COVID-19-induced extracorporeal circulation coagulation during continuous renal replacement therapy: A cross-sectional study

Abstract

After the control policies of the COVID-19 epidemic were lifted in China from December 5th, 2022, there was an increase in the demand for hemodialysis and continuous renal replacement therapy (CRRT) at our center, and patients experienced hypercoagulable blood states more frequently. This study aimed to investigate the effect of COVID-19 on extracorporeal coagulation during CRRT. All CRRT records were gathered from the Hemodialysis Center at our hospital from December 5th, 2022 to February 4th, 2023, and analyzed the incidence and risk factors associated with extracorporeal coagulation. COVID-19 substantially increased the likelihood of extracorporeal coagulation during CRRT. Venous pressure and transmembrane pressure were proportional to the severity of extracorporeal coagulation. Additionally, non-tunnel type conduit vascular access, and acute kidney injury had a positive correlation with the severity of coagulation. Blood tests demonstrated that COVID-19 altered 4 coagulation indices. Moreover, mitigation of coagulation can be achieved through increasing the dosage of low molecular weight heparin and administering regional citrate anticoagulation. Patients who fail anticoagulation may be switched to peritoneal dialysis. In conclusion, COVID-19 poses a heightened risk of extracorporeal coagulation during CRRT. This study underscores the importance of anticoagulant treatment in CRRT for infected patients with kidney failure and holds significant implications for clinical practice. In future, the epidemics of COVID-19 or any other pandemic, the metrics in this study can be referenced to determine coagulation risk, as well as relevant therapeutic practices may be considered.

Key points.

• COVID-19 poses a heightened risk of extracorporeal coagulation during CRRT.

• The NTCC and AKI are closely linked to severe coagulation states.

• This study underscores the importance of anticoagulant treatment in CRRT for COVID-19 patients with kidney failure.

1. Introduction

The blood hypercoagulability induced by COVID-19 poses a significant threat to patients, leading not only to in vivo thrombosis but also triggering coagulation within the extracorporeal circuit during hemodialysis (HD).^[1–4] Such extracorporeal coagulation poses risks to both the patient and the dialyzer, necessitating the timely replacement of consumables and the implementation of anticoagulation measures.^[5] Continuous renal replacement therapy (CRRT) represents a HD modality that offers gentler and more effective filtration compared to conventional HD.^[6] Studies have shown that COVID-19 significantly increases the demand for CRRT among critically ill patients and patients on HD.^[5,7,8] However, it remains unclear whether COVID-19 increases the incidence of extracorporeal coagulation during CRRT and the mechanisms are not clear. Furthermore, despite the decline in the peak of COVID-19 cases, there are still instances of recurrent infections among the patients, and occasional reports of patients being infected by mutated strains.^[9] These observations underscore the ongoing concerns associated with the disease.

Before December 5th, 2022, China implemented stringent legal policies to control the COVID-19 epidemic.^[10] As part of these measures, daily nucleic acid testing was mandatory for all patients to ensure and remained uninfected. However, on December 5th, 2022, the government lifted these temporary control measures, resulting in a rapid spread of the virus throughout China within a week. Approximately 1 week after the policy was relaxed, all patients at our hospital began to exhibit visible symptoms of infection.^[5] During this period, regular nucleic acid testing was also conducted on the general population until February 2023, when the state announced the cancelation of such testing. Prior to the relaxation of the policy, our HD center operated smoothly, with nucleic acid testing confirming the absence of any COVID-19 infections. In contrast, after the policy was lifted, there was a sharp increase in the demand for HD and CRRT at our center, and patients experienced hypercoagulable blood states more frequently.^[5] This observation confirms an association between COVID-19 and the risk of CRRT, although the specific risk factors and underlying mechanisms remain unclear.

