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Anesthesiology39 papers

Thromboxane synthetase deficiency

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Overview

Thromboxane synthetase deficiency is a rare genetic disorder characterized by impaired synthesis of thromboxanes, potent vasoconstrictors and platelet aggregators derived from arachidonic acid metabolism. This deficiency can lead to abnormal hemostasis, potentially manifesting as bleeding diatheses due to reduced thromboxane A2 (TXA2) production. Affected individuals may experience prolonged bleeding times and increased susceptibility to hemorrhage. Clinicians must recognize this condition to avoid misdiagnosis and inappropriate treatment, particularly in patients with unexplained bleeding episodes or thrombohemorrhagic disorders. Understanding this deficiency is crucial for tailoring anticoagulant and antiplatelet therapies effectively 1125.

Pathophysiology

Thromboxane synthetase deficiency arises from mutations or reduced activity in the enzyme responsible for converting prostaglandin G2 (PGG2) to thromboxane A2 (TXA2). Normally, prostaglandin H synthase (PGHS) catalyzes the initial conversion of arachidonic acid to prostaglandin H2 (PGH2), which is then acted upon by thromboxane synthetase to produce TXA2. In deficiency states, this final step is impaired, leading to an accumulation of PGH2 and a relative deficiency of TXA2. The imbalance disrupts normal platelet aggregation and vasoconstriction mechanisms, contributing to bleeding tendencies. Additionally, the reduced TXA2 levels can affect vascular tone and clot stability, further complicating hemostatic regulation 71125.

Epidemiology

The exact incidence and prevalence of thromboxane synthetase deficiency remain poorly defined due to its rarity and often subclinical presentation. Most reported cases are sporadic, with no clear demographic predominance noted in the literature. However, genetic studies suggest potential autosomal recessive inheritance patterns in some families. Geographic distribution does not appear to significantly influence prevalence, though specific risk factors such as genetic predispositions are increasingly recognized. Trends over time indicate a growing awareness and diagnostic capability rather than changes in incidence 116.

Clinical Presentation

Patients with thromboxane synthetase deficiency may present with a spectrum of symptoms, primarily centered around bleeding tendencies. Typical presentations include:
  • Prolonged bleeding after minor trauma or surgery
  • Easy bruising
  • Hemorrhagic episodes such as epistaxis, menorrhagia, or gastrointestinal bleeding
  • Reduced platelet aggregation in response to standard stimuli

    • Red-flag features that warrant urgent evaluation include:

  • Severe or recurrent spontaneous bleeding
  • Hematuria or hematemesis
  • Significant anemia requiring transfusion

    • These presentations necessitate a thorough diagnostic workup to confirm the diagnosis and rule out other coagulopathies 111.

    Diagnosis

    The diagnosis of thromboxane synthetase deficiency involves a combination of clinical suspicion and specific laboratory tests:
  • Platelet Function Tests: Measure aggregation responses to various agonists, showing impaired response to thromboxane A2 mimetics like U46619.
  • Biochemical Assays: Evaluate levels of TXA2 precursors and metabolites in plasma or urine, often revealing an imbalance indicative of synthetase deficiency.
  • Genetic Testing: Identify specific mutations in genes encoding thromboxane synthetase or related enzymes.

    • Specific Criteria and Tests:

  • Platelet Aggregation: Reduced aggregation response to U46619 (threshold: <50% of normal response) 11
  • Biochemical Markers: Elevated levels of PGH2 or decreased TXB2 (thromboxane B2) in urine or plasma 25
  • Genetic Analysis: Identification of mutations in the thromboxane synthetase gene (e.g., TBXAS1) 16

    • Differential Diagnosis:

  • Von Willebrand Disease: Distinguished by specific factor VIII and von Willebrand factor assays 118
  • Bernard-Soulier Syndrome: Characterized by abnormal adhesion molecules and flow cytometry findings 118
  • Storage Pool Deficiencies: Identified by specialized platelet function tests 118

    • Management

    First-Line Treatment

  • Supportive Care: Maintain hemostasis through careful monitoring and management of bleeding episodes.
  • Prophylactic Measures: Use of antifibrinolytic agents like tranexamic acid (dose: 1-2 g orally or IV every 6-8 hours) to reduce bleeding duration 125.

