Component

Blood platelet

Blood platelet. Anucleate, so it cannot resynthesise cyclooxygenase and carries an acetylated enzyme for the rest of its life. Species, exposure and limitations are retained in each linked claim.

10 recorded relationships. Experimental role, claim status and evidence remain attached to each record.

Read recorded mechanisms Open recursive mind map

How nutrients influence it

Every nutrient with a recorded effect on this component, credited to the nutrient that acted rather than the chapter that recorded it. Open a nutrient to see the findings and the conditions they were measured under.

How nutrients reach it in more than one step

Chains of two or more recorded steps that end here, grouped by the nutrient they start from. Each step is a separate finding, so a chain is a route a mechanism could take, not proof that it does.

Tracing routes…

What it does

Every recorded relationship this component is part of, grouped by its role. Plain wording comes first; the technical statement follows.

Recorded relationships

Where it participates (unsigned role)

  1. In human platelet extracts PDE2, PDE3 and PDE5 were identified with no PDE1 or PDE4, cyclic GMP hydrolytic activity was about six times higher than cyclic AMP hydrolytic activity, platelets were among the tissues richest in PDE5, and the selective inhibitor E4021 up to 10 micromolar did not inhibit thromboxane-analogue-induced aggregation on its own while E4021 plus the nitric oxide donor SIN-1, at concentrations that had little effect individually, did inhibit aggregation.

    E4021, a selective PDE5 inhibitor → Platelet aggregation source_derived_draftungraded
    Experimental context and source evidence
    evidence_span
    {"source_cache": "artifacts/sildenafil-research/9115850.abstract.txt", "locator": "Indexed abstract; zero-based, end-exclusive Unicode character offsets", "file_sha256": "ff6132fc80fceda8601406e8827a621afbb66fb4ebaf2bcd4f722ac875c73a54", "start_char": 0, "end_char": 1152, "text_sha256": "ff6132fc80fceda8601406e8827a621afbb66fb4ebaf2bcd4f722ac875c73a54"}
    experimental_model
    Phosphodiesterase isoenzyme separation from human platelet extracts with aggregometry
    exposure
    A selective PDE5 inhibitor alone and combined with the nitric oxide donor SIN-1
    limitations
    Establishes the enzyme complement of the platelet and tests whether inhibiting it is sufficient. It uses E4021 rather than sildenafil, which is recorded on the claim.
    nutrient_topic
    Sildenafil research collection; topical membership is not evidence of a direct clinical effect, and the drug is recorded separately from its N-desmethyl metabolite and its target enzyme from the homologous retinal PDE6. · Sildenafil
    organism
    Human
    plain_language
    The tissue richest in this enzyme is unaffected by blocking it unless something is making the messenger.
    primary_references
    [sil-p9115850] Characterization of the isoenzymes of cyclic nucleotide phosphodiesterase in human platelets and the effects of E4021. (1996). https://pubmed.ncbi.nlm.nih.gov/9115850/ DOI: 10.1016/s0898-6568(96)00112-x
    tissue_or_cell_type
    Platelets

    Sildenafil: the enzyme it occupies instead of the substrate, why it cannot start a signal it can only preserve, the organic nitrate interaction that follows from that, the homologous retinal enzyme ten-fold away, and the pulmonary circulation where the same mechanism became a second indication (2026-09-22) · lines 340–351

    AI-assisted literature curation; primary study URLs and scope retained in the document and extraction. Not publisher full text. · supports · Phosphodiesterase isoenzyme separation from human platelet extracts with aggregometry · source_derived_draft · unverified_draft

    ### sil-inhibition-alone-is-not-enough In human platelet extracts PDE2, PDE3 and PDE5 were identified with no PDE1 or PDE4, cyclic GMP hydrolytic activity was about six times higher than cyclic AMP hydrolytic activity, platelets were among the tissues richest in PDE5, and the selective inhibitor E4021 up to 10 micromolar did not inhibit thromboxane-analogue-induced aggregation on its own while E4021 plus the nitric oxide donor SIN-1, at concentrations that had little effect individually, did inhibit aggregation. Condition category: normal nutrient_topic: Sildenafil research collection; topical membership is not evidence of a direct clinical effect, and the drug is recorded separately from its N-desmethyl metabolite and its target enzyme from the homologous retinal PDE6. plain_language: The tissue richest in this enzyme is unaffected by blocking it unless something is making the messenger. organism: Human tissue_or_cell_type: Platelets experimental_model: Phosphodiesterase isoenzyme separation from human platelet extracts with aggregometry limitations: Establishes the enzyme complement of the platelet and tests whether inhibiting it is sufficient. It uses E4021 rather than sildenafil, which is recorded on the claim. exposure: A selective PDE5 inhibitor alone and combined with the nitric oxide donor SIN-1 evidence_span: {"source_cache": "artifacts/sildenafil-research/9115850.abstract.txt", "locator": "Indexed abstract; zero-based, end-exclusive Unicode character offsets", "file_sha256": "ff6132fc80fceda8601406e8827a621afbb66fb4ebaf2bcd4f722ac875c73a54", "start_char": 0, "end_char": 1152, "text_sha256": "ff6132fc80fceda8601406e8827a621afbb66fb4ebaf2bcd4f722ac875c73a54"} [sil-p9115850] Characterization of the isoenzymes of cyclic nucleotide phosphodiesterase in human platelets and the effects of E4021. (1996). https://pubmed.ncbi.nlm.nih.gov/9115850/ DOI: 10.1016/s0898-6568(96)00112-x
    Complete structured claim and evidence

  2. Image analysis of purified bovine rod phosphodiesterase 6 revealed the three-dimensional dimeric arrangement of the alpha-beta-delta complex and the internal organization of each catalytic subunit into three distinct domains corresponding to the catalytic and two GAF domains, and the three-dimensional molecular organization of human platelet phosphodiesterase type 5 appears highly homologous to that of bovine rod phosphodiesterase 6 as predicted by similarities in their primary sequences.

