1. Compound Identification

Name: Thrombin-Binding Aptamer 15 (TBA15), also referred to as HD1, TBA, or G15D

Type: Single-stranded DNA oligonucleotide aptamer (not a small molecule drug, biologic, or protein therapeutic)

Sequence: 5′-GGTTGGTGTGGTTGG-3′

Length: 15 nucleotides

Molecular formula (unmodified): Approximate empirical formula C₁₄₆H₁₈₅N₅₇O₈₉P₁₄

Molecular weight: ~4,726 Da (unmodified sodium salt form); reported in the range of ~4,700–4,800 Da depending on counterion and modification status

Structure: TBA15 folds into a unimolecular, antiparallel, chair-type G-quadruplex consisting of two stacked G-quartets (guanine tetrads) connected by two TT loops and one TGT loop. The structure is stabilized by Hoogsteen hydrogen bonding between guanines and by monovalent cation coordination (K⁺ preferred over Na⁺) between the G-quartet planes. A potential T–T base pair forms across the diagonal of the top G-quartet between the two TT loops (Schultze et al. 1994; Padmanabhan et al. 1993; Macaya et al. 1993).

CAS number: No CAS Registry Number has been assigned to TBA15. The oligonucleotide is identified by its sequence (5′-GGTTGGTGTGGTTGG-3′) and by literature names (TBA, HD1, TBA15, G15D).

Source: TBA15 was first isolated by in vitro selection (SELEX) from a combinatorial DNA library by Bock et al. (1992). It is synthesized via standard solid-phase phosphoramidite chemistry and is commercially available from multiple oligonucleotide vendors (e.g., IDT, Eurofins Genomics, Sigma-Aldrich custom oligos) at research grade.

Complementary antidote sequence: 5′-CCAACCACACCAACC-3′ (Watson-Crick complement; disrupts G-quadruplex folding upon hybridization, rapidly reversing anticoagulant activity)

2. Therapeutic Application

Proposed indication: Adjunct anticoagulation targeting fibrin amyloid microclot formation in post-acute sequelae of SARS-CoV-2 infection (PASC / long COVID), specifically in patients presenting with:

  • Persistent fibrin amyloid microclots detectable by thioflavin T fluorescence microscopy in platelet-poor plasma (Pretorius et al. 2021; Grobbelaar et al. 2021)
  • Elevated markers of ongoing thrombin generation (D-dimer, thrombin–antithrombin complexes, prothrombin fragment 1+2)
  • Symptoms consistent with microvascular occlusion: fatigue, exertional intolerance, cognitive dysfunction (“brain fog”), dyspnea, and exercise intolerance with post-exertional malaise

Rationale for TBA15 in this application:

  1. Direct thrombin inhibition at the point of fibrin formation. COVID-19-associated coagulopathy involves sustained thrombin generation driven by endothelial inflammation, tissue factor expression, complement activation, and neutrophil extracellular trap (NET) formation (Iba et al. 2020; Connors & Levy 2020). Thrombin is the terminal serine protease converting fibrinogen to fibrin. TBA15 binds thrombin exosite I (the fibrinogen recognition site) and directly blocks this conversion at nanomolar concentrations.

  2. Amyloid-resistant fibrin as the pathological target. Pretorius, Kell, and colleagues demonstrated that fibrin(ogen) in long COVID patients clots into an anomalous amyloid form resistant to plasmin-mediated fibrinolysis (Kell et al. 2022, Biochemical Journal 479:537–559). Once formed, these amyloid fibrin microclots are difficult to degrade. Prevention of formation — by inhibiting the thrombin that catalyzes fibrin polymerization — is mechanistically preferable to attempting lysis after the fact.

  3. Rapid, controllable reversibility. Unlike heparin (requires protamine, incomplete reversal), warfarin (requires vitamin K, slow onset), or direct oral anticoagulants (reversal agents expensive or limited), TBA15 anticoagulation is reversed within 1–2 minutes by administration of the complementary oligonucleotide antidote (Rusconi et al. 2004, Nature Biotechnology 22:1423–1428; Bompiani et al. 2012). This addresses the bleeding-risk concern that currently limits aggressive anticoagulation in long COVID patients.

