Low total testosterone levels in men have been associated with hyper-inflammatory syndrome and respiratory failure116, and total testosterone levels are inversely associated with increased risk of ICU admission or death92; thus, the (most probably transitory) hypogonadism caused by SARS-CoV-2 infection was suggested to promote severe outcomes92. Bogoch, I. I. et al. and C.G.S. Mehmet Kaynar, Ana Lusa Quinta Gomes, Murat Gl, R. Clayton Edenfield & Charles A. Easley IV, Hayder M. Al-kuraishy, Ali I. Al-Gareeb, Gaber El-Saber Batiha, Abdolreza Haghpanah, Fatemeh Masjedi, Anahita Dehghani, Yasushi Matsuzawa, Kazuo Kimura, Kouichi Tamura, Shigeru Shibata, Hisatomi Arima, Hiroshi Itoh, Alessio Pecoraro, Simone Morselli, Mauro Gacci, Nature Reviews Urology But we have seen how it can affect multiple organs, including the liver, pancreas, small intestine and even gallbladder. JAMA Oncol. The authors attributed the protective effect of ADT to its ability to decrease TMPRSS2 levels108, which has an important role in the fusion process of cellular and viral membranes20, and to a reduction of the risk of a cytokine storm by decreasing the number and function of circulating neutrophils107,109. Thus, in the early stages of the pandemic, treatment with androgen deprivation therapy (ADT)32 in men with prostate cancer was hypothesized to be protective against COVID-19 infection106. Drake, T. M. et al. Acute kidney injury in patients hospitalized with COVID-19. An intense discussion on the role of testosterone in the high prevalence of severe COVID-19 complications is in place. Rev. Steril. However, in another prospective multicentre cohort study including 85,687 patients, only 2,198 patients (2.6%) received kidney replacement therapy34, indicating that the need for this therapy in patients with COVID-19 and AKI might be lower than previously suggested32. Hoffmann, M. et al. Res. Furthermore, androgen-dependent prostate cancer cells highly express TMPRSS2 (a key mediator in viral invasion20) in response to androgens23. Eur. fast heartbeat. in StatPearls [Internet] (StatPearls, 2022). J. Clin. De Vincentiis, L., Carr, R. A., Mariani, M. P. & Ferrara, G. Cancer diagnostic rates during the 2020 lockdown, due to COVID-19 pandemic, compared with the 20182019: an audit study from cellular pathology. Studies from around the world suggest that 7% to 31% of Covid-19 patients experience some sort of cardiac injury. Fertil. Our study describes the potential for a highly effective bladder vaccine that can not only eradicate residual bladder bacteria but also prevent future infections," says senior author Soman Abraham, Ph.D., a professor of Pathology, Immunology and Molecular Genetics & Microbiology with Duke University's School of Medicine. The absence of statistically significant differences in IPSS before and during COVID-19 in patients <50 years might be explained by the small sample size of this age group in this study (n=32)70. 101, 15761579 (2008). Endocr. Garg, R. K., Paliwal, V. K. & Gupta, A. Encephalopathy in patients with COVID-19: a review. In most patients, secondary hypogonadism was observed (luteinizing hormone 9.2 mUI/ml). Left untreated, a bladder infection can travel to the kidneys and cause a serious illness. Med. Andrology https://doi.org/10.1111/andr.13019 (2021). USA 118, e2021450118 (2021). De novo urinary symptoms associated with COVID-19, such as increased urinary frequency and nocturia, were also reported in another study including SARS-CoV-2-positive outpatients (n=39)68. In another study, SARS-CoV-2 could be detected in testis tissue samples from deceased patients with COVID-19 (n=6) by transmission electron microscopy, and the density of ACE2 receptors (quantified through immunofluorescence) was reported to be inversely proportional to the level of spermatogenesis, defined as impaired if full spermatogenesis was not visualized in all observed tubules80. Soc. Rev. 108, 244251 (2021). Keywords: Kidney Int. Sperm parameters were evaluated at three different time points after the infection: short (031 days, n=35); intermediate (3262 days, n=51); and long (63 days, n=34)87. OAB was significantly associated with higher risk and greater changes in worsening storage LUTS. Mieusset, R. & Bujan, L. The potential of mild testicular heating as a safe, effective and reversible contraceptive method for men. Wang, K. et al. Adverse events reported after administration of BNT162b2 and mRNA-1273 COVID-19 vaccines among hospital workers: A cross-sectional survey-based study in a Spanish hospital. So, here's the scoop on what to do if you suspect you have a bladder infection: UTI Symptoms Telltale symptoms of a UTI may include: Cloudy urine Frequent urination Painful urination Passing small amounts of urine Pelvic pain Urine with a foul smell PubMed On this basis, cell types with >1% of ACE2+ cells were defined as being at a high risk of SARS-CoV-2 infection17. The authors declare no conflict of interest. 