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.
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