  4. Adjunct, not replacement. TBA15 is proposed as an adjunct to, not a replacement for, existing anticoagulation strategies. Triple anticoagulant therapy (clopidogrel + aspirin + apixaban) has shown symptom resolution in small cohorts (Pretorius et al. 2021, Research Square; Laubscher et al. 2023, Research Square), but bleeding risk limits dose escalation and treatment duration. TBA15 could provide an additional layer of thrombin inhibition during acute microclot burden periods, with rapid reversibility if bleeding occurs.

3. Proposed Protocol

Important disclaimer: No human randomized controlled trial has been conducted for TBA15 in post-COVID microclot management. The following protocol is derived from published preclinical pharmacokinetic and pharmacodynamic data on TBA15 and related thrombin aptamers, and from the clinical precedent of aptamer-based anticoagulants in other settings.

Route of administration:

  • Intravenous (IV) infusion: Preferred for acute-phase treatment or in monitored clinical settings. TBA15 has been studied via IV administration in animal models (Nimjee et al. 2006; De Cristofaro & De Candia 2003). Continuous or intermittent IV infusion allows dose titration guided by real-time coagulation monitoring (PT, aPTT, thrombin time).

  • Subcutaneous (SC) injection: Potential for outpatient maintenance dosing. Modified aptamers with polyethylene glycol (PEG) conjugation or locked nucleic acid (LNA) substitutions show improved serum half-life suitable for SC dosing intervals (Riccardi et al. 2021).

Dosing (preclinical extrapolation):

  • TBA15 inhibits thrombin-catalyzed fibrin clot formation at concentrations of 25–200 nM in vitro (Bock et al. 1992).
  • In animal models, effective anticoagulation has been achieved at IV doses in the range of 0.5–5 mg/kg for thrombin-targeting aptamers (Nimjee et al. 2005; Rusconi et al. 2002).
  • Unmodified TBA15 has a short plasma half-life (~1–2 minutes in vivo due to nuclease degradation), necessitating either continuous infusion or chemical modification (2′-O-methyl, phosphorothioate backbone, PEGylation, or LNA substitutions) for practical dosing intervals.
  • Modified TBA analogues (e.g., TBAB with 8-bromo-2′-deoxyguanosine substitutions) show significantly improved nuclease resistance and thermal stability (~30°C higher Tm) while retaining or enhancing anticoagulant activity (IJMS 2025).

Monitoring:

  • Coagulation panel (PT, aPTT, thrombin time, fibrinogen) at baseline and during treatment
  • Thioflavin T fluorescence assay for microclot burden in platelet-poor plasma (as per Pretorius protocol)
  • D-dimer and thrombin–antithrombin complex levels as surrogate markers of thrombin generation
  • Standard bleeding assessment (clinical observation, hemoglobin trending)

Antidote protocol:

  • In the event of bleeding or need for rapid reversal, administer complementary oligonucleotide antidote (5′-CCAACCACACCAACC-3′) at equimolar or 1.5× molar ratio to the estimated circulating TBA15 dose.
  • Expected reversal time: <2 minutes based on in vitro and in vivo data (Rusconi et al. 2004).
  • Antidote durability: reversal has been shown to persist for >2 hours in animal models.

Treatment duration (hypothesized):

  • Acute phase: 5–14 days of IV infusion in monitored setting, guided by microclot burden and coagulation parameters.
  • Maintenance phase (if warranted): SC administration of modified TBA analogue, duration guided by longitudinal microclot and D-dimer monitoring.

4. Mechanism of Action

The mechanism of TBA15 anticoagulation in the context of post-COVID microclot pathology operates through the following pathway:

Step 1 — G-quadruplex formation. In physiological K⁺-containing buffer or plasma, the 15-nucleotide sequence 5′-GGTTGGTGTGGTTGG-3′ spontaneously folds into an antiparallel, chair-type unimolecular G-quadruplex. Two G-quartets stack with a K⁺ ion coordinated between them. This folded structure presents a specific three-dimensional surface complementary to thrombin exosite I (Padmanabhan et al. 1993; Macaya et al. 1993).