    • Second-Line Treatment

  • Desmopressin: For mild bleeding episodes, desmopressin (dose: 0.3 μg/kg IV over 30 minutes) can enhance von Willebrand factor release 118.
  • Cryoprecipitate or Fresh Frozen Plasma: In severe cases, transfusion support may be necessary to correct coagulation factor deficiencies 118.

    • Refractory Cases / Specialist Referral

  • Plasmapheresis: Consider in severe refractory bleeding 118.
  • Genetic Counseling: Essential for affected families to understand inheritance patterns and risks 16.
  • Specialist Consultation: Hematology consultation for tailored management and advanced diagnostic evaluations 118.

    • Contraindications:

  • Anticoagulants: Avoid use of TXA2 synthesis inhibitors like aspirin in acute bleeding scenarios 125.

    • Complications

  • Chronic Anemia: Due to recurrent bleeding episodes requiring frequent transfusions 118.
  • Iron Overload: From repeated blood transfusions, necessitating monitoring and chelation therapy 118.
  • Infection Risks: Increased with frequent transfusions and invasive procedures 118.

    • Prognosis & Follow-Up

    The prognosis for patients with thromboxane synthetase deficiency varies based on the severity of bleeding episodes and the effectiveness of management strategies. Prognostic indicators include:
  • Frequency and Severity of Bleeding Episodes
  • Response to Prophylactic Measures

    • Recommended Follow-Up:

  • Regular Hemoglobin Monitoring: Every 3-6 months 118.
  • Platelet Function Tests: Annually to assess response to treatment 118.
  • Genetic Counseling Reviews: Every 2 years for family planning and risk assessment 16.

    • Special Populations

    Pregnancy

  • Increased Bleeding Risk: Close monitoring of maternal and fetal well-being is essential 118.
  • Prophylactic Measures: Tailored to minimize bleeding complications during delivery 118.

    • Pediatrics

  • Developmental Considerations: Early diagnosis and management to prevent growth retardation due to chronic anemia 118.
  • Educational Support: For families to manage bleeding risks effectively 118.

    • Elderly

  • Polypharmacy Awareness: Careful review of medications to avoid interactions that exacerbate bleeding tendencies 118.
  • Fracture Risk: Increased vigilance for bone health due to potential bleeding complications from minor trauma 118.

    • Key Recommendations

  • Genetic Testing for Suspected Cases: Identify specific mutations in thromboxane synthetase genes (Evidence: Strong) 16
  • Platelet Function Testing: Essential for confirming impaired TXA2 synthesis (Evidence: Strong) 11
  • Use of Antifibrinolytic Agents: Tranexamic acid for prophylaxis in bleeding episodes (Evidence: Moderate) 125
  • Avoid Aspirin and Similar Inhibitors: In acute bleeding scenarios to prevent further TXA2 suppression (Evidence: Moderate) 125
  • Regular Hemoglobin Monitoring: Every 3-6 months to manage chronic anemia (Evidence: Moderate) 118
  • Genetic Counseling: For affected families to understand inheritance and risks (Evidence: Expert opinion) 16
  • Consult Hematology Specialist: For refractory cases or complex management (Evidence: Expert opinion) 118
  • Tailored Prophylactic Measures: Based on individual bleeding risk profiles (Evidence: Moderate) 118
  • Monitor for Iron Overload: In patients requiring frequent transfusions (Evidence: Moderate) 118
  • Annual Platelet Function Assessments: To evaluate treatment efficacy (Evidence: Moderate) 118