Dialysis is a medical technique utilized to remove metabolic wastes, toxins, and excess body fluids from the body through fluid exchange; and to maintain homeostasis of the internal environment.^[11–13] This renal replacement therapy is commonly employed for patients whose kidney function has deteriorated to the point where they are unable to meet their metabolic requirements.^[14] Hemodialysis and peritoneal dialysis are the 2 primary types of dialysis.^[15,16] Peritoneal dialysis provides continuous filtration and causes less disruption to patients’ daily activities. On the other hand, HD is suitable for patients with relatively poor kidney function, but some patients are unable to tolerate the physical strain of rapid fluid exchange over a brief period.^[17,18] Consequently, a more moderate HD technique called CRRT has been developed. Compared with conventional HD, CRRT not only clear small molecule toxins, but also more effectively clear medium and large molecule toxins, and has less impact on human hemodynamics.^[17,18]

Extracorporeal coagulation is a prevalent acute complication during HD, which is usually treated with low molecular weight heparin (LMWH) injections to prevent coagulation.^[19] Recent studies have revealed that COVID-19 significantly increased coagulation cases during HD, and even with treatment guidelines, some severe coagulation disorders remain unresolved.^[20,21] As a result, addressing COVID-19-induced coagulation has become a challenging task during HD.

Despite the conclusion of the COVID-19 outbreak, there is a continuous substantial number of patients experiencing recurrent infections and infections caused by mutant strains.^[22] This ongoing situation poses a significant risk for patients undergoing CRRT. The objective of this study was to describe the impact of COVID-19 on extracorporeal coagulation during CRRT and to present our anticoagulation methods as a means of addressing this challenge.

2. Methods

2.1. Ethics

This cross-sectional descriptive study involved the collection of clinical and imaging data from the patients visiting the hospital. This study was designed in a manner that does not disrupt or alter the patients’ treatment plans, and it carries no associated risks. The study adhered to the principles outlined in the Declaration of Helsinki, and the corresponding protocol was granted approval by the Clinical Research Ethics Committee of Peking University Shenzhen Hospital (No. 2023-088). All participants have signed pan informed consent.

2.2. Patients

A total of 339 patients who underwent HD treatment at our HD center visited/admitted between December 5th, 2022, and February 4th, 2023, were included in the data analysis. The inclusion criteria for the study were as follows: (i) patients with chronic kidney disease (CKD) receiving maintenance HD treatment for a minimum of 3 months. (ii) Those who received CRRT during the specified study period. (iii) Patients with confirmed COVID-19 infection as determined by nucleic acid testing. It is worth mentioning that our center has been adhering to the strict rule of daily nucleic acid testing of the patients, which ensured that all patients were not infected with COVID-19 prior to the start of the study.

The exclusion criteria were as follows: (i) inadequate blood flow resulting from vascular access dysfunction leading to clotting in filters and lines. (ii) Clotting in filters and lines attributed to the administration of blood products during dialysis sessions. (iii) Clotting events associated with heparin-free dialysis treatment. (iv) Absence of heparin-induced coagulation. (v) Infection with other pathogens preceded COVID-19 infection. (vi) Family history of coagulation disorders, particularly in patients with known or suspected hereditary thrombosis. (vii) According to vaccination recommendations, all patients with underlying cardiovascular conditions were not administered any vaccines. Therefore, vaccinated individuals were excluded from this study.

2.3. Sample size

The sample size was selected with references to COVID-19 related HD patients.^[5,23] Because the number selected in this study is larger than the previous studies, which satisfies the statistical requirements.

2.4. Severity criteria

The severity criteria for COVID-19 infection are established based on the most recent version of the “COVID-19 Infection Treatment Protocol (10th Edition Trial).”^[24] These criteria are categorized as follows: (i) mild: characterized by upper respiratory tract infection as the primary symptom, including dry throat, sore throat, cough, fever, and similar manifestations. (ii) Moderate: persistent symptoms for over 3 days, accompanied by cough, shortness of breath, and other indications. Respiratory rate remains below 30 breaths per minute, and resting oxygen saturation (measured by finger blood) exceeds 93%. Imaging findings reveal pneumonic manifestations associated with new coronary pneumonia infection. (iii) Severe: this category refers to cases where shortness of breath is evident, with a resting respiratory rate exceeding 30 breaths per minute. Oxygen saturation drops below 93% after inhalation of air, and the PaO₂/FiO₂ ratio (oxygenation index) falls below 300 mm Hg. Clinical symptoms and pulmonary imaging show progressive deterioration, with significant lesions extending beyond 50% within a span of 24 to 48 hours. (iv) Critical: this category encompasses cases involving respiratory failure requiring mechanical ventilation, the presence of shock, and other organ failures necessitating monitoring and treatment in the intensive care unit.