Step 2 — Binding to thrombin exosite I. The folded TBA15 G-quadruplex binds to thrombin anion-binding exosite I (ABE-I), which is the fibrinogen recognition site on thrombin. The TT loops of the aptamer make direct contacts with residues in the exosite I region. Binding affinity (Kd) is in the range of 25–200 nM depending on buffer conditions and measurement method (Bock et al. 1992; Russo Krauss et al. 2012). This is the same site that fibrinogen must access to be cleaved into fibrin.

Step 3 — Competitive inhibition of fibrinogen-to-fibrin conversion. By occupying exosite I, TBA15 competitively blocks thrombin from cleaving fibrinopeptides A and B from fibrinogen. This directly prevents fibrin monomer generation and subsequent polymerization into fibrin fibers and clots.

Step 4 — Reduced de novo microclot formation. In the post-COVID coagulopathy context, ongoing thrombin generation (driven by persistent endothelial damage, circulating spike protein fragments, complement activation, and NET formation) continuously converts fibrinogen into fibrin, some of which adopts the pathological amyloid conformation that resists fibrinolysis (Kell et al. 2022). By reducing the rate of thrombin-mediated fibrin generation, TBA15 would decrease the input of new fibrin into the amyloid microclot pool, potentially allowing endogenous (or therapeutically enhanced) fibrinolysis to clear existing microclots over time.

Step 5 — Reversibility via complementary oligonucleotide antidote. Administration of the Watson-Crick complementary sequence (5′-CCAACCACACCAACC-3′) disrupts the G-quadruplex structure by forming a stable DNA duplex with TBA15. This unfolds the aptamer, abolishing the exosite I binding surface and restoring full thrombin activity within 1–2 minutes (Rusconi et al. 2004). This antidote mechanism is independent of patient metabolic state, liver function, or renal clearance — a significant advantage over reversal of conventional anticoagulants.

Additional mechanistic considerations:

  • TBA15 does not inhibit thrombin’s exosite II (heparin-binding site), meaning it could theoretically be co-administered with heparin-based anticoagulants for synergistic inhibition without competitive interference at the same site.
  • TBA15 does not directly affect platelet aggregation via non-thrombin pathways, making it potentially complementary to antiplatelet agents (aspirin, clopidogrel) used in triple therapy regimens.
  • The G-quadruplex structure of TBA15 is itself influenced by the ionic environment; K⁺ stabilizes the active conformation while Na⁺ is less favorable. Clinical formulation should account for the patient’s electrolyte status.

5. Evidence Summary

5.1 TBA15 Discovery and Characterization

  • Bock, L. C., Griffin, L. C., Latham, J. A., Vermaas, E. H., & Toole, J. J. (1992). Selection of single-stranded DNA molecules that bind and inhibit human thrombin. Nature, 355(6360), 564–566. — Original SELEX isolation of TBA15; demonstrated binding to thrombin with Kd ~25–200 nM and inhibition of fibrin clot formation at nanomolar concentrations.

  • Macaya, R. F., Schultze, P., Smith, F. W., Roe, J. A., & Feigon, J. (1993). Thrombin-binding DNA aptamer forms a unimolecular quadruplex structure in solution. Proceedings of the National Academy of Sciences, 90(8), 3745–3749. — NMR solution structure revealing the antiparallel G-quadruplex fold with two G-quartets and TT/TGT loops.

  • Padmanabhan, K., Padmanabhan, K. P., Ferrara, J. D., Sadler, J. E., & Tulinsky, A. (1993). The structure of α-thrombin inhibited by a 15-mer single-stranded DNA aptamer. Journal of Biological Chemistry, 268(24), 17651–17654. — X-ray crystal structure of TBA15–thrombin complex confirming exosite I binding.

  • Tasset, D. M., Kubik, M. F., & Steiner, W. (1997). Oligonucleotide inhibitors of human thrombin that bind distinct epitopes. Journal of Molecular Biology, 272(5), 688–698. — Characterization of thrombin-binding aptamers targeting different exosites; established TBA15 as exosite I binder and identified HD22 (29-mer) as exosite II binder.