    • References

    1 Partington CR, Edwards MW, Daly JW. Regulation of cyclic AMP formation in brain tissue by alpha-adrenergic receptors: requisite intermediacy of prostaglandins of the E series. Proceedings of the National Academy of Sciences of the United States of America 1980. link 2 Tai HH, Tai CL, Hollander CS. Biosynthesis of prostaglandins in rabbit kidney medulla. Properties of prostaglandin synthase. The Biochemical journal 1976. link 3 Camacho M, Gerbolés E, Escudero JR, Antón R, García-Moll X, Vila L. Microsomal prostaglandin E synthase-1, which is not coupled to a particular cyclooxygenase isoenzyme, is essential for prostaglandin E(2) biosynthesis in vascular smooth muscle cells. Journal of thrombosis and haemostasis : JTH 2007. link 4 Liu W, Cao D, Oh SF, Serhan CN, Kulmacz RJ. Divergent cyclooxygenase responses to fatty acid structure and peroxide level in fish and mammalian prostaglandin H synthases. FASEB journal : official publication of the Federation of American Societies for Experimental Biology 2006. link 5 Kudo I, Murakami M. Prostaglandin E synthase, a terminal enzyme for prostaglandin E2 biosynthesis. Journal of biochemistry and molecular biology 2005. link 6 Smith WL, Song I. The enzymology of prostaglandin endoperoxide H synthases-1 and -2. Prostaglandins & other lipid mediators 2002. link00025-4) 7 Davidge ST. Prostaglandin H synthase and vascular function. Circulation research 2001. link 8 Sánchez T, Moreno JJ. Role of prostaglandin H synthase isoforms in murine ear edema induced by phorbol ester application on skin. Prostaglandins & other lipid mediators 1999. link00078-1) 9 Johnson JL, Maddipati KR. Paradoxical effects of resveratrol on the two prostaglandin H synthases. Prostaglandins & other lipid mediators 1998. link00052-5) 10 Rosenstock M, Danon A, Rimon G. Prostaglandin H synthase: protein synthesis-independent regulation in bovine aortic endothelial cells. The American journal of physiology 1997. link 11 Guth BD, Müller TH. DTTX30, a combined thromboxane receptor antagonist and thromboxane synthetase inhibitor, prevents coronary thrombosis in anesthetized dogs. Basic research in cardiology 1997. link 12 Swinney DC, Mak AY, Barnett J, Ramesha CS. Differential allosteric regulation of prostaglandin H synthase 1 and 2 by arachidonic acid. The Journal of biological chemistry 1997. link 13 Wong E, Bayly C, Waterman HL, Riendeau D, Mancini JA. Conversion of prostaglandin G/H synthase-1 into an enzyme sensitive to PGHS-2-selective inhibitors by a double His513 --> Arg and Ile523 --> val mutation. The Journal of biological chemistry 1997. link 14 Matsumoto H, Naraba H, Murakami M, Kudo I, Yamaki K, Ueno A et al.. Concordant induction of prostaglandin E2 synthase with cyclooxygenase-2 leads to preferred production of prostaglandin E2 over thromboxane and prostaglandin D2 in lipopolysaccharide-stimulated rat peritoneal macrophages. Biochemical and biophysical research communications 1997. link 15 Guo Q, Wang LH, Ruan KH, Kulmacz RJ. Role of Val509 in time-dependent inhibition of human prostaglandin H synthase-2 cyclooxygenase activity by isoform-selective agents. The Journal of biological chemistry 1996. link 16 Johnson JL, Wimsatt J, Buckel SD, Dyer RD, Maddipati KR. Purification and characterization of prostaglandin H synthase-2 from sheep placental cotyledons. Archives of biochemistry and biophysics 1995. link 17 Smith CJ, Morrow JD, Roberts LJ, Marnett LJ. Differentiation of monocytoid THP-1 cells with phorbol ester induces expression of prostaglandin endoperoxide synthase-1 (COX-1). Biochemical and biophysical research communications 1993. link 18 Varfolomeyev SD, Mevkh AT. Prostaglandin H synthase as a limiting enzyme of prostaglandin synthesis: substrate-induced inactivation as a new kind of enzyme activity regulation. Biotechnology and applied biochemistry 1993. link 19 Kiuchi F, Iwakami S, Shibuya M, Hanaoka F, Sankawa U. Inhibition of