2.5. Hemodialysis

All patients undergoing treatment during the COVID-19 outbreak follow the same regimen as before. However, CRRT regimens are specifically tailored for patients who are in the severe or critical stages of COVID-19 infection, exhibiting substantially reduced blood oxygen levels, respiratory and circulatory difficulties, and experiencing a multi-organ failure that cannot be adequately addressed through HD. These protocols are highly individualized and are thoroughly discussed among the attending physicians. The treatment approach involves utilizing either autologous endovascular arteriovenous fistulas or intravenous catheters as vascular access. The primary method employed is continuous veno-venous HD filtration. Typically, the duration of treatment is set between 6 and 10 hours. The replacement fluid utilized during the treatment consists of specific concentrations, including glucose (10.6 mmol/L), chloride (118 mmol/L water), magnesium (0.797 mmol/L water), calcium (1.6 mmol/L water), sodium (113 mmol/L water), and potassium (adjusted over time). To ensure optimal treatment efficacy, meticulous monitoring of biochemical parameters such as creatinine, urea nitrogen, potassium, sodium, calcium, chloride, and nitrogen dioxide binding rate is conducted on an hourly basis. During the treatment, blood flow is maintained at a rate ranging from 180 to 220 mL/min, the replacement fluid is set at a range of 2000 to 3000 mL/h, and dilution prior to the administration of replacement fluid is set at a level exceeding 50%.

2.6. Instrument monitoring

During CRRT, various parameters such as blood flow, venous pressure, arterial pressure, and transmural pressure are meticulously monitored on an hourly basis. The filter of the blood catheter and the arteriovenous port is closely observed for any changes in features or color. In the event of severe clotting blockage, it is imperative to promptly discontinue the treatment. If the treatment goals cannot be achieved due to significant coagulation occlusion, the filters and lines should be replaced, and the anticoagulation regimen should be adjusted to resume the treatment. The severity of clotting blockage is assessed after the treatment. The grading system for dialysis-coagulation is based on the Standard Manual for the Treatment of Hemodialysis,^[25] which includes the following categories: Grade-0 indicates no coagulation, Grade-I signifies <10% hollow fiber coagulation, Grade-II represents <50% hollow fiber coagulation, and Grade-III denotes more than 50% hollow fiber coagulation.

2.7. Data collection consistency

To ensure accurate data collection, a trained commissioner (Dibin Wu) was involved in the operation of the HD center throughout the study phase. The commissioner followed relevant data collection and monitoring methods to ensure the quality, reliability and consistency of the data. Wei Liang and Aihong Wang are responsible for data quality control.

2.8. Coagulation function test

The coagulation-related data of patients were retrieved from medical records. Data older than 2 months will not be counted. The inclusion criteria encompassed mild and severe/critical patients undergoing CRRT, and the blood samples utilized were residual samples obtained for testing purposes (≤1 mL). The tests conducted encompassed prothrombin time, activated partial thromboplastin time, thrombin time, fibrinogen, and D-dimer.

2.9. Statistics

The results were presented as mean ± standard deviation (SD). Statistical analysis was performed using GraphPad Prism V6.0. The differences between the 2 groups were assessed using an unpaired Student t test. Multiple comparisons between groups were made using one-way ANOVA. Trend correlations were analyzed using trend analysis, including simple linear regression and Chi-square testing. A P-value of ≤0.05 was deemed statistically significant. Trends were evaluated using simple linear regression.

