Covid-19 is known to generate uniquely numerous, large, and insoluble micro clots. These clots contain high levels of inflammatory markers, eg. alpha 2 antiplasmin (a fibrinolysis inhibitor), which prevent these clots from breaking down (fibrinolysis). Further, these clots are highly resistant to trypsinization, and thus traditional micro clotting markers (eg. D-Dimer tests), are often unable to pick them up. Currently, manual fluorescent microscopy is required for their diagnostic. Standard scientific microscopes can be used, if the plating procedure is done correctly. Further validation is required to determine whether microclots are a precise and accurate LC diagnostic, but the initial results are promising. Developing high throughput, efficient microclotting diagnostics will be crucial for more widespread use of microclotting as a diagnosis.
Proposed mechanism of action:
Endothelial inflammation → micro-clotting → hypo-poerfusion → hypoxia to different organs → multiple symptoms
- significant failure in the fibrinolytic process during COVID-19 and also in patients with lingering Long COVID/PASC symptom
- Plasma samples from Long COVID/PASC still contain large anomalous (amyloid) deposits (microclots).
- These microclots in both acute COVID-19 and Long COVID/PASC plasma samples are resistant to fibrinolysis even after trypsinization
- After a second trypsinization, the persistent pellet deposits (microclots) were solubilized. We detected various inflammatory molecules that are substantially increased in both the supernatant and trapped in the solubilized pellet deposits of acute COVID-19 and Long COVID/PASC
- Substantial increase in α(2)-antiplasmin (α2AP), various fibrinogen chains, as well as Serum Amyloid A (SAA) that were trapped in the solubilized fibrinolytic-resistant pellet deposits.
- hypercoagulability due to significant increases in inflammatory molecules, (ii) circulating microclots and hyperactivated platelets, and (iii) an aberrant fibrinolytic system, are all driven by a dysfunction in clotting protein and lytic enzyme supply and demand. Central to hypofibrinolysis and persistent microclots is the presence of a significant increase in α2AP
- Spike protein from severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) binds to the blood coagulation factor fibrinogen and induces structurally abnormal blood clots with heightened proinflammatory activity
- COVID-19 patients had fibrin autoantibodies that persisted long after acute infection
- reveal a procoagulant role for the SARS-CoV-2 Spike and propose fibrin-targeting interventions (eg. Monoclonal antibody 5B8) as a treatment for thromboinflammation in COVID-19
- Massively increased levels of von Willebrand Factor (VWF) lead to overwhelming platelet activation, as well as activation of the enzymatic (intrinsic) clotting pathway. In addition, there is an impaired fibrinolysis, caused by, amongst others, increased levels of alpha-(2) antiplasmin.
- The end result is hypercoagulation (proven by thromboelastography® (TEG®)) and reduced fibrinolysis, inevitably leading to a difficult-to-overcome hypercoagulated physiological state. Platelets in circulation also plays a significant role in clot formation, but they themselves may also drive hypercoagulation when they are overactivated due to the interactions of their receptors with the endothelium, immune cells or circulating inflammatory molecules.
- One variant of postural tachycardia syndrome (POTS), designated low-flow POTS, is associated with decreased peripheral blood flow related to impaired local vascular regulation.
- flow-dependent nitric oxide release is reduced in low-flow POTS
- Observed a high frequency of CD4+T cell-platelet aggregates in COVID-19 inpatients that inversely correlated with lymphocyte counts.
- Platelets from COVID-19 inpatients but not from healthy donors (HD) inhibited the up-regulation of CD25 expression and TNF-α production by CD4+T cells.
- In addition, IFN-γ production was increased by platelets from HD but not from COVID-19 inpatients
- A high expression of PD-L1 was found in platelets from COVID-19 patients to be inversely correlated with IFN-γ production by activated CD4+T cells co-cultured with platelets. We also found that a PD-L1 blocking antibody significantly restored platelet-ability to stimulate IFN-γ production by CD4+T cells.
- Suggests that platelets might contribute to disease progression in COVID-19 not only by promoting thrombotic and inflammatory events, but also by affecting CD4+T cells functionality.
- Most symptoms of Gulf War Illness (GWI) are similar to Chronic Fatigue Syndrome (CFS) and/or Fibromyalgia (FM).
- They investigated whether these symptoms are associated with an activated coagulation system as has been reported in some cases of CFS/FM.
- The coagulation assays include activation markers of the cascade, platelet activation and hereditary risk factors.
- Their findings show activation of the coagulation system in GWI. This evidence of a hypercoagulable state suggests that symptoms may be due to poor blood flow and, therefore, a basis for the potential utility of anticoagulant therapy.
- Clogged Pipes and Micro Clots: Are ME/CFS, Fibromyalgia and Long COVID Endothelial Cell Diseases?
- PolyBio Interview with Dr. Pretorious
Key Players #
- Dr. Resia Pretorious
- Dr. Asad Khan
- Dr. Anna Brooks:
- Working to develop flow cytometry micro clotting diagnostics