    Rod PDE6 complex → Phosphodiesterase 5 family source_derived_draftungraded
    Experimental context and source evidence
    evidence_span
    {"source_cache": "artifacts/sildenafil-research/11453687.abstract.txt", "locator": "Indexed abstract; zero-based, end-exclusive Unicode character offsets", "file_sha256": "54fdc1cf336b81568055fa21b19ad21600db5bf276dc5dc9e1dcb490cb63de30", "start_char": 0, "end_char": 1312, "text_sha256": "54fdc1cf336b81568055fa21b19ad21600db5bf276dc5dc9e1dcb490cb63de30"}
    experimental_model
    Electron microscopy and single-particle image analysis of purified bovine rod phosphodiesterase 6
    exposure
    Solubilised rod PDE6 depleted of its gamma subunits, with immunolabelling
    limitations
    A structural comparison at 2.8 nanometre resolution rather than atomic detail. The comparison with PDE5 is inferred from sequence similarity and the reconstructed organisation.
    nutrient_topic
    Sildenafil research collection; topical membership is not evidence of a direct clinical effect, and the drug is recorded separately from its N-desmethyl metabolite and its target enzyme from the homologous retinal PDE6. · Sildenafil
    organism
    Cattle
    plain_language
    The retinal enzyme and the target enzyme are built to the same plan, which is why a drug for one reaches the other.
    primary_references
    [sil-p11453687] Molecular organization of bovine rod cGMP-phosphodiesterase 6. (2001). https://pubmed.ncbi.nlm.nih.gov/11453687/ DOI: 10.1006/jmbi.2001.4813
    tissue_or_cell_type
    Retinal rod outer segment

    Sildenafil: the enzyme it occupies instead of the substrate, why it cannot start a signal it can only preserve, the organic nitrate interaction that follows from that, the homologous retinal enzyme ten-fold away, and the pulmonary circulation where the same mechanism became a second indication (2026-09-22) · lines 249–260

    AI-assisted literature curation; primary study URLs and scope retained in the document and extraction. Not publisher full text. · supports · Electron microscopy and single-particle image analysis of purified bovine rod phosphodiesterase 6 · source_derived_draft · unverified_draft

    ### sil-pde5-and-pde6-are-built-alike Image analysis of purified bovine rod phosphodiesterase 6 revealed the three-dimensional dimeric arrangement of the alpha-beta-delta complex and the internal organization of each catalytic subunit into three distinct domains corresponding to the catalytic and two GAF domains, and the three-dimensional molecular organization of human platelet phosphodiesterase type 5 appears highly homologous to that of bovine rod phosphodiesterase 6 as predicted by similarities in their primary sequences. Condition category: normal nutrient_topic: Sildenafil research collection; topical membership is not evidence of a direct clinical effect, and the drug is recorded separately from its N-desmethyl metabolite and its target enzyme from the homologous retinal PDE6. plain_language: The retinal enzyme and the target enzyme are built to the same plan, which is why a drug for one reaches the other. organism: Cattle tissue_or_cell_type: Retinal rod outer segment experimental_model: Electron microscopy and single-particle image analysis of purified bovine rod phosphodiesterase 6 limitations: A structural comparison at 2.8 nanometre resolution rather than atomic detail. The comparison with PDE5 is inferred from sequence similarity and the reconstructed organisation. exposure: Solubilised rod PDE6 depleted of its gamma subunits, with immunolabelling evidence_span: {"source_cache": "artifacts/sildenafil-research/11453687.abstract.txt", "locator": "Indexed abstract; zero-based, end-exclusive Unicode character offsets", "file_sha256": "54fdc1cf336b81568055fa21b19ad21600db5bf276dc5dc9e1dcb490cb63de30", "start_char": 0, "end_char": 1312, "text_sha256": "54fdc1cf336b81568055fa21b19ad21600db5bf276dc5dc9e1dcb490cb63de30"} [sil-p11453687] Molecular organization of bovine rod cGMP-phosphodiesterase 6. (2001). https://pubmed.ncbi.nlm.nih.gov/11453687/ DOI: 10.1006/jmbi.2001.4813
    Complete structured claim and evidence

  3. Human platelets were found to contain PDE5 which was inhibited by sildenafil with a half-maximal inhibitory concentration of 6.3 nanomolar consistent with the value in corpus cavernosum, sildenafil alone had no direct effect on platelet function but it potentiated the in vitro antiaggregatory activity of sodium nitroprusside on rabbit and human platelets, and in phenylephrine-contracted rabbit aortic rings it enhanced glyceryl trinitrate relaxation.

    Sildenafil → Platelet aggregation source_derived_draftungraded
    Experimental context and source evidence
    evidence_span
    {"source_cache": "artifacts/sildenafil-research/10078537.abstract.txt", "locator": "Indexed abstract; zero-based, end-exclusive Unicode character offsets", "file_sha256": "dceb60af4400fe67b4ffaf73a0aadb8d2e5fad0966b3372a3e46a91c0e0ccee5", "start_char": 0, "end_char": 2610, "text_sha256": "dceb60af4400fe67b4ffaf73a0aadb8d2e5fad0966b3372a3e46a91c0e0ccee5"}
    experimental_model
    Immunochemical distribution of phosphodiesterase activity across human tissues with isolated organ bath studies and platelet aggregometry
    exposure
    Anti-PDE1 and anti-PDE5 antibodies with functional testing, and sildenafil against sodium nitroprusside on platelets
    limitations
    Maps where the target enzyme is and is not, which is what predicts where the drug acts. Antibody-based detection, so absence of signal is weaker evidence than presence.
    nutrient_topic
    Sildenafil research collection; topical membership is not evidence of a direct clinical effect, and the drug is recorded separately from its N-desmethyl metabolite and its target enzyme from the homologous retinal PDE6. · Sildenafil
    organism
    Human, rabbit and dog
    plain_language
    Platelets carry the same enzyme, and again the drug does nothing to them until a nitric oxide donor is present.
    primary_references
    [sil-p10078537] Tissue distribution of phosphodiesterase families and the effects of sildenafil on tissue cyclic nucleotides, platelet function, and the contractile responses of trabeculae carneae and aortic rings in vitro. (1999). https://pubmed.ncbi.nlm.nih.gov/10078537/ DOI: 10.1016/s0002-9149(99)00042-9
    tissue_or_cell_type
    Cardiac ventricle, saphenous vein, mesenteric artery, corpus cavernosum and platelets