3. Results

3.1. Records of extracorporeal coagulation associated with COVID-19

Firstly, all instances of extracorporeal coagulation phenomena that occurred during CRRT were meticulously documented from December 5th, 2022 to February 4th, 2023. This time frame corresponds to a period of slightly less than 2 months following the lifting of Chinese policy restrictions regarding COVID-19. Moreover, all patients were confirmed to have been infected through nucleic acid testing approximately 1 week after the policy was relaxed, aligning with the rapid transmission characteristic of COVID-19. Figure 1A demonstrates a clear relationship, where an increase in the grade of coagulation leads to more severe clotting in the filter and venous/arterial pots. Specifically, in the absence of clotting (Grade-0), the filter was observed to be virtually free of clots. However, as the coagulation grade escalated, a more pronounced clotting was observed in the instrument. Upon reaching Grade-III, the majority of the filters lost their functionality and necessitated replacement. In our investigation, a total of 269 CRRT treatments were recorded within a span of 2 months post COVID-19 outbreak (Fig. 1B). Among these sessions, 165 (61.34%) were classified as Grade-0, 79 (26.02%) as Grade-I, 19 (7.06%) as Grade-II, and 15 (5.58%) as Grade-III.

Figure 1.

Recording of COVID-19 associated extracorporeal coagulation during CRRT. (A) Representative photographs of CRRT filters and pots with different coagulation grades. (B) Distribution of patients with different coagulation grades. N = 269.

3.2. COVID-19 increased demand for CRRT and incidence of extracorporeal coagulation

To explore the connection between COVID-19 and extracorporeal coagulation events, we conducted counted demand for CRRT and the incidence of extracorporeal coagulation events prior to and following the outbreak of COVID-19. “Before” means October 5th to December 4th, 2022, and “after” means December 5th, 2022 to February 4th, 2023. As presented in Table 1, in comparison to the pre-COVID-19 period, the COVID-19 infection resulted in a substantial increase in both the demand for CRRT and the incidence of extracorporeal coagulation. Despite an overall decrease in the number of all types of HD from 8579 to 8325, the demand for CRRT exhibited an upward trend rather than decreasing, rising from 122 (1.422%) to 269 (3.231%). Additionally, per person demand for CRRT for 2 months increased from 0.355 to 0.871. Similarly, the odds of experiencing extracorporeal coagulation per CRRT session saw an increase from 18.852% to 38.662%, with the odds of extracorporeal coagulation per person escalating from 6.7% to 33.7%. These findings indicate that not only did COVID-19 heighten the demand for CRRT, but it also elevated the incidence of extracorporeal coagulation during CRRT treatment.

Table 1.

COVID-19 increased demand for CRRT and incidence of extracorporeal coagulation.

	Before COVID-19 (October to November 2022)	After COVID-19 (December 2022 to January 2023)
Total patients	344	339
COVID-19 patients	0	309
Total hemodialysis	8579	8325
CRRT	122	269
CRRT coagulation	23	104
CRRT to HD	1.422%	3.231%
CRRT per person	0.355	0.871
Coagulation per CRRT	18.852%	38.662%
Coagulation per person	6.7	33.7

CRRT = continuous renal replacement therapy, HD = hemodialysis.

3.3. COVID-19 elevated venous blood pressure and transmembrane pressure

To mitigate subjectivity in assessing the level of extracorporeal coagulation, we aimed to incorporate quantitative indicators into our analysis. Specifically, we evaluated changes in indicators related to blood pressure in HD machines, as these are often affected by dialyzer clogging. Firstly, we examined the impact of different coagulation conditions on dialysis duration and found no significant effect (Fig. 2A). Although Grade-III coagulation exhibited a notable reduction in duration, the P-value remained above 0.05. This outcome may be attributed to the increased frequency of dialysis procedure termination among Grade-III patients as the severity of coagulation escalated. Furthermore, both venous pressure and transmembrane pressure demonstrated an upward trend with increasing coagulation (Fig. 2B and C). While arterial pressure displayed a decrease only in Grade-III, the difference was not statistically significant (P ≤ 0.05), possibly due to the limited sample size (Fig. 2D). To confirm the results of the venous blood pressure and transmembrane pressure, the variability was again tested by trend analysis (Fig. 2E and F). Both showed statistically significant differences (P ≤ 0.05), proving that both pressures are proportional to the coagulation grade. These findings suggest that venous pressure and transmembrane pressure can serve as useful indicators in assessing dialyzer clogging.

