Novel mechanism of the COVID-19 associated coagulopathy (CAC … – Nature.com

The severe acute respiratory syndrome coronavirus 2; SARS-CoV-2 is responsible for coronavirus disease1,2. COVID-19 induced coagulopathy appears to be different from the traditional coagulopathy in many ways since it meets the criteria for the relatively newly defined entity of sepsis-induced coagulopathy (SIC) that is characterized, and quantified according to reduced platelet counts, increased international normalized ratio (INR), and higher organ dysfunction in SARS-CoV-2 patients3. The findings during the last few years after COVID-19 pandemic have suggested that SARS-CoV-2 has a connection with various blood disorders, including a higher risk of clot formation and sometimes bleeding problems in acutely infected patients4,5,6,7. During infection, the frequently observed micro- and macro- thrombotic events are due to the perpetuation of a state of hypercoagulability that has been termed as the COVID-19-associated coagulopathy (CAC) and, in fact, it is different from the regular clotting problems8. The so-called CAC represents a key aspect for the development of multi-organ damage in patients. In CAC the changes are represented by high levels of D-dimer and fibrinogen; however, CAC also has some common features with disseminated intravascular coagulation (DIC) and SIC, but there are differences between these clinical observations. It appears that the pathogenesis of CAC is more complex and is influenced by an interconnection between the inflammatory system and coagulation, in the phenomenon of immuno-thrombosis and thrombo-inflammation. In CAC many factors come into play including the neutrophils, inflammatory cytokines, complement system as well as fibrinolytic system. Finally, changes in platelet function coupled with endothelial dysfunction also play roles in CAC. Though we are still piecing together exactly how it happens, several factors such as problems with endothelial lining, inflammation, and an intense immune system response affects in raising the risk of clotting. Moreover, in severely acute infection, the immune system can go off the track. This can lead to additional issues with a part of the immune system called the complement system, which can also damage blood vessels making clotting problems worse9.

When platelets get activated, they stick together and release chemicals that promote inflammation. This makes blood clot formation more easily. In regular clotting, the making of thrombin helps turn fibrinogen into fibrin the material that makes up clots. Conditions like hemophilia, where some clotting factors are missing, or DIC, where too much of this process happens, lead to standard clotting problems. So, the main differences between CAC and regular clotting problems lie in how they happen. In regular clotting problems, making of thrombin is important for clotting to occur but in CAC, the risk of blood clots arises from a mix of inflammation, problems with blood vessel lining, platelet activation, and issues with the immune systems response9. The spike protein or SP also interacts with the clotting process. This contributes to the unique clotting situation seen in CAC. Understanding these aspects of CAC is crucial for devising care for COVID-19 patients, especially for people with weakened immune systems like diabetics, who face clotting-related problems more often than those without diabetes10,11,12,13,14,15,16.

Briefly, the coronaviruses that cause severe acute respiratory syndrome (SARS), such as SARS-CoV, MERS-CoV (responsible for the middle east respiratory syndrome), and SARS-CoV-2, need transmembrane serine protease 2 (TMPRSS2) for their entry into the host cells. Subsequent studies have also shown that SARS-CoV-2 requires the angiotensin-converting enzyme 2 (ACE2) as the main receptor together with TMPRSS2 for infecting the host cells productively17,18,19. SARS-CoV-2 is a single-stranded ribonucleic acid (RNA) virus that encodes a variety of proteins, including 4 structural proteins such as (1) Membrane/Matrix (M), (2) Envelope (E), and (3) Spike (S) proteins that assemble around (4) Nucleocapsid (N) and its RNA. As mentioned above, the virus infects host cells upon binding to ACE2 receptor, and subsequent action of proteases, including the transmembrane protease serine 2 (TMPRSS2). The virus exhibits a high infectious rate and can provoke a wide array of symptoms beginning with the cytokine storm20,21. The recent pandemic is the third outbreak due to a highly pathogenic -coronavirus in only just two decades. Thus, there is a tremendous need to acquire in-depth knowledge of the virus infection cycle, as well as the cellular and molecular pathways that are involved in the viral replication and mounting of the innate and adaptive immune responses in the host. We believe that answers to these fundamental questions will help us in the development of safer, and efficient therapeutics and pan--coronavirus vaccines against emerging SARS-CoV-2 variants and their subvariants of concern22. ACE turns angiotensin I into angiotensin II, which has multiple effects throughout our body such as increase in blood pressure. Angiotensin I is cleaved by angiotensin-converting enzyme (ACE) to produce angiotensin II, and then Angiotensin II binds to its receptors and exerts its effects in the brain, kidney, adrenal, vascular wall, and the heart. Although SARS-CoV-2 spike protein (SP) masks the ACE2, but it increases the availability of angiotensin (Ang II; 18) and decreases the Ang (17), suggesting a role in hypertension23,24,25,26. Although COVID-19 has been linked to orthostatic tachycardia (OT), again the mechanisms are largely unknown. The heart rate of the patient increases by ~30 beats/min; however, the blood flow to the brain decreases that causes hypoperfusion, and vascular contributions to cognitive impairment and dementia (VCID). This also suggests a role of vascular coagulopathy, and thrombosis for the decrease in the blood flow to brain27. Since so many complications are associated with COVID-19 including the vascular coagulopathy/thromboembolism, endothelial dysfunction, stiffness, fibrosis, and extracellular matrix (ECM) fragmentation9,28,29,30,31,32,33,34,35,36, but the underlying mechanisms of these events are unclear.

