Anticoagulant therapy for sepsis-induced coagulopathy in severe COVID patients

Study context

As previously described in several studies, severe SARS-CoV-2 (COVID-19) infection is commonly associated with coagulopathy . We also know that the septic context favors the appearance of disseminated intravascular coagulation (DIC). Finally, prolonged bed rest may not favor the risk of occurrence of deep vein thrombosis (DVT). 

It is for these reasons that the use of anticoagulants has been recommended by several consensus of experts in China in the treatment of patients with severe COVID-19 infection. However, this efficacy has not been validated by a clinical trial. 

The International Society of Thrombosis and Haemostasis (ISTH) has proposed a new category to identify an earlier phase of sepsis-induced DIC called : ” Sepsis-Induced Coagulopathy ” (SIC). 

It has already been mentioned in certain publications that patients with this type of coagulopathy could benefit from the introduction of heparin therapy. This study is therefore designed from a retrospective analysis to validate the use of the SIC score and other coagulation parameters in order to select the patients who would benefit from the introduction of heparin therapy.     

Experimental protocol

The authors performed a retrospective analysis of patients admitted with severe infection SARS-CoV-2 at Tongji Hospital (Wuhan) from 1 th January and 13 February 2020. 

The exclusion criteria were as follows : major bleeding, hospitalization <7 days, absence of coagulation parameters or information on the treatments delivered. The events (28-day mortality) were collected until March 13, 2020. 

Severe infection was defined by the criteria established by the National Health Comission of China : Respiratory frequency ≥ 30 / min, saturation ≤ 93% at rest and a PaO / FIO ratio ≤ 300 mmHg.   

In addition to calculating the SIC score, the D-dimers and prothrombin time (PT) time were also reported at the time of diagnosis of severe infection.

The anticoagulant group was defined by patients who received treatment with unfractionated heparin (HNF) or low molecular weight heparin (LMWH) for at least 7 days.

Promising results 

Four hundred forty-nine patients (181 women and 268 men) with severe COVID-19 infection were included from the 1786 confirmed cases. The mean age was 65.1 ± 12.0 years. Two hundred and seventy-two patients (60.6%) had comorbidities, mainly : hypertension (n = 177, 39.4%), diabetes (n = 93, 20.7%) or cardiovascular disease (n = 41, 9.1%). Ninety-nine patients (22.0%) received heparin therapy for at least 7 days, including 94 LMWH (40-60 mg / day) and 5 UFH (10,000 – 15,000 U / day) . Ninety-seven patients (21.6%) had sepsis-induced coagulopathy (SIC score ≥ 4). 

At the end of the data collection, 315 patients (70.2%) were still alive and 134 (28.8%) had died. There was no significant difference in 28-day mortality between people on heparin and those without heparin (p = 0.910).

A multivariate analysis model was carried out to identify the factors associated with mortality. D-dimers, TP, age and platelet count were significantly correlated with an increase in 28-day mortality.

The association between heparin therapy and mortality was stratified based on the SIC score or D-dimers. Heparin treatment was significantly associated with lower mortality in patients with a SIC score ≥ 4 (40.0% vs 64.2% p = 0.029) but this association was not visible for patients with a score < 4 (29.0% vs 22.6% p = 0.419). When patients were stratified by the level of D-dimers, mortality was similar in patients treated with heparin but in untreated patients, mortality increased in proportion to the level of D-dimers. Thus for a rate> 3.0 ug / mL, a drop in mortality of around 20% was observed in patients on heparin (32.8% vs 52.4%, p = 0.017).

What do other studies say?

The inflammation-induced endothelial cell dysfunction causes an increase in the generation of thrombin and a decrease in fibrinolysis which induces a state of hyper-coagulation in patients presenting with a viral infection in particular. In addition, hypoxia induced by respiratory involvement can cause thrombosis by increasing blood viscosity, but also by increasing transcription factors inducible by hypoxia.

Obviously, the formation of micro-thrombis in the pulmonary micro capillaries seems to participate in the pathogenesis of the respiratory picture observed in patients suffering from SARS-CoV-2 infection.

It is for this reason that early use of anticoagulation has been suggested. LMWHs were the most used anticoagulants in this follow-up to prevent the onset of DIC and DVT but also for their anti-inflammatory effect. The prophylactic dose was the most commonly used and bleeding complications were rare or mild but it is not known if higher doses would have been beneficial.

However, the use of anticoagulants to prevent CIVD in sepsis is not entirely consensual, Japanese recommendations being even against the use of these molecules to prevent CIVD  . Other studies suggest the need to rigorously select patients who can benefit from this therapy. In sepsis, mortality being correlated with thrombocytopenia and increased PT, ISTH has developed SIC criteria to guide the initiation of anticoagulation and the usefulness of this score has already been validated.

Perhaps due to the increase in thrombopoietin during pulmonary inflammation, the platelet count does not appear to be a sufficiently sensitive marker to identify patients with coagulopathy.

In this study, only 21.6% of patients had sepsis-induced coagulopathy, suggesting that a small proportion of patients benefit from the initiation of anticoagulation. Furthermore, as an indirect marker of activation of coagulation, a high level of D-dimers (> 3ug / mL) suggested a benefit in a larger number of patients with severe infection (161 out of 449, 35.9% ).

Activation of coagulation nevertheless seems to compartmentalize pathogens and reduce their dissemination. This pathophysiological phenomenon may partly explain the excess mortality in patients on heparin and having D-dimers ≤ 1 ULN even if this observed difference was not significant (p = 0. 260).  

This study has several limitations : 

  1. Selection bias due to its retrospective nature 
  2. Due to the lack of medical resources in the initial phase of the epidemic, the mortality encountered in follow-up may not be representative
  3. the influence of other therapies including antiretrovirals has not been evaluated.

To conclude

This study suggests that the use of anticoagulation (mainly LMWHs) is not beneficial without careful selection of patients. The criteria semblance validated to select patients benefiting from the introduction of heparin are a SIC score ≥ 4 or a D-dimer values> 3 pg / m L . 

More prospective studies are needed to confirm these results. 

SIC score ( coagulopathy linked to sepsis if score ≥ 4):  

What should we learn from this study?

  1. Heparin treatment is recommended for severe SARS-CoV-2 infections, but its efficacy has not been demonstrated.
  2. The 28-day mortality was compared between a group of patients treated with heparin and an untreated group.
  3. Mortality at 28 days was reduced in patients treated with heparin and who had a Sepsis Induced Coagulopathy (SIC) score ≥ 4 or a D-dimer level> 3.0 ug / mL .
  4. Heparin therapy appears to be associated with a better prognosis in patients with severe SARS-CoV-2 infection with coagulopathy .