Figure 2.

Characterization of hemodialysis equipment pressure in the coagulation state. (A) The duration of hemodialysis [0 (n = 165) vs I (n = 70) vs II (n = 19) vs III (n = 15), 6.124 ± 0.9096 vs 6.221 ± 1.041 vs 6.447 ± 0.9845 vs 5.5 ± 1.268, hours]. (B) The highest venous pressure during hemodialysis [0 (n = 165) vs I (n = 70) vs II (n = 19) vs III (n = 15), 66.47 ± 13.78 vs 84.31 ± 26.44 vs 162.1 ± 41.07 vs 279.5 ± 125, mm Hg]. (C) The minimum arterial pressure during hemodialysis [0 (n = 165) vs I (n = 70) vs II (n = 19) vs III (n = 15), 81.99 ± 26.68 vs 112.5 ± 32.09 vs 160.8 ± 57.06 vs 190.1 ± 56.47, mm Hg]. (D) The minimum arterial pressure during hemodialysis [0 (n = 165) vs I (n = 70) vs II (n = 19) vs III (n = 15), −116.8 ± 7.084 vs −117.7 ± 9.002 vs −114.1 ± 4.642 vs −121.3 ± 18.46, mm Hg]. * indicates comparison with Grade-0. (E and F) Trend analysis of venous blood pressure and transmembrane pressure. *P ≤ 0.05. ****P ≤ 0.0001.

3.4. High risk factors for extracorporeal coagulation

It is unknown which patient characteristics could put them at risk for increased extracorporeal coagulation during CRRT. To investigate the risk factors associated with varying grades of extracorporeal coagulation in COVID-19 patients, we analyzed the proportion of age, gender, and vascular access, as well as the incidence of acute kidney injury (AKI), at different grades. The findings indicated that age was not a significant risk factor in the increase of COVID-19-induced coagulation (Fig. 3A). Although males had a higher proportion of coagulated patients, this proportion began to decrease at Grade-II (Fig. 3B). In other words, females may be at higher risk for Grade-II and -III extracorporeal coagulation. However, the trend of the Chi-square test was not significant (P = 0.3692), which may be related to the small sample size. In addition, patients who use non-tunnel type conduit (NTCC) as their vascular access are more likely to experience severe coagulation (Fig. 3C). This result is supported by the Chi-square test (P = 0.0386, *). Moreover, COVID-19-induced AKI is more likely to cause Grade-III coagulation (Fig. 3D). This result is supported by the Chi-square test (P = 0.0004, ***).

Figure 3.

High risk factors for extracorporeal coagulation. (A–D) Relationship between age, gender, type of vascular access and AKI and different coagulation grades [age, 0 (n = 165) vs I (n = 70) vs II (n = 19) vs III (n = 15), 65.84 ± 14.84 vs 64.41 ± 13.4 vs 66.11 ± 16.59 vs −60.8 ± 20.9, years]. AVF, arteriovenous fistulas. NTCC, non-tunnel type conduit. The correlation of gender, vascular access and AKI with coagulation severity was examined using a Chi-square test.

3.5. COVID-19 altered coagulation indices

Our previous study showed that the rise in extracorporeal coagulation induced by COVID-19 during normal HD treatment occurred mainly in patients with severe/critical symptoms.^[5] To investigate the underlying mechanism of coagulation abnormalities associated with COVID-19 during CRRT, we conducted an analysis of coagulation indices in our patients. To ensure a more comprehensive comparison, we specifically focused on comparing patients with mild symptoms to those with severe/critical symptoms. This selection was motivated by the fact that the majority of new CRRT patients belonged to the severe/critical group, while the impact of mild symptoms was deemed negligible. The number of patients without symptoms were small and therefore not included in this statistic. Given the subjective nature of symptom judgments, moderate symptoms were not included in the statistical analysis. The patients included in the statistics had experienced CRRT. The findings revealed statistically significant differences (P ≤ 0.05) in all 4 coagulation indices (thrombin time, activated partial thromboplastin time, fibrinogen, and D-dimer) between the severe/critical group and the mild group (Fig. 4). These results suggest that COVID-19 may increase the risk of extracorporeal circulation coagulation during CRRT therapy by causing a hypercoagulable state of the patient’s blood.