    Sildenafil: the enzyme it occupies instead of the substrate, why it cannot start a signal it can only preserve, the organic nitrate interaction that follows from that, the homologous retinal enzyme ten-fold away, and the pulmonary circulation where the same mechanism became a second indication (2026-09-22) · lines 327–338

    AI-assisted literature curation; primary study URLs and scope retained in the document and extraction. Not publisher full text. · supports · Immunochemical distribution of phosphodiesterase activity across human tissues with isolated organ bath studies and platelet aggregometry · source_derived_draft · unverified_draft

    ### sil-platelets-need-a-donor-too Human platelets were found to contain PDE5 which was inhibited by sildenafil with a half-maximal inhibitory concentration of 6.3 nanomolar consistent with the value in corpus cavernosum, sildenafil alone had no direct effect on platelet function but it potentiated the in vitro antiaggregatory activity of sodium nitroprusside on rabbit and human platelets, and in phenylephrine-contracted rabbit aortic rings it enhanced glyceryl trinitrate relaxation. Condition category: normal nutrient_topic: Sildenafil research collection; topical membership is not evidence of a direct clinical effect, and the drug is recorded separately from its N-desmethyl metabolite and its target enzyme from the homologous retinal PDE6. plain_language: Platelets carry the same enzyme, and again the drug does nothing to them until a nitric oxide donor is present. organism: Human, rabbit and dog tissue_or_cell_type: Cardiac ventricle, saphenous vein, mesenteric artery, corpus cavernosum and platelets experimental_model: Immunochemical distribution of phosphodiesterase activity across human tissues with isolated organ bath studies and platelet aggregometry limitations: Maps where the target enzyme is and is not, which is what predicts where the drug acts. Antibody-based detection, so absence of signal is weaker evidence than presence. exposure: Anti-PDE1 and anti-PDE5 antibodies with functional testing, and sildenafil against sodium nitroprusside on platelets evidence_span: {"source_cache": "artifacts/sildenafil-research/10078537.abstract.txt", "locator": "Indexed abstract; zero-based, end-exclusive Unicode character offsets", "file_sha256": "dceb60af4400fe67b4ffaf73a0aadb8d2e5fad0966b3372a3e46a91c0e0ccee5", "start_char": 0, "end_char": 2610, "text_sha256": "dceb60af4400fe67b4ffaf73a0aadb8d2e5fad0966b3372a3e46a91c0e0ccee5"} [sil-p10078537] Tissue distribution of phosphodiesterase families and the effects of sildenafil on tissue cyclic nucleotides, platelet function, and the contractile responses of trabeculae carneae and aortic rings in vitro. (1999). https://pubmed.ncbi.nlm.nih.gov/10078537/ DOI: 10.1016/s0002-9149(99)00042-9
    Complete structured claim and evidence

  4. When platelets were isolated and resuspended in homologous drug-free plasma, slow recovery of thromboxane production was seen after indomethacin with 50% of control activity regained in 100 minutes, whereas ibuprofen-treated platelets, exposed to a competitive inhibitor of cyclooxygenase, recovered nearly completely immediately on being resuspended in drug-free plasma.

    Ibuprofen → Reversible, competitive inhibition of cyclooxygenase source_derived_draftungraded
    Experimental context and source evidence
    evidence_span
    {"source_cache": "artifacts/ibuprofen-research/3088675.abstract.txt", "locator": "Indexed abstract; zero-based, end-exclusive Unicode character offsets", "file_sha256": "ee49ae775f6c268fd63afc816cda206f0bdab5efe9ce86b4f97fd8ee6bda3a1a", "start_char": 0, "end_char": 1400, "text_sha256": "ee49ae775f6c268fd63afc816cda206f0bdab5efe9ce86b4f97fd8ee6bda3a1a"}
    experimental_model
    Kinetics of recovery of platelet thromboxane production after single doses, with platelets resuspended in drug-free plasma
    exposure
    Indomethacin and ibuprofen compared, with isolated platelets and platelet microsomes
    limitations
    The resuspension experiment is what separates a reversible inhibitor from a slowly reversible one. It uses indomethacin as the contrast and reports ibuprofen as the reference reversible drug.
    nutrient_topic
    Ibuprofen research collection; topical membership is not evidence of a direct clinical effect, and the racemate is recorded separately from each of its two enantiomers. · Ibuprofen
    organism
    Human
    plain_language
    Wash the drug away and the platelet enzyme is working again at once, which is the opposite of what aspirin does.
    primary_references
    [ibu-p3088675] Time-dependent inhibition of platelet cyclooxygenase by indomethacin is slowly reversible. (1986). https://pubmed.ncbi.nlm.nih.gov/3088675/ DOI: 10.1016/0090-6980(86)90170-x
    tissue_or_cell_type
    Platelets

    Ibuprofen: the enantiomer that works, the one that was called inactive, the one-way chemistry that turns one into the other, and the targets that are not cyclooxygenase (2026-09-22) · lines 279–290

    AI-assisted literature curation; primary study URLs and scope retained in the document and extraction. Not publisher full text. · supports · Kinetics of recovery of platelet thromboxane production after single doses, with platelets resuspended in drug-free plasma · source_derived_draft · unverified_draft