The ongoing research in our laboratory is based on our previous studies that have shown activation of inflammatory M1 macrophages with renal infiltrates in the hACE2 mice administered with SP, intranasally37. In COVID-19 patients there is an elevated level of neopterin (NPT)38,39. Because NPT is generated by activated pro-inflammatory macrophages (M1) in response to COVID-19 via inducible nitric oxide synthase (iNOS), tetrahydrobiopterin (BH4), and peroxinitrite (ONOO-) along with activation of proteinases. We are of the opinion that iNOS generates NPT and decreases BH4, eNOS activity and a disintegrin and metalloproteinase thrombospondin 13 domain (ADAMTS13), anti-thrombosis/anti-coagulant but at the same time activates urinary neutrophil gelatinase associated lipocalin2 (NGAL2, pro-thrombosis/pro-coagulant), and transmembrane serine proteinase S2 (TMPTSS2, proteolytic factor processing of COVID-19) and matrix metalloproteinases (MMPs), leading to renal dysfunction and failure18,40,41,42,43. NGAL and FGF23 (vascular hypertrophic factor) are high and ADAMTS13 is low post COVID-19 sequelae44,45,46,47,48. Again, the recognition of endothelial dysfunction within the realm of COVID-19 is emerging as a pivotal and defining aspect of SARS-CoV-2 infection, and its post infection implications especially against the background of the intricate interplay between endothelial cells and immune constituents, exemplified by the dynamic interaction with neutrophils in the context of thromboembolism, assumes paramount significance. This alliance between endothelial cells lining and immune effector molecules that our work has reported earlier prompts a series of inquiries that underscore the pivotal role of endothelial cells in the intricate landscape of thromboembolic events37. A further deeper exploration into the mechanisms underpinning endothelial dysfunction can unravel its contribution to the disruption of coagulation equilibrium, particularly within the intricate milieu of CAC. This knowledge will enhance our comprehension of the pathophysiological mechanisms at play but also to pave the way for the identification of strategic interventions aimed at safeguarding our patients during the throes of acute infection. Hence, by delving into the nuanced of how endothelial dysfunction precipitates coagulation dysregulation, particularly within the context of COVID-19 related coagulopathic manifestations, a potential roadmap might emerge via an understanding of the molecular interactions that could hold the promise of unveiling therapeutic avenues designed to shield afflicted patients during the critical phase of acute infection49.

Interestingly, CAC in glomerular capillaries-microvascular wall, the interaction between macrophages, neutrophil and immune cells, causes build-up layers of damage endothelial via iNOS, NGAL2, eNOS, and ADAMTS13, sets the stage of pro-thrombotic and pro-coagulant processes. This also contributes to focal glomerulosclerosis lesions in COVID-19 patients50,51. The levels of transmembrane (TMPRSS2), EMMPRIN (CD147) and ECM proteinases are elevated post COVID-1918. These proteinases are associated with collagen/elastin breakdown during renal glomerular remodeling. However, because the turnover of collagen is rapid than elastin, the degraded elastin is replaced by collagen, causing fibrosis, stiffness, and thickening of the basement membrane in the glomeruli, instigating impaired glomerular filtration rate (GFR)52. Therefore, an increase in M1 macrophages iNOS decreases BH4 bioavailability to eNOS, causing glomerular capillary microvascular endothelial dysfunction. The oxidative peroxinitrite (ONOO-) activates NGAL2 and FGF23 and decrease in ADAMTS1353,54. The transmembrane serine (TMPRSS2), EMMPRIN and MMPs/TIMPs are activated, leading to renal dysfunction. Interestingly, there appears to be evidence of fibrosis with hypertrophy in the glomeruli of hACE2 mice administered with SP within 4 weeks post COVID-19 sequelae, as expected, since this will suggest that there is acute kidney injury (AKI) with preserved glomerular filtration rate (GFR), that can be reversed by iNOS blocker37. However, if there is chronic thickening of the basement membrane, post COVID-19, this will suggest that there is chronic kidney disease (CKD). In that situation an inhibitor of proteinases, such as TMPRSS2 will be able to mitigate the COVID-19 induced CKD. This is important and novel in the sense that post COVID-19 morbidities, and mortalities can be halted with a TMPRSS2 inhibitor.

