Abstract
Background
Convalescent plasma infusion (CPI) was given to patients with COVID-19 during the early pandemic with mixed therapeutic efficacy. However, the impacts of CPI on the ADAMTS13-von Willebrand factor (VWF) axis and vascular endothelial functions are not known.
Objectives
To determine the impacts of CPI on the ADAMTS13-VWF axis and vascular endothelial functions.
Methods
Sixty hospitalized patients with COVID-19 were enrolled in the study; 46 received CPI and 14 received no CPI. Plasma ADAMTS13 activity, VWF antigen, endothelial syndecan-1, and soluble thrombomodulin (sTM) were assessed before and 24 hours after treatment.
Results
Patients with severe and critical COVID-19 exhibited significantly lower plasma ADAMTS13 activity than the healthy controls. Conversely, these patients showed a significantly increased VWF antigen. This resulted in markedly reduced ratios of ADAMTS13 to VWF in these patients. The levels of plasma ADAMTS13 activity in each patient remained relatively constant throughout hospitalization. Twenty-four hours following CPI, plasma ADAMTS13 activity increased by ∼12% from the baseline in all patients and ∼21% in those who survived. In contrast, plasma levels of VWF antigen varied significantly over time. Patients who died exhibited a significant reduction of plasma VWF antigen from the baseline 24 hours following CPI, whereas those who survived did not. Furthermore, patients with severe and critical COVID-19 showed significantly elevated plasma levels of syndecan-1 and sTM, similar to those found in patients with immune thrombotic thrombocytopenic purpura. Both syndecan-1 and sTM levels were significantly reduced 24 hours following CPI.
Conclusion
Our results demonstrate the relative deficiency of plasma ADAMTS13 activity and endothelial damage in patients with severe and critical COVID-19, which could be modestly improved following CPI therapy.
KeyWords: ADAMTS13, convalescent plasma, COVID-19, endothelial injury, sydecan-1, thrombomodulin, VWF
Abbreviations: CPI, Convalescent plasma infusion; COVID-19, Coronavirus disease 2019; ADAMTS13, A Disintegrin And Metalloprotease with ThromboSpondin Type 1 Repeats, 13; VWF, von Willebrand factor; sTM, Soluble thrombomodulin; iTTP, Immune thrombotic thrombocytopenic purpura; TPE, Therapeutic plasma exchange; IQR, Interquartile range
Essentials
-
•
Patients with severe COVID-19 show reduced plasma ADAMTS13 and increased von Willebrand factor.
-
•
Plasma ADAMTS13 levels do not fluctuate greatly in patients with COVID-19 during hospitalization.
-
•
Convalescent plasma infusion improves ADAMTS13-von Willebrand factor axis and endotheliopathy in severe COVID-19.
-
•
Our findings support the use of convalescent plasma in a subset of patients with COVID-19.
1. Introduction
Convalescent plasma infusion (CPI) therapy uses plasma from individuals who have recovered from an illness to help others recover. In 2020, the United States Food and Drug Administration gave emergency authorization for the use of CPI obtained from donors who recovered from COVID-19 [1], caused by the SARS-CoV-2 virus.
CPI therapy has been used to treat patients infected with other SARS-CoVs such as avian flu, middle east respiratory syndrome coronavirus (MERS-CoV), and Ebola virus [2]. Convalescent plasma isolated from a recovered patient with COVID-19 is expected to provide a source of specific antibodies against SARS-CoV-2. The antibodies may directly neutralize the virus, thus suppressing the viremia. They may also provide anti-inflammatory activity [3,4]. A systematic review and meta-analysis has demonstrated that CPI therapy is able to reduce viral load, alleviate symptomatology, and reduce the duration of infection and mortality [5]. However, the exact mechanism of how CPI achieves such a protective benefit for patients with severe and critical COVID-19 is not fully understood.
Recent studies have demonstrated that an unbalanced level of plasma ADAMTS13 to von Willebrand factor (VWF) in patients with COVID-19 may contribute to thrombosis, inflammation, microvascular injury, and mortality [[6], [7], [8]]. Thus, therapeutic plasma exchange (TPE) was proposed as a rescue therapy for those with severe and critical diseases [9]. TPE has been successfully used to treat thrombocytopenia-associated multiple organ failure [10] and immune thrombotic thrombocytopenic purpura (iTTP) [11,12]. The goals of TPE are to remove acute inflammatory cytokines and damage-associated molecular patterns and to replenish missing or inhibited ADAMTS13 as in the cases of iTTP [10,12,13].
The present study aims to determine how CPI may alter the delicate balance of plasma ADAMTS13 and VWF, which might alleviate endothelial injury (eg, the release of endothelial syndecan-1 and sTM) in patients with severe and critical COVID-19.
2. Patients and Methods
2.1. Patients
Institutional Review Boards of the University of Kansas Medical Center approved the study protocol (STUDY00145631). A total of 123 hospitalized patients with confirmed COVID-19 between May and August 2020 were screened for eligibility for CPI. This is a prospective, case-controlled, nonblinded, observational study to assess the effectiveness and safety of CPI as part of an optional substudy of the Mayo Clinic Expanded Access Program [14]. Written informed consent was obtained from each patient or the patient’s immediate representative.
2.2. Inclusion and exclusion criteria
The inclusion criteria were as follows: 1) age ≥ 18 years; 2) laboratory-confirmed infection of SARS-CoV-2; 3) admission to the hospital for the treatment of COVID-19 or its related complications; and 4) severe or life-threatening COVID-19 based on any of the following: respiratory rate > 30/min, O2 saturation < 93%, PO2/FiO2 < 300, lung infiltrate >50% within 24 to 48 hours, respiratory failure, septic shock, or multiorgan failure. Breastfeeding mothers were excluded. A control group was selected from patients with COVID-19 admitted at the same time who were eligible for CPI but declined to participate or did not receive it because of lack of compatible plasma. These patients were managed with the standard of care.
2.3. Convalescent plasma
The criteria for individuals to be eligible to donate convalescent plasma included a history of laboratory-confirmed COVID-19 and donating at least 14 days after the resolution of symptoms. Plasma was distributed from the Community Blood Center, Kansas City, Kansas, to our hospitals at or below −18 °C according to standard operating procedure. The plasma obtained was labeled and coded following the model of the internationally standardized International Society of Blood Transfusion system for the identification and labeling of each blood product [15].
Each patient received 1 or 2 units of ABO-compatible convalescent plasma (600 mL) at 25 mL/h for the first 15 minutes, then increased to ∼150 mL/h. All adverse events during the observation period were closely monitored. Adjustments of the infusion rates were allowed according to the patient’s risk for volume overload or tolerance. CPI was terminated in any patient with a severe transfusion reaction. Patients were closely followed for the next 28 days, and survival was recorded.