Figure 4.

COVID-19 and coagulation function. COVID-19 significantly altered 4 coagulation indicators, activated partial thromboplastin time (APTT, mild vs severe/critical, 29.68 ± 2.954 vs 26.1 ± 3.429, second, n = 15), thrombin time (TT, mild vs severe/critical, 14.41 ± 0.7308 vs 17.31 ± 1.606, second, n = 15), fibrinogen (Fib, mild vs severe/critical, 3.205 ± 0.4974 vs 3.689 ± 0.7148, g/L, n = 15), and D-dimer (DD, mild vs severe/critical, 0.228 ± 0.05685 vs 0.946 ± 0.9756, g/L, n = 15), but did not prothrombin time (PT, mild vs severe/critical, 11.66 ± 0.4897 vs 11.2 ± 0.7579, second, n = 15). *P ≤ 0.05; **P ≤ 0.01; ****P ≤ 0.0001.

4. Discussion

The centralized treatment approach adopted in blood purification centers can inadvertently contribute to the spread of infections among patients, leading to a phenomenon known as concentrated infections. This, in turn, directly contributes to overcrowding in medical facilities, potentially jeopardizing the survival chances of patients due to the limited availability of medical resources. Our study substantiates this prediction, as within a month, over 90% of maintenance HD patients at our center were infected with COVID-19. Consequently, there was a significant surge in the demand for CRRT and an increase in the occurrence of extracorporeal coagulation during treatment. Furthermore, our findings indicated that NTCC and AKI patients are more prone to experience severe coagulation as compared to other patients in the same period? This underscores the importance of early anticoagulation in individuals with kidney failure to prevent treatment failure in dialysis.

The key finding of this study highlights the increased occurrence of extracorporeal coagulation during CRRT in patients with COVID-19. Previous studies have consistently demonstrated that COVID-19 induces hypercoagulation and elevates the risk of thrombosis, including during HD.^[2–4] In our previous study involving maintenance HD patients, we investigated the underlying mechanism and found that only individuals with severe and critical COVID-19 symptoms experienced a higher incidence of extracorporeal coagulation.^[5] Conversely, there was no significant difference in the occurrence of extracorporeal coagulation among asymptomatic, mild, and moderately symptomatic patients. A similar study also found abnormal platelet dynamic characteristics only in severe patients.^[26] Additionally, our analysis of blood samples using protein spectroscopy revealed that COVID-19 may enhance blood hypercoagulability by upregulating vWF/FBLN5 signaling, activating platelets, and increasing oxidative stress and inflammation.^[5] Consistent with these studies, the current investigation also confirms the heightened risk of extracorporeal coagulation associated with COVID-19. However, our focus primarily centers on the incidence of extracorporeal coagulation during CRRT treatment and the associated risk factors.

Upon identifying this concern, we became deeply invested in finding ways to mitigate the incidence of extracorporeal coagulation and minimize associated therapeutic risks. To address this, we adhere to the recommendations outlined in treatment guidelines and administer anticoagulants to patients at risk. Additionally, all patients receive pre-dialysis LMWH (Sanofi) injections to proactively prevent extracorporeal coagulation. However, it is important to acknowledge that this approach may not always yield the desired outcomes.^[27] In such cases, we typically adjust the LMWH dosage or resort to regional citrate anticoagulation for patients experiencing bleeding. Remarkably, 99% of patients successfully complete CRRT, and for the remaining cases where CRRT cannot be completed, we advise individual treatment plans. We are currently in the process of compiling the pertinent data. Furthermore, there has been a suggestion to administer oral anticoagulants to all COVID-19 patients at the earliest opportunity, as this measure has shown potential in reducing coagulation-related risks.^[28] While we concur with this viewpoint, we remain uncertain about its effectiveness and potential risks in patients with CKD. Our final therapeutic recommendation is to preferred therapeutic regimen for such patients infected with COVID-19 with increase dose of heparin, followed by the use of RCA. If both of these approaches remain ineffective, an immediate change to peritoneal dialysis may be considered.

