Some people infected with the SARS-CoV-2 virus that causes COVID-19 can experience long-term health effects from the infection and can be referred to as Long COVID. As there are no clear definitions, other names or terms which refer to the same circumstance and symptoms include:

• post-acute sequelae of COVID (PASC),
• post-COVID conditions,
• long-haul COVID,
• post-acute COVID-19,
• long-term effects of COVID,
• chronic COVID, and
• post-acute sequelae of SARS-CoV-2 infection.

To date there is no effective treatment for long COVID. Investigating the mechanism and impact of Long COVID thrombosis will assist with improving an understanding of early antithrombotic treatment and avoid thrombotic sequelae. Symptoms of Long COVID can vary; they include fatigue, brain fog, loss of concentration, forgetfulness, shortness of breath and joint or muscle pain.

Ongoing vascular endothelial cell damage is one of the long-term effects of COVID-19. This damage promotes adhesion and coagulation, resulting in the impairment of various organ functions. In addition, thrombosis will exacerbate vasculitis contributing to further deterioration. Therefore, making Long COVID a thrombotic sequela.

Evidence shows there is coagulation abnormalities leading to thrombosis associated with Long COVID. One posit is that extracellular vesicles (EVs) discharged by various cells can carry SARS-CoV-2 within the circulatory system and attack tissues, organs and specific components, which can aggravate thrombosis. The virus hitches a ride on the EV transporters, which then disembark at various stops around the body. There is no reference range for how long the virus remains in the body after infection, however, the virus is usually present for 30 days in an average body, and the longest bouts of viral infection reported is between 169-505 days.  Given the persistence of the virus, chronic inflammation and endothelial damage are unavoidable.

Numerous studies found several vein thrombi (DVT, PE, splanchnic vein) persists in COVID-19 patients months post recovery. Thrombosis biomarkers are elevated 2 months after hospital discharge, whereby 73% of patients having elevated erythrocyte sedimentation rate and C-reactive protein. Other research findings after 4 months post-infection showed enhanced thrombin-generating capacity and decreased plasma fibrinolytic potential, demonstrating a sustained prothrombotic state. Other factors include endothelial cell biomarkers which are significantly elevated in COVID-19 recovered individuals.

Another research pathway found that microclot and platelet pathologies were associated with Long COVID/PASC symptoms. These findings suggest that fibrin amyloid microclots block capillaries and inhibit the transport of oxygen to tissues; together with platelet hyperactivity, this may offer some clarification for the symptoms linked with long COVID. Another study believes that the ability of fibrin amyloid microclots (fibrinaloids) to block capillaries and restricts blood flow and oxygen exchange, could potentially underpin the majority of long COVID symptoms.

Post-pulmonary thrombosis syndrome can also manifest as persistent thrombosis in Long COVID. Lung vulnerability, in the early stage of COVID-19, and damage to the local vascular endothelial cells is difficult to predict. However, impairment to these cells often serve as the initial site of thrombosis. At this stage, activated vascular ECs are frequently ignored, however, they remain suspect initiators of long COVID after hospital discharge. Pulmonary hypertension, embolism and fibrosis are common sequelae of the lungs. The heightened defence system will unavoidably cause tissue damage while killing the virus. Together with initiating the coagulation cascade system, activating Factor X and promoting thrombin production, this combination catalyses the conversion of fibrinogen to fibrin resulting in pulmonary microthrombi production, leading to an adverse outcome for haemostasis.

PBI Research

Perth Blood Institute are partnering with Gamma Diagnostics to study the role that Gamma Prime Fibrinogen (GPF) plays in various inflammatory disease states. The Long COVID Syndrome Study (GPF LoCov Study) will be investigating if a certain coagulation factor, Gamma Prime Fibrinogen (GPF) is elevated in patients with acute and long COVID. As GPF is also an inflammatory marker associated with cardiovascular disease (Appiah et al. 2015), a secondary aim of the study is to see if there is a correlation between GPF and other coagulation, inflammatory and endothelial markers. 

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Glossary

Endothelial cells – form the barrier between vessels and tissue; control the flow of substances and fluid into and out of a tissue; line blood vessels.

Sequelae – a pathological condition resulting from a prior disease, injury or attack.

Extracellular vesicles – structures released by cells which can mediate cell-to-cell communication and participate in normal haemostatic processes as well as pathological disease states.

Erythrocyte sedimentation rate (ESR) – a blood test that shows inflammation in the body.

C-reactive protein – a coagulation protein where high levels in the blood indicate inflammation in the body.

Factor X – a coagulation protein with critical roles in the coagulation cascade.

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References

• Appiah, D. et al. (2015). Association of plasma gamma fibrinogen with incident cardiovascular disease: The atherosclerosis risk in communities (ARIC) study. Arterioscler Thromb Vasc Biol. 35(12):2700-6. doi:10.1161/ATVBAHA.115.306284.
• Wang, C., Yu, C., Jing, H., Wu, X., Novakovic, V.A., Xie, R. & Shi, J. (2022) Long COVID: The nature of thrombotic sequelae determines the necessity of early anticoagulation. Cell. Infect. Microbiol. 12:861703. doi: 10.3389/fcimb.2022.861703
• Zifkos, K., Dubois, C. & Schäfer, K. (2021). Extracellular vesicles and thrombosis: Update on the clinical and experimental evidence. Int J Mol Sci. 27;22(17):9317. doi:10.3390/ijms22179317
• Camire, R.M. (2021). Blood coagulation factor X: molecular biology, inherited disease, and engineered therapeutics. J Thromb Thrombolysis. 52(2):383-390. doi: 10.1007/s11239-021-02456-w
• Kell, D.B., Laubscher, G.J., & Pretorius, E. (2022). A central role for amyloid fibrin microclots in long COVID/PASC: origins and therapeutic implications. Biochem J. 17;479(4):537-559. doi: 10.1042/BCJ20220016.
• Erythrocyte Sedimentation Rate (ESR): MedlinePlus Medical Test
• C-reactive protein test - Mayo Clinic