Thrombo-Inflammation in COVID-19 and Sickle Cell Disease: Two Faces of the Same Coin
Abstract
:1. Introduction
2. Pathophysiology of Sickle Cell Disease and COVID-19
3. Mechanisms of Multicellular Adhesion and Thrombo-Inflammation in Sickle Cell Disease and COVID-19
3.1. Endothelial Cell Injury and Activation: Role in Thrombo-Inflammation in SCD and COVID-19
3.2. Platelet Activation: Role in Thrombo-Inflammation in SCD and COVID-19
3.3. P-Selectin: Role in Thrombo-Inflammation in SCD and COVID-19
3.4. Tissue Factor: Role in Thrombo-Inflammation in SCD and COVID-19
3.5. CD40L: Role in Thrombo-Inflammation in SCD and COVID-19
3.6. NLRP3 Inflammasome: Role in Thromboinflammation in SCD and COVID-19
3.7. Nitric Oxide: Role in Thrombo-Inflammation in SCD and COVID-19
3.8. TGFβ: Role in Thromboinflammation in SCD and COVID-19
3.9. Lipoxygenase: Role in Thrombo-Inflammation in SCD and COVID-19
4. Thromboxane A2-A Key Mediator of Thrombo-inflammation by Regulation of Platelet Activation, NO Synthesis, and Expression of P-Selectin, CD40L, Tissue Factor, and TGF-β
4.1. Thromboxane A2-Mediated P-Selectin Expression
4.2. Thromboxane A2-Mediated Tissue Factor Expression
4.3. Thromboxane A2-Mediated CD40L Expression
4.4. Thromboxane A2-Induced Suppression of NO Synthesis
4.5. Thromboxane A2-Induced TGF-β Release
5. Thromboxane A2 in Post-Capillary Venoconstriction in SCD and COVID-19
5.1. Post-Capillary Pulmonary Venous Constriction
5.2. Post-Capillary Efferent Arteriole Constriction in Kidney Injury
6. Complement Activation as an Inducer of Thrombo-Inflammation in SCD and COVID-19
7. Thromboxane A2 Is Enzymatically Converted into 11-Dehydro-Thromboxane A2, a Full Agonist of the Prostaglandin D2/DP2 Receptor Leading to Fibrosis and Inflammation
8. Therapeutic Options for Thrombo-inflammation in COVID-19 and SCD: Past, Present, and Future
9. Conclusions
Author Contributions
Funding
Institutional Review Board Statement
Informed Consent Statement
Data Availability Statement
Acknowledgments
Conflicts of Interest
Abbreviations
References
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Subjects | Age/Reference | Plasma D-Dimer Levels | p-Value Compared to Controls | |
---|---|---|---|---|
Control | Disease State | |||
Sickle Cell Disease | Adult [76] | HD (n = 35) 79 ± 25 ngh | Steady State SCD n = 25 (Samples = 28) 566 ± 739 ng/mL | p < 0.001 |
SCD Painful Crisis n = 21 (Samples = 40) 1038 ± 1010 ng/mL | p < 0.001 | |||
12–37 years [75] | SCD with pain crisis and normal chest X-ray (n episodes = 32) 584.2 µg/L (250–3119 µg/L) | SCD with pain crisis and abnormal chest X-ray (n episodes = 13) 2117.0 µg/L (250–9143 µg/L) | N/A | |
Unventilated: 62.5 ± 8.4 Ventilated: 53.8 ± 9.3 [77] | Hospitalized COVID-19 patients did not require artificial ventilation (n = 18) 650 ± 175 ng/mL | Hospitalized COVID-19 patients requiring artificial ventilation (n = 11) 1250 ± 210 ng/mL | p < 0.05 | |
COVID-19 | 65.57 ± 13 years [78] | COVID-19 patients without pulmonary embolism (n = 118) 1310 ng/mL (800–2335) | COVID-19 patients with pulmonary embolism (n = 44) 5364 ng/mL (2928–12,275) | p = 0.001 |
Subjects | Source and Analyte | Thromboxane Levels | p-Value Compared to Controls | |
---|---|---|---|---|
Control | Disease State | |||
Sickle Cell Disease | Plasma 2,3 dinor-TxB2 [140] (µg/L) (Mean ± SEM) | HD (n = 12) 2.75 ± 0.83 | Steady State SCD (n = 15) 21.53 ± 5.10 | p < 0.001 |
Plasma TxB2 [140] (µg/L) (Mean ± SEM) | HD (n = 12) <0.005 | Steady State SCD (n = 15) 0.543 ± 0.101 | p < 0.05 | |
Urinary TxB2 [140] (pg/mg creatinine) (Mean ± SEM) | HD (n = 12) 0.41 ± 0.30 | Steady State SCD (n = 15) 0.91 ± 0.13 | p < 0.05 | |
Urinary 2,3 dinor-TxB2 [140] (pg/mg creatinine) (mean ± SEM) | HD (n = 12) 1.70 ± 0.032 | Steady State SCD (n = 15) 2.81 ± 0.13 | p < 0.01 | |
