Abstract
Introduction
SARS-CoV-2 infection is associated with hypercoagulability in COVID-19 patients. We used a vein-to-vein database to examine the impact of transfusion of plasma units from blood donors with recent SARS-CoV-2 infection.
Study Design and Methods:
We linked donor SARS-CoV-2 serology data with plasma transfusions occurring between 6/1/2020 and 3/31/2022. Using multivariable regression, we examined changes in the international normalized ratio (INR) and subsequent transfusion requirements following plasma transfusion relative to the timing of donor SARS-CoV-2 anti-N Ab positivity.
Results:
We identified 2,350 adults who received 5,397 plasma units with donor SARS-CoV-2 serology data as part of 3,721 plasma transfusion events. 8.1% (436/5,397) of plasma units were from anti-N Ab positive donors, and median time from index seropositivity to donation was 89 days (interquartile range [IQR] 0–210). In recipients of plasma units from recently SARS-CoV-2 infected donors (<120 days), the adjusted odds of a 0.25 per unit lowering of the INR were increased (aOR1.6 [1.1–2.5]; p=0.03) and the odds of additional plasma transfusions within 24 hours were decreased (aOR 0.6 [0.4–0.9]; p=0.04).
Conclusion:
Plasma transfusions from blood donors with recent SARS-CoV-2 infection were more likely to have reductions in the INR and subsequent plasma transfusion requirements.
Introduction:
SARS-CoV-2 infection and associated immune complexes have been shown to cause hypercoagulability and increase the risk of thrombotic events in the setting of COVID-19.1–4 Plasma units from blood donors with prior SARS-CoV-2 infection have not been associated with thrombosis in transfused patients without COVID-19.5 However, blood donor SARS-CoV-2 infection may impact the function of donated plasma and transfusion outcomes in recipients. We leveraged a vein-to-vein database to examine changes in the International Normalized Ratio (INR) and subsequent transfusion requirements in recipients of plasma units from blood donors with recent SARS-CoV-2 infection.
Methods:
We linked blood donor SARS-CoV-2 serology data with Kaiser Permanente Northern California (KPNC) adult patients without active SARS-CoV-2 infection who were transfused plasma products between 6/1/2020 and 3/31/2022. Information on blood donors and donations was obtained from Vitalant and the American Red Cross, which supply blood components to all 21 KPNC medical centers. Both blood collection organizations participated in universal SARS-CoV-2 screening of all blood donations from June 2020 to June 2021 and subsequently as part of the CDC-funded Nationwide Blood Donor Serosurveillance study.6 Beginning in January 2021, blood donors were surveyed regarding the receipt and timing of COVID-19 vaccination prior to each donation.
Blood donor samples were tested for antibodies against the S1 portion of the spike protein (S-Ab) using the VITROS chemiluminescent S1 total Ig assay (Ortho Clinical Diagnostics). Specimens with S-Ab were tested for nucleocapsid antibodies (anti-N Ab) to assess for SARS-CoV-2 infection using the chemiluminescent Elecsys Total Ig Assay (Roche Diagnostics). The timing of donation from the date of the first (index) donation with anti-N Ab seropositivity was calculated. We grouped timing of index anti-N Ab seropositivity to donation from 0 to 119 days, 120–239 days, and greater than or equal to 240 days.
We included all adult KPNC inpatients and outpatients who were transfused plasma for an INR greater than 1.4 during one or more transfusion events. Recipient details included age, sex, BMI, and the issue date of the transfused plasma units. We collected INR levels measured by the clinical laboratory prior to and following each transfusion event. Given the small sample size and relative infrequency of donor SARS-CoV-2 infection, any donor anti-N Ab seropositivity was considered an exposure in multi-unit transfusion events.
