Inflammation and blood clotting in very severe cases of COVID-19 may be caused by the antibodies


Inflammation and blood clotting seen in very severe cases of COVID-19 may be caused by the antibodies sent to fight the disease activating unnecessary platelet activity in the lungs.

A new paper published in the journal Blood reveals how antibodies produced by our bodies to protect against COVID-19 are triggering increased function of platelets, which may be causing fatal blood clots in patients with severe disease.

Platelets are small cells found in blood which form clots to stop or prevent bleeding, but where platelets don’t function properly this can lead to serious health concerns such as strokes and heart attacks.

The study took antibodies produced to fight the coronavirus’s spike protein, from people with severe COVID-19 infections, and cloned them in a lab to study. The team found that the small sugars found on the surface of these antibodies were different to antibodies from healthy individuals, and when those cloned antibodies were introduced in a lab to blood cells taken from healthy donors, there was an observed increase in platelet activity.

The study team also found that it was possible to reduce or stop platelets from responding in this way in the laboratory by treating blood with active ingredients from different medication which is known to either inhibit platelet function or immune responses.

The findings suggest that it may be possible for drugs that are currently used to treat immune system problems to reduce or stop the cells from producing an exaggerated platelet response.

A trial led by Imperial College London and Imperial College Healthcare NHS Trust – called MATIS – is already testing these drugs in clinical trials with patients at hospital sites across the UK to see whether they will reduce serious clotting for hospitalised COVID-19 patients.

The lab-based study of human cells provides key evidence to support the scientific basis for the MATIS trial and, while there are yet to be any results reported from this clinical trial, the two teams will continue to work closely together as the clinical trial develops.

Professor Jon Gibbins, Director of the Institute for Cardiovascular and Metabolic Research at the University of Reading said:

“Until now, we have only had assumptions about why platelets involved in clotting were being activated during COVID-19 infection.

“One way to think of what is happens is that the immune response that is designed to protect you from the infection in some cases, particularly in severely ill patients, actually causes more damage. In this case, the antibodies that are produced to stop COVID-19 from spreading trigger infected cells to induce platelet activity which causes clotting even though there is no wound that needs healing.

“We are particularly excited because our studies of platelets in the laboratory establishes important mechanisms that explain how and why dangerous blood clots may occur in severely ill COVID-19 patients, and importantly, also provides clues as to how this may be prevented.”

Co-author Nichola Cooper, reader at Imperial College London and consultant haematologist at Imperial College Healthcare NHS Trust, who also designed and leads the MATIS trial said: “Early on in the COVID-19 pandemic it was clear that the infection was causing an overwhelming immune response, including blood clotting, and that many of the more severe cases and deaths were related to this.

“Having been involved in early research around blood clotting related to inflammation, it occurred to me that the drugs we already use for other disorders could be easily accessible treatments for COVID-19. We are yet to see results from the MATIS trial so we do not yet know how these drugs will work in patients, but our hope is that we can both inhibit the inflammatory response and prevent severe disease and blood clots.

It is exciting to see our collaboration with Reading backing our theory already and providing a solid scientific basis for clinical trials.”

The universal phenomenon of blood clotting is well known to be protective in external cellular/ tissue injury. However, the emergence of unusual thrombotic presentations in COVID-19 patients is the real concern. Interaction of the spike glycoprotein with ACE2 receptor present in the host cell surface mediates the entry of SARS-CoV-2 causing COVID-19 infection.

New clinical findings of SARS-CoV-2 pathogenesis are coming out every day, and one such mystery is the formation of mysterious blood clots in the various tissues and organs of COVID-19 patients, which needs critical attention. To address this issue, we hypothesis that, high ACE2 expression in the endothelium of blood vessels facilitates the high-affinity binding of SARS-CoV-2 using spike protein, causing infection and internal injury inside the vascular wall of blood vessels.

This viral associated injury may directly/indirectly initiate activation of coagulation and clotting cascades forming internal blood clots. However, the presence of these clots is undesirable as they are responsible for thrombosis and need to be treated with anti-thrombotic intervention.

