Thrombotic Microangiopathy & Precision Medicine
What’s to be learned from the Pandemic?
At various times in history, medical science has been catapulted forward during times of crisis. Such was the case with advancements made through field medicine in wartime, and with past outbreaks of infectious disease. What are some of the relevant lessons learned, and new questions arising, from how targeted treatments for COVID-19 might shed light on aspects of thrombotic microangiopathy (TMA)? This formation of tiny blood clots, which can impact organ function throughout the body, has been seen in patients infected with the SARS-CoV-2 virus but many different diseases can result in TMA (Johns Hopkins Medicine).
Thrombotic microangiopathy or TMA has these word origins: thrombotic (meaning issues with blood clotting) and microangiopathy (meaning problems within small blood vessels). A diagnosis of TMA in part indicates that abnormal clotting may occur anywhere in the body that blood flows, to include any organ or body system. An infection, medical condition, or genetic disease can cause the body’s normal clotting process or immune system to not function as usual. Blood platelets can be consumed in creation of such clots, leaving patients with a low platelet count called thrombocytopenia. (Read more on this aspect of TMA: M Scully). Sometimes thrombotic microangiopathy can cause severe organ damage, as is the case with TMA and kidney function, and TMA is a noted feature of atypical HUS as well as other medical conditions.
News articles during the recent coronavirus pandemic have surfaced with mention of clots found in the body’s blood vessels and causing damage to major organs. Some news outlets focus on purported upticks in doctors providing anti-coagulants to decrease risk for clots, with others noting clot formation as a major issue for hospitalized COVID-19 patients. In a 24 April 2020 article by Kerin Miller for the medical magazine Prevention, reference was made to a Dutch paper (Klock et al. 2020) where “Overall, 31% of the patients had some kind of clotting complication, which researchers noted was “remarkably high” for patients in the ICU.” Clotting complications within veins and arteries can have serious implications for COVID-19 patients, as noted in a recent article by a team at an academic hospital in Milan (Lodigiani et al). Since scientific and medical research must face a rigorous review process prior to publication, expect an influx of future articles on COVID-19 and clotting issues in the coming months. As a few case studies begin to trickle in, perhaps the clotting associated with COVID-19 may be an area ripe to expand the knowledge base for diseases that involve TMA or some aspect of clotting dysregulation as part of its clinical profile.
Skin involvement, neurological issues, kidney damage, and other medical issues have been reported in popular culture and in medical literature during this pandemic. Will the treatment of COVID-19, and its varied severe complications, be predicated on assessing an individual’s genetics, lifestyle, or environmental factors – best targeted, in other words, by the field of Precision Medicine? While it seems logical why frail individuals or those with underlying medical conditions might experience more severe issues, what impact might obesity or other risk factors have regarding infection risk and viable treatment options? Regarding skin vasculitis and COVID-19 with the so-called ‘COVID Toes’ noted in dermatology, is this related to clotting or part of the inflammatory response (or both)? Nations and people around the world are experiencing the COVID-19 outbreak differently, so are variations in disease severity or patient outcomes somehow related to genetic, cultural, socio-economic or other factors? Can better understanding of disease mechanisms or genetic sequencing of the SARS-CoV-2 virus responsible for COVID-19 help us target best therapeutic drugs, or create an effective vaccine?
Raising Questions, Seeking Answers
Atypical hemolytic uremic syndrome, also known as atypical HUS or aHUS, is a rare disease where part of the body’s immune system (complement system) cannot properly regulate itself. When complement over-activates, cells that line the blood vessels can cause clots to form and negatively affect the function of major organs. Most notably damage from aHUS is to kidney function, the ‘uremic’ portion of the disease name atypical hemolytic uremic syndrome, but aHUS activity may potentially damage the heart, lungs and other organs. (FMI about aHUS)
Complement associated damage has been noted in medical articles and in news articles related to COVID-19 as well. Terminology for atypical HUS is highly variable, with increased use of new nomenclature for atypical HUS as CM-aHUS (complement-mediated aHUS) or grouped together with other forms of CM-TMA (complement-mediated thrombotic microangiopathy). Yet it’s important to note that CM-aHUS isn’t quite precise when speaking about DGKE and atypical HUS. In an article for Nature Genetics S. Quaggin wrote, “Notably, mutations in DGKE are not associated with activation of the complement pathway, the only other identified cause of this disorder so far, and have important implications for patient management.” Aside from study of complement-inhibitors for COVID-19, other avenues of interest include TMA therapeutic drugs, and an expanded research interface into care of autoimmune disorders such as systemic lupus erythematosus (SLE) and inflammatory disorders like rheumatoid arthritis (RA).
Pharmaceutical companies as well as academic research teams have branched out with different approaches to: target different disease activation mechanisms, halt the viral replication process, and boost antibody production and efficacy. It seems likely that medical discoveries related to the COVID-19 pandemic will create a broader knowledge base for complement therapeutics, syndromes of thrombotic microangiopathies, anti-inflammatory drugs and our understanding of immunology. Given the varied expressions of the disease and its severity, it is unlikely that a ‘one size fits all’ solution will be found across different geographic, environmental, and socio-economic groups. The current pandemic seems tailor-made for deepening our understanding of TMA through precision medicine, to treat individuals with certain common characteristics.