Our two outcomes were the change in the INR following plasma transfusion (post-transfusion INR minus pre-transfusion INR) and the incidence of additional plasma transfusions within 24 hours of the index transfusion event. We used stepwise logistic regression and generalized estimating equations to select model variables (p<0.20) and account for repeated transfusion events in a given recipient, respectively. Based on post-transfusion changes in INR from a prior study7 and optimal regression model fit, we examined the odds of a greater than 0.25 lowering of the INR per transfused plasma unit in relation to the timing of donor anti-N Ab seropositivity. In parallel, we estimated the odds of an additional plasma transfusion occurring within 24 hours of the index transfusion event.
Results:
From 6/1/2020 through 3/31/2022, we identified 2,350 adults who received 5,397 plasma units for which donor SARS-CoV-2 serology data were available as part of 3,721 plasma transfusion events. Baseline recipient characteristics are presented in Table 1. The mean recipient age was 64 years (standard deviation [SD] 19), 55.7% of recipients (n=1,310) were male, the median pre-transfusion INR was 2.2 (interquartile range [IQR] 1.8–2.9), 45.2% of plasma transfusions were 2-unit events, and median change in the INR after transfusion per plasma unit was 0.2 [IQR 0.1–0.5]. Over the study period, 8.1% (436/5,397) of units were from SARS-CoV-2 Anti-N Ab positive donors, and the median days from index anti-N Ab positivity to donation was 89 (IQR 0–210). There were no differences in recipient pre-transfusion INR relative to the time from index anti-N Ab positivity to donation (Table 2). The INR decreased by 0.25 per plasma unit in 34.6% (1,288/3,721) of transfusion events and 30.2% (1,123/3,721) of transfusion events were followed by an additional plasma transfusion within 24 hours. After stepwise variable selection (p<0.20), final regression models included recipient age, sex, BMI, pre-transfusion INR, and time from plasma transfusion to post-transfusion INR. Increasing pre-transfusion INR, recipient age, and time to post-transfusion INR were associated with increased odds of a 0.25 per unit reduction of the INR (all p<0.05), while male recipient sex and increasing pre-transfusion INR were associated with increased odds of additional plasma transfusions within 24 hours (both p<0.05).
Table 1:
Blood donor, component, and transfusion recipient characteristics
| N (transfusion events) = 3,721 | |
|---|---|
| Blood Donor Characteristics | All (n=5,397) |
| Sex (% male) | 3,804 (70.4) |
| Age in years (SD) | 54 (15) |
| (+) Rh status (%) | 4,799/5,397 (88.9) |
| Blood type | |
| A | 2,010/5,397 (37.2) |
| AB | 1,117/5,397 (20.7) |
| B | 653/5,397 (12.1) |
| O | 1,617/5,397 (30.0) |
| SARS-CoV-2 anti-N seropositivity, (%) | 436 (8.1) |
| Days from index anti-N seropositivity to donation, median (IQR) | 89 (0–210) |
| History of SARS-CoV-2 vaccination (%) | 1,639 (30.4) |
| Transfusion Recipient Characteristics | N=2,350 |
| Sex (% male) | 1,310 (55.7%) |
| Age (SD) | 64 (19) |
| Body mass index (median, (IQR)) | 27 (23–33) |
| (+) Rh status (%) | 2,654 (90.4) |
| Blood type | |
| A | 846 (36.0) |
| B | 83 (3.5) |
| AB | 331 (14.1) |
| O | 1,090 (46.4) |
| Surgical hospitalization (%) | 732 (31.1) |
| Hepatic/gastrointestinal primary diagnoses (%) | 444 (18.9) |
| Intensive care admission (%) | 968 (41.2) |
| Transfusion Event Characteristics | N=3,721 |