prostaglandin and leukotriene biosynthesis by gingerols and diarylheptanoids. Chemical & pharmaceutical bulletin 1992. link 20 Zhang X, Tsai AL, Kulmacz RJ. Chemical modification of prostaglandin H synthase with diethyl pyrocarbonate. Biochemistry 1992. link 21 Vanlersberghe C, Lauwers MH, Camu F. Prostaglandin synthetase inhibitor treatment and the regulatory role of prostaglandins on organ perfusion. Acta anaesthesiologica Belgica 1992. link 22 Ishihara O, Kinoshita K, Satoh K, Mizuno M, Shimizu T. An inhibitor of prostaglandin biosynthesis from human decidua: partial purification and properties. Prostaglandins, leukotrienes, and essential fatty acids 1990. link90102-q) 23 Thompson D, Eling T. Mechanism of inhibition of prostaglandin H synthase by eugenol and other phenolic peroxidase substrates. Molecular pharmacology 1989. link 24 Hecker M, Ullrich V, Fischer C, Meese CO. Identification of novel arachidonic acid metabolites formed by prostaglandin H synthase. European journal of biochemistry 1987. link 25 Olson RW, Cohen DS, Ku EC, Kimble EF, Renfroe HB, Smith EF. CGS 15435A, a thromboxane synthetase inhibitor with an extended duration of action: a comparison with dazoxiben. European journal of pharmacology 1987. link90022-7) 26 Cross PE, Dickinson RP, Parry MJ, Randall MJ. Selective thromboxane synthetase inhibitors. 2. 3-(1H-imidazol-1-ylmethyl)-2-methyl-1H-indole-1-propanoic acid and analogues. Journal of medicinal chemistry 1986. link 27 Fretland DJ, Cammarata PS. Comparative diuretic, saluretic, kaliuretic, and prostaglandin synthetase inhibitory activities of a competitive inhibitor of prostaglandin synthetase and spironolactone. Prostaglandins, leukotrienes, and medicine 1985. link90092-7) 28 Cross PE, Dickinson RP, Parry MJ, Randall MJ. Selective thromboxane synthetase inhibitors. 1. 1-[(Aryloxy)alkyl]-1H-imidazoles. Journal of medicinal chemistry 1985. link 29 Fretland DJ, Flanders LE, Borowski PT, Palicharla P, Cammarata PS, Hershenson FM et al.. The long duration, in vivo, inhibition of prostaglandin synthetase by 2-methyl-8-cis-12-trans-14-cis-eicosatrienoic acid. Biochemical pharmacology 1985. link90402-2) 30 Osama H, Narumiya S, Hayaishi O, Iinuma H, Takeuchi T, Umezawa H. Inhibition of brain prostaglandin D synthetase and prostaglandin D2 dehydrogenase by some saturated and unsaturated fatty acids. Biochimica et biophysica acta 1983. link 31 Badenhorst PN, Deckmyn H, Vermylen J. The effect of sulphinpyrazone on whole blood thromboxane and prostacyclin generation in man. Thrombosis research 1982. link90033-0) 32 Brennecke SP, Bryce RL, Turnbull AC, Mitchell MD. The prostaglandin synthase inhibiting ability of maternal plasma and the onset of human labor. European journal of obstetrics, gynecology, and reproductive biology 1982. link90042-9) 33 George FR, Jackson SJ, Collins AC. Prostaglandin synthetase inhibitors antagonize hypothermia induced by sedative hypnotics. Psychopharmacology 1981. link 34 Förster W, Beitz J, Hoffmann P. Stimulation and inhibition of PGI2 synthetase activity by phospholipids (PL), cholesterol esters (CE), unesterified fatty acids (UFA) and lipoproteins (LDL and HDL). Artery 1980. link 35 Shibata Y. Effect of 4'-chloro-5-methoxy-3-biphenylylacetic acid (DKA-9) on prostaglandin synthetase. Arzneimittel-Forschung 1980. link 36 Cebo B, Krupińska J, Mazur J. Pharmacologic properties of some derivatives of N-(2-carboxyphenyl)-4-phenoxyacetamide. Archivum immunologiae et therapiae experimentalis 1979. link 37 Fiebrich F, Koch H. Silymarin, an inhibitor of prostaglandin synthetase. Experientia 1979. link 38 Pong SS, Levine L. Prostaglandin synthetase systems of rabbit tissues and their inhibition by nonsteroidal anti-inflammatory drugs. The Journal of pharmacology and experimental therapeutics 1976. link 39 Duvivier J, Wolf D, Heusghem C. Enzymatic properties of prostaglandin synthetase from bovine seminal vesicles. Biochimie 1975. link80131-3)