Urinary 11-dehydro-TxB2 [141] (pg/mg creatinine) (Mean ± SEM) | HD (n = 33) 299 ± 20 | Steady State SCD (n = 49) 1227 ± 191 | p = 0.0002 | |
Vaso-Occlusive SCD (n = 15) 1836 ± 536 | p = 0.0005 | |||
COVID-19 | BALF TxB2 [52] (nmol/L) (Means) | HD (n = 25) <0.250 | Severe COVID-19 (n = 33) 12.0 | p < 0.0001 |
Plasma TxB2 [23] (ng/mL) (Median) | HD (n = 11) 4.0 | Severe COVID-19 (n = 35) 7.5 | p < 0.05 | |
Urinary 11-dehydro-TxB2 [143] (pg/mg creatinine) (Median (95% CI)) | Without Events (n = 47) 4890 (5049–8290) | With Events (n = 18) 7603 (7541–19,791) | p = 0.002 | |
<10 d of hospitalization (n = 35) 4801 (3817–9196) | ≥10 d of hospitalization (n = 30) 8614 (7990–14,316) | p = 0.02 | ||
No death (n = 48) 5360 (5907–10,038) | Death (n = 6) 15,069 (1915–42,007) | p = 0.004 | ||
No Mechanical Ventilation (n = 56) 5137 (4498–7512) | Mechanical Ventilation (n = 9) 20,121 (5364–41,015) | p < 0.001 | ||
Atopic Asthmatics | BALF TxB2 [144] (nmol/L) (Mean ± SEM) | Before Allergen Challenge (n = 8) 0.130 ± 0.021 | After Allergen Challenge (n = 8) 0.430 ± 0.108 | p < 0.05 |
Study Design | Study Population | Intervention | Primary Outcome Measure and Result |
---|---|---|---|
Phase IIb Multicenter, double-blind, double-dummy, randomized, placebo-controlled, parallel-group [213] | ● Have SCD [homozygous sickle cell (HbSS) or sickle beta-zero thalassemia (HbSβ0)] ● Ages 18–30 years (mean 22.2 years old) ● Have ≥4 days of pain during the 4-week single-blind placebo baseline period prior to randomization ● If on hydroxycarbamide, a stable dose for 3 months prior to enrollment required ● If on erythropoietin, drug must have been prescribed 6 months before and at a stable dose for ≥3 months prior to randomization (n = 194) | ● Ticagrelor 10 mg plus matching placebo for ticagrelor 45 mg ● Ticagrelor 45 mg plus matching placebo for ticagrelor 10 mg ● Matching placebo for ticagrelor 10 and 45 mg Duration: 12 weeks | Proportions of days with diary-reported SCD pain No significant difference between placebo and ticagrelor treatment groups |
Phase III Multinational, double-blind, randomized, placebo-controlled, parallel-group [212] | ● Have SCD [homozygous sickle cell (HbSS) or sickle beta-zero thalassemia (HbSβ0)] ● Are participants with SCD who have had ≥2 episodes of vaso-occlusive crisis (VOC) in the past year ● Have a body weight ≥ 19 kilogram (kg) and are ≥ 2 and <18 years of age, inclusive at the time of screening ● If participants are ≥2 and ≤16 years of age, they must have had a transcranial Doppler within the last year (n = 341) | ● Prasugrel 0.08–0.12 mg/kg po once daily ● Placebo Duration: 9–24 months | Number of Vaso-Occlusive Crisis (VOC) Events Per Participant Per Year (Rate of VOC) Terminated due to lack of efficacy |
Phase III Double-blind crossover study [211] | ● Have sickle hemoglobinopathy observed regularly ● Ages 2–17 years old (mean 7.7 years old) ● The hematologic diagnosis was confirmed by cellulose acetate electrophoresis at pH 8.6 and citrate agar electrophoresis at pH 6.4 ● At least 50% compliant (n = 49) | ● Low dose aspirin ● Placebo | Frequency and severity of VOC No significant difference between placebo and aspirin treatment groups |
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Chiang, K.C.; Gupta, A.; Sundd, P.; Krishnamurti, L. Thrombo-Inflammation in COVID-19 and Sickle Cell Disease: Two Faces of the Same Coin. Biomedicines 2023, 11, 338. https://doi.org/10.3390/biomedicines11020338
Chiang KC, Gupta A, Sundd P, Krishnamurti L. Thrombo-Inflammation in COVID-19 and Sickle Cell Disease: Two Faces of the Same Coin. Biomedicines. 2023; 11(2):338. https://doi.org/10.3390/biomedicines11020338
Chicago/Turabian StyleChiang, Kate Chander, Ajay Gupta, Prithu Sundd, and Lakshmanan Krishnamurti. 2023. "Thrombo-Inflammation in COVID-19 and Sickle Cell Disease: Two Faces of the Same Coin" Biomedicines 11, no. 2: 338. https://doi.org/10.3390/biomedicines11020338