Severe Bleeding Associated With Defective Thromboxane Synthetase

Mestel, F.; Oetliker, O; Beck, Eugene A.; Felix, R.; Imbach, Paul; Wägner, Hans

doi:10.1016/s0140-6736(80)90642-x

Cited by 42 publications

(15 citation statements)

References 7 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…The TXAS Ϫ/Ϫ mice mimic human TXAS deficiency in many aspects, such as prolonged bleeding time, defective AA-induced platelet aggregation, and altered AA metabolism, 39,40 with absent TXA 2 but more prominent PGE 2 , PGD 2 , and PGF 2␣ productions. 35 Our TXAS KO mice, like humans with TXAS deficiency, have a mild hemostatic defect without overt spontaneous bleeding.…”

Section: Discussionmentioning

confidence: 99%

“…on May 11, 2018. by guest www.bloodjournal.org From severe bleeding episodes and others had mild bleeding problems. 35,39,40 Whether this is due to different mutations in the TXAS gene resulting in variable degree of loss of TXAS activity is not conclusive because genetic defects of these patients were not fully characterized. Furthermore, evaluation of platelet abnormalities tended to rely on functional analysis without direct biochemical measurements.…”

mentioning

confidence: 99%

See 1 more Smart Citation

TXAS-deleted mice exhibit normal thrombopoiesis, defective hemostasis, and resistance to arachidonate-induced death

Lin²,

Huang³

et al. 2004

Blood

View full text Add to dashboard Cite

Besides its well-recognized role in hemostasis and thrombosis, thromboxane A 2 synthase (TXAS) is proposed to be involved in thrombopoiesis and lymphocyte differentiation. To evaluate its various physiologic roles, we generated TXAS-deleted mice by gene targeting. TXAS ؊/؊ mice had normal bone marrow megakaryocytes, normal blood platelet counts, and normal CD4 and CD8 lymphocyte counts in thymus and spleen. Platelets from TXAS ؊/؊ mice failed to aggregate or generate thromboxane B 2 in response to arachidonic acid (AA) but produced increased prostaglandin-E 2 (PGE