    ### ibu-ibuprofen-washes-straight-out When platelets were isolated and resuspended in homologous drug-free plasma, slow recovery of thromboxane production was seen after indomethacin with 50% of control activity regained in 100 minutes, whereas ibuprofen-treated platelets, exposed to a competitive inhibitor of cyclooxygenase, recovered nearly completely immediately on being resuspended in drug-free plasma. Condition category: normal nutrient_topic: Ibuprofen research collection; topical membership is not evidence of a direct clinical effect, and the racemate is recorded separately from each of its two enantiomers. plain_language: Wash the drug away and the platelet enzyme is working again at once, which is the opposite of what aspirin does. organism: Human tissue_or_cell_type: Platelets experimental_model: Kinetics of recovery of platelet thromboxane production after single doses, with platelets resuspended in drug-free plasma limitations: The resuspension experiment is what separates a reversible inhibitor from a slowly reversible one. It uses indomethacin as the contrast and reports ibuprofen as the reference reversible drug. exposure: Indomethacin and ibuprofen compared, with isolated platelets and platelet microsomes evidence_span: {"source_cache": "artifacts/ibuprofen-research/3088675.abstract.txt", "locator": "Indexed abstract; zero-based, end-exclusive Unicode character offsets", "file_sha256": "ee49ae775f6c268fd63afc816cda206f0bdab5efe9ce86b4f97fd8ee6bda3a1a", "start_char": 0, "end_char": 1400, "text_sha256": "ee49ae775f6c268fd63afc816cda206f0bdab5efe9ce86b4f97fd8ee6bda3a1a"} [ibu-p3088675] Time-dependent inhibition of platelet cyclooxygenase by indomethacin is slowly reversible. (1986). https://pubmed.ncbi.nlm.nih.gov/3088675/ DOI: 10.1016/0090-6980(86)90170-x
    Complete structured claim and evidence

  5. Acetaminophen inhibited prostaglandin H synthase activity with a half-maximal inhibitory concentration of 4.3 micromolar in interleukin-1-alpha-stimulated human umbilical vein endothelial cells against 1,870 micromolar in the platelet with 2 micromolar arachidonic acid as substrate, and this difference is not caused by isoform selectivity because acetaminophen inhibits purified ovine prostaglandin H synthase-1 and murine recombinant synthase-2 equally.

    Paracetamol → Selectivity of a drug between cell types rather than between enzyme isoforms source_derived_draftungraded
    Experimental context and source evidence
    availability_state
    biomarker_context Imported condition classification; unverified.
    evidence_span
    {"source_cache": "artifacts/paracetamol-research/12011469.abstract.txt", "locator": "Indexed abstract; zero-based, end-exclusive Unicode character offsets", "file_sha256": "7e599890f658a63c52471fbc7e6853d7db6a5ecbe892241a39c8a633b3ab2d0d", "start_char": 0, "end_char": 1561, "text_sha256": "7e599890f658a63c52471fbc7e6853d7db6a5ecbe892241a39c8a633b3ab2d0d"}
    experimental_model
    Interleukin-1-alpha-stimulated human endothelial cells and human platelets compared, with hydroperoxide addition
    exposure
    Acetaminophen with 2 micromolar arachidonic acid, and with prostaglandin G2, 12-hydroperoxyeicosatetraenoic acid or tert-butyl hydroperoxide added back
    limitations
    The decisive record of the chapter: it measures a 435-fold difference between two human cell types, shows it is not isoform selectivity, and reverses it by adding the peroxide back.
    nutrient_topic
    Paracetamol research collection; topical membership is not evidence of a direct clinical effect, and the drug is recorded separately from the metabolites NAPQI and AM404. · Paracetamol
    organism
    Human
    plain_language
    The same drug is four hundred times weaker in a platelet than in an inflamed blood vessel, and it is not because the enzymes differ.
    primary_references
    [apap-p12011469] Determinants of the cellular specificity of acetaminophen as an inhibitor of prostaglandin H(2) synthases. (2002). https://pubmed.ncbi.nlm.nih.gov/12011469/ DOI: 10.1073/pnas.102588199
    tissue_or_cell_type
    Endothelium and platelets
    trigger_kind
    biomarker_context Imported condition classification; unverified.

    Paracetamol: the enzyme it reduces rather than blocks, the isoform that turned out not to exist, the metabolite that carries the analgesia, and the metabolite that destroys the liver (2026-09-22) · lines 90–101

    AI-assisted literature curation; primary study URLs and scope retained in the document and extraction. Not publisher full text. · supports · Interleukin-1-alpha-stimulated human endothelial cells and human platelets compared, with hydroperoxide addition · source_derived_draft · unverified_draft

    ### apap-four-hundred-fold-cell-difference Acetaminophen inhibited prostaglandin H synthase activity with a half-maximal inhibitory concentration of 4.3 micromolar in interleukin-1-alpha-stimulated human umbilical vein endothelial cells against 1,870 micromolar in the platelet with 2 micromolar arachidonic acid as substrate, and this difference is not caused by isoform selectivity because acetaminophen inhibits purified ovine prostaglandin H synthase-1 and murine recombinant synthase-2 equally. Condition category: biomarker_context nutrient_topic: Paracetamol research collection; topical membership is not evidence of a direct clinical effect, and the drug is recorded separately from the metabolites NAPQI and AM404. plain_language: The same drug is four hundred times weaker in a platelet than in an inflamed blood vessel, and it is not because the enzymes differ. organism: Human tissue_or_cell_type: Endothelium and platelets experimental_model: Interleukin-1-alpha-stimulated human endothelial cells and human platelets compared, with hydroperoxide addition limitations: The decisive record of the chapter: it measures a 435-fold difference between two human cell types, shows it is not isoform selectivity, and reverses it by adding the peroxide back. exposure: Acetaminophen with 2 micromolar arachidonic acid, and with prostaglandin G2, 12-hydroperoxyeicosatetraenoic acid or tert-butyl hydroperoxide added back evidence_span: {"source_cache": "artifacts/paracetamol-research/12011469.abstract.txt", "locator": "Indexed abstract; zero-based, end-exclusive Unicode character offsets", "file_sha256": "7e599890f658a63c52471fbc7e6853d7db6a5ecbe892241a39c8a633b3ab2d0d", "start_char": 0, "end_char": 1561, "text_sha256": "7e599890f658a63c52471fbc7e6853d7db6a5ecbe892241a39c8a633b3ab2d0d"} [apap-p12011469] Determinants of the cellular specificity of acetaminophen as an inhibitor of prostaglandin H(2) synthases. (2002). https://pubmed.ncbi.nlm.nih.gov/12011469/ DOI: 10.1073/pnas.102588199
    Complete structured claim and evidence

  6. Increasing the peroxide product of the cyclooxygenase, prostaglandin G2, by elevating the concentration of either enzyme or substrate reverses the inhibitory action of acetaminophen, as does adding prostaglandin G2 itself, 0.3 micromolar 12-hydroperoxyeicosatetraenoic acid which is a major product of the platelet completely reverses the action on synthase-1, and inhibition in endothelial cells is abrogated by tert-butyl hydroperoxide, supporting the hypothesis that hydroperoxide concentration contributes to the cellular selectivity.