2.4. Samples and data collection
Citrated whole-blood samples were prospectively collected prior to CPI (D0) and daily following CPI (D1-D10). Plasma was separated from cellular components within 4 hours of collection and stored at −80 °C before use. The patients’ demographic, clinical, and laboratory data were collected from electronic medical records.
2.4.1. Plasma from patients with iTTP
A subset of plasmas from patients with iTTP described in our previous studies [16,17] were selected for the analysis of endothelial markers sydecan-1 and sTM. All these patients showed plasma ADAMTS13 activity of <5% of normal with positive inhibitors against ADAMTS13 in their admission samples prior to the initiation of TPE.
2.4.2. Assays for plasma ADAMTS13 activity
Plasma ADAMTS13 activity was determined using our in-house fluorescence resonance energy transfer (FRETS)-VWF73 assay as previously described [18,19]. The intra-assay and interassay coefficients of variation (CVs) of this assay were <5% and 10%, respectively.
2.4.3. Assay for plasma VWF antigen
The plasma level of von Willebrand factor antigen (VWFAg) was determined using in-house ELISA as described previously [20]. The intra-assay and interassay CVs of this assay were also <5% and <10%, respectively.
2.4.4. Assay for plasma syndecan-1
The plasma level of syndecan-1 was determined using a human sydecan-1 ELISA kit (CD-138) (Abcam number ab46506) according to the manufacturer’s instructions. The intra-assay and interassay CVs were 6.2% and 10.2%, respectively.
2.4.5. Assay for plasma sTM
The plasma levels of sTM were determined using a human thrombomodulin/BDCA-3 Quantikine ELISA kit (R&D Systems) according to the manufacturer’s instructions. The intra-assay and interassay CVs were 2.9% and 6.9%, respectively.
2.5. Outcomes
The time to clinical improvement within 28 days was determined. Clinical improvement was defined as a patient being discharged or with a 2-point reduction on a 6-point disease severity scale [21]. The scale was defined as follows: 6 points for death; 5 points for hospitalization plus extracorporeal membrane oxygenation or invasive mechanical ventilation; 4 points for hospitalization plus noninvasive ventilation or high-flow supplemental oxygen; 3 points for hospitalization plus supplemental oxygen (not high-flow or noninvasive ventilation); 2 points for hospitalization with no supplemental oxygen; and 1 point for hospital discharge.
Other outcomes adjudicated include 30-day mortality, the length of hospitalization, the days from CPI treatment to discharge, the length of intensive care unit stay, and adverse events. All clinical outcomes were extracted and determined by investigators who were blinded to the therapeutic interventions.
2.6. Statistical analysis
Continuous variables were expressed as means ± standard deviations (SDs) or medians ± interquartile ranges (IQRs) as appropriate. A paired or an unpaired Student’s t-test or a Mann–Whitney U-test was used for comparison between the 2 groups, depending on the distribution of the data. Kruskal–Wallis 1-way analysis of variance was used for comparison among ≥3 groups. All categorical variables were described as the number and percentage, and Fisher exact test (or chi-squared test) was used for statistical analysis using SPSS statistics, version 26.0 (IBM), or the GraphPad Prism 8.0 software.
3. Results
3.1. Patient characteristics
Of 123 patients initially screened in the clinical trial, 93 received CPI therapy and 30 were eligible but did not receive CPI because of logistic issues, compatibility, and blood product preference (the no-CPI group). Of 93 patients who received CPI, 42 were excluded from the biomarker study because of the lack of initial blood sample (note: blood sample collection was not part of the initial design of the clinical trial). This left 51 patients in the CPI group for longitudinal sampling. Another 5 patients were excluded from the final analysis because of lack of follow-up samples. In the no-CPI group, only 14 patients were included, and 16 were excluded from the final analysis for the same reason (either lack of an initial sample or no follow-up sample). A detailed diagram is presented to illustrate the patients who were included in or excluded from the biomarker study (Figure 1 and Supplementary Table 1).
Figure 1.
Patient recruiting flow chart. This is the flowchart showing how patients with COVID-19 were enrolled into the study, based on the inclusion and exclusion criteria described in the Methods section. Here, convalescent plasma infusion (CPI) is convalescent plasma infusion. Started from 123 patients screened for the clinical trial, only 60 patients (46 in the CPI group and 14 in the no-CPI group) were included in the final analysis. Other 63 patients were not included in the biomarker study because of the lack of initial or follow-up samples
Overall, 375 blood samples were collected and analyzed from 60 patients enrolled (46 in the CPI group and 14 in the no-CPI group). There were no adverse events following CPI therapy, except for 1 patient who was reported to have temporary hypoxia (O2 saturation < 92%). There was no significant difference in demographic features between the 2 groups. The average age of all the patients was 58 years. Forty-two (66.7%) patients were men. The percentage of White patients and Black patients was the same (at 30% each). Patients of other races accounted for ∼40% of the total. In terms of comorbidities, the 2 groups exhibited similar prevalence of diabetes mellitus, cardiovascular disease, chronic obstructive pulmonary disease, hyperlipidemia, and history of malignancy and thrombotic events, except for hypertension (P =.008). The intensive care unit admission rate was 68%. The median interval (IQR) between the onset of symptoms and the enrollment of the study was 7 (5-8) days in the no-CPI group but 9 days (7-14) in the CPI group (P =.02). In terms of oxygen support, 8 in the CPI and 2 in the no-CPI group required invasive ventilation, 11 in the CPI and 2 in the no-CPI group required high-flow oxygen therapy, and 26 in the CPI and 10 in the non-CPI group required nasal cannula oxygen support (Table 1).
Table 1.