  • Riccardi, C., Napolitano, E., Platella, C., Musumeci, D., & Montesarchio, D. (2021). G-quadruplex-based aptamers targeting human thrombin: Discovery, chemical modifications and antithrombotic effects. Pharmacology & Therapeutics, 217, 107649. — Comprehensive review of TBA15 and modified analogues; discusses chemical modifications for improved nuclease resistance, thermal stability, and anticoagulant potency.

5.2 Aptamer Antidote / Reversibility

  • Rusconi, C. P., Roberts, J. D., Pitoc, G. A., Nimjee, S. M., White, R. R., Quick, G., Scardino, E., Fay, W. P., & Sullenger, B. A. (2004). Antidote-mediated control of an anticoagulant aptamer in vivo. Nature Biotechnology, 22(11), 1423–1428. — Demonstrated rapid (<2 min) in vivo reversal of aptamer anticoagulation using complementary oligonucleotide antidote in porcine models.

  • Bompiani, K. M., Woodruff, R. S., Becker, R. C., Nimjee, S. M., & Sullenger, B. A. (2012). Antidote control of aptamer therapeutics: the road to a safer class of drug agents. Current Pharmaceutical Biotechnology, 13(10), 1924–1934. — Review of antidote-controllable aptamer anticoagulants; established the general principle of complementary strand reversal as a universal safety mechanism for therapeutic aptamers.

  • Nimjee, S. M., Keys, J. R., Pitoc, G. A., Quick, G., Rusconi, C. P., & Sullenger, B. A. (2006). A novel antidote-controlled anticoagulant reduces thrombin generation and inflammation and improves cardiac function in cardiopulmonary bypass surgery. Molecular Therapy, 14(3), 408–415. — Preclinical evidence for aptamer-based anticoagulation with antidote reversal in a surgical model.

5.3 COVID-19 Coagulopathy and Fibrin Amyloid Microclots

  • Pretorius, E., Vlok, M., Venter, C., Bezuidenhout, J. A., Laubscher, G. J., Steenkamp, J., & Kell, D. B. (2021). Persistent clotting protein pathology in Long COVID/Post-Acute Sequelae of COVID-19 (PASC) is accompanied by increased levels of antiplasmin. Cardiovascular Diabetology, 20, 172. — Demonstrated elevated fibrin amyloid microclots and increased α2-antiplasmin in long COVID patient plasma.

  • Grobbelaar, L. M., Venter, C., Vlok, M.,";";"; “; “; “;”; “;”; “; & Pretorius, E. (2021). SARS-CoV-2 spike protein S1 induces fibrin(ogen) resistant to fibrinolysis: implications for microclot formation in COVID-19. Bioscience Reports, 41(8), BSR20210611. — Showed that spike protein S1 directly induces anomalous fibrin clots resistant to trypsin digestion.

  • Kell, D. B., Laubscher, G. J., & Pretorius, E. (2022). A central role for amyloid fibrin microclots in long COVID/PASC: origins and therapeutic implications. Biochemical Journal, 479(4), 537–559. — Comprehensive review establishing the amyloid fibrin microclot hypothesis as a central mechanism in long COVID pathophysiology; proposed that blocking microclot formation or promoting their degradation could be therapeutic.

  • Connors, J. M., & Levy, J. H. (2020). COVID-19 and its implications for thrombosis and anticoagulation. Blood, 135(23), 2033–2040. — Early characterization of COVID-19-associated coagulopathy (CAC); documented elevated D-dimer, fibrinogen, and thrombin generation in hospitalized COVID-19 patients.

  • Iba, T., Levy, J. H., Levi, M., & Thachil, J. (2020). Coagulopathy in COVID-19. Journal of Thrombosis and Haemostasis, 18(9), 2103–2109. — Described the multi-factorial coagulopathy of COVID-19 involving endothelial dysfunction, complement activation, and NET formation driving thrombin generation.