Further, in the landscape of biomarkers linked to endothelial dysfunction, the circulating inflammatory coagulation markers assume a pivotal role, notably the fibrin(ogen), D-dimer, P-selectin, and von Willebrand Factor (VWF). These biomarkers, in their close relationship with endothelial cells, platelets, and erythrocytes, contribute significantly to the pathological progression observed in acute COVID-19 cases55. For example, the fibrin(ogen) and D-dimer are indicative of ongoing coagulation and fibrinolysis processes, exhibiting a dynamic connection with MMP-2, MMP-9, and MMP-1356. These MMPs can potentially modulate the stability of blood clots, thereby impacting both clot formation and dissolution. The interplay between these biomarkers might amplify the coagulopathic tendencies observed in severe COVID-19 patients, thus accentuating the pro-thrombotic environment. Interestingly, the Von Willebrand Factor (VWF) and P-selectin are integral to platelet adhesion and aggregation, and intersect with ADAMTS-13, a critical regulator of VWF cleavage57,58. Thus, a dysregulation of ADAMTS-13 in COVID-19 could lead to increased VWF activity, thereby fostering the microvascular thrombosis. This interaction, coupled with the intricate role of MMPs, might contribute to the endothelial activation and damage central to the disease pathogenesis. On the other hand, the renal NGAL, is a biomarker of kidney injury, and that usually reflects the broader systemic impact of inflammation and coagulation in COVID-19 patients59. Its interplay with MMP-7 or matrilysins (it was originally described as PUMP-1; putative uterine metalloprotease-1), and was long considered a third member of the stromelysin family, although it appeared only distantly related to the other stromelysins, and later dubbed MMP-7, a possible reference to ion transporters, underscores the systemic implications of electrolyte imbalance in severely ill patients, potentially affecting both coagulation and vascular health60,61. Furthermore, TMPRSS2, an enzyme facilitating viral entry, adds another layer to this complex narrative. Its interplay with these biomarkers might signify a feedback loop where the virus-induced dysregulation contributes to coagulopathic tendencies, potentially mediated by the interplay of endothelial cells, platelets, and erythrocytes62,63,64,65,66. In a nutshell, the interaction between fibrin(ogen), D-dimer, P-selectin, VWF, and biomarkers like MMPs, ADAMTS-13, renal NGAL, PUMP, and TMPRSS2 intertwine within the context of acute COVID-19. This intricate interplay encompasses endothelial dysfunction, platelet aggregation, coagulopathy, and systemic impact, collectively contributing to the complex pathogenesis observed in severe cases. Understanding these connections will aid not only in deciphering disease mechanisms but also in the identification of potential avenues for therapeutic intervention for the patients.

In the intricate landscape of biomarkers linked to endothelial dysfunction, certain circulating inflammatory coagulation biomarkers assume a pivotal role, notably the fibrin(ogen), D-dimer, P-selectin, and von Willebrand Factor (VWF). These biomarkers, in their close relationship with endothelial cells, platelets, and erythrocytes, contribute significantly to the pathological progression observed in acute COVID-19 cases. For example, the fibrin(ogen) and D-dimer are indicative of ongoing coagulation and fibrinolysis processes, exhibiting a dynamic connection with MMP-2, MMP-9, and MMP-13. These MMPs can potentially modulate the stability of blood clots, thereby impacting both clot formation and dissolution. The interplay between these biomarkers might amplify the coagulopathic tendencies observed in severe COVID-19 patients, thus accentuating the pro-thrombotic environment. Interestingly, the Von Willebrand Factor (VWF) and P-selectin are integral to platelet adhesion and aggregation, and intersect with ADAMTS-13, a critical regulator of VWF cleavage. Thus, a dysregulation of ADAMTS-13 in COVID-19 could lead to increased VWF activity, thereby fostering the microvascular thrombosis. This interaction, coupled with the intricate role of MMPs, might contribute to the endothelial activation and damage central to the disease pathogenesis. On the other hand, the renal NGAL, is a biomarker of kidney injury, and that usually reflects the broader systemic impact of inflammation and coagulation in COVID-19 patients. Its interplay with MMP-7 or matrilysins (it was originally described as putative uterine metalloprotease-1 (PUMP-1) in 1988, and was long considered a third member of the stromelysin family, although it appeared only distantly related to the other stromelysins, and later dubbed MMP-7, a possible reference to ion transporters, underscores the systemic implications of electrolyte imbalance in severely ill patients, potentially affecting both coagulation and vascular health. Furthermore, the TMPRSS2, an enzyme facilitating viral entry, adds another layer to this complex narrative. Its interplay with these biomarkers might signify a feedback loop where the virus-induced dysregulation contributes to coagulopathic tendencies, potentially mediated by the interplay of endothelial cells, platelets, and erythrocytes. In summary, the interaction between fibrin(ogen), D-dimer, P-selectin, VWF, and the mentioned biomarkers like MMPs, ADAMTS-13, renal NGAL, PUMP, and TMPRSS2 intertwines within the context of acute COVID-19. This intricate interplay encompasses endothelial dysfunction, platelet aggregation, coagulopathy, and systemic impact, collectively contributing to the complex pathogenesis observed in severe cases. Understanding these connections will aid not only in deciphering disease mechanisms but also in identifying potential avenues for therapeutic interventions.

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Novel mechanism of the COVID-19 associated coagulopathy (CAC ... - Nature.com