Baseline clinical and laboratory characteristics between patients receiving convalescent plasma infusion and those receiving standard of care (no convalescent plasma infusion).
| Characteristics | CPI (n = 46) | No CPI (n = 14) | P value |
|---|---|---|---|
| Sex (male/female) | 29/17 | 11/3 | .07 |
| Age (year ± SD) | 58.0 ± 16.0 | 59.5 ± 17.4 | .76 |
| BMI, kg/m2 | 28.9 (26.0-33.6)a | 28.4 (26.9-42.4) | .63 |
| White individuals, n (%) | 16 (34.8) | 2 (14.3) | .28 |
| Black individuals, n (%) | 12 (26.1) | 6 (42.9) | |
| Others, n (%) | 18 (39.1) | 6 (42.9) | |
| Comorbidities | |||
| Diabetes mellitus, n (%) | 15 (32.6) | 6 (42.9) | .70 |
| Hypertension, n (%) | 21 (45.7) | 12 (85.7) | .008b |
| Cardiovascular disease, n (%) | 9 (19.6) | 4 (28.6) | .73 |
| COPD, n (%) | 4 (8.7) | 2 (14.3) | .62 |
| Hyperlipoidemia, n (%) | 11 (23.9) | 7 (50.0) | .13 |
| History of malignancy, n (%) | 7 (15.2) | 2 (14.3) | 1.00 |
| History of thrombotic events | 5 (10.8) | 2 (14.2) | 1.00 |
| DVT, n (%) | 2 (4.3) | 1 (7.1) | .56 |
| Stroke, n (%) | 3 (6.5) | 1 (7.1) | 1.00 |
| ICU admission, n (%) | 33 (71.7) | 8 (57.1) | .48 |
| Symptom onset to hospital admission, d | 4.5 (3-8) | 3.5 (2-7) | .18 |
| Symptom onset to CPI or enrollment, dc | 9 (7-14) | 7 (5-8) | .023b |
| Laboratory parameters | |||
| WBC count (4.5-11.0 × 109/L) (mean ± SD) |
8.2 ± 4.1 | 8.0 ± 3.8 | .82 |
| Neutrophil count (1.8 × 109/L-7.0 × 109/L) | 6.3 (3.2-8.4)a | 6.3 (3.7-8.6) | .85 |
| Lymphocyte count (1.0 × 109/L-4.8 × 109/L) | 0.88 (0.56-1.03) | 0.86 (0.59-1.01) | .68 |
| Platelet count (150 × 109/L-400 × 109/L) | 237 (157-321) | 218 (135-315) | .59 |
| CRP (<1.0 mg/dL) | 10.5 (3.3-14.7) | 11.2 (6.0-12.9) | .64 |
| D-dimer (<500 ng/mL FEU) | 670 (466-1665) | 916 (647-1449) | .63 |
| Albumin (35-50 g/L) (mean ± SD) | 32.8 ± 3.8 | 31.2 ± 3.6 | .17 |
| LDH (100-210 U/L) | 327 (275-421) | 341 (270-502) | .53 |
| Ferritin (100-200 ng/mL) | 564 (342-981) | 700 (462-1449) | .22 |
| Creatinine (0.4-1.0 mg/dL) | 0.85 (0.65-1.24) | 1.11 (0.90-2.23) | .009b |
BMI, body mass index; COPD, chronic obstructive pulmonary disease; CPI, convalescent plasma infusion; CRP, C reaction protein; DVT, deep vein thrombosis; ICU, intensive care unit; LDH, lactate dehydrogenase; WBC, white blood cell.
All data are presented as median and IQR unless specified otherwise.
P values of <.05 are considered statistically significant.
Number of days with symptoms before CPI or control treatment or until the date of enrollment to the study.
3.2. Laboratory parameters, clinical procedures, and outcomes
Routine and special laboratory parameters in all 60 patients at enrollment are shown in Table 1. There were no significant differences between the CPI group and the no-CPI group regarding white blood cell, neutrophil, lymphocyte, and platelet counts, and certain coagulation and inflammatory profiles, as well as the distribution on the 6-point disease severity scale, except for serum creatinine. The no-CPI group had a relatively higher median (IQR) level of creatinine than the CPI group (P =.009) (Table 1).
There was no significant difference between these 2 groups with regard to acute events during hospitalization, including septic shock, acute kidney injury, stroke, and gastrointestinal bleeding. In terms of time to clinical improvement, the patients who survived in the CPI group had a shorter time to recover (median, 5; IQR, 3-9.5 days) than those in the no-CPI group (median, 12; IQR, 6.5-17 days) (P =.03). There was no significant difference in the clinical improvement rate within 28 days: 71.7% (33/46) in the CPI group versus 64.3% (9/14) in the no-CPI group (HR, 1.4; 95% CI, 0.4-5) (P =.82). There was also no significant difference in the 30-day mortality rate (21.7% in the CPI group vs 21.4% in the no-CPI group) or the days of hospitalization (median, 9.5; IQR, 6-17 in the CPI group vs median, 11.5; IQR, 7-19 in the no-CPI group) (P =.65) (Table 2).
Table 2.
Comparison of special laboratory features and outcomes between patients receiving convalescent plasma infusion and those receiving standard of care (no convalescent plasma infusion).a
| Parameters | CPI (n = 46) | No CPI (n = 14) | P value |
|---|---|---|---|
| ADAMTS13 activity (%) at d 0 | 52.5 (41.2-81.9) | 49.2 (42.9-66.2) | .83 |
| VWFAg (%) at d 0 | 405 (204-554) | 343 (257-393) | .49 |
| ADAMTS13 activity/VWFAg ratio at d 0 | 0.15 (0.08-0.29) | 0.17 (0.13-0.22) | .71 |
| Syndecan-1 (ng/mL) at d 0 | 174 (105-494) | 196 (120-459) | .47 |
| sTM (ng/mL) at d 0 | 4.5 (3.3-6.5) | ND | ND |
| Acute events in hospitalization | |||
| Septic shock, n (%) | 7 (15.2) | 2 (14.3) | 1.00 |
| AKI (KDIGO: 2-4), n (%) | 16 (34.8) | 6 (42.9) | .58 |
| Stroke, n (%) | 1 (2.2) | 0 (0.0) | 1.00 |
| Gastrointestinal bleeding, n (%) | 3 (6.5) | 0 (0) | 1.00 |
| Outcomes | |||
| Time to clinical improvement (d) (IQR) | 5 (3-9.5) | 12 (6.5-17) | .038b |
| Improvement rate, n (%) | |||
| At d 7 | 23 (50.0) | 3 (21.4) | .06 |
| At d 14 | 31(67.4) | 7 (50.0) | .24 |
| At d 28 | 33 (71.7) | 9 (64.3) | .84 |
| Mortality at 30-d after CPI, n (%) | 10 (21.7) | 3 (21.4) | 1.00 |
| Length of hospitalization (d) | 9.5 (6-17) | 11.5 (7-19) | .65 |
| Length of ICU stay (d) | 2.5 (0-10) | 1.5 (0-6) | .24 |
| Time from CPI or enrollment to Discharge (d) | 5.5 (4-10.5) | 10 (4.5-14.5) | .26 |
| Time from CPI or enrollment to death (d) | 15.5 (10-27) | 8 (4-21) | .29 |
AKI, acute kidney injury; CPI, convalescent plasma infusion; ICU, intensive care unit; KDIGO, Kidney Disease Improving Global Outcomes; ND, no data; sTM, soluble thrombomodulin; VWFAg, von Willebrand factor antigen.
All data are presented as the median, interquartile range (IQR) unless specified otherwise.