Origin of hypothesis
The hypothesis for the formation of blood clots in the vessels is retrieved from the classical concept of blood clotting. The mechanism of blood clotting is like a two-edged sword, wherein the case of severe external injury, clotting is very crucial for preventing the blood loss, whereas, in the case of internal blood vessels injury, it, unfortunately, leads to the formation of blood clots, causing vascular blockades and thrombosis, expanding to every organ leading to severe and fatal outcomes.

The above concept is substantiated by the following three facts:

Recognition of ACE2 receptor-expressing endothelial cells of the blood vessels by spike protein of SRAS-CoV-2.

Direct injury to the endothelial cell by SARS-CoV-2 infection resulting in vascular damage.

Indirect damage due to immune-mediated cytokine release syndrome (CRS) causing inflammation and cell death.

To protect the direct and/or indirect damage caused by SARS-CoV-2 to endothelial cells lining the blood vessels, host innate defensive mechanism of blood clotting activates, recruiting the activated platelets at the injury site to form a clot which although reduce the damage but negatively may lead to obstruction of blood vessels and vasoconstriction causing more damage.

The virus enters into the peripheral blood causing viremia and gets transmitted to the different organs such as the heart, kidney, gastrointestinal tract resulting in multiple organ failure. As it is evident that blood clots were observed in both live and dead COVID-19 patients, so it is out most interesting to decode the mystery.

Hypothesis statement
Considering the above facts and recent unusual reports, a hypothesis develops for the blood clots formation in the COVID-19 patients (Fig. 1 ), states that “Due to an internal injury in the endothelium of blood vessels, either directly by SARS-CoV-2 infection (co-expression and binding of the spike protein with the ACE2) or my virus-mediated inflammatory immune response, may result in vasoconstriction and the activation of coagulation and blood clotting pathways, resulting in the formation of blood clots”.

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Fig. 1
Schematic representation showing the mechanism of clot formation in the blood vessels when the endothelial cells rich in ACE2 receptors are targeted by SARS-CoV-2 and resulted in the internal blood vessel injury, resulting in the cascade of blood clot formation.

Theoretical evaluation and validation

During COVID-19 infection, SARS-CoV-2 enters into the systemic circulation and binds with the ACE2 expressing endothelial cells (endothelium) lining the blood vessels. Binding facilitates the virus internalization, causing infection and injury in the vascular wall of blood vessels. The vascular injury might result in vasoconstriction, which may further reduce the blood flow at the site of injury. Also, injury to endothelial cells reduces the expression of fibrinolytic heparin and thrombomodulin. Conversely, high expression and secretion of the Von Willebrand factor enhance the aggregation of platelets at the site of injury in blood vessels and activate the coagulation cascade for the formation of blood clots.

Immediately within a few seconds of endothelial cells injury in a blood vessel, platelets along with collagen, recruit at the injury site to swell and aggregate. Soon the coagulation is initiated and fibrin strands begin to intersperse among the wound to form a complete platelet plug. Viruses like Dengue and Herpes simplex virus (HSV) are known to infect endothelial and circulating blood cells, activating coagulation cascade by promoting tissue factor [12].

Interestingly, lysis of fibrin known as fibrinolysis by fibrinolytic molecule plasminogen and plasmin proved to induce deleterious inflammation and defective fibrin clot formation in Influenza A viruses (IAV) [13]. In addition to viral stimulation, binding of an extracellular proteolytic enzyme known as urokinase-type plasminogen activator (uPA) with its receptor, uPAR is crucial for the activation of plasminogen to plasmin as reported in various malignancies [14]. Detrimental inflammation in the endothelial cells may initiate the cascade of cytokine release and subsequently leads to the blood vessel injury.

Similarly, the SARS-CoV-2 induced vascular trauma/injury, activates the platelets exposed endothelium or collagen following the intrinsic pathway. Following the injury to blood vessels, near-by platelets stick to the vascular proteins, get degranulated, releasing prothrombin activator, serotonin, adenosine diphosphate (ADP), and thromboxane A2 for further activation of platelets.

The mechanism for the formation of clots in the blood vessels may start sequentially by 12 clotting factors, i.e. activating the factor XII, converting prothrombin to thrombin and later fibrinogen to long and insoluble fibrin which may entangle with platelets by covalent cross-linking, forming a stable interlocking fibrous network of a fibrin clot at the site of injury. This may slow down the blood flow, but platelets in the clot begin to shrink to initiate the wound healing process with intrinsic and extrinsic coagulation pathways.