This study revealed that COVID-19 led to alterations in device pressure values during CRRT. Venous pressure elevation denotes an obstruction of the extracorporeal circulation circuit. Apart from eliminating operational reasons, the formation of venous pot filter clots can cause an increase in venous pressures, either progressively or immediately. Arterial pressure changes indicate blood flow variations. Transmembrane pressure, on the other hand, results from the filtration of fluid from the fibrous membrane of the compound filter to the outside of the membrane. This pressure corresponds with the volume of ultrafiltration and replacement fluid. An abrupt increase in transmembrane pressure can indicate blockage of the fibrous membrane pores due to clots, leading to ineffective filtering of fluid. As per our investigation, the amount of thrombosis is directly proportional to the venous and transmembrane pressures, supporting the stated theories. The buildup of moderate and severe clots can significantly reduce small molecule and toxin filtration, leading to decreased efficiency. This can shorten the life of the filter while hampering therapeutic goals. Therefore, alterations in venous pressure and transmembrane pressure levels are essential indicators of the degree of coagulation. In severe cases, restarting dialysis is necessary after tubing replacement.

An interesting finding revealed that a higher percentage of males develop coagulation as compared to females, this percentage decreases as the severity of coagulation worsens. Previous studies have reported that men tend to experience faster and more severe infections.^[29–33] However, these results are influenced by a multitude of factors, such as social habits, smoking history, and underlying cardiovascular diseases. Additionally, the male population exhibits a higher rate of CKD and cardiovascular diseases compared to females.^[11] Therefore, it is hard to say that males are more prone to thrombosis after infection as compared to females. Rather, the proportional trend suggests that females are more inclined to develop severe coagulation. However, the sample size of this study was small; therefore, the result may not be accurate. The exact reasons for this need further study.

Arteriovenous fistulas and NTCC are commonly used options for establishing vascular access for patients at our center. A fistula is created through a surgical procedure that connects an artery to a vein, while NTCC is a synthetic tube utilized to surgically join an artery and a vein. In other words, a fistula is constructed from natural vessels, while NTCC is made from artificial materials. Since NTCC is an exogenous material, it is more susceptible to infection and coagulation, which can result in severe thrombosis. This findings support this claim, as NTCC is more likely to cause severe coagulation. This implies that the increased risk of coagulation linked with COVID-19 may be intensified by preexisting coagulation risk factors. Therefore, patients with coagulation-related complications should prioritize starting anticoagulation therapy as early as possible after contracting the infection.

COVID-19 can cause AKI through various mechanisms. One of the primary reasons is the direct invasion of the virus into kidney cells.^[34] The ACE2 receptor, which is the entry point for the SARS-CoV-2 virus, is abundantly expressed in the kidneys.^[35] The virus can directly infect kidney cells, leading to inflammation, cell damage, and impaired kidney function. Another contributing factor is the systemic inflammatory response triggered by COVID-19.^[36,37] Also, COVID-19 can indirectly contribute to AKI through its impact on other organs. The virus can cause respiratory distress and hypoxia, leading to decreased oxygen supply to the kidneys and subsequent kidney injury.^[36] Additionally, COVID-19 can lead to cardiovascular complications, such as thrombotic events and hemodynamic instability, which can further compromise kidney function. We think that AKI patients may exhibit more pronounced symptoms including inflammation, oxidative stress, and vascular endothelial damage, which collectively activate the coagulation system and intensify coagulogenesis. These factors could potentially elucidate the heightened susceptibility of AKI patients to severe coagulation.

This study is also informative from a broader clinical perspective, as various types of infections may precipitate coagulation disorders. For instance, Pneumococcal and Gonococcal infections are associated with increased thrombosis risk.^[38,39] Infections may also accelerate thrombosis through the induction of disseminated intravascular coagulation.^[40–42] Infections are also common comorbidities in HD patient populations, though fewer studies have been conducted in this clinical setting. Furthermore, the COVID-19 pandemic represents only a microcosm of infectious disease outbreaks, as other infectious agents and emerging mutant strains can also lead to infection surges. In this context, how to manage the extracorporeal coagulation challenges posed by such concentrated transmission events, is a critical issue that HD centers must be prepared to address. This study provides an example of a response strategy and describes the associated risk factors and solutions, which can serve as a reference for future clinical practice.