    Ambient cellular hydroperoxide concentration → Paracetamol source_derived_draftungraded
    Experimental context and source evidence
    availability_state
    biomarker_context Imported condition classification; unverified.
    evidence_span
    {"source_cache": "artifacts/paracetamol-research/12011469.abstract.txt", "locator": "Indexed abstract; zero-based, end-exclusive Unicode character offsets", "file_sha256": "7e599890f658a63c52471fbc7e6853d7db6a5ecbe892241a39c8a633b3ab2d0d", "start_char": 0, "end_char": 1561, "text_sha256": "7e599890f658a63c52471fbc7e6853d7db6a5ecbe892241a39c8a633b3ab2d0d"}
    experimental_model
    Interleukin-1-alpha-stimulated human endothelial cells and human platelets compared, with hydroperoxide addition
    exposure
    Acetaminophen with 2 micromolar arachidonic acid, and with prostaglandin G2, 12-hydroperoxyeicosatetraenoic acid or tert-butyl hydroperoxide added back
    limitations
    The decisive record of the chapter: it measures a 435-fold difference between two human cell types, shows it is not isoform selectivity, and reverses it by adding the peroxide back.
    nutrient_topic
    Paracetamol research collection; topical membership is not evidence of a direct clinical effect, and the drug is recorded separately from the metabolites NAPQI and AM404. · Paracetamol
    organism
    Human
    plain_language
    Put the peroxide back and the drug stops working, which is why the platelet is untouched.
    primary_references
    [apap-p12011469] Determinants of the cellular specificity of acetaminophen as an inhibitor of prostaglandin H(2) synthases. (2002). https://pubmed.ncbi.nlm.nih.gov/12011469/ DOI: 10.1073/pnas.102588199
    tissue_or_cell_type
    Endothelium and platelets
    trigger_kind
    biomarker_context Imported condition classification; unverified.

    Paracetamol: the enzyme it reduces rather than blocks, the isoform that turned out not to exist, the metabolite that carries the analgesia, and the metabolite that destroys the liver (2026-09-22) · lines 103–114

    AI-assisted literature curation; primary study URLs and scope retained in the document and extraction. Not publisher full text. · supports · Interleukin-1-alpha-stimulated human endothelial cells and human platelets compared, with hydroperoxide addition · source_derived_draft · unverified_draft

    ### apap-peroxide-reverses-it Increasing the peroxide product of the cyclooxygenase, prostaglandin G2, by elevating the concentration of either enzyme or substrate reverses the inhibitory action of acetaminophen, as does adding prostaglandin G2 itself, 0.3 micromolar 12-hydroperoxyeicosatetraenoic acid which is a major product of the platelet completely reverses the action on synthase-1, and inhibition in endothelial cells is abrogated by tert-butyl hydroperoxide, supporting the hypothesis that hydroperoxide concentration contributes to the cellular selectivity. Condition category: biomarker_context nutrient_topic: Paracetamol research collection; topical membership is not evidence of a direct clinical effect, and the drug is recorded separately from the metabolites NAPQI and AM404. plain_language: Put the peroxide back and the drug stops working, which is why the platelet is untouched. organism: Human tissue_or_cell_type: Endothelium and platelets experimental_model: Interleukin-1-alpha-stimulated human endothelial cells and human platelets compared, with hydroperoxide addition limitations: The decisive record of the chapter: it measures a 435-fold difference between two human cell types, shows it is not isoform selectivity, and reverses it by adding the peroxide back. exposure: Acetaminophen with 2 micromolar arachidonic acid, and with prostaglandin G2, 12-hydroperoxyeicosatetraenoic acid or tert-butyl hydroperoxide added back evidence_span: {"source_cache": "artifacts/paracetamol-research/12011469.abstract.txt", "locator": "Indexed abstract; zero-based, end-exclusive Unicode character offsets", "file_sha256": "7e599890f658a63c52471fbc7e6853d7db6a5ecbe892241a39c8a633b3ab2d0d", "start_char": 0, "end_char": 1561, "text_sha256": "7e599890f658a63c52471fbc7e6853d7db6a5ecbe892241a39c8a633b3ab2d0d"} [apap-p12011469] Determinants of the cellular specificity of acetaminophen as an inhibitor of prostaglandin H(2) synthases. (2002). https://pubmed.ncbi.nlm.nih.gov/12011469/ DOI: 10.1073/pnas.102588199
    Complete structured claim and evidence

  7. Acetaminophen inhibited lipopolysaccharide-induced whole blood prostaglandin E2 and thromboxane B2 production with half-maximal inhibitory concentrations of 44 and 94 micromolar, at therapeutic concentrations of 100 and 300 micromolar it reduced prostaglandin E2 more than thromboxane B2, but in isolated monocytes both were maximally reduced by only 60%, and at the same concentrations it caused a similar and incomplete inhibition of platelet prostaglandin E2 and thromboxane B2 during whole blood clotting, so that in the presence of plasma the drug almost completely suppressed inducible prostaglandin E2 biosynthesis through effects on both cyclooxygenase-2 and inducible prostaglandin E synthase.