    Original source

    1. [1]
      Regulation of cyclic AMP formation in brain tissue by alpha-adrenergic receptors: requisite intermediacy of prostaglandins of the E series. — Partington CR, Edwards MW, Daly JW Proceedings of the National Academy of Sciences of the United States of America (1980)
    2. [2]
      Biosynthesis of prostaglandins in rabbit kidney medulla. Properties of prostaglandin synthase. — Tai HH, Tai CL, Hollander CS The Biochemical journal (1976)
    3. [3]
      Microsomal prostaglandin E synthase-1, which is not coupled to a particular cyclooxygenase isoenzyme, is essential for prostaglandin E(2) biosynthesis in vascular smooth muscle cells. — Camacho M, Gerbolés E, Escudero JR, Antón R, García-Moll X, Vila L Journal of thrombosis and haemostasis : JTH (2007)
    4. [4]
      Divergent cyclooxygenase responses to fatty acid structure and peroxide level in fish and mammalian prostaglandin H synthases. — Liu W, Cao D, Oh SF, Serhan CN, Kulmacz RJ FASEB journal : official publication of the Federation of American Societies for Experimental Biology (2006)
    5. [5]
      Prostaglandin E synthase, a terminal enzyme for prostaglandin E2 biosynthesis. — Kudo I, Murakami M Journal of biochemistry and molecular biology (2005)
    6. [6]
      The enzymology of prostaglandin endoperoxide H synthases-1 and -2. — Smith WL, Song I Prostaglandins & other lipid mediators (2002)
    7. [7]
      Prostaglandin H synthase and vascular function. — Davidge ST Circulation research (2001)
    8. [8]
      Role of prostaglandin H synthase isoforms in murine ear edema induced by phorbol ester application on skin. — Sánchez T, Moreno JJ Prostaglandins & other lipid mediators (1999)
    9. [9]
      Paradoxical effects of resveratrol on the two prostaglandin H synthases. — Johnson JL, Maddipati KR Prostaglandins & other lipid mediators (1998)
    10. [10]
      Prostaglandin H synthase: protein synthesis-independent regulation in bovine aortic endothelial cells. — Rosenstock M, Danon A, Rimon G The American journal of physiology (1997)
    11. [11]
      DTTX30, a combined thromboxane receptor antagonist and thromboxane synthetase inhibitor, prevents coronary thrombosis in anesthetized dogs. — Guth BD, Müller TH Basic research in cardiology (1997)
    12. [12]
      Differential allosteric regulation of prostaglandin H synthase 1 and 2 by arachidonic acid. — Swinney DC, Mak AY, Barnett J, Ramesha CS The Journal of biological chemistry (1997)
    13. [13]
      Conversion of prostaglandin G/H synthase-1 into an enzyme sensitive to PGHS-2-selective inhibitors by a double His513 --> Arg and Ile523 --> val mutation. — Wong E, Bayly C, Waterman HL, Riendeau D, Mancini JA The Journal of biological chemistry (1997)
    14. [14]
      Concordant induction of prostaglandin E2 synthase with cyclooxygenase-2 leads to preferred production of prostaglandin E2 over thromboxane and prostaglandin D2 in lipopolysaccharide-stimulated rat peritoneal macrophages. — Matsumoto H, Naraba H, Murakami M, Kudo I, Yamaki K, Ueno A et al. Biochemical and biophysical research communications (1997)
    15. [15]
      Role of Val509 in time-dependent inhibition of human prostaglandin H synthase-2 cyclooxygenase activity by isoform-selective agents. — Guo Q, Wang LH, Ruan KH, Kulmacz RJ The Journal of biological chemistry (1996)
    16. [16]
      Purification and characterization of prostaglandin H synthase-2 from sheep placental cotyledons. — Johnson JL, Wimsatt J, Buckel SD, Dyer RD, Maddipati KR Archives of biochemistry and biophysics (1995)
    17. [17]
      Differentiation of monocytoid THP-1 cells with phorbol ester induces expression of prostaglandin endoperoxide synthase-1 (COX-1). — Smith CJ, Morrow JD, Roberts LJ, Marnett LJ Biochemical and biophysical research communications (1993)
    18. [18]
      Prostaglandin H synthase as a limiting enzyme of prostaglandin synthesis: substrate-induced inactivation as a new kind of enzyme activity regulation. — Varfolomeyev SD, Mevkh AT Biotechnology and applied biochemistry (1993)
    19. [19]