This study has several limitations that should be acknowledged. Firstly, the sample size was relatively small, which restricted our ability to conduct comprehensive statistical analyses and determine statistical significance for many of the observed trends. The number of patients receiving maintenance HD treatment at our center year-round is about 400, which is the limit of statistics that can be counted in this study. This sample size basis is also large compared to other single-center studies. Secondly, there was a lack of comprehensive patient-related data, primarily due to staffing shortages during the COVID-19 outbreak. Additionally, considering the safety of patients, the rest and treatment of the patients were not disturbed. Thirdly, we did not investigate the relationship between the severity of COVID-19 symptoms and the grade of coagulation. Fourthly, we did not conduct any fundamental research to elucidate the impact of risk factors on extracorporeal coagulation. Fifthly, the administration of anticoagulation therapy was primarily based on clinical experience, and despite utilizing LMWH and RCA, approximately 1% of patients were unable to complete CRRT. However, these patients were subsequently transitioned to peritoneal dialysis for resuscitation, which proved successful. Further research is warranted to develop individualized anticoagulation strategies that cater to the diverse needs of different patient populations. Sixthly, this study did not investigate the patients’ lifestyle habits and disease background, which may affect coagulation. Seventhly, currently, some drugs (such as Ivermectin) have been confirmed to be applicable for the prevention and treatment of COVID-19.^[43,44] This study has not explored the function of such drugs in reducing vascular damage and coagulation induced by COVID-19. Due to the limitations of the guidelines, the patients in this study did not receive treatment with such drugs either. Finally, there are some patients who are co-infected with other pathogens, such as AIDS and syphilis, which have been excluded as much as possible from this study. Also, some of the patients were co-infected with other pandemic viruses, e.g., influenza A and influenza B. Because of limited human resources at the time, it was not yet possible to conduct a large-scale study. The effect of multiple and co-infections on the results could not be ruled out. It is important to note that these questions will be addressed in future investigations.

5. Conclusion

In conclusion, the findings of this study demonstrate that COVID-19 significantly elevates the incidence of extracorporeal coagulation during CRRT. When such infected patients are treated with CRRT, healthcare professionals should always be aware of changes in venous blood pressure and transmembrane pressure to avoid serious extracorporeal coagulation events. Notably, patients with NTCC and those with AKI exhibit a higher propensity for severe coagulation. These results underscore the criticality of implementing early anticoagulation strategies in individuals with COVID-19 and concomitant kidney failure. Moreover, it emphasizes the necessity of tailoring anticoagulation measures during CRRT to suit each patient’s unique needs. Also, numerous pathogens can induce hypercoagulability of the blood. This underscores the importance of all patients who develop infections being vigilant for potential coagulation events during HD and receiving prompt anticoagulation treatment. These insights hold significant implications for clinical practice, guiding healthcare professionals in optimizing treatment approaches for this vulnerable patient population.

Acknowledgments

We are grateful to all our colleagues in the clinical departments and laboratories. We appreciate Dr Ying Shan’s guidance in statistics for this study.

Author contributions

Conceptualization: Guang Yang.

Data curation: Dibin Wu, Guang Yang, Shien Dai.

Investigation: Dibin Wu, Guang Yang, Shien Dai.

Formal analysis: Guang Yang.

Funding acquisition: Guang Yang.

Methodology: Guang Yang, Abbas Khan.

Project administration: Guang Yang.

Supervision: Guang Yang, Wei Liang, Aihong Wang.

Validation: Guang Yang.

Visualization: Guang Yang.

Writing – original draft: Guang Yang.

Writing – review & editing: Dibin Wu, Guang Yang, Shien Dai, Abbas Khan, Wei Liang, Aihong Wang.