P <.05 is considered statistically significant.
3.3. Reduced ADAMTS13 activity in patients with severe and critical COVID-19
To assess the status of plasma ADAMTS13–VWF axis in severe and critical COVID-19 patients before and after CPI or standard of care, we determined the daily plasma levels of ADAMTS13 activity using the FRETS-VWF73 assay and of VWF antigen using an ELISA-based assay as described in the Methods section. As shown, plasma ADAMTS13 activity in the patients with COVID-19 before CPI or no-CPI (median, 51.3%; IQR, 41.3%-73.6%) was significantly lower than that in the healthy controls (median, 106%; IQR, 87.8%-125%) (P <.001) (Figure 2A). However, there was no significant difference in the baseline plasma ADAMTS13 activity between those before receiving CPI (median 52.5%, IQR 41.2%–81.9%) and those receiving the standard of care (the no-CPI group) (median 49.2%, IQR 42.9%–66.2%) (P =.83) (Table 2 and Figure 2B).
Figure 2.
Plasma ADAMTS13 activity, von Willebrand factor (VWF) antigen, and the ratios of ADAMTS13 to VWF in patients with severe and critical COVID-19. (A) Plasma ADAMTS13 activity in patients with COVID-19 and healthy controls. (B) Plasma ADAMTS13 activity in patients who received convalescent plasma infusion (CPI) and those treated with standard of care (no CPI). (C) Plasma VWF antigen levels in patients with COVID-19 and healthy controls. (D) Plasma VWF antigen levels in patients with CPI and those with no CPI; (E) The ratios of plasma ADAMTS13 (A13) activity to VWF antigen in patients with COVID-19 and healthy controls. (F) The ratios of plasma ADAMTS13 (A13) to VWF in patients with CPI and no CPI. The data shown are the median and IQR, as well as individual values. n.s. refers to no statistical significance, and ∗∗∗ indicates a P value of <.005 (statistically highly significant)
3.4. Increased VWF antigen in patients with severe and critical COVID-19
Conversely, the baseline level of plasma VWF antigen in patients with COVID-19 before CPI or standard of care (median, 378%; IQR, 207%-549%) was significantly higher than those in the healthy control (median, 145%; IQR, 104%-177%) (P <.001) (Figure 2C). Again, there was no significant difference in the baseline levels of plasma VWF antigen between these 2 groups (median, 405%; IQR, 203%-554% vs median, 343%; IQR, 244%-422%) (P =.49) (Table 2 and Figure 2D). This resulted in dramatically reduced ratios of plasma ADAMTS13 activity to VWF antigen in these patients (median, 0.16; IQR, 0.10-0.27) compared with those in the healthy controls (median, 0.77; IQR, 0.53-1.26) (P < 0.001) (Figure 2E). Again, there was no significant difference in the baseline levels of ADAMTS13 to VWF ratio between 2 groups (median, 0.15; IQR, 0.08-0.29 in the CPI group vs median, 0.17; IQR, 0.13-0.22 in the no-CPI group) (P =.71) (Table 2 and Figure 2F).
3.5. Dynamic changes of plasma ADAMTS13 activity and VWF antigen in patients with severe and critical COVID-19
To assess whether CPI treatment alters the plasma ADAMTS13-VWF axis, we determined daily plasma levels of ADAMTS13 activity and VWF antigen for a period of 5 to 10 days during hospitalization. As shown, plasma ADAMTS13 activity remained relatively constant throughout hospitalization in the patients treated with CPI (Figure 3A) or standard of care (no-CPI) (Figure 3B). Plasma ADAMTS13 activity was significantly increased 24 hours following CPI (median, 65.4%; IQR, 47.6%-88.8%) from the baseline level (median, 52.5%; IQR, 41.2%-82.3%) (P <.001) (Figure 3C). Such an increase in ADAMTS13 activity was not observed in patients treated with the standard of care (no CPI) (P =.24) (Figure 3D). There was no statistically significant difference between CPI and no-CPI group regarding plasma ADAMTS13 activity, VWF antigen, and the ratio of ADAMTS13 to VWF on any given day during the hospitalization (Supplementary Figure 1). However, the daily plasma VWF antigen level appeared to be more variable than daily plasma ADAMTS13 activity over time in these patients regardless of the treatment modality (Figure 4A, B). As such, there was no detectable trend in plasma VWF levels 24 hours following either CPI (P =.76) (Figure 4C) or no CPI (P =.99) (Figure 4D) in these patients.
Figure 3.
Longitudinal changes of plasma ADAMTS13 activity in patients with severe and critical COVID-19. (A, B) The daily plasma ADAMTS13 activity levels over 5 to 10 days in patients with convalescent plasma infusion (CPI) and in those with the standard of care (no CPI), respectively. (C, D) Changes in plasma ADAMTS13 activity before (D0) and 24 hours (D1) following CPI and no CPI, respectively. Data are analyzed using a paired 2-tailed t-test. Here, n.s. refers to no statistical significance, and ∗∗∗ indicates a P value of <.005 (statistically highly significant)
Figure 4.
Longitudinal changes of plasma von Willebrand factor (VWF) levels in patients with severe and critical COVID-19. (A, B) The daily plasma VWF levels over 5 to 10 days in hospitalized patients with COVID-19 treated with convalescent plasma infusion (CPI) and standard of care (no CPI), respectively. (C, D) Changes in plasma VWF levels before (D0) and 24 hours (D1) following CPI and no CPI, respectively. Data were analyzed using a paired 2-tailed t-test. Here, n.s. indicates no statistical significance
3.6. Changes in plasma ADAMTS13 activity and VWF antigen in patients with severe and critical COVID-19 who survived or died
To determine whether the change of plasma ADAMTS13 activity is a predictive marker for the outcome, we compared the changes in ADAMTS13 activity 24 hours following treatments from baseline. As shown, plasma ADAMTS13 activity following CPI (D1) was increased by ∼21% from the baseline (D0) in patients who survived (P <.001) (Figure 5A) but only by 3.6% in patients who died (Figure 5B) (P =.88). There was no significant change in plasma VWF levels in patients who survived (P =.68) (Figure 5C) but paradoxically reduced by 140% in those who died (P =.03) (Figure 5D). These results suggest that ongoing thrombus formation and/or endothelial exhaustion exists in patients with fatality.
Figure 5.