70, 214218 (2016). }); jQuery(function($) { As males and older adults are more susceptible to COVID-19 in general, it seems that LUTS may be part of an overall higher burden of illness in these groups. jQuery(function($) { This process might take decades; thus, until this point, a judgement call on how vulnerable people can be protected and how many deaths society is willing to tolerate is needed154. The impact of the COVID-19 pandemic on cancer deaths due to delays in diagnosis in England, UK: a national, population-based, modelling study. Antibiotics will only help if a person has a bacterial infection. Prostate cancer diagnosis, staging, and treatment in Sweden during the first phase of the COVID-19 pandemic. Can diet help improve depression symptoms? Testosterone has also been hypothesized to have a role in sex differences in COVID-19 outcomes, as it regulates ACE2 and TMPRSS2 expression103,104. The presence of SARS-Cov-2 viral RNA in ejaculate has only been reported in four studies to date62,63,64,65 (6.66%62, 15.8%63, 2.3%64 and 14.3%65 of patients). Front. Incidence of VTE and bleeding among hospitalized patients with coronavirus disease 2019: a systematic review and meta-analysis. Google Scholar. Reprod. Arterioscler. 30, 484487 (2020). A higher mortality rate for COVID-19 in men than in women has been reported in multiple studies99,100. Doctors may try existing treatments instead. $('.mega-back-button-deepdives').on('click', function(e) { Intern. Med. One possible pathophysiological mechanism of AKI in COVID-19 is a cytokine-storm-induced systemic inflammatory response31,41. In the meantime, to ensure continued support, we are displaying the site without styles Infect. Vaccines. Zhang, J. et al. J. Clin. In a study analysing kidney biopsy samples from 14patients with COVID-19, 5 patients had collapsing glomerulopathy, 1 had minimal change disease, 2 had membranous glomerulopathy, 1 had crescentic transformation of lupus nephritis, 1 had anti-glomerular basement membrane nephritis and 4 had isolated acute tubular injury41. Results from a single-cell transcriptome analysis of 15 kidney samples from healthy individuals showed co-expression of ACE2 and TMPRSS in the kidney, especially in proximal tubular cells and podocytes55. However, the underlying mechanisms of thromboembolism in patients with COVID-19 seem to be different from COVID-19-independent thromboembolism. No detection of SARS-CoV-2 from urine, expressed prostatic secretions, and semen in 74 recovered COVID-19 male patients: a perspective and urogenital evaluation. Early evidence suggests that about 50 percent of people who've died from COVID-19 also had a secondary bacterial or fungal infection, some of which were resistant to antibiotics. In neurology, systemic inflammatory responses induced by COVID-19 can result in devastating hypoxic and metabolic changes that can lead to encephalopathy and encephalitis13. eCollection 2019. The risk of new urinary symptoms was also high in people who had COVID-19 with no symptoms two times higher than people with no COVID-19. Fallara, G. et al. Cell Biol. Cancer Discov. Rev. Travel. Samuel, R. M. et al. The effect of androgen deprivation therapy on COVID-19 survival is still debated. Soc. Blood 135, 20332040 (2020). Hypotheses 145, 110375 (2020). J. Michelen, M. et al. According to a 2022 study, COVID-19 can affect the: It is unclear how many people have LUTS, but the researchers in this study found that the prevalence of urinary symptoms was relatively high.. Farouk, S. S., Fiaccadori, E., Cravedi, P. & Campbell, K. N. COVID-19 and the kidney: what we think we know so far and what we dont. Suriano, F. et al. Angiotensin-converting enzyme 2 (ACE2) expression levels in testes are amongst the highest in the body77 and can be found in Sertoli cells, Leydig cells and cells of the seminiferous ducts78. 