    Paracetamol → Inducible prostaglandin E synthase source_derived_draftungraded
    Experimental context and source evidence
    evidence_span
    {"source_cache": "artifacts/paracetamol-research/12598417.abstract.txt", "locator": "Indexed abstract; zero-based, end-exclusive Unicode character offsets", "file_sha256": "e5796a25a03c77d12e8376a60aa094e481bd0c2ab58b29ddcb70027ab477b267", "start_char": 0, "end_char": 1894, "text_sha256": "e5796a25a03c77d12e8376a60aa094e481bd0c2ab58b29ddcb70027ab477b267"}
    experimental_model
    Human whole blood and isolated monocytes and platelets with parallel prostaglandin E2 and thromboxane B2 measurement
    exposure
    Acetaminophen at therapeutic plasma concentrations of 100 and 300 micromolar, in whole blood and in isolated cells
    limitations
    The whole blood against isolated cell comparison shows plasma components matter, and measuring two prostanoids in parallel separates the synthase from the downstream synthase. Ex vivo only.
    nutrient_topic
    Paracetamol research collection; topical membership is not evidence of a direct clinical effect, and the drug is recorded separately from the metabolites NAPQI and AM404. · Paracetamol
    organism
    Human
    plain_language
    In whole blood it nearly abolishes the inflammatory prostaglandin; in isolated cells it manages only sixty per cent.
    primary_references
    [apap-p12598417] Effects of acetaminophen on constitutive and inducible prostanoid biosynthesis in human blood cells. (2003). https://pubmed.ncbi.nlm.nih.gov/12598417/ DOI: 10.1038/sj.bjp.0705078
    tissue_or_cell_type
    Monocytes and platelets

    Paracetamol: the enzyme it reduces rather than blocks, the isoform that turned out not to exist, the metabolite that carries the analgesia, and the metabolite that destroys the liver (2026-09-22) · lines 272–283

    AI-assisted literature curation; primary study URLs and scope retained in the document and extraction. Not publisher full text. · supports · Human whole blood and isolated monocytes and platelets with parallel prostaglandin E2 and thromboxane B2 measurement · source_derived_draft · unverified_draft

    ### apap-plasma-changes-the-answer Acetaminophen inhibited lipopolysaccharide-induced whole blood prostaglandin E2 and thromboxane B2 production with half-maximal inhibitory concentrations of 44 and 94 micromolar, at therapeutic concentrations of 100 and 300 micromolar it reduced prostaglandin E2 more than thromboxane B2, but in isolated monocytes both were maximally reduced by only 60%, and at the same concentrations it caused a similar and incomplete inhibition of platelet prostaglandin E2 and thromboxane B2 during whole blood clotting, so that in the presence of plasma the drug almost completely suppressed inducible prostaglandin E2 biosynthesis through effects on both cyclooxygenase-2 and inducible prostaglandin E synthase. Condition category: normal nutrient_topic: Paracetamol research collection; topical membership is not evidence of a direct clinical effect, and the drug is recorded separately from the metabolites NAPQI and AM404. plain_language: In whole blood it nearly abolishes the inflammatory prostaglandin; in isolated cells it manages only sixty per cent. organism: Human tissue_or_cell_type: Monocytes and platelets experimental_model: Human whole blood and isolated monocytes and platelets with parallel prostaglandin E2 and thromboxane B2 measurement limitations: The whole blood against isolated cell comparison shows plasma components matter, and measuring two prostanoids in parallel separates the synthase from the downstream synthase. Ex vivo only. exposure: Acetaminophen at therapeutic plasma concentrations of 100 and 300 micromolar, in whole blood and in isolated cells evidence_span: {"source_cache": "artifacts/paracetamol-research/12598417.abstract.txt", "locator": "Indexed abstract; zero-based, end-exclusive Unicode character offsets", "file_sha256": "e5796a25a03c77d12e8376a60aa094e481bd0c2ab58b29ddcb70027ab477b267", "start_char": 0, "end_char": 1894, "text_sha256": "e5796a25a03c77d12e8376a60aa094e481bd0c2ab58b29ddcb70027ab477b267"} [apap-p12598417] Effects of acetaminophen on constitutive and inducible prostanoid biosynthesis in human blood cells. (2003). https://pubmed.ncbi.nlm.nih.gov/12598417/ DOI: 10.1038/sj.bjp.0705078
    Complete structured claim and evidence

  8. Single doses of 6 to 100 milligrams of aspirin produced a linear inhibition of platelet thromboxane B2 production ranging from 12 to 95% after 24 hours, and a daily dose of 0.45 milligrams per kilogram for 7 days produced cumulative and virtually complete inhibition without significantly reducing urinary excretion of prostaglandin E2, prostaglandin F2-alpha or 6-keto-prostaglandin F1-alpha in both men and women, an effect maintained unaltered through one month of therapy with no cumulative inhibition of renal prostaglandin synthesis, while furosemide-induced renal prostacyclin synthesis and renin release were unaffected.

    Aspirin / acetylsalicylic acid → Serum thromboxane B2 after whole blood clotting source_derived_draftungraded
    Experimental context and source evidence
    availability_state
    biomarker_context Imported condition classification; unverified.
    evidence_span
    {"source_cache": "artifacts/aspirin-research/7045161.abstract.txt", "locator": "Indexed abstract; zero-based, end-exclusive Unicode character offsets", "file_sha256": "58bb82650f675f1ba3dd21b6dcf3d83b71a56c437a687f72d2af9dcdc07abadb", "start_char": 0, "end_char": 1963, "text_sha256": "58bb82650f675f1ba3dd21b6dcf3d83b71a56c437a687f72d2af9dcdc07abadb"}
    experimental_model
    Radioimmunoassay of serum thromboxane B2 and urinary prostaglandin excretion in 46 healthy subjects given single or repeated oral aspirin
    exposure
    Single doses of 6 to 100 milligrams, and 0.45 milligrams per kilogram daily for 7 days and up to one month
    limitations
    The dose-ranging design across 46 subjects is what makes the selectivity claim testable. Urinary prostaglandin excretion is an indirect measure of renal synthesis.
    nutrient_topic
    Aspirin research collection; topical membership is not evidence of a direct clinical effect, and aspirin is recorded separately from salicylate, the metabolite it becomes. · Aspirin / acetylsalicylic acid
    organism
    Human
    plain_language
    A very small daily dose wipes out platelet thromboxane and leaves the kidney untouched.
    primary_references
    [asa-p7045161] Selective cumulative inhibition of platelet thromboxane production by low-dose aspirin in healthy subjects. (1982). https://pubmed.ncbi.nlm.nih.gov/7045161/ DOI: 10.1172/jci110576
    tissue_or_cell_type
    Platelets and kidney
    trigger_kind
    biomarker_context Imported condition classification; unverified.