Changes in plasma ADAMTS13 activity and von Willebrand factor levels in patients with COVID-19 who survived or died following convalescent plasma infusion. (A, B) Changes in plasma ADAMTS13 activity in the survivors and nonsurvivors, respectively, prior to (D0) and 24 hours (D1) following convalescent plasma infusion. (C, D) Plasma von Willebrand factor levels in the survivors and nonsurvivors, respectively. Data were analyzed using a paired 2-tailed t-test. Here, n.s. refers to no statistical significance, and ∗ and ∗∗∗ indicate a P value of <.05, and <.005, respectively. VWF, von Willebrand factor
3.7. Plasma syndecan-1 and soluble thrombomodulin in patients with severe and critical COVID-19
To assess the extent of endothelial damage in patients with severe and critical COVID-19, we determined the plasma levels of syndecan-1 and sTM prior to (D0) and 24 hours (D1) following CPI or no CPI. As shown, the baseline plasma levels of syndecan-1 in patients with severe and critical COVID-19 (median, 174; IQR, 110-458 ng/mL) were significantly higher than those in the healthy controls (median, 49.5; IQR, 38.1-62.1 ng/mL) (P <.0001). The levels of syndecan-1 in patients with COVID-19 appeared to be even higher than those in patients with iTTP (median, 93.4; IQR, 82.2-123 ng/mL, P =.02) (Figure 6A). A similar but less dramatic increase in the plasma levels of sTM in patients with severe and critical COVID-19 and iTTP compared with that in the healthy controls (Figure 6B). However, plasma levels of syndecan-1 (Figure 6C) and sTM (Figure 6D) were significantly reduced in most patients with COVID-19 24 hours following CPI but not in those with the standard of care (or no CPI). Additionally, the reduction of syndecan-1 and sTM following CPI treatment was only observed in patients who survived but not in those who died (Supplementary Figure 2). Together, these results demonstrate that the improvement of endotheliopathy following CPI is associated with COVID-19 survival.
Figure 6.
Changes in plasma syndecan-1 and soluble thrombomodulin levels in patients with severe and critical COVID-19. (A, B) Baseline plasma levels of syndecan-1 and soluble thrombomodulin, respectively, in patients with COVID-19, immune thrombotic thrombocytopenic purpura, and healthy individuals. Kruskal–Wallis 1-way analysis of variance determined the statistical significance. (C, D) The changes of plasma levels of syndecan-1 and soluble thrombomodulin, respectively, before (D0) and 24 hours (D1) following convalescent plasma infusion in patients with severe and critical COVID-19. Data were analyzed using a paired 2-tailed t-test. Here, n.s. refers to no statistical significance, and ∗, ∗∗, and ∗∗∗∗ indicate a P value of <.05, <.01, and <.001, respectively. CPI, convalescent plasma infusion; iTTP, immune thrombotic thrombocytopenic purpura; sTM, soluble thrombomodulin
4. Discussion
The present study demonstrates that patients with severe and critical COVID-19 exhibit a modest deficiency of plasma ADAMTS13 activity, a significant elevation of plasma VWF, and a significant increase in the markers of vascular endothelial damage. CPI treatment in these patients has shown a modest but significant improvement to their ADAMTS13-VWF axis and the integrity of the vascular endothelium. An unbalanced ADAMTS13-VWF axis [7,[22], [23], [24], [25], [26], [27], [28], [29]] and an elevated plasma marker of endothelial damage [30,31] are associated with COVID-19 disease severity and may predict the mortality associated with severe COVID-19.
The mechanism underlying the modest reduction of plasma ADAMTS13 activity and the significant elevation of plasma VWF antigen is not fully understood. Inflammatory cytokines, such as interleukin (IL)-4, IL-6, and tissue necrosis factor (TNF)-α may activate endothelium to release VWF [32,33]. Conversely, these cytokines may suppress the synthesis of ADAMTS13 in hepatic stellate cells and endothelial cells [34,35]. Low ADAMTS13 activity may also be the result of increased consumption as plasma VWF is shown to be a negative regulator of plasma ADAMTS13 activity in healthy individuals [36]. The significant increase in plasma levels of VWF coupled with a modest reduction of plasma ADAMTS13 activity results in a dramatic decrease in the ratio of ADAMTS13 to VWF. This may result in compromised microvascular functions, which leads to organ damage and death in patients with severe and critical COVID-19 [9,37,38].
Plasma ADAMTS13 activity in each patient with COVID-19 is relatively stable over time during hospitalization. Plasma ADAMTS13 activity increases by ∼12% to 20% on average 24 hours following CPI treatment. Such a modest increase in plasma ADAMTS13 activity is similar to that (∼13%) following 1 plasma volume exchange (with 5% albumin as the replacement fluid) in patients with severe and critical COVID-19 [9]. This increase in plasma ADAMTS13 activity is not observed in patients treated with the standard of care (or no CPI). These results indicate that CPI may not only provide additional ADAMTS13 but also neutralize antibodies against SARS-CoV-2 [39], thus improving the overall health of patients with COVID-19. The improvement of plasma ADAMTS13 activity appears to be even greater (∼21%) in those who survived than in those who did not, further supporting a potential role of ADAMTS13 increment following therapy as a biomarker for predicting outcomes in patients with severe and critical COVID-19. Our results are consistent with the reports in the literature. Low levels of plasma ADAMTS13 activity are associated with disease severity, renal insufficiency, and mortality in patients with COVID-19 [7,23,26,27,40]. More recent studies have demonstrated that plasma levels of ADAMTS13 activity are modestly reduced and plasma levels of VWF remain elevated in patients with long COVID syndrome [41,42].
Although there is also a trend toward lowering plasma VWF levels following CPI, the difference is not statistically significant, likely because of individual and temporal variability of plasma VWF levels and the small sample size. Paradoxically, the patients who died, but not those who survived, show a significantly reduced level of plasma VWF 24 hours following CPI therapy, suggesting the potential endothelial exhaustion or consumption during ongoing thrombus formation in critical COVID-19. Such a paradoxical reduction in the levels of VWF antigen and VWF multimer size has been previously reported in patients with TTP [43] and severe and critical COVID-19 [6]. For instance, ultralarge VWF multimers are only detected in some [37,44] but not in other patients [[6], [7], [8],45]. We did not detect consistent changes in plasma VWF multimers prior to and following CPI (data not shown). This may be related to consumption during thrombus formation, preanalytic issues, and the sensitivity of the multimer assay.
Endothelial injuries and microvascular thrombosis are common pathogenic features of severe COVID-19 [33] and TTP [16,46,47]. Syndecan-1 and sTM are released following endothelial injuries resulting from SARS-CoV-2 infection [30,[48], [49], [50]]. We demonstrated a significant increase in the baseline plasma levels of syndecan-1 and sTM in patients with severe and critical COVID-19 compared with those in the healthy controls. The plasma syndecan-1 and sTM levels are significantly reduced 24 hours following CPI but not in those treated with the standard of care (not shown). Our results support the hypothesis that CPI treatment may reduce COVID-19–associated endothelial injury and prevent the degradation of endothelial glycocalyx and shedding of membrane-bound thrombomodulin. Such a protective effect of CPI may offer some explanation why CPI reduces an early (7- and 14-day) but not late (30-day) mortality rate [51,52].
