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Review
. 2022 Apr 5:12:861703.
doi: 10.3389/fcimb.2022.861703. eCollection 2022.

Long COVID: The Nature of Thrombotic Sequelae Determines the Necessity of Early Anticoagulation

Chengyue Wang  1   2 , Chengyuan Yu  1   3 , Haijiao Jing  1 , Xiaoming Wu  1 , Valerie A Novakovic  4 , Rujuan Xie  2 , Jialan Shi  1   4   5
Affiliations
Review

Long COVID: The Nature of Thrombotic Sequelae Determines the Necessity of Early Anticoagulation

Chengyue Wang et al. Front Cell Infect Microbiol. .

Abstract

Many discharged COVID-19 patients affected by sequelae experience reduced quality of life leading to an increased burden on the healthcare system, their families and society at large. Possible pathophysiological mechanisms of long COVID include: persistent viral replication, chronic hypoxia and inflammation. Ongoing vascular endothelial damage promotes platelet adhesion and coagulation, resulting in the impairment of various organ functions. Meanwhile, thrombosis will further aggravate vasculitis contributing to further deterioration. Thus, long COVID is essentially a thrombotic sequela. Unfortunately, there is currently no effective treatment for long COVID. This article summarizes the evidence for coagulation abnormalities in long COVID, with a focus on the pathophysiological mechanisms of thrombosis. Extracellular vesicles (EVs) released by various types of cells can carry SARS-CoV-2 through the circulation and attack distant tissues and organs. Furthermore, EVs express tissue factor and phosphatidylserine (PS) which aggravate thrombosis. Given the persistence of the virus, chronic inflammation and endothelial damage are inevitable. Pulmonary structural changes such as hypertension, embolism and fibrosis are common in long COVID. The resulting impaired lung function and chronic hypoxia again aggravates vascular inflammation and coagulation abnormalities. In this article, we also summarize recent research on antithrombotic therapy in COVID-19. There is increasing evidence that early anticoagulation can be effective in improving outcomes. In fact, persistent systemic vascular inflammation and dysfunction caused by thrombosis are key factors driving various complications of long COVID. Early prophylactic anticoagulation can prevent the release of or remove procoagulant substances, thereby protecting the vascular endothelium from damage, reducing thrombotic sequelae, and improving quality of life for long-COVID patients.

Keywords: chronic hypoxia; early anticoagulation; endothelial injury; extracellular vesicles; inflammation; long COVID; phosphatidylserine; thrombosis.

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Conflict of interest statement

The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.

Figures

Figure 1
Figure 1
Pathophysiological mechanism of long COVID thrombosis. SARS-CoV-2 enters cells through ACE2 and TMPRSS2 receptors and conducts RNA and protein synthesis and replication. SARS-CoV-2 buds in the ERGIC compartment or Golgi apparatus and exits the cell via a biosynthetic secretory pathway. In long-COVID, SARS-CoV-2 may hide in these EVs and re-attack various tissues and organs through the circulatory system. In addition, PS exposure on EVs creates a catalytic surface for clotting factors to facilitate the conversion of prothrombin to thrombin. After cell activation and injury, ATP production is reduced and consumption increases. With the resulting increase in intracellular Ca2+, two ATP-dependent transposases (flippase and floppase) are blocked, and ATP-independent scramblases are activated. This leads to the exposure of PS in the outer cell membrane, accompanied by the shedding of microparticles (MPs). PS promotes the decryption of tissue factor (TF) to form TF-FVIIa complex and provides binding sites for procoagulant complexes (endogenous and exogenous fXase and prothrombinase) leading to the generation of thrombin. Pulmonary hypertension, pulmonary embolism and pulmonary fibrosis are common in long COVID resulting in impaired lung function. With the change of lung function, chronic hypoxia inevitably occurs. Hypoxia-induced inflammation may further exacerbate capillary dysfunction and promote thrombosis. Due to SARS-CoV-2 persistence, chronic inflammation in long COVID may be a mechanism that stimulates ECs, platelets and other inflammatory cells, promotes the upregulation of procoagulant factors, and destroys the protective function of vascular endothelium, thereby causing abnormal coagulation.
Figure 2
Figure 2
Mechanisms of endothelial injury promoting thrombosis and CLS in acute COVID-19 and long COVID. After vascular endothelial injury, there may be weakened anticoagulant properties, increased permeability and leukocyte adhesion. TF expression on ECs surface is up-regulated. Antithrombin III, TF pathway inhibitor and protein C system are damaged and lose anticoagulant properties. Injured ECs can release vWF, factor VIII and PS exposure to promote a hypercoagulable state. Furthermore, ECs can increase the expression of chemokines on their surface, promote neutrophil recruitment, and participate in thrombosis. SARS-CoV-2 and cytokines (such as TNF-α, IL-1, IL-6) damage the vascular endothelium, resulting in ECs contraction, connections separating and the appearance of intracellular gaps. The general increase in capillary permeability forms a local or SCLS. The increased permeability of pulmonary capillary endothelial injury can lead to plasma entering the alveolar cavity and form hypoxemia. Furthermore, hypoxia aggravates the contraction of pulmonary capillary ECs which thicken and narrow the capillaries, ultimately causing pulmonary hypertension. The plasma and some erythrocytes in the pulmonary capillaries are pushed into the alveolar space, further aggravating respiratory dysfunction and ARDS. As the disease progresses, injury to circulating blood cells and vascular endothelium can activate cytokines release, resulting in extensive capillary ECs damage, increasing the transport channel diameter and vessels permeability, and albumin leakage in the blood vessels.
Figure 3
Figure 3
Thrombotic sequelae and possible outcomes of early anticoagulation in long COVID. (A) In long COVID, EV-delivered virus persistently attacks systemic systems, coupled with chronic hypoxia and persistent inflammatory responses, which collectively damage the vascular endothelium. The above factors also lead to PS exposure on the surface of various types of cells and EVs from which they are derived. These factors influence each other and together promote thrombosis. (B) We propose a hypothesis that early prophylactic anticoagulation in COVID-19 can quickly remove a variety of procoagulant substances, thereby protecting the blood system and surrounding tissues and organs from damage, inhibiting PS exposure to initiate coagulation, and avoiding thrombosis and sequelae.
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