    Aspirin: the serine it acetylates, the enzyme that acetylation creates, the dose that separates platelet from vessel wall, and the metabolite that is a different drug (2026-09-22) · lines 364–375

    AI-assisted literature curation; primary study URLs and scope retained in the document and extraction. Not publisher full text. · supports · Radioimmunoassay of serum thromboxane B2 and urinary prostaglandin excretion in 46 healthy subjects given single or repeated oral aspirin · source_derived_draft · unverified_draft

    ### asa-cumulative-and-selective Single doses of 6 to 100 milligrams of aspirin produced a linear inhibition of platelet thromboxane B2 production ranging from 12 to 95% after 24 hours, and a daily dose of 0.45 milligrams per kilogram for 7 days produced cumulative and virtually complete inhibition without significantly reducing urinary excretion of prostaglandin E2, prostaglandin F2-alpha or 6-keto-prostaglandin F1-alpha in both men and women, an effect maintained unaltered through one month of therapy with no cumulative inhibition of renal prostaglandin synthesis, while furosemide-induced renal prostacyclin synthesis and renin release were unaffected. Condition category: biomarker_context nutrient_topic: Aspirin research collection; topical membership is not evidence of a direct clinical effect, and aspirin is recorded separately from salicylate, the metabolite it becomes. plain_language: A very small daily dose wipes out platelet thromboxane and leaves the kidney untouched. organism: Human tissue_or_cell_type: Platelets and kidney experimental_model: Radioimmunoassay of serum thromboxane B2 and urinary prostaglandin excretion in 46 healthy subjects given single or repeated oral aspirin limitations: The dose-ranging design across 46 subjects is what makes the selectivity claim testable. Urinary prostaglandin excretion is an indirect measure of renal synthesis. exposure: Single doses of 6 to 100 milligrams, and 0.45 milligrams per kilogram daily for 7 days and up to one month evidence_span: {"source_cache": "artifacts/aspirin-research/7045161.abstract.txt", "locator": "Indexed abstract; zero-based, end-exclusive Unicode character offsets", "file_sha256": "58bb82650f675f1ba3dd21b6dcf3d83b71a56c437a687f72d2af9dcdc07abadb", "start_char": 0, "end_char": 1963, "text_sha256": "58bb82650f675f1ba3dd21b6dcf3d83b71a56c437a687f72d2af9dcdc07abadb"} [asa-p7045161] Selective cumulative inhibition of platelet thromboxane production by low-dose aspirin in healthy subjects. (1982). https://pubmed.ncbi.nlm.nih.gov/7045161/ DOI: 10.1172/jci110576
    Complete structured claim and evidence

  9. Following ingestion of 650 milligrams of acetylsalicylate as compressed tablets, platelet cyclooxygenase activity was inhibited 95% within 45 minutes, enzyme activity was observed to increase within 8 hours and reached 10% of control level by 24 hours, a pattern suggesting that only circulating platelets are affected by ingestion; enteric-coated tablets gave comparable inhibition with a delayed onset reflecting delayed appearance of acetylsalicylate in plasma, and returned to control along a similar pattern.

    Aspirin / acetylsalicylic acid → The cyclooxygenase activity of prostaglandin endoperoxide synthase source_derived_draftungraded
    Experimental context and source evidence
    evidence_span
    {"source_cache": "artifacts/aspirin-research/7355437.abstract.txt", "locator": "Indexed abstract; zero-based, end-exclusive Unicode character offsets", "file_sha256": "01e0a159576fdabca8185271b0d6acd2e790cff32c06ba1e68906afb3a63544a", "start_char": 0, "end_char": 909, "text_sha256": "01e0a159576fdabca8185271b0d6acd2e790cff32c06ba1e68906afb3a63544a"}
    experimental_model
    High pressure liquid chromatography of plasma acetylsalicylate and salicylate with radiometric platelet cyclooxygenase assay
    exposure
    650 milligrams of aspirin as compressed or enteric-coated tablets
    limitations
    Measures the parent drug and the metabolite separately alongside the enzyme effect, which is exactly the distinction this chapter turns on. Healthy subjects and a single dose.
    nutrient_topic
    Aspirin research collection; topical membership is not evidence of a direct clinical effect, and aspirin is recorded separately from salicylate, the metabolite it becomes. · Aspirin / acetylsalicylic acid
    organism
    Human
    plain_language
    The drug catches the platelets that are in the blood at the time, and nothing else.
    primary_references
    [asa-p7355437] Plasma acetylsalicylate and salicylate and platelet cyclooxygenase activity following plain and enteric-coated aspirin. (1980). https://pubmed.ncbi.nlm.nih.gov/7355437/ DOI: 10.1161/01.str.11.1.9
    tissue_or_cell_type
    Plasma and platelets

    Aspirin: the serine it acetylates, the enzyme that acetylation creates, the dose that separates platelet from vessel wall, and the metabolite that is a different drug (2026-09-22) · lines 403–414

    AI-assisted literature curation; primary study URLs and scope retained in the document and extraction. Not publisher full text. · supports · High pressure liquid chromatography of plasma acetylsalicylate and salicylate with radiometric platelet cyclooxygenase assay · source_derived_draft · unverified_draft