There are a few limitations of this study that should be considered. Not all patients in our center who participated in this large clinical trial are included in the study. Thus, the sample size remains small. Additionally, not all patients have >3 longitudinal follow-up samples resulting from early discharge or death. This may decrease the statistical power to detect the difference between various biomarkers over time.
Nevertheless, this is the first study we are aware of that has examined how CPI may improve the balance of the plasma ADAMTS13-VWF axis and endothelial dysfunction in patients with severe and critical COVID-19. Although CPI therapy is no longer recommended for patients with COVID-19, the results offer a glimpse of how CPI may improve microvascular circulation. However, it is unknown whether these findings have an implication for reducing long-term complications of COVID-19 after convalescent plasma administration, but this is worthy of future study.
Acknowledgments
This study was supported in part by grants from the National Heart, Lung, and Blood Institute (R01HL144552 and R01HL157975-01A1 to X.L.Z). The authors thank Ms Kathleen Gooley and other staff at the laboratories of hematology and coagulation, University of Kansas Medical Center, Kansas City, Kansas, for their assistance with specimen collection, processing, and storage.
Funding
This study was supported in part by grants from the National Heart, Lung, and Blood Institute, USA (R01HL144552 and R01HL157975-01A1 to X.L.Z).
Author contributions
Q.Z., Z.Y., and X.L.Z. designed, executed, and interpreted the results and drafted the manuscript. P.M., C.J., A.L., A.B., and N.Y. helped with specimen collection. Z.Y. contributed to patient recruitment and informed consent and sample collections. All authors revised and approved the final version of the manuscript.
Relationship Disclosure
X.L.Z. is a consultant for Alexion, Sanofi, and Takeda, as well as a cofounder of Clotsolution. Other authors have nothing to declare.
Informed patient consent
Written informed consent was obtained from each patient or patient immediate representative.
Data availability
The datasets used and/or analyzed during the current study are available from the corresponding author upon request.
Footnotes
Funding information National Heart, Lung, and Blood Institute (R01HL144552 and R01HL157975-01A1 to X.L.Z.).
Handling Editor: Spronk, H
Quan Zhang and Zhan Ye contributed equally to this study.
The online version contains supplementary material available at https://doi.org/10.1016/j.rpth.2022.100010
Supplementary material
References
- 1.Tanne J.H. Covid-19: FDA approves use of convalescent plasma to treat critically ill patients. BMJ. 2020;368:m1256. doi: 10.1136/bmj.m1256. [DOI] [PubMed] [Google Scholar]
- 2.Mair-Jenkins J., Saavedra-Campos M., Baillie J.K., Cleary P., Khaw F.M., Lim W.S., et al. The effectiveness of convalescent plasma and hyperimmune immunoglobulin for the treatment of severe acute respiratory infections of viral etiology: a systematic review and exploratory meta-analysis. J Infect Dis. 2015;211:80–90. doi: 10.1093/infdis/jiu396. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 3.Franchini M., Glingani C., Liumbruno G.M. Potential mechanisms of action of convalescent plasma in COVID-19. Diagnosis (Berl) 2021;8:413–420. doi: 10.1515/dx-2020-0161. [DOI] [PubMed] [Google Scholar]
- 4.Rojas M., Rodriguez Y., Monsalve D.M., Acosta-Ampudia Y., Camacho B., Gallo J.E., et al. Convalescent plasma in Covid-19: possible mechanisms of action. Autoimmun Rev. 2020;19 doi: 10.1016/j.autrev.2020.102554. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 5.Fernández-Lázaro D., Ortega C.D., Sánchez-Serrano N., Beddar Chaib F., Jerves Donoso D., Jiménez-Callejo E., et al. Convalescent plasma therapy, therapeutic formulations of repurposed drugs in 20th century epidemics against COVID-19: a systematic review. Pharmaceutics. 2022;14:1020. doi: 10.3390/pharmaceutics14051020. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 6.Ward S.E., Fogarty H., Karampini E., Lavin M., Schneppenheim S., Dittmer R., et al. ADAMTS13 regulation of VWF multimer distribution in severe COVID-19. J Thromb Haemost. 2021;19:1914–1921. doi: 10.1111/jth.15409. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 7.Mancini I., Baronciani L., Artoni A., Colpani P., Biganzoli M., Cozzi G., et al. The ADAMTS13–von Willebrand factor axis in COVID-19 patients. J Thromb Haemost. 2021;19:513–521. doi: 10.1111/jth.15191. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 8.Doevelaar A.A., Bachmann M., Hölzer B., Seibert F.S., Rohn B.J., Bauer F., et al. von Willebrand factor multimer formation contributes to immunothrombosis in coronavirus disease 2019. Crit Care Med. 2021;49:e512–e520. doi: 10.1097/CCM.0000000000004918. [DOI] [PubMed] [Google Scholar]
- 9.Seibert F.S., Blazquez-Navarro A., Hölzer B., Doevelaar A.A., Nusshag C., Merle U., et al. Effect of plasma exchange on COVID-19 associated excess of von Willebrand factor and inflammation in critically ill patients. Sci Rep. 2022;12:1–8. doi: 10.1038/s41598-022-08853-2. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 10.Fortenberry J.D., Nguyen T., Grunwell J.R., Aneja R.K., Wheeler D., Hall M., et al. Therapeutic plasma exchange in children with thrombocytopenia-associated multiple organ failure: the thrombocytopenia-associated multiple organ failure network prospective experience. Crit Care Med. 2019;47:e173–e181. doi: 10.1097/CCM.0000000000003559. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 11.Zheng X.L., Vesely S.K., Cataland S.R., Coppo P., Geldziler B., Iorio A., et al. ISTH guidelines for treatment of thrombotic thrombocytopenic purpura. J Thromb Haemost. 2020;18:2496–2502. doi: 10.1111/jth.15010. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 12.Zheng X.L., Kaufman R.M., Goodnough L.T., Sadler J.E. Effect of plasma exchange on plasma ADAMTS13 metalloprotease activity, inhibitor level, and clinical outcome in patients with idiopathic and nonidiopathic thrombotic thrombocytopenic purpura. Blood. 2004;103:4043–4049. doi: 10.1182/blood-2003-11-4035. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 13.Kesici S., Yavuz S., Bayrakci B. Get rid of the bad first: therapeutic plasma exchange with convalescent plasma for severe COVID-19. Proc Natl Acad Sci U S A. 2020;117:12526–12527. doi: 10.1073/pnas.2006691117. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 14.Joyner M.J., Wright R.S., Fairweather D., Senefeld J.W., Bruno K.A., Klassen S.A., et al. Early safety indicators of COVID-19 convalescent plasma in 5000 patients. J Clin Invest. 2020;130:4791–4797. doi: 10.1172/JCI140200. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 15.Aandahl G.S., Knutsen T.R., Nafstad K. Implementation of ISBT 128, a quality system, a standardized bar code labeling of blood products worldwide, electronic transfusion pathway: four years of experience in Norway. Transfusion. 2007;47:1674–1678. doi: 10.1111/j.1537-2995.2007.01340.x. [DOI] [PubMed] [Google Scholar]
- 16.Lu R., Sui J., Zheng X.L. Elevated plasma levels of syndecan-1 and soluble thrombomodulin predict adverse outcomes in thrombotic thrombocytopenic purpura. Blood Adv. 2020;4:5378–5388. doi: 10.1182/bloodadvances.2020003065. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 17.Sui J., Lu R., Halkidis K., Kocher N.K., Cao W., Marques M.B., et al. Plasma levels of S100A8/A9, histone/DNA complexes, and cell-free DNA predict adverse outcomes of immune thrombotic thrombocytopenic purpura. J Thromb Haemost. 2021;19:370–379. doi: 10.1111/jth.15176. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 18.Zhang L., Lawson H.L., Harish V.C., Huff J.D., Knovich M.A., Owen J. Creation of a recombinant peptide substrate for fluorescence resonance energy transfer-based protease assays. Anal Biochem. 2006;358:298–300. doi: 10.1016/j.ab.2006.06.022. [DOI] [PubMed] [Google Scholar]
- 19.Raife T.J., Cao W., Atkinson B.S., Bedell B., Montgomery R.R., Lentz S.R., et al. Leukocyte proteases cleave von Willebrand factor at or near the ADAMTS13 cleavage site. Blood. 2009;114:1666–1674. doi: 10.1182/blood-2009-01-195461. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 20.Kumar M., Cao W., McDaniel J.K., Pham H.P., Raju D., Nawalinski K., et al. Plasma ADAMTS13 activity and von Willebrand factor antigen and activity in patients with subarachnoid haemorrhage. Thromb Haemost. 2017;117:691–699. doi: 10.1160/TH16-11-0834. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 21.Wang Y., Zhang D., Du G., Du R., Zhao J., Jin Y., et al. Remdesivir in adults with severe COVID-19: a randomised, double-blind, placebo-controlled, multicentre trial. Lancet. 2020;395:1569–1578. doi: 10.1016/S0140-6736(20)31022-9. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 22.Delrue M., Siguret V., Neuwirth M., Joly B., Beranger N., Sène D., et al. von Willebrand factor/ADAMTS13 axis and venous thromboembolism in moderate-to-severe COVID-19 patients. Br J Haematol. 2021;192:1097–1100. doi: 10.1111/bjh.17216. [DOI] [PubMed] [Google Scholar]
- 23.Henry B.M., Benoit S.W., de Oliveira M.H., Lippi G., Favaloro E.J., Benoit J.L. ADAMTS13 activity to von Willebrand factor antigen ratio predicts acute kidney injury in patients with COVID-19: evidence of SARS-CoV-2 induced secondary thrombotic microangiopathy. Int J Lab Hematol. 2020;43:129–136. doi: 10.1111/ijlh.13415. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 24.Escher R., Breakey N., Lammle B. ADAMTS13 activity, von Willebrand factor, factor VIII and D-dimers in COVID-19 inpatients. Thromb Res. 2020;192:174–175. doi: 10.1016/j.thromres.2020.05.032. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 25.Ladikou E.E., Sivaloganathan H., Milne K.M., Arter W.E., Ramasamy R., Saad R., et al. von Willebrand factor (vWF): marker of endothelial damage and thrombotic risk in COVID-19? Clin Med (Lond) 2020;20:e178–e182. doi: 10.7861/clinmed.2020-0346. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 26.Rodriguez M.R., Quismondo N.C., Torres D.Z., Alos D.G., Ayala R., Martine-Lopez J. Increased von Willebrand factor antigen and low ADAMTS13 activity are related to poor prognosis in covid-19 patients. Int J Lab Hematol. 2021;43:O152–O155. doi: 10.1111/ijlh.13476. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 27.Sweeney J.M., Barouqa M., Krause G.J., Gonzalez-Lugo J.D., Rahman S., Gil M.R. Low ADAMTS13 activity correlates with increased mortality in COVID-19 patients. TH Open. 2021;5:e89–e103. doi: 10.1055/s-0041-1723784. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 28.Pascreau T., Zia-Chahabi S., Zuber B., Tcherakian C., Farfour E., Vasse M. ADAMTS 13 deficiency is associated with abnormal distribution of von Willebrand factor multimers in patients with COVID-19. Thromb Res. 2021;204:138–140. doi: 10.1016/j.thromres.2021.02.008. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 29.Philippe A., Chocron R., Gendron N., Bory O., Beauvais A., Peron N., et al. Circulating von Willebrand factor and high molecular weight multimers as markers of endothelial injury predict COVID-19 in-hospital mortality. Angiogenesis. 2021;24:505–517. doi: 10.1007/s10456-020-09762-6. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 30.Zhang D., Li L., Chen Y., Ma J., Yang Y., Aodeng S., et al. Syndecan-1, an indicator of endothelial glycocalyx degradation, predicts outcome of patients admitted to an ICU with COVID-19. Mol Med. 2021;27:1–12. doi: 10.1186/s10020-021-00412-1. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 31.Wibowo A., Pranata R., Lim M.A., Akbara M.R., Martha J.W. Endotheliopathy marked by high von Willebrand factor (vWF) antigen in COVID-19 is associated with poor outcome: a systematic review and meta-analysis. Int J Infect Dis. 2022;117:267–273. doi: 10.1016/j.ijid.2021.06.051. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 32.Bernardo A., Ball C., Nolasco L., Moake J.F., Dong J.F. Effects of inflammatory cytokines on the release and cleavage of the endothelial cell-derived ultralarge von Willebrand factor multimers under flow. Blood. 2004;104:100–106. doi: 10.1182/blood-2004-01-0107. [DOI] [PubMed] [Google Scholar]