13, 39773990 (2020). Spratt, D. I. Altered gonadal steroidogenesis in critical illness: is treatment with anabolic steroids indicated? More than 40% of individuals experience recurrent infection. Agents 4, 8993 (1994). Evol. A pneumonia outbreak of unknown aetiology was reported in Wuhan at the end of 2019 (ref.1). Health experts. This cross-sectional st Cardiologists report that COVID-19-induced myocarditis can lead to fulminant myocardial dysfunction and is associated with poor overall prognosis12. Nephrol. Carlsen, E., Andersson, A. M., Petersen, J. H. & Skakkebaek, N. E. History of febrile illness and variation in semen quality. A multi-center retrospective cohort study defines the spectrum of kidney pathology in coronavirus 2019 disease (COVID-19). Urol. 2021;10:5338. doi: 10.3390/jcm10225338. Moreover, ischaemia-related priapism was reported as a thromboembolic complication in a 62-year-old patient with COVID-19 (ref.132). COVID-19; adverse effects; lower urinary tract symptoms; vaccines. However, bacteria, allergies, fungi, and other viruses can also cause sinusitis. Use the Previous and Next buttons to navigate the slides or the slide controller buttons at the end to navigate through each slide. In patients with so-called long COVID (a complex condition characterized by prolonged heterogeneous symptoms following SARS-CoV-2 infection, such as weakness, general malaise or fatigue15), mounting evidence of impairment or scarring of multiple organs has been reported16. The situation seems to be different for urethral swabs: in a case series, all ten of the patients tested had a negative urethral swab for SARS-CoV-2 RNA, despite having a positive rhino-oropharyngeal test60. Klein, S. L. & Flanagan, K. L. Sex differences in immune responses. Viruses in the mammalian male genital tract and their effects on the reproductive system. A survey of prostate-specific antigen test requests during a local outbreak. Med. Microbiol. Dis. In another study evaluating the potential association between COVID-19 and testicular pain or epididymo-orchitis in 91 patients with COVID-19, 11% of patients reported scrotal pain83. Med. Hepatol. However, contradictory evidence makes it difficult to understand whether or not hormonal imbalance in patients recovering from COVID-19 is only a temporary phenomenon of the acute stage of infection90,97. Urol. Acute kidney injury in COVID-19: are kidneys the target or just collateral damage? However, results from another study including 1,779 men with prostate cancer reported opposite findings: no significant differences in the number of SARS-CoV-2 infections were observed between patients treated with ADT (5.6%) and patients who did not receive ADT (5.8%; OR 0.93, 95% CI 0.541.61, P=0.8)110. 11, 1446 (2020). $('mega-back-specialties').on('click', function(e) { PubMed Central Expert. Severe COVID-19 can also damage the kidneys, which may prevent them from working as they should. A bladder infection is a type of urinary tract infection (UTI). Department of Urology, University of Texas Southwestern, Dallas TX. Med. The pathogenesis and treatment of the cytokine storm in COVID-19. Cardiol. The PubMed wordmark and PubMed logo are registered trademarks of the U.S. Department of Health and Human Services (HHS). Rev. 2017 Nov 21;17(1):108. doi: 10.1186/s12894-017-0294-3. The androgen-regulated protease TMPRSS2 activates a proteolytic cascade involving components of the tumor microenvironment and promotes prostate cancer metastasis. J. Med. J. Impot. OAB was significantly associated with an increased risk of worsening urinary urgency (p = 0.030), frequency (p = 0.027), and seeking medical assistance due to urinary adverse events (p < 0.001) after vaccination. & Lakatta, E. G. The dilemma of coronavirus disease 2019, aging, and cardiovascular disease: insights from cardiovascular aging science. Aschwanden, C. Five reasons why COVID herd immunity is probably impossible. Gastrointestinal coronavirus disease 2019: epidemiology, clinical features, pathogenesis, prevention, and management. Is the ketogenic diet right for autoimmune conditions? A systematic review on the investigation of SARS-CoV-2 in semen. Res. de-Madaria, E. & Capurso, G. COVID-19 and acute pancreatitis: examining the causality. PubMed Central Pract. Pathol. Background: In this case report, we describe a potential association between the Pfizer-BioNTech COVID-19 vaccine and development of a vulvar aphthous ulcer in a virginal 14-year-old girl. Everyone has them. Gonzalez, D. C. et al. There is a link between COVID-19 and symptoms that resemble overactive