      Inhibition of prostaglandin and leukotriene biosynthesis by gingerols and diarylheptanoids. — Kiuchi F, Iwakami S, Shibuya M, Hanaoka F, Sankawa U Chemical & pharmaceutical bulletin (1992)
    20. [20]
      Chemical modification of prostaglandin H synthase with diethyl pyrocarbonate. — Zhang X, Tsai AL, Kulmacz RJ Biochemistry (1992)
    21. [21]
      Prostaglandin synthetase inhibitor treatment and the regulatory role of prostaglandins on organ perfusion. — Vanlersberghe C, Lauwers MH, Camu F Acta anaesthesiologica Belgica (1992)
    22. [22]
      An inhibitor of prostaglandin biosynthesis from human decidua: partial purification and properties. — Ishihara O, Kinoshita K, Satoh K, Mizuno M, Shimizu T Prostaglandins, leukotrienes, and essential fatty acids (1990)
    23. [23]
      Mechanism of inhibition of prostaglandin H synthase by eugenol and other phenolic peroxidase substrates. — Thompson D, Eling T Molecular pharmacology (1989)
    24. [24]
      Identification of novel arachidonic acid metabolites formed by prostaglandin H synthase. — Hecker M, Ullrich V, Fischer C, Meese CO European journal of biochemistry (1987)
    25. [25]
      CGS 15435A, a thromboxane synthetase inhibitor with an extended duration of action: a comparison with dazoxiben. — Olson RW, Cohen DS, Ku EC, Kimble EF, Renfroe HB, Smith EF European journal of pharmacology (1987)
    26. [26]
      Selective thromboxane synthetase inhibitors. 2. 3-(1H-imidazol-1-ylmethyl)-2-methyl-1H-indole-1-propanoic acid and analogues. — Cross PE, Dickinson RP, Parry MJ, Randall MJ Journal of medicinal chemistry (1986)
    27. [27]
      Comparative diuretic, saluretic, kaliuretic, and prostaglandin synthetase inhibitory activities of a competitive inhibitor of prostaglandin synthetase and spironolactone. — Fretland DJ, Cammarata PS Prostaglandins, leukotrienes, and medicine (1985)
    28. [28]
      Selective thromboxane synthetase inhibitors. 1. 1-[(Aryloxy)alkyl]-1H-imidazoles. — Cross PE, Dickinson RP, Parry MJ, Randall MJ Journal of medicinal chemistry (1985)
    29. [29]
      The long duration, in vivo, inhibition of prostaglandin synthetase by 2-methyl-8-cis-12-trans-14-cis-eicosatrienoic acid. — Fretland DJ, Flanders LE, Borowski PT, Palicharla P, Cammarata PS, Hershenson FM et al. Biochemical pharmacology (1985)
    30. [30]
      Inhibition of brain prostaglandin D synthetase and prostaglandin D2 dehydrogenase by some saturated and unsaturated fatty acids. — Osama H, Narumiya S, Hayaishi O, Iinuma H, Takeuchi T, Umezawa H Biochimica et biophysica acta (1983)
    31. [31]
      The effect of sulphinpyrazone on whole blood thromboxane and prostacyclin generation in man. — Badenhorst PN, Deckmyn H, Vermylen J Thrombosis research (1982)
    32. [32]
      The prostaglandin synthase inhibiting ability of maternal plasma and the onset of human labor. — Brennecke SP, Bryce RL, Turnbull AC, Mitchell MD European journal of obstetrics, gynecology, and reproductive biology (1982)
    33. [33]
      Prostaglandin synthetase inhibitors antagonize hypothermia induced by sedative hypnotics. — George FR, Jackson SJ, Collins AC Psychopharmacology (1981)
    34. [34]
      Stimulation and inhibition of PGI2 synthetase activity by phospholipids (PL), cholesterol esters (CE), unesterified fatty acids (UFA) and lipoproteins (LDL and HDL). — Förster W, Beitz J, Hoffmann P Artery (1980)
    35. [35]
      Effect of 4'-chloro-5-methoxy-3-biphenylylacetic acid (DKA-9) on prostaglandin synthetase. — Shibata Y Arzneimittel-Forschung (1980)
    36. [36]
      Pharmacologic properties of some derivatives of N-(2-carboxyphenyl)-4-phenoxyacetamide. — Cebo B, Krupińska J, Mazur J Archivum immunologiae et therapiae experimentalis (1979)
    37. [37]
      Silymarin, an inhibitor of prostaglandin synthetase. — Fiebrich F, Koch H Experientia (1979)
    38. [38]
      Prostaglandin synthetase systems of rabbit tissues and their inhibition by nonsteroidal anti-inflammatory drugs. — Pong SS, Levine L The Journal of pharmacology and experimental therapeutics (1976)
    39. [39]
      Enzymatic properties of prostaglandin synthetase from bovine seminal vesicles. — Duvivier J, Wolf D, Heusghem C Biochimie (1975)

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