- 33.Zhang J., Tecson K.M., McCullough P.A. Endothelial dysfunction contributes to COVID-19-associated vascular inflammation and coagulopathy. Rev Cardiovasc Med. 2020;21:315–319. doi: 10.31083/j.rcm.2020.03.126. [DOI] [PubMed] [Google Scholar]
- 34.Cao W.J., Niiya M., Zheng X.W., Shang D.Z., Zheng X.L. Inflammatory cytokines inhibit ADAMTS13 synthesis in hepatic stellate cells and endothelial cells. J Thromb Haemost. 2008;6:1233–1235. doi: 10.1111/j.1538-7836.2008.02989.x. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 35.Bockmeyer C.L., Claus R.A., Budde U., Kentouche K., Schneppenheim R., Lösche W., et al. Inflammation-associated ADAMTS13 deficiency promotes formation of ultra-large von Willebrand factor. Haematologica. 2008;93:137–140. doi: 10.3324/haematol.11677. [DOI] [PubMed] [Google Scholar]
- 36.Mannucci P.M., Capoferri C., Canciani M.T. Plasma levels of von Willebrand factor regulate ADAMTS-13, its major cleaving protease. Br J Haematol. 2004;126:213–218. doi: 10.1111/j.1365-2141.2004.05009.x. [DOI] [PubMed] [Google Scholar]
- 37.Philippe A., Chocron R., Gendron N., Bory O., Beauvais A., Peron N., et al. Circulating Von Willebrand factor and high molecular weight multimers as markers of endothelial injury predict COVID-19 in-hospital mortality. Angiogenesis. 2021;24:505–517. doi: 10.1007/s10456-020-09762-6. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 38.Cotter A.H., Yang S.T., Shafi H., Cotter T.M., Palmer-Toy D.E. Elevated von Willebrand factor antigen is an early predictor of mortality and prolonged length of stay for coronavirus disease 2019 (COVID-19) inpatients. Arch Pathol Lab Med. 2022;146:34–37. doi: 10.5858/arpa.2021-0255-SA. [DOI] [PubMed] [Google Scholar]
- 39.Voss W.N., Hou Y.J., Johnson N.V., Kim J.E., Delidakis G., Horton A.P., et al. Prevalent, protective, and convergent IgG recognition of SARS-CoV-2 non-RBD spike epitopes in COVID-19 convalescent plasma. Science. 2020;372:1108–1112. doi: 10.1126/science.abg5268. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 40.Joly B.S., Darmon M., Dekimpe C., Dupont T., Dumas G., Yvin E., et al. Imbalance of von Willebrand factor and ADAMTS13 axis is rather a biomarker of strong inflammation and endothelial damage than a cause of thrombotic process in critically ill COVID-19 patients. J Thromb Haemost. 2021;19:2193–2198. doi: 10.1111/jth.15445. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 41.Fogarty H., Ward S.E., Townsend L., Karampini E., Elliott S., Conlon N., et al. Sustained VWF-ADAMTS-13 axis imbalance and endotheliopathy in long COVID syndrome is related to immune dysfunction. J Thromb Haemost. 2022;20:2429–2438. doi: 10.1111/jth.15830. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 42.Prasannan N., Heightman M., Hillman T., Wall E., Bell R., Kessler A., et al. Impaired exercise capacity in post-COVID syndrome: the role of VWF-ADAMTS13 axis. Blood Adv. 2022;6:4041–4048. doi: 10.1182/bloodadvances.2021006944. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 43.Moake J.L., Rudy C.K., Troll J.H., Weinstein M.J., Colannino N.M., Azocar J., et al. Unusually large plasma factor VIII: von Willebrand factor multimers in chronic relapsing thrombotic thrombocytopenic purpura. N Engl J Med. 1982;307:1432–1435. doi: 10.1056/NEJM198212023072306. [DOI] [PubMed] [Google Scholar]
- 44.Turecek P.L., Peck R.C., Rangarajan S., Reilly-Stitt C., Laffan M.A., Kazmi R., et al. Recombinant ADAMTS13 reduces abnormally up-regulated von Willebrand factor in plasma from patients with severe COVID-19. Thromb Res. 2021;201:100–112. doi: 10.1016/j.thromres.2021.02.012. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 45.Rock G., Clark W.F., Anderson D., Benny B., Sutton D., Leblond P., et al. ADAMTS-13 may not predict disease or outcome in patients with thrombotic thrombocytopenic purpura. Thromb Res. 2013;131:308–312. doi: 10.1016/j.thromres.2013.01.024. [DOI] [PubMed] [Google Scholar]
- 46.Moake J.L., Rudy C.K., Troll J.H., Weinstein M.J., Colannino N.M., Hong S.L., et al. von Willebrand factor abnormalities and endothelial cell perturbation in a patient with acute thrombotic thrombocytopenic purpura. Am J Med Sci. 1986;291:47–50. doi: 10.1097/00000441-198601000-00009. [DOI] [PubMed] [Google Scholar]
- 47.Moake J.L. Thrombotic thrombocytopenic purpura: the systemic clumping “plague”. Annu Rev Med. 2002;53:75–88. doi: 10.1146/annurev.med.53.082901.103948. [DOI] [PubMed] [Google Scholar]
- 48.Ogawa F., Oi Y., Nakajima K., Matsumura R., Nakagawa T., Miyagawa T., et al. Temporal change in Syndecan-1 as a therapeutic target and a biomarker for the severity classification of COVID-19. Thromb J. 2021;19:1–9. doi: 10.1186/s12959-021-00308-4. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 49.Fogarty H., Townsend L., Morrin H., Ahmad A., Comerford C., Karampini E., et al. Persistent endotheliopathy in the pathogenesis of long COVID syndrome. J Thromb Haemost. 2021;19:2546–2553. doi: 10.1111/jth.15490. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 50.Won T., Wood M.K., Hughes D.M., Talor M.V., Ma Z., Schneider J., et al. Endothelial thrombomodulin downregulation caused by hypoxia contributes to severe infiltration and coagulopathy in COVID-19 patient lungs. EBioMedicine. 2022;75 doi: 10.1016/j.ebiom.2022.103812. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 51.Shenoy A.G., Hettinger A.Z., Fernandez S.J., Blumenthal J., Baez V. Early mortality benefit with COVID-19 convalescent plasma: a matched control study. Br J Haematol. 2021;192:706–713. doi: 10.1111/bjh.17272. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 52.Joyner M.J., Carter R.E., Senefeld J.W., Klassen S.A., Mills J.R., Johnson P.W., et al. Convalescent plasma antibody levels and the risk of death from COVID-19. N Engl J Med. 2021;384:1015–1027. doi: 10.1056/NEJMoa2031893. [DOI] [PMC free article] [PubMed] [Google Scholar]
Associated Data
This section collects any data citations, data availability statements, or supplementary materials included in this article.
Supplementary Materials
Data Availability Statement
The datasets used and/or analyzed during the current study are available from the corresponding author upon request.