5.4 Triple Anticoagulant Therapy in Long COVID

  • Pretorius, E., Venter, C., Laubscher, G. J., Kotze, M. J., Ober, J., ; Phase, W.,”; “; “; “; & Kell, D. B. (2021). Combined triple treatment of fibrin amyloid microclots and platelet pathology in individuals with Long COVID/Post-Acute Sequelae of COVID-19 (PASC) can resolve their persistent symptoms. Research Square (preprint), rs-1205453/v1. — Reported symptom resolution in 24 long COVID patients receiving clopidogrel 75mg + aspirin 75mg + apixaban 5mg BID + pantoprazole 40mg daily for 1 month.

  • Laubscher, G. J., Lourens, P. J., Venter, C.,”; “; Kell, D. B., & Pretorius, E. (2023). Treatment of Long COVID symptoms with triple anticoagulant therapy. Research Square (preprint), rs-2697680/v1. — Expanded cohort (91 patients); confirmed symptom resolution in majority with triple anticoagulant therapy; no serious adverse bleeding events.

5.5 Thrombin Aptamer Modifications and Enhanced Analogues

  • International Journal of Molecular Sciences (2025). Probing the Effects of Chemical Modifications on Anticoagulant and Antiproliferative Activity of Thrombin Binding Aptamer. IJMS, 26(1), 134. — TBAB (8-bromo-2′-deoxyguanosine modification) showed ~30°C improved thermal stability and higher anticoagulant activity than native TBA15.

  • Riccardi, C., et al. (2023). The Regioselective Conjugation of the 15-nt Thrombin Aptamer with an Optimized Tripeptide Sequence Greatly Increases the Anticoagulant Activity of the Aptamer. Pharmaceutics, 15(2), 604. — TBA-GLE conjugate inhibited thrombin ~6-fold more efficiently than unmodified TBA, approaching potency of NU172.

  • Russo Krauss, I., Merlino, A., Randazzo, A., Novellino, E., Mazzarella, L., & Sica, F. (2012). High-resolution structures of two complexes between thrombin and thrombin-binding aptamer shed light on the role of cations in the aptamer inhibitory activity. Nucleic Acids Research, 40(16), 8119–8128. — Demonstrated K⁺-dependent enhancement of TBA15 anticoagulant activity through structural studies.

6. Patent Landscape

The following patents and patent applications are relevant to the intersection of thrombin aptamers, anticoagulant aptamers, and COVID-19 anticoagulation:

6.1 Thrombin Aptamer Patents

  • US5,582,981 (1996). Toole, J. J., Bock, L. C., Griffin, L. C. “Nucleic acid ligands that bind to thrombin.” Assigned to NeXstar Pharmaceuticals (later Gilead Sciences). This is the original patent covering the TBA15 sequence and its use as a thrombin inhibitor. Expired (filed 1992, 20-year term exhausted). The TBA15 sequence and its basic anticoagulant use are now fully in the public domain.

  • US7,998,939 B2 (2011). Diener, J. L., Wagner-Whyte, J., Fontana, D. “Aptamers that bind thrombin with high affinity.” Assigned to Archemix Corp. Covers modified aptamers binding thrombin with enhanced affinity. Expired (fee-related expiration; expiration date March 5, 2027, but lapsed for non-payment).

  • US20230119254A1 (2023). AstraZeneca AB / APT Therapeutics Inc. “Synergistic and targeting compositions for treatment of arterial and venous thrombosis.” Covers aptamer-based (APT402) compositions for thrombosis treatment. Pending. Does not specifically claim post-COVID microclot application.

6.2 COVID-19 Anticoagulation Patents

  • US11,865,110 B2 (2024). Verseon International Corp. “Thrombin inhibitors, formulations, and uses thereof.” Covers small-molecule thrombin inhibitors (not aptamers) for various thrombotic indications. Filed July 2019 (pre-pandemic). Does not specifically claim aptamer-based COVID anticoagulation.

6.3 Gap This Disclosure Addresses

No identified patent or patent application specifically claims:

  • The use of TBA15 (or sequence-identified thrombin-binding DNA aptamers) for treatment of post-COVID / long COVID fibrin amyloid microclot coagulopathy
  • The combination of TBA15 with triple anticoagulant therapy (DAPT + DOAC) in a post-COVID context
  • The use of complementary oligonucleotide antidote reversal as a safety mechanism in a post-COVID anticoagulation protocol
  • The use of modified TBA analogues (TBAB, TBA-GLE, PEGylated TBA) for long COVID microclot management

This disclosure is published to establish dated, enabling prior art covering these specific applications before any method-of-use patent claims can be filed.