    ### asa-only-circulating-platelets Following ingestion of 650 milligrams of acetylsalicylate as compressed tablets, platelet cyclooxygenase activity was inhibited 95% within 45 minutes, enzyme activity was observed to increase within 8 hours and reached 10% of control level by 24 hours, a pattern suggesting that only circulating platelets are affected by ingestion; enteric-coated tablets gave comparable inhibition with a delayed onset reflecting delayed appearance of acetylsalicylate in plasma, and returned to control along a similar pattern. Condition category: normal nutrient_topic: Aspirin research collection; topical membership is not evidence of a direct clinical effect, and aspirin is recorded separately from salicylate, the metabolite it becomes. plain_language: The drug catches the platelets that are in the blood at the time, and nothing else. organism: Human tissue_or_cell_type: Plasma and platelets experimental_model: High pressure liquid chromatography of plasma acetylsalicylate and salicylate with radiometric platelet cyclooxygenase assay limitations: Measures the parent drug and the metabolite separately alongside the enzyme effect, which is exactly the distinction this chapter turns on. Healthy subjects and a single dose. exposure: 650 milligrams of aspirin as compressed or enteric-coated tablets evidence_span: {"source_cache": "artifacts/aspirin-research/7355437.abstract.txt", "locator": "Indexed abstract; zero-based, end-exclusive Unicode character offsets", "file_sha256": "01e0a159576fdabca8185271b0d6acd2e790cff32c06ba1e68906afb3a63544a", "start_char": 0, "end_char": 909, "text_sha256": "01e0a159576fdabca8185271b0d6acd2e790cff32c06ba1e68906afb3a63544a"} [asa-p7355437] Plasma acetylsalicylate and salicylate and platelet cyclooxygenase activity following plain and enteric-coated aspirin. (1980). https://pubmed.ncbi.nlm.nih.gov/7355437/ DOI: 10.1161/01.str.11.1.9
    Complete structured claim and evidence

  10. Megakaryocyte thromboxane production was depressed by 70% and that of platelets by 85% at two hours after 20 milligrams per kilogram oral aspirin, full megakaryocyte thromboxane recovery occurred by 72 hours and preceded complete platelet recovery by 24 hours, megakaryocyte synthesis showed substantial recovery by 36 hours while platelet recovery did not begin for 24 hours, and the authors conclude that thromboxane synthesis develops in rat megakaryocytes after approximately 48 hours of cytoplasmic differentiation toward platelet shedding.

    Megakaryocyte → Recovery of platelet cyclooxygenase activity after aspirin source_derived_draftungraded
    Experimental context and source evidence
    evidence_span
    {"source_cache": "artifacts/aspirin-research/6812167.abstract.txt", "locator": "Indexed abstract; zero-based, end-exclusive Unicode character offsets", "file_sha256": "fd3cbdc85225aabdb23690613d2ba4bd49151f144c362d6121721eb45e969389", "start_char": 0, "end_char": 1366, "text_sha256": "fd3cbdc85225aabdb23690613d2ba4bd49151f144c362d6121721eb45e969389"}
    experimental_model
    Radioimmunoassay of megakaryocyte and platelet thromboxane B2 recovery in rats after a single oral aspirin dose
    exposure
    20 milligrams per kilogram oral aspirin dissolved in dimethyl sulphoxide
    limitations
    Follows the precursor cell rather than the platelet, which is where the recovery kinetics are actually set. A rat study and the maturation timing is inferred from transit times.
    nutrient_topic
    Aspirin research collection; topical membership is not evidence of a direct clinical effect, and aspirin is recorded separately from salicylate, the metabolite it becomes. · Aspirin / acetylsalicylic acid
    organism
    Rat
    plain_language
    The marrow recovers first and the blood follows, because new platelets have to be built and released.
    primary_references
    [asa-p6812167] Aspirin inhibits rat megakaryocyte thromboxane synthesis. (1982). https://pubmed.ncbi.nlm.nih.gov/6812167/ DOI: 10.1016/0090-6980(82)90128-9
    tissue_or_cell_type
    Bone marrow megakaryocytes and platelets

    Aspirin: the serine it acetylates, the enzyme that acetylation creates, the dose that separates platelet from vessel wall, and the metabolite that is a different drug (2026-09-22) · lines 416–427

    AI-assisted literature curation; primary study URLs and scope retained in the document and extraction. Not publisher full text. · supports · Radioimmunoassay of megakaryocyte and platelet thromboxane B2 recovery in rats after a single oral aspirin dose · source_derived_draft · unverified_draft

    ### asa-recovery-starts-in-the-marrow Megakaryocyte thromboxane production was depressed by 70% and that of platelets by 85% at two hours after 20 milligrams per kilogram oral aspirin, full megakaryocyte thromboxane recovery occurred by 72 hours and preceded complete platelet recovery by 24 hours, megakaryocyte synthesis showed substantial recovery by 36 hours while platelet recovery did not begin for 24 hours, and the authors conclude that thromboxane synthesis develops in rat megakaryocytes after approximately 48 hours of cytoplasmic differentiation toward platelet shedding. Condition category: normal nutrient_topic: Aspirin research collection; topical membership is not evidence of a direct clinical effect, and aspirin is recorded separately from salicylate, the metabolite it becomes. plain_language: The marrow recovers first and the blood follows, because new platelets have to be built and released. organism: Rat tissue_or_cell_type: Bone marrow megakaryocytes and platelets experimental_model: Radioimmunoassay of megakaryocyte and platelet thromboxane B2 recovery in rats after a single oral aspirin dose limitations: Follows the precursor cell rather than the platelet, which is where the recovery kinetics are actually set. A rat study and the maturation timing is inferred from transit times. exposure: 20 milligrams per kilogram oral aspirin dissolved in dimethyl sulphoxide evidence_span: {"source_cache": "artifacts/aspirin-research/6812167.abstract.txt", "locator": "Indexed abstract; zero-based, end-exclusive Unicode character offsets", "file_sha256": "fd3cbdc85225aabdb23690613d2ba4bd49151f144c362d6121721eb45e969389", "start_char": 0, "end_char": 1366, "text_sha256": "fd3cbdc85225aabdb23690613d2ba4bd49151f144c362d6121721eb45e969389"} [asa-p6812167] Aspirin inhibits rat megakaryocyte thromboxane synthesis. (1982). https://pubmed.ncbi.nlm.nih.gov/6812167/ DOI: 10.1016/0090-6980(82)90128-9
    Complete structured claim and evidence

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