| Hours between pre-Tx INR & Tx, median, (IQR) | 4 (2–7) |
| Hours between Tx & post-TX INR, median, (IQR) | 4 (2–12) |
| Pre-transfusion INR, median, (IQR) | 2.2 (1.8–2.9) |
| Number of transfused plasma units, median (IQR) | 1 (1–2) |
| Change in INR after transfusion per plasma unit, median, (IQR) | 0.2 (0.1–0.5) |
| Post-transfusion INR, median (IQR) | 1.8 (1.5–2.3) |
| Plasma transfusion within 24 hours | 1,123 (30.2%) |
SD: standard deviation; IQR: interquartile range; Tx: transfusion; INR: international normalized ratio
Table 2:
Changes in recipient INR and 24-hour plasma transfusion events in relation to timing of blood donor SARS-CoV-2 Anti-N Ab seropositivity
| Days from initial donor SARS-CoV-2 anti-N Ab positivity to donation | ||||
|---|---|---|---|---|
| Anti-N Ab negative (n=3,422) |
0–119 days (n=174) |
120–240 days (n=69) |
>240 days (n=56) |
|
| Pre-transfusion INR [IQR]* | 2.1 [1.8–2.9] | 2.1 [1.9–2.6] | 2.1 [1.7–2.6] | 2.4 [1.8–3.3] |
| 0.25 change in INR [95% CI] | ||||
| Unvaccinated | 35% [33–36] | 43% [35–50]2 | 32% [16–47] | 33% [12–53] |
| Vaccinated | 33% [31–36] | 38% [28–47] | 36% [25–48] | 33% [21–44] |
| 24-hour Plasma Tx [95% CI] | ||||
| Unvaccinated | 30% [28–35] | 21% [14–29]^ | 22% [5–40] | 34% [7–62] |
| Vaccinated | 32% [29–35] | 27% [16–38] | 27% [14–40] | 15% [5–26]# |
Anti-N Ab: SARS-CoV-2 nucleocapsid antibody; Tx: transfusion; CI: confidence interval
Models adjusted for recipient age, sex, ABO, BMI, pre-Tx PT/INR
0.25 change in INR: Greater than 0.25 per unit change in the INR after plasma transfusion
Adj Plasma: adjusted incidence of plasma transfusion for 24-hour period after index plasma transfusion
P=0.69 - p-value for differences in pre-transfusion INR by status and timing of donor SARS-CoV-2 anti-N seropositivity
P=0.03; ^3 P=0.04; # P=0.03 – p-values of differences in outcomes compared to that of the reference group of unvaccinated, anti-N Ab negative transfusion events.
Compared to anti-N Ab negative units, plasma units from recently seroconverted (<120 days) donors were associated with increased odds of a 0.25 per unit lowering of the INR (aOR 1.6 [95% CI 1.1–2.5]; p=0.03) and lower odds of an additional plasma transfusion within 24 hours (aOR 0.7 [95% CI 0.5–0.9]; p=0.04). In contrast, plasma units from SARS-CoV-2 vaccinated but uninfected donors (Table 2) were not associated with increased odds of a 0.25 per unit lowering of the INR (aOR 0.9 [95% CI 0.7–1.1]; p=0.20) or additional plasma transfusions within 24 hours (aOR 1.1 [95% CI 0.9–1.3]; p=0.41). The odds of a lowering of the INR were significantly increased in plasma units from recently (<120 days) infected unvaccinated donors (aOR 2.0 [95% CI 1.1–3.7]; p=0.02; Table 2) but not from recently infected, previously vaccinated donors (aOR 1.1 [95% CI 0.6–2.3]; p=0.67]. Reduced odds of 24-hour plasma transfusion events were identified in recipients of plasma units from recently infected unvaccinated donors (aOR 0.6 [95% CI 0.4–0.9]; p=0.04] and also in vaccinated donors with evidence of initial infection greater than 240 days prior to donation (aOR 0.4 [95% CI 0.2–0.9]; p=0.03). A sensitivity analysis examining only the first donation following seroconversion showed similar model coefficients for plasma units from recently seroconverted (<120 days) donors when examining our outcomes of a 0.25 per unit lowering of the INR (aOR 1.7 [95% CI 1.0–2.7]; p=0.04) and additional plasma transfusion within 24 hours (aOR 0.7 [95% CI 0.5–1.1]; p=0.10).