7. Public-Domain Dedication

This disclosure and all its contents are dedicated to the public domain under the Creative Commons CC0 1.0 Universal Public Domain Dedication.

CC0 1.0 Universal — Public Domain Dedication

To the extent possible under law, the author has waived all copyright and related or neighboring rights to this work. This work is published from the United States.

The author affirms that this disclosure is made for the purpose of establishing prior art under 35 U.S.C. § 102(a)(1) and equivalent patent law provisions in other jurisdictions. Any person, entity, or autonomous agent may use, reproduce, modify, distribute, or build upon the information contained herein without restriction.

No patent rights are claimed. No trade secret protection is asserted. The publication date of this document, verifiable through Git commit history and platform timestamps, establishes the earliest date at which this disclosure was publicly accessible.

8. Limitations and Disclaimer

Evidence level: This disclosure operates at the evidence level of preclinical data combined with mechanistic hypothesis. The individual components — TBA15 as a thrombin inhibitor and the amyloid fibrin microclot hypothesis of long COVID — are each supported by published peer-reviewed evidence. However, the specific combination (TBA15 for post-COVID microclot management) has not been tested in any human clinical trial, animal model of long COVID, or in vitro model of post-COVID microclot formation using TBA15 specifically.

What is established:

  • TBA15 binds thrombin and inhibits fibrin clot formation (Bock et al. 1992; extensively replicated)
  • TBA15 anticoagulation is rapidly reversible via complementary oligonucleotide (Rusconi et al. 2004; replicated in multiple animal models)
  • Long COVID involves persistent fibrin amyloid microclots resistant to fibrinolysis (Pretorius et al. 2021; Kell et al. 2022)
  • Anticoagulant therapy (including thrombin-pathway targeting) has shown symptomatic benefit in long COVID cohorts (Pretorius et al. 2021; Laubscher et al. 2023)

What is hypothesized (not yet validated):

  • That TBA15 specifically reduces amyloid fibrin microclot formation in post-COVID plasma (not tested)
  • That the dosing regimen described would achieve therapeutic anticoagulation in humans with acceptable safety (extrapolated from preclinical data)
  • That adjunct TBA15 provides benefit beyond existing triple anticoagulant therapy (no comparative data)
  • That modified TBA analogues would retain specificity for the pathological coagulopathy without off-target effects in the complex post-COVID inflammatory milieu

Clinical disclaimer: This document is a defensive prior art disclosure, not medical advice, a treatment recommendation, or a clinical protocol. The proposed application has not been approved by any regulatory agency. Any clinical investigation of TBA15 in post-COVID patients would require institutional review board approval, informed consent, and appropriate Phase I/II safety and efficacy trials. Off-label use based on this disclosure alone would be inappropriate and potentially dangerous.

Legal disclaimer: This is not legal advice. While this disclosure is structured to meet the enablement and public accessibility requirements for anticipatory prior art under 35 U.S.C. § 102, no guarantee is made that it will successfully anticipate any specific patent claim. Patent validity challenges require formal legal proceedings.

Conflict of interest: The author has no financial interest in any company developing thrombin aptamers, COVID therapeutics, or anticoagulants. This disclosure is motivated solely by the goal of preserving public-domain freedom to operate.

References

  1. Bock, L. C., Griffin, L. C., Latham, J. A., Vermaas, E. H., & Toole, J. J. (1992). Selection of single-stranded DNA molecules that bind and inhibit human thrombin. Nature, 355(6360), 564–566.

  2. Macaya, R. F., Schultze, P., Smith, F. W., Roe, J. A., & Feigon, J. (1993). Thrombin-binding DNA aptamer forms a unimolecular quadruplex structure in solution. Proceedings of the National Academy of Sciences, 90(8), 3745–3749.

  3. Padmanabhan, K., Padmanabhan, K. P., Ferrara, J. D., Sadler, J. E., & Tulinsky, A. (1993). The structure of α-thrombin inhibited by a 15-mer single-stranded DNA aptamer. Journal of Biological Chemistry, 268(24), 17651–17654.

