Sunday, April 26, 2020

Is Coagulopathy the Real Culprit in COVID-19 Deaths?


SARS-CoV-2 is a new disease and the scientific community is still learning about it. COVID-19 emerged as a respiratory disease from China in the December, 2019. In recent studies on SARS-CoV-2, it has been found that there are unusual diffuse small thromboses in the lungs tissue of patients, as well as vascular damage in different tissues and organs. Evidence from post-mortem findings of occlusion and microthrombosis formation in pulmonary small vessels of deceased with critical COVID-19 has been reported. The features prompted some scientists to describe the disease as a disease of vascular system.
After, SARS-Cov infects the body, it up-regulates the expression of related genes in the coagulation pathway, leading to activation of coagulation. Studies have shown that the abnormal characteristics of blood coagulation indexes caused by SARS-CoV-2 are not the same as SARS-CoV, and it is more likely to cause multiple organ failures other than the lungs.
Dysregulated coagulation with hypercoagulability has been found to be common in COVID-19 and can progress to disseminated intravascular coagulation (DIC). A retrospective analysis of patients admitted with severe SARS-CoV-2 infection found that 71.4% of patients who ultimately died from COVID-19 developed overt DIC compared with only 0.6% of survivors. On admission, non-surviving patients presented with higher D-dimer levels and prolonged prothrombin times (PT) and activated partial thromboplastin times (aPTT) compared with surviving.
SARS-CoV-2 infection damages human immune system and results in systematic inflammatory response. Activation of monocytes produce cytokines, such as interleukin 6, tumor necrosis factor, and many more, which in turn induce activation of the endothelial cells and tissue factor that trigger the blood coagulation cascade.  Activation of the vascular endothelium, platelets, and leukocytes results in dysregulated thrombin generation that occurs both systemically and locally in the lungs of patients with severe pneumonia, resulting in the deposition of fibrin with subsequent tissue damage and microangiopathic pathology. The effects of dysregulated thrombin generation are further exacerbated by an inhibition of fibrinolysis and the impairment of natural anticoagulant mechanisms. In addition, the hypoxia found in severe COVID-19 can stimulate thrombosis through not only increasing blood viscosity, but also a hypoxia-inducible transcription factor-dependent signaling pathway. All events may lead to DIC.
The activation of blood coagulation is essential in counteracting viral infections along with the immune system trapping viruses by forming a fibrin network, thus limiting their dissemination. However, a massive inflammatory and coagulative response is dangerous because it can lead to a local thrombosis in the lungs. Acute respiratory distress syndrome (ARDS) has been described in approximately 40% of 201 patients with COVID-19 pneumonia, in a study, and it was crucial in increasing the risk of death. ARDS may result from pulmonary vascular microthrombosis.
The concept of pulmonary thrombosis has been recently proposed for conditions such as pneumonia, asthma, and chronic obstructive pulmonary disease. It is known that viral diseases such as those from EBOLA and cytomegaloviruses can induce DIC. Therefore, it is not surprising that SARS-CoV-2 could be capable of doing the same.

Elevated plasmin(ogen) is a common feature in people with underlying medical conditions, including hypertension, diabetes, cardiovascular disease, cerebrovascular disease, and chronic renal illness, who are susceptible to SARS-CoV-2 infection. Plasmin enhances the virulence and infectivity of SARS-CoV-2 virus by cleaving its spike proteins. Extremely increased D-dimer in COVID-19 patients results from plasmin-associated hyperactive fibrinolysis. D-dimer and viral load are independent risk factors of disease severity and mortality. Antiproteases targeting plasmin(ogen) may be a promising approach to combat COVID-19.

Measuring D-dimers, prothrombin time and platelet count (decreasing order of importance) in all patients who present with COVID-19 infection, may help in stratifying patients who may need admission and close monitoring or not. Any underlying condition (e.g.; liver disease) or medication (e.g.; anticoagulants) which may alter should be accounted for while using the algorithm.
Measuring D-dimer had been recommended for Covid-19 patients, however, the optimal cut off for D-dimer remains to be well-established. D-dimer = 2.0 ug/ml (fourfold increase) on admission might be the optimum cut off to predict in-hospital mortality for Covid-19. The in-hospital mortality was significant higher in patients with D-dimer 2.0 ug/ml than those who had D-dimer < 2.0 ug/ml on admission. Among routine tests, D-dimer might be the best early marker to improve management of Covid-19.
According to researchers, heparin treatment has been recommended for COVID-19, however, its’ efficacy remains to be validated. The 28-day mortality between heparin users and nonusers were compared in stratified patients. The 28-day mortality of heparin users were lower than nonusers in patients with SIC score ≥4 or D-dimer > 3.0 ug/mL. Heparin treatment appears to be associated with better prognosis in severe COVID-19 patients with coagulopathy.
They suggested, based on a review of the very limited current peer-reviewed literature with low quality of evidence combined with discussions with international clinicians on the frontlines

  • All patients with COVID-19 should undergo coagulation studies at admission, in particular: D-dimer, prothrombin time, and platelet count.
  • Because of the possibility of patients to develop coagulopathy later in their hospital course, routine serial measurements of coagulation studies should be undertaken in all COVID-19 patients. The ideal interval has not yet been defined.

  • All patients with COVID-19 should be placed on prophylactic doses of anticoagulation, preferably with LMWH, unless there is a contraindication, such as acute kidney injury (AKI), wherein unfractionated heparin is preferred.
  • Therapeutic anticoagulation should be strongly considered in patients at high-risk for coagulopathy (including CRRT and ECMO), demonstrating signs of microthrombi-induced organ dysfunction, or with documented or strongly suspected macro-thromboembolism.
  • Determination of high-risk patients by laboratory measures of coagulopathy may include: platelet count, prothrombin time, fibrinogen, fibrinogen-degradation products, D-dimer, and TEG. Of note, some centers are therapeutically anticoagulating all patients on admission when no absolute contraindications exist.

  • Given the significant rate of AKI seen in COVID, intravenous contrast for imaging should be used with caution. Duplex ultrasonography, echocardiography, and clinical suspicion can play an increased role in these cases.
  • Some early reports support use of larger bolus-dose tPA (50mg or 100mg bolus) without holding anticoagulation in order to prevent recurrence of the suspected pulmonary microvascular thrombosis underlying COVID-19 ARDS, is worthy of consideration in  COVID-19 ARDS associated exceptionally high mortality, weighed against the risks of tPA having ~1% risk of catastrophic bleeding in non-stroke patients.
  • Aspirin should be considered in cases with elevated troponin and cardiac dysfunction, particularly with elevated maximal amplitude on TEG.

This information has been compiled from the study of various literatures on the subject.


Credit:

1.      Wiley Online Library: Covid-19: Novel Coronavirus Outbreak

2.      COVID-19 complicated with DIC: 2 cases report and literatures review

 

 








...

Get my updates delivered into your inbox; Privacy Policy :

Click here to Subscribe news feed from "Clinicianonnet; so that you do not miss out anything that can be valuable to you !!

...

Related Posts Plugin for WordPress, Blogger...