The background story to the discovery of microscopic fibrin aggregates in our patients with pulmonary embolism (PE) is unusual. We were collaborating with colleagues from Krakow in Poland to investigate the structure of blood clots in patients with acute PE, before and after treatment with low-molecular weight heparin (LMWH), a blood thinning drug. Our aim was to identify patients in which LMWH heparin was most effective. We took blood donations from each patient, using sodium citrate to chelate calcium and thus prevent the blood from clotting, and centrifuged the sample to separate blood plasma from the cells. These samples were then frozen and shipped to Leeds, UK. Next we defrosted the samples in Leeds, re-calcified the plasma and added a small dose of thrombin (pivotal coagulation factor) to make clots. This was followed with detailed biophysical and microscopic analysis of the structure of each clot, which is made from fibrin strands that form a 3D network constituting the backbone structure of the blood clot. These experiments were performed during spring to early summer 2019.
We saw structures that we had not seen before, consisting of lots of microscopic aggregates embedded into the fibrin strands. We presented some of these finding at the European Congress on Thrombosis and Haemostasis (ECTH) in Glasgow, October 2019. We have extensive experience with the analysis of clot structure in healthy volunteers and in different patients, but had never seen similar structures. This made us suspicious of the nature of our observations. Could there be something wrong with the way the samples were collected and processed? And why did the aggregates not separate out with the blood cell fraction after centrifugation, since some of the aggregates were at least the same size as for example red blood cells, sometimes larger? In view of these uncertainties, we decided to park our observations for further investigation at a later date.
In the next 6-12 months, the world was taken by surprise by the COVID-19 pandemic, locking down normal life as we knew it, minimising social interactions to limit the spread of the SARS-CoV2 virus responsible for the disease. In 2020 reports started emerging from one laboratory that patients with COVID-19 showed aggregates in their plasma which the authors called ‘microclots’. In 2021 and 2022, ‘microclots’ were also reported by the same laboratory in the plasma of patients with long-COVID, also called post-COVID syndrome. Long-COVID is a severely debilitating disease, in which patients continue to show symptoms of fatigue, shortness of breath, chest pain, memory and concentration issues and other symptoms, the combination and severity of which vary among patients.
The similarities between the ‘microclots’ reported in COVID-19 or long-COVID and the microscopic fibrin aggregates that we found back in 2019 in patients with PE (note that this was before the COVID-19 outbreak) were striking and led us to proceed with publication of our data. We felt it important to publish our data for two key reasons: 1) the data act as independent confirmation of previous reports all originating from one laboratory about the presence of fibrin aggregates in the blood plasma from patients with thrombotic disease, 2) we report the presence of fibrin aggregates in patients with PE.
Nevertheless, we feel it really important to outline a number of critical research questions that remain unanswered regarding ‘microclots’ or aggregates and their relationship to disease. First, it is surprising that the aggregates remain in the plasma after centrifugation as they should be large enough to precipitate with the blood cells. We tried double centrifugation but that did not eliminate the particles. This raises the question if the particles are formed after the blood is taken (in the test tube) or if they occur in circulation. Thus far there is no direct evidence that they actually occur in the circulation. Second, if they do occur in the circulation, we don’t know how these microscopic aggregates are generated. Are they caused by systemic low-grade coagulation activity? Or are the microscopic fragments that break off from clots elsewhere in the body? Or are they generated through another, as yet unknown, mechanism? Third, we do not know if the aggregates are consequence, or cause of disease.
There is an urgent need to address these crucial research questions. This should be done before inferences are made about their possible role in diseases such as PE, COVID-19 and long-COVID, and before risky and unsubstantiated treatments are undertaken targeted at removing ‘microclots’ or aggregates. Some patients with long-COVID are choosing to undergo plasmapheresis at private clinics, a technique which replaces the blood plasma through extracorporeal filtration, followed by triple anticoagulation (oral anticoagulants, antiplatelets and LWMH). Plasmapheresis is not without risk of infection, and the largest risk of the triple anticoagulation is severe bleeding.
In view of the severity of long-COVID and the lack of treatments for the disease, it is understandable that patients may want to try anything that could help. However, there is only anecdotal but no reliable trial evidence that plasmapheresis works to reduce long-COVID symptoms. Moreover, there is no scientific evidence that the treatment works to eliminate ‘microclots’. There are no studies showing a reduction of ‘microclots’ after plasmapheresis treatment compared to before. Crucially, above research questions regarding the nature and causality of ‘microclots’ need to be addressed before we attempt costly treatments that could do more harm than good. We hope that our study provides a stimulus to do more research in this area. It is urgently needed for those who await the development of successful treatment.
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