  4. Tasset, D. M., Kubik, M. F., & Steiner, W. (1997). Oligonucleotide inhibitors of human thrombin that bind distinct epitopes. Journal of Molecular Biology, 272(5), 688–698.

  5. Rusconi, C. P., Roberts, J. D., Pitoc, G. A., Nimjee, S. M., White, R. R., Quick, G., Scardino, E., Fay, W. P., & Sullenger, B. A. (2004). Antidote-mediated control of an anticoagulant aptamer in vivo. Nature Biotechnology, 22(11), 1423–1428.

  6. Nimjee, S. M., Keys, J. R., Pitoc, G. A., Quick, G., Rusconi, C. P., & Sullenger, B. A. (2006). A novel antidote-controlled anticoagulant reduces thrombin generation and inflammation and improves cardiac function in cardiopulmonary bypass surgery. Molecular Therapy, 14(3), 408–415.

  7. Bompiani, K. M., Woodruff, R. S., Becker, R. C., Nimjee, S. M., & Sullenger, B. A. (2012). Antidote control of aptamer therapeutics: the road to a safer class of drug agents. Current Pharmaceutical Biotechnology, 13(10), 1924–1934.

  8. Russo Krauss, I., Merlino, A., Randazzo, A., Novellino, E., Mazzarella, L., & Sica, F. (2012). High-resolution structures of two complexes between thrombin and thrombin-binding aptamer shed light on the role of cations in the aptamer inhibitory activity. Nucleic Acids Research, 40(16), 8119–8128.

  9. Connors, J. M., & Levy, J. H. (2020). COVID-19 and its implications for thrombosis and anticoagulation. Blood, 135(23), 2033–2040.

  10. Iba, T., Levy, J. H., Levi, M., & Thachil, J. (2020). Coagulopathy in COVID-19. Journal of Thrombosis and Haemostasis, 18(9), 2103–2109.

  11. Riccardi, C., Napolitano, E., Platella, C., Musumeci, D., & Montesarchio, D. (2021). G-quadruplex-based aptamers targeting human thrombin: Discovery, chemical modifications and antithrombotic effects. Pharmacology & Therapeutics, 217, 107649.

  12. Pretorius, E., Vlok, M., Venter, C., Bezuidenhout, J. A., Laubscher, G. J., Steenkamp, J., & Kell, D. B. (2021). Persistent clotting protein pathology in Long COVID/Post-Acute Sequelae of COVID-19 (PASC) is accompanied by increased levels of antiplasmin. Cardiovascular Diabetology, 20, 172.

  13. Grobbelaar, L. M., Venter, C., Vlok, M., et al. (2021). SARS-CoV-2 spike protein S1 induces fibrin(ogen) resistant to fibrinolysis: implications for microclot formation in COVID-19. Bioscience Reports, 41(8), BSR20210611.

  14. Pretorius, E., Venter, C., Laubscher, G. J., et al. (2021). Combined triple treatment of fibrin amyloid microclots and platelet pathology in individuals with Long COVID/Post-Acute Sequelae of COVID-19 (PASC) can resolve their persistent symptoms. Research Square (preprint), rs-1205453/v1.

  15. Kell, D. B., Laubscher, G. J., & Pretorius, E. (2022). A central role for amyloid fibrin microclots in long COVID/PASC: origins and therapeutic implications. Biochemical Journal, 479(4), 537–559.

  16. Laubscher, G. J., Lourens, P. J., Venter, C., Kell, D. B., & Pretorius, E. (2023). Treatment of Long COVID symptoms with triple anticoagulant therapy. Research Square (preprint), rs-2697680/v1.

  17. Riccardi, C., et al. (2023). The Regioselective Conjugation of the 15-nt Thrombin Aptamer with an Optimized Tripeptide Sequence Greatly Increases the Anticoagulant Activity of the Aptamer. Pharmaceutics, 15(2), 604.

  18. International Journal of Molecular Sciences (2025). Probing the Effects of Chemical Modifications on Anticoagulant and Antiproliferative Activity of Thrombin Binding Aptamer. IJMS, 26(1), 134.