Coagulopathy, the formation of small blood clots that go on to wreck respiratory and neurologic havoc, has long been a clinical hallmark of COVID, and now it's oft-ignored Long COVID. A new study suggests that fibrin, a key component of blood clots, plays a role.
Fibrin provides structure to a blood clot and is derived from fibrinogen, a soluble blood protein when the coagulation cascade is activated. If you think of a blood clot as nature’s way of plugging a leak, fibrin deposition is frequently found where there is damage to the walls of blood vessels and the vessels making up the blood-brain barrier. Fibrin serves as a plug and a signal for a greater inflammatory and immune response.
Given the unique clinical presentation of clotting in COVID compared to other respiratory viruses, the researchers hypothesized that COVID directly binds to fibrinogen, promoting blood clot formation and altering clot structure and function. They found that the spike protein of the virus binds to fibrinogen and fibrin at specific binding sites, suggesting that the virus might contribute to abnormal clotting by interacting with fibrinogen.
They found that the spike protein altered the structure of clots, making them denser and more resistant to the body’s natural means of removing clots, a process called fibrinolysis. Additionally, the spike protein enhanced the inflammatory signals from fibrin, increasing oxidative forces (reactive oxygen species or ROS) released from macrophages, a first responder of the immune system.
In converting fibrinogen to fibrin, the spike's binding site (epitope) is exposed. Therapeutically, having identified binding regions, the research found that antibodies could disrupt and reduce these pro-inflammatory effects implicated in acute and long COVID. Among the inflammatory effects reduced by blocking the actions of fibrinogen was the deposition of collagen in the lungs, which creates a barrier to oxygen passage and helps to explain the refractory response to supplemental oxygen we have seen in patients.
Fibrin also suppresses natural killer (NK) cells, which are called "natural killers" because they can recognize and kill stressed cells without prior exposure to a particular pathogen, making them critical first responders. The suppression of NK cell activity results in enhancing viral persistence and lung inflammation.
In additional studies in mice, the researchers found that this fibrin-dependent inflammatory response occurs independently of the active virus, suggesting a potential mechanism for persistent symptoms in Long COVID. [1] Therapeutically, in their mouse model, the use of a monoclonal antibody targeting the fibrin epitope, in addition to reducing the lung’s inflammatory response, reduced neuroinflammation (associated with long COVID’s brain fog). There were reductions in fibrin deposition and microglial reactivity “leading to improved neuronal survival and reduced white-matter injury.” Microglia are the primary immune cells of the central nervous system.
To summarize:
- Coagulopathy in COVID-19 is a primary driver of thrombo-inflammation and neuropathology rather than a consequence of systemic inflammation.
- Fibrin plays a causal immunomodulatory role in promoting hyperinflammation, neuropathological alterations, and increased viral load in COVID-19 by modulating NK cells, macrophages, and microglia.
- Elevated fibrinogen levels and BBB permeability in COVID-19 contribute to neuropathology, and targeting fibrin may offer a dual mechanism of action by inhibiting fibrin-spike interactions and exerting anti-inflammatory effects. A fibrin-targeting antibody effectively blocks many pathological effects of fibrin, providing neuroprotection and reducing thrombo-inflammation.
Their findings have limitations, including how they measured changes in brain tissue, the use of mouse models, and the fact that our inflammatory response may have more than one pathway that results in COVID-19’s deleterious effects. For Long COVID, the fibrin-targeted antibody does not interfere with normal clotting, acting solely on fibrin's inflammatory responses, making it a candidate to protect against pulmonary and cognitive impairment; that will, of course, require clinical trials.
And there you have it—the silent saboteur behind the lingering specter of Long COVID. Fibrin is not just a bystander in the aftermath of COVID-19; it's a key player driving the chronic symptoms that continue to baffle patients and clinicians alike. The discovery that the virus’s spike protein meddles with fibrin, transforming it into a resilient, inflammatory force, opens a new frontier in the fight against the pandemic’s long tail. The research, though groundbreaking, is still in its early days, confined to animal models, and the complexities of human biology could introduce new challenges.
But if the science holds, targeting fibrin could offer a two-for-one punch against the clotting and inflammation that underpin much of the damage COVID-19 leaves in its wake. For the millions grappling with the enduring effects of Long COVID, this could be a glimmer of hope—a chance to reclaim their lives.
[1] The inquisitive with a conspiratorial bent might link these inflammatory responses in the absence of infection to deaths felt to be due to the COVID vaccines, which employ the spike as antigenic stimulus. The researchers note that most hematologic changes are triggered by the vaccine vector (an adenovirus) and that “COVID-19 RNA vaccines lead to small amounts of spike protein accumulating locally and within draining lymph nodes where the immune response is initiated, and the protein is eliminated.”
Source: Fibrin drives thrombo-inflammation and neuropathology in COVID-19 Nature DOI: 10.1038/s41586-024-07873-4
Chuck Dinerstein, MD, MBA
Director of Medicine
Dr. Charles Dinerstein, M.D., MBA, FACS is Director of Medicine at the American Council on Science and Health. He has over 25 years of experience as a vascular surgeon.