Discussion:
Our results indicate that plasma transfusion from donors with recent SARS-CoV-2 infection was associated with higher odds of a lowering of the INR and lower odds of requiring a subsequent plasma transfusion. We accounted for various factors in our multivariable analysis that could influence our outcomes, including patient demographics, pre-transfusion INR, and repeated transfusion events. After adjusting for these variables, we found a persistent association of donor SARS-CoV-2 anti-N Ab infection on transfusion recipient outcomes.
Our study suggests that the impact of SARS-CoV-2 infection on plasma transfusion outcomes is transient, observed only within 120 days of index anti-N Ab seroconversion in unvaccinated donors. The hypercoagulable state associated with SARS-CoV-2 infection is thought to peak around the third to fourth week of illness.8,9 However, some studies have demonstrated prolonged elevation in fibrinogen levels up to 18 months in some post-COVID-19 patients.10 While the exact timing of infection prior to donation is not known in our study, our findings suggest that alteration in coagulation factors may persist for several months. SARS-CoV-2 reinfection is also known to increase the risk of coagulopathy through mechanisms similar to those seen in initial infection, with additive risk for thrombotic complications reported.11,12 In our study, we identified a significant reduction in downstream plasma transfusion events in recipients of units from distantly infected (>240 days) vaccinated donors. This reduction in subsequent plasma transfusion may be due to donor re-infection events which our SARS-CoV-2 serologic assays were not calibrated to account for.13
Several limitations must be acknowledged in addition to the observational nature of our study and a limited sample of blood donors with prior SARS-CoV-2 infection. First, we may be underestimating the time of donor SARS-CoV-2 infection as we used the timing of nucleocapsid seropositivity as a proxy for the time of infection, as previous studies have done.6,14 Second, the outcome of downstream plasma transfusion events serves as an indirect measure of plasma function and residual confounding may persist. Third, our study did not allow for the study of specific SARS-CoV-2 variants or account for repeated donor exposures to SARS-CoV-2 infection on outcomes of plasma transfusion.13 We did exclude recipients with recent SARS-CoV-2 infection (within 30 days of transfusion) to avoid confounding related to receipt of COVID-19 convalescent plasma as well as other indications for plasma transfusion where the pre-transfusion INR was less than 1.5. Lastly, we did not account for the administration of phytonadione or factor concentrates, though their use would not confound associations related to the timing of donor SARS-CoV-2 infection.
In conclusion, our study suggests that recently acquired SARS-CoV-2 infection may enhance the effectiveness of plasma transfusions. The unique scenario of the COVID-19 pandemic allowed the study of a widespread infection on outcome measures of plasma transfusion. Further studies of the effects of SARS-CoV-2 infection on stored plasma could inform approaches to improve the effectiveness of plasma transfusions in clinical practice.
Funding/Support:
Funding for this project was provided by the National Heart, Lung, and Blood Institute (R01 HL126130 and NHLBI contract HHSN 75N92019D00033). We would like to acknowledge funding provided by the US Centers for Disease Control and Prevention (contract no. 75D30120C08170) for SARS-CoV-2 spike and nucleocapsid antibody testing as part of the Nationwide Blood Donor Seroprevalence study.
Role of the Funder/Sponsor:
The funding agencies had no role in the design and conduct of the study; collection, management, analysis, and interpretation of the data; preparation, review, or approval of the manuscript; and decision to submit the manuscript for publication.
Footnotes
Conflict-of-interest disclosure: The authors declare no competing financial interests.