bladder (OAB). J. Clin. These results indicate that, although the testes might be heavily affected by a SARS-CoV-2 infection under other circumstances79,81, in these patients, the cause of the imbalances in total testosterone levels lies in the central nervous system, as secondary hypogonadism indicates a problem in the pituitary gland or hypothalamus94. Given the common prevalence of many of these reported symptoms in the general population, there does not appear to be a correlation between vaccination and urologic symptoms, but as the vaccination criteria expands, further monitoring of the VAERS is needed.Copyright 2021. These contradictory findings might be explained by the anti-inflammatory properties of testosterone113,114, which could also explain why men with COVID-19 and high levels of testosterone (2.9ng/ml total testosterone at hospital admission) test positive for SARS-CoV-2 for a shorter time frame than those with total testosterone levels of <2.9ng/ml (median time to negative PCR test: 26 days versus 18days; P=0.002)115. Urol. A phase 2 trial of the effect of antiandrogen therapy on COVID-19 outcome: no evidence of benefit, supported by epidemiology and in vitro data. Maiese, A. et al. There are no specific treatments for COVID-19-related urinary symptoms. In another study, impaired sperm quality in patients with COVID-19 was attributed to recurrent fever81, which has been shown to have a detrimental effect on sperm quality84, potentially owing to the thermal dependence of spermatogenesis85,86. The deterioration of storage LUTS was assessed as the increased score of OABSS following vaccination. In summary, AKI is a serious and frequently reported complication in patients with COVID-19 (ref.31), but the pathophysiological background of AKI is not fully understood. Basiratnia, M., Derakhshan, D., Yeganeh, B. S. & Derakhshan, A. Med. MNT is the registered trade mark of Healthline Media. Adam, D. Will Omicron end the pandemic? Enikeev, D. et al. When will the COVID-19 Pandemic End? Multivariate regression revealed that pre-vaccinated OAB (p = 0.003) was a risk for the deterioration of storage LUTS. Salonia, A. et al. Cancer symptom experience and help-seeking behaviour during the COVID-19 pandemic in the UK: a cross-sectional population survey. Int. COVID-19: angiotensin-converting enzyme 2 (ACE2) expression and tissue susceptibility to SARS-CoV-2 infection. Hedges, S. & Svanborg, C. The mucosal cytokine response to urinary tract infections. Article Int. 75, e13753 (2020). Flaifel, A. et al. The mortality was 50% in patients with AKI and 8% in patients without AKI32. Comparison of venous thromboembolism risks between COVID-19 pneumonia and community-acquired pneumonia patients. Inflammation of the prostate gland may lead to similar symptoms. It is unclear how often this happens with urinary symptoms, but generally, people with long COVID symptoms tend to gradually improve over time. Clipboard, Search History, and several other advanced features are temporarily unavailable. Health 39, 489495 (2021). Int. Overall, these results indicate that detection of SARS-CoV-2 in urine and semen is possible, but is a rare event58,61,62,63,64,65. In summary, published data made one point clear: COVID-19 is also a urological matter (Fig. A survey in multiple European countries showed that 3858% of individuals who had planned to have a baby in 2020 were going to postpone this decision76, although expected financial challenges caused by the pandemic was the main reason for this choice. 40, 905919 (2021). F. S Rev. Fajgenbaum, D. C. & June, C. H. Cytokine storm. A study including 184 patients with COVID-19 pneumonia in the ICU reported a remarkably high incidence of thromboembolic complications in these patients (31%), including deep vein thrombosis or pulmonary embolism119. 12, 615621 (2020). Kidney J. Med. However, no data on histopathological changes in patients with non-fatal COVID-19 are available; therefore, whether the alterations in testes are a general consequence of COVID-19 or exclusively occur in patients with fatal COVID-19 is still unclear. Characterising long COVID: a living systematic review. Learn about the possible causes of frequent urination, its symptoms and diagnosis, and how to manage the condition. And that's because of clearly a . 