As we review the medical literature and peruse daily news about COVID-19, our thoughts gravitate to questions like those below. Such concerns from the aHUS global community are not new. In fact many were raised by an international group of aHUS patient organizations in a 4 year project that generated fifteen questions, categorized within five topic areas, to create Global aHUS Patients Research Agenda. (Click HERE to read this aHUS Alliance document, with rationale, video, pdf in ES, FR, EN)
Note: Links below are a snapshot of available articles, provided only as examples of the robust array of articles and research online. The aHUS Alliance doesn’t promote, supply, or endorse medical advice. Discuss personal health and treatment plans, or raise concerns and care questions, with their own physicians or clinical team..
The aHUS Alliance seeks to highlight information and efforts of broad interest to the global community and its stakeholders, and amplifies the voices of atypical HUS families and patient organizations in over 30 countries. More about the aHUS Alliance may be found HERE. FMI about our initiatives, or contact us about this or other articles please email us at info@aHUSallianceAction.org
1. Hallmarks of the rare disease atypical HUS include low red blood cell and platelet counts, with tiny clot formation that can damage organs, especially the kidneys.
Will new diagnostic capabilities arise for thrombotic microangiopathies such as aHUS? Will COVID-19 research yield more therapeutic drugs that will prove effective to also treat TMA clotting common in atypical HUS? Will new discoveries about blood clot formation and treatment learned during the pandemic translate into better care or improved outcomes for patients with TMA or aHUS?
2. Multiple drugs and treatment approaches for COVID-19 patients are currently under study. As of 6 May 2020, there were 1254 studies found using the search term ‘COVID-19’ on ClinicalTrials.gov.
Is there optimum time or ‘sweet spot’ for effective treatment? Can collaboration among nations, companies, and research teams bring cost effective and accessible complement inhibitors to market? What role can a precision medicine approach play a role in determining optimal care for certain diseases with specific patient profiles and clinical attributes?
3. Atypical HUS patients can experience multi-organ damage due to clotting activity (TMA).
Many COVID-19 patients have presented with damage to major organs, so what discoveries will arise about a multi-disciplinary approach to TMA prevention and treatment? Will new tools or algorithms be created that have potential cross-over for predicting organ damage via extended application for those with TMA?
4. Damage to kidney function has been noted in some people diagnosed with COVID-19.
COVID-19 has stressed dialysis services and supplies, but to what extent? To what extent will new information about acute kidney injury (AKI) during the pandemic impact guidelines or treatment protocols for those with rare genetic kidney diseases. Will there be increased demand for donor organs and kidney transplants, and if so, how would this impact renal transplant wait lists as compared to the ‘pre-Coronavirus’ period?
5. People with atypical HUS can benefit from genetic testing, particularly when a renal transplant is needed due to kidney failure. In medical literature those aHUS patients with a Factor H mutation have been associated with higher risk of disease recurrence, while clinical aspects or response to therapy may vary for other genetic mutations (Bu et al, 2012). Atypical HUS is sometimes called ‘familal aHUS’ but the topic of aHUS genetics and its implications are quite complex.
How will knowing one’s genetic profile impact treatment? Can genetic profiles predict which COVID-19 patients are likely to experience severe responses such as organ damage or need for a ventilator, and if so might this translate for other conditions? How might a person’s genetic makeup impact their medical care? Is it more clinically effective, or having a cost-effectiveness component, to having genetic test results guide treatment and care plans? How might the rare disease drug discovery landscape change, with new information from mRNA research during the pandemic?
In closing, we end this article with a brief ‘Glimpse into Coronavirus History’ to bring us back to a central theme – sometimes very difficult circumstances provide new opportunities for advancements and future growth.
SARS-CoV-2: A Perspective
A Glimpse into Coronavirus History
The 1918 influenza pandemic (sometimes called the ‘Spanish Flu’) established the first widespread use of plasma from recovering patients, known as ‘convalescent plasma’ or CBP, which was also adopted for the treatment during the Ebola outbreak in 2013 (see JAMA article). In 2003 the SARS (Severe Acute Respiratory Syndrome or SARS-CoV) outbreak affected an estimated 26 nations, and launched study into coronaviruses as well as into possible vaccines (source: WHO).
COVID-19 like SARS or MERS is a disease caused by a form of coronavirus, a previously unknown virus known as SARS-CoV-2 which causes the disease COVID-19 (“Co” refers to corona, “vi” to virus, “d” to disease, and “19” for 2019). Reports from the frontlines of the COVID-19 outbreak note utilization of convalescent plasma, or an infusion of plasma from people previously recovered and containing antibodies against this coronavirus, as a potential therapeutic for patients seriously ill with COVID-19. As information and research unfold, and evidence-backed data rolls in, new therapeutic options and socio-economic impact from the pandemic will continue to have global focus both now and for future generations.
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