CITATIONS
- 1.Helms J, Tacquard C, Severac F, et al. High risk of thrombosis in patients with severe SARS-CoV-2 infection: a multicenter prospective cohort study. Intensive Care Med. Jun 2020;46(6):1089–1098. doi: 10.1007/s00134-020-06062-x [DOI] [PMC free article] [PubMed] [Google Scholar]
- 2.Martins-Gonçalves R, Hottz ED, Bozza PT. Acute to post-acute COVID-19 thromboinflammation persistence: Mechanisms and potential consequences. Curr Res Immunol. 2023;4:100058. doi: 10.1016/j.crimmu.2023.100058 [DOI] [PMC free article] [PubMed] [Google Scholar]
- 3.Ryu JK, Yan Z, Montano M, et al. Fibrin drives thromboinflammation and neuropathology in COVID-19. Nature. Sep 2024;633(8031):905–913. doi: 10.1038/s41586-024-07873-4 [DOI] [PMC free article] [PubMed] [Google Scholar]
- 4.Sutanto H, Soegiarto G. Risk of Thrombosis during and after a SARS-CoV-2 Infection: Pathogenesis, Diagnostic Approach, and Management. Hematol Rep. Apr 3 2023;15(2):225–243. doi: 10.3390/hematolrep15020024 [DOI] [PMC free article] [PubMed] [Google Scholar]
- 5.Roubinian NH, Greene J, Spencer BR, et al. Blood donor SARS-CoV-2 infection or vaccination and adverse outcomes in plasma and platelet transfusion recipients. Transfusion. Mar 2025;65(3):485–495. doi: 10.1111/trf.18159 [DOI] [PMC free article] [PubMed] [Google Scholar]
- 6.Busch MP, Stone M. Serosurveillance for Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) Incidence Using Global Blood Donor Populations. Clin Infect Dis. Jan 27 2021;72(2):254–256. doi: 10.1093/cid/ciaa1116 [DOI] [PMC free article] [PubMed] [Google Scholar]
- 7.Triulzi D, Gottschall J, Murphy E, et al. A multicenter study of plasma use in the United States. Transfusion. Jun 2015;55(6):1313–9; quiz 1312. doi: 10.1111/trf.12970 [DOI] [PMC free article] [PubMed] [Google Scholar]
- 8.Corrêa TD, Cordioli RL, Campos Guerra JC, et al. Coagulation profile of COVID-19 patients admitted to the ICU: An exploratory study. PLoS One. 2020;15(12):e0243604. doi: 10.1371/journal.pone.0243604 [DOI] [PMC free article] [PubMed] [Google Scholar]
- 9.Friedrich MS, Studt JD, Braun J, Spahn DR, Kaserer A. Coronavirus-induced coagulopathy during the course of disease. PLoS One. 2020;15(12):e0243409. doi: 10.1371/journal.pone.0243409 [DOI] [PMC free article] [PubMed] [Google Scholar]
- 10.Ranucci M, Baryshnikova E, Anguissola M, Pugliese S, Falco M, Menicanti L. The Long Term Residual Effects of COVID-Associated Coagulopathy. International Journal of Molecular Sciences. 2023;24(6):5514. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 11.Conway EM, Mackman N, Warren RQ, et al. Understanding COVID-19-associated coagulopathy. Nat Rev Immunol. Oct 2022;22(10):639–649. doi: 10.1038/s41577-022-00762-9 [DOI] [PMC free article] [PubMed] [Google Scholar]
- 12.Bowe B, Xie Y, Al-Aly Z. Acute and postacute sequelae associated with SARS-CoV-2 reinfection. Nat Med. Nov 2022;28(11):2398–2405. doi: 10.1038/s41591-022-02051-3 [DOI] [PMC free article] [PubMed] [Google Scholar]
- 13.Grebe E, Chacreton D, Stone M, et al. Detection of SARS-CoV-2 Reinfections Using Nucleocapsid Antibody Boosting. Emerg Infect Dis. May 2025;31(5):958–966. doi: 10.3201/eid3105.250021 [DOI] [PMC free article] [PubMed] [Google Scholar]
- 14.Jones JM, Stone M, Sulaeman H, et al. Estimated US Infection- and Vaccine-Induced SARS-CoV-2 Seroprevalence Based on Blood Donations, July 2020-May 2021. JAMA. Oct 12 2021;326(14):1400–1409. doi: 10.1001/jama.2021.15161 [DOI] [PMC free article] [PubMed] [Google Scholar]