4, 13101325 (2014). Deidda, S. et al. J. Urol. The role of intravesical prostatic protrusion in the evaluation of overactive bladder in male patients with LUTS. Viral infection of the testes can result in a reduction of sperm quality and endocrine function, and possible long-term effects include oncogenic outcomes or vertical transmission of virus-induced mutations75. FOIA A severe increase in the number of avoidable cancer deaths owing to COVID-19-induced lockdowns is still expected151. 33, 309311 (2021). Kudose, S. et al. PubMed Annu. Endocrinol. Eur. Immunol. Oligozoospermia, reduced sperm motility and sperm vitality, as well as leukocytospermia, are reported frequently in the acute phase of COVID-19 infection79,87,90. and J.-N.M. researched data for the article. $('.mega-back-button-specialties').on('click', function(e) { Learn More. Case: A 14-year-old patient reported vulvar pain and visible lesion. 28, 196200 (2022). 76, 431435 (2020). Fountain, J. H. & Lappin, S. L. Physiology, Renin Angiotensin System. Gacci, M. et al. Nature Reviews Urology thanks A. Kadioglu and the other, anonymous, reviewer(s) for their contribution to the peer review of this work. Vasc. Cooper, T. G. et al. Beyerstedt, S., Casaro, E. B. SARS-CoV-2 could also be unstable in urine, but a PCR test should still detect it. Foo, Y. J. Clin. Thus, the existence, in kidney and bladder, of a higher risk of cell damage than other organs remains unclear17 (Fig. Montopoli, M. et al. Vahidy, F. S. et al. 15, 4150 (2021). Risk factors known to increase SARS-CoV-2 infection and disease severity (such as diabetes, asthma or immune suppressive diseases)102,111,112 were equally distributed between the two cohorts, although men receiving ADT were marginally older (75.5 versus 73.8 years, P=0.009), more likely to have smoked (68.1% versus 59.3%, P=0.005) and had more likely taken steroids (43.8% versus 23.3%, P<0.001) than patients with prostate cancer not treated with ADT110. Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations. Other strategies target post-receptor-binding steps: the serine protease inhibitor camostat mesylate acts on TMPRSS2, blocking the TMPRSS2-mediated entry pathway; hydroxychloroquine and chloroquine block endosomal acidification, which is necessary for cathepsin activity, acting on the cathepsin-mediated entry pathway. Is there any association of COVID-19 with testicular pain and epididymo-orchitis? Department of Urology, Ludwig-Maximilians-University, Munich, Germany, Benedikt Ebner,Yannic Volz,Jan-Niclas Mumm,Christian G. Stief&Giuseppe Magistro, You can also search for this author in The effect of COVID-19 on fertility potential in the acute stage of the infection was assessed in a multicentre study including 69 patients aged 2045 years who previously had COVID-19 but had recovered at least 3 months earlier88. Characterisation of in-hospital complications associated with COVID-19 using the ISARIC WHO Clinical Characterisation Protocol UK: a prospective, multicentre cohort study. AKI was reported to be the most common complication of COVID-19 in a multicentre cohort study including 80,388 patients with COVID-19 (ref.33). Analysis of the effects of COVID-19 infection on male reproductive health through histopathological examinations showed that testicular tissue can be severely damaged by SARS-CoV-2 infection79,81 (Fig. PubMed Central Carneiro, F. et al. 2021;36:e153. People avoiding hospitals during the pandemic might be the cause of decreased overall survival in patients with uro-oncological malignancies, owing to missed diagnoses or delayed treatments. Eur. 1). In this study, no evidence of direct SARS-CoV-2 infection was found in the examined kidney biopsy samples44, whereas, in other studies, the virus could be detected in some kidney samples, although this event seems to be rare and depends on the method of detection. Chan, L. et al. Cardiol. WHO. Acute Cardiovasc. However, the Omicron variant induces a considerably milder disease at the population level and has been shown to trigger cross-protective immunity towards the Delta variant135. Whether the inflammation in the urinary tract of patients with COVID-19 directly depends on SARS-CoV-2 or is secondary to renal excretion of plasma interleukins is still unclear. COVID-19-associated acute kidney injury: consensus report of the 25th Acute Disease Quality Initiative (ADQI) Workgroup. EClinicalMedicine 28, 100604 (2020). Proc. The detection of SARS-CoV-2 in urine and semen is very rare; however, a possible risk of transmission through these body fluids has not yet been ruled out. CAS Cell Stem Cell 27, 876889.e812 (2020). Furthermore, patients with a recovery time from COVID-19 of 90days had a significantly lower total sperm count than patients who recovered in less than 90 days (152 million versus 224million, P=0.0369)90. Pulmonary pathology and COVID-19: lessons from autopsy. PubMed Central The invisible impact of COVID-19: indirect mortality in urology. Andrologia 53, e13912 (2021). Other sources refer to the symptoms as COVID-19-related lower urinary tract symptoms (LUTS). As the virus spread, new findings were published on a daily basis and, although the respiratory tract seemed to be the main field of interest, attention soon focused on extra-pulmonary manifestations of the infection5. In this article, we will explain the link between urinary symptoms and COVID-19, as well as the symptoms a person may experience. Patients with highly prevalent risk factors, such as diabetes, obesity or hypertension, are at an increased risk of developing SARS-CoV-2-mediated AKI (adjusted odds ratio (OR): 1.76 for diabetes, 1.11 for obesity and 1.25 for hypertension)36,37. 43, 13991412 (2020). Moreover, many urological symptoms overlap with common diseases and, therefore, a causal attribution to SARS-CoV-2 is difficult to prove. Genet. Is prostate infarction and acute urinary retention a possible complication of severe COVID-19 infection? 74, 187189 (2021). Int Urol Nephrol. Giuseppe Magistro. INTRODUCTION AND OBJECTIVES: Emerging evidence suggests that the bladder is one of many organs targeted by Severe Acute Respiratory Syndrome Coronavirus 2 (SARSCoV-2), which contributes. $("mega-back-mediaresources .mega-sub-menu").show(); Ye, Q., Wang, B. and G.M. Thank you for visiting nature.com. Gastroenterol. The spread of the Delta variant caused a set-back for high-income countries in the race to reach herd immunity152,153. In this Review, data concerning the effects of COVID-19 on the urogenital system are discussed to provide further information for the medical treatment of patients with COVID-19 and evaluate the risk of possible long-term damage. Vaccines for COVID-19. 2022;21:533540. Yigit, M., Ozkaya-Parlakay, A. 88, 970.e971977 (2007). Kidney infarction in patients with COVID-19. Diagnosis of OAB was made using pre-vaccinated OABSS. Anal swab as a potentially optimal specimen for SARS-CoV-2 detection to evaluate hospital discharge of COVID-19 patients. In vitro cell-binding assays showed that SARS-CoV-2 can also bind to ACE2 on the surface of these cells53,78. Adverse reactions of the second dose of the BNT162b2 mRNA COVID-19 vaccine in healthcare workers in Korea. Gressens, S. B. et al. Stopsack, K. H., Mucci, L. A., Antonarakis, E. S., Nelson, P. S. & Kantoff, P. W. TMPRSS2 and COVID-19: serendipity or opportunity forintervention? Lifshitz, E. & Kramer, L. Outpatient urine culture: does collection technique matter? 12, 681682 (2020). No detection of SARS-CoV-2 RNA on urethral swab in patients with positive nasopharyngeal swab. There is no single test for OAB or CAC, so a doctor may recommend tests that look for an underlying cause. B.E. World J. Urol. Exam findings were consistent with vulvar aphthous ulcers. Released: Mar 13, 2023 . 69, 11811189 (2020). In the wake of the pandemic: Preparing for Long COVID (World Health Organization, 2021). In the COVIDENZA trial, including men and women >50 years old, the effect of the inhibition of testosterone signalling through enzalutamide on the outcome of hospitalized patients with COVID-19 was evaluated117. Mukherjee, A., Ghosh, R. & Furment, M. M. Case report: COVID-19 associated renal infarction and ascending aortic thrombosis. A median decrease of 62% in requested total PSA tests was observed during the local lockdown period in Italy (10 March to 17 May 2020)147. Lin, B. et al. 289, 114273 (2021). We investigated the storage lower urinary tract symptoms (LUTS) before and after the first dose of coronavirus disease 2019 (COVID-19) vaccine and the association between pre-vaccinated overactive bladder (OAB) and the worsening of storage LUTS following COVID-19 vaccination. Bioinformatic and mouse model reveal the potential high vulnerability of Leydig cells on SARS-CoV-2. COVID-19-associated coagulopathy is characterized by an isolated elevation of D-dimer (a degradation product from fibrin used as a biomarker of coagulation and fibrinolysis125) and is associated with disease severity and numerous thrombotic complications123.

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