However, the upregulation of the expression of fibrinogen subunits FGA, FGB, and FGG also plays a very significant role in the formation of the clot. Various thrombotic complications and coagulation abnormalities are associated with COVID-19 like sepsis-induced coagulopathy (SIC), disseminated intravascular coagulation (DIC), venous thromboembolism (VTE), pulmonary embolism (PE), micro-thrombosis, microvascular thrombosis, and thrombotic micro-angiopathy.

Intense endothelial inflammation may be the involved mechanism leading to microvascular thrombosis as suggested in lung pathology contributing to ARDS [15]. SIC is hypercoagulability, characterized by elevated fibrinogen and D-dimer levels causing endothelial dysfunction, micro-thrombosis, and stroke [16].

Additionally, vasoconstriction has an inverse relation with ACE2. During systemic infection, the ACE2 expressed blood vessels’ endothelial cells, might attach to the viral spike protein resulting in the unavailability of ACE2. Renin-angiotensin-aldosterone system (RAAS) may drive the formation of micro-thrombin in COVID-19 patients stimulating Angiotensin II (Ag II) to induce tissue factor (TF) and plasminogen activator inhibitor-1 (PAI-1) expression by endothelial cells. Ag II acts on the CNS to increase vasopressin production which causes vasoconstriction.

Depletion of ACE2 by SARS-CoV-2, PAI-1/tPA imbalance, and a hyper-coagulable state may favor tissue injury and stroke [17]. This may explain the unresolved mystery of unresolved fibrin deposits in the alveoli of patients with general ARDS [18].

ACE2 converts Ag II to Ag (1–7), protecting endothelial cell function and prevent early atherosclerosis which can be caused by a clot in the blood vessels [19]. Profound hypoxemia in the pulmonary capillaries may result in the activation of hypoxia-inducible factors (HIFs) resulting in inducing or inhibition of TF and PAI-1 respectively, and vasoconstriction thereby promoting vascular occlusion [20], [21], [22].

The deposition of the C56-9 component of the complement system in the damaged vessel results in micro thrombosis as an anti-phospholipid syndrome [23]. Neutrophil extracellular traps (NET) are associated with elevated levels of histones, activating increased thrombin production [24]. In a study including 362 closed COVID-19 cases from Italy, high mortality attributed to pulmonary embolism (PE) and pulmonary thrombosis with VTE and ischemic stroke as primary and DIC as a secondary outcome.

Thromboembolic events occurred in 28 (7.7%) cases, with VTE in 16 (36%), PE in 10 (33%) and, DIC in 8 (2.2%) patients [25]. High-risk coagulation abnormalities are associated with an elevated concentration of D-dimer and a reduction in platelet count [11]. Thrombotic microangiopathy in the lungs autopsies showing aggregates of CD4 around thrombosed small vessels and are significantly associated with hemorrhage. [26].

VTE may develop via immunologic activation of intravascular and platelet-releases thrombin. Severe derangement of hemostasis, accompanied by reduced platelet count and fibrinogen, may explain the events of venous thromboembolism supporting hypercoagulability in COVID-19 positive patients [27]. Incidence of VT increase between 25% and 49% in severe COVID-19 patients, with pulmonary embolism being the most common thrombotic complication [28], [29].

Microvascular thrombotic complications are indicative of a strong interaction between the SARS-CoV-2 and coagulation. More than 80% of lung autopsies reported platelet–fibrin thrombi, especially in the small pulmonary vasculature [30]. The presence of antiphospholipid antibodies is a serious complication causing thrombotic stroke in young patients [31].

SO, in COVID-19 patients, the SARS-CoV-2 mediated endothelial inflammation, thrombin generation, platelet, and leukocyte recruitment, complement activation, and the initiation of innate and adaptive immune responses, forming clots, culminate in immunothrombosis, ultimately resulting in thrombotic complications, stroke, and finally death.

reference link :

More information: Alexander P Bye et al, Aberrant glycosylation of anti-SARS-CoV-2 IgG is a pro-thrombotic stimulus for platelets, Blood (2021). DOI: 10.1182/blood.2021011871



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