulmonary arteriolar thrombosis was seen with SARS but has not yet been described in the case reports of autopsies from patients with COVID-19 (Xu et al). Pulmonary vasculature thrombosis is likely to be a result of the severe hypoxia for hypoxia is a profound stimulant of coagulation (Ten et al). While therapeutic anticoagulation has been used empirically in some severe COVID-19 patients in Wuhan, it seems more logical to reduce the hypoxia if possible, rather than to submit patients to a therapy with no published efficacy and a high bleeding risk.
There is no proven benefit in correcting abnormal coagulation with replacement of missing coagulation factors (Hunt)
Abnormal coagulation results do not require correction in patients who are not bleeding.
Management of bleeding in COVID-19
In minor bleeding monitor FBC and coagulation screen &/or TEG/ROTEM
TEG/ROTEM should only be used if risk assessment shows they do not cause risk of aerosolisation of blood or they can be used in a Safety hood.
If major bleeding, (an arbitrary definition of major haemorrhage is bleeding which leads to a systolic blood pressure less than 90mm Hg and/or heart rate more than 110 beats per minute.)
For patients with major bleeding give empirical FFP and red cells followed by blood products determined by repeat coagulation screens, using PT/INR >1.5 or APTT > 1.5 as an indication to give FFP 15-25mg/Kg. For fibrinogen <1.5g/l give cryoprecipitate or fibrinogen concentrate, if platelets <50x 109/l give a pool of platelets. If the patient does not have DIC then also give tranexamic acid 1gm IV.
Management of disseminated intravascular coagulation in COVID-19
DIC is common in many patients in ITU as part of multiorgan failure. It is uncertain whether COVID-19 has unique characteristics to cause DIC. As DIC is usually only seen in severely ill patients, this seems unlikely. It seems more plausible that DIC develops in patients with COVID-19 after they become hypoxic, and/or have secondary bacterial infection. The diagnosis of DIC is easiest using the ISTH DIC score calculator. A score < 5 means DIC is not present and the score should be recalculate every 1-2 days as necessary. The best management of DIC is to identify and treat underlying condition, which with COVID-19 is difficult. Lastly Recovery from DIC is dependent on endogenous fibrinolysis breaking down the disseminated thrombi. This process will be inhibited by tranexamic acid which is an antifibrinolytic
Manage bleeding with blood product replacement as per managing major bleeding as above: i.e. if PT/INR or APTT ratios are greater than 1.5 then give FFP 15-25mg/Kg; if fibrinogen is <1.5g/l then give a source of fibrinogen- either cryoprecipitate or fibrinogen concentrate; if platelet are < 50x 109/l then give platelets
Do not use tranexamic acid in COVID-associated DIC
Lastly if overt thromboembolism or organ failure due to clot (i.e. purpura fulminans) consider low dose anticoagulation with unfractionated heparin pump to switch off stimulus to coagulation activation. Be mindful that there has been no mortality benefit of therapeutic anticoagulation and so run aPTT target < 1.5 or anti-Xa levels at a low rate in DIC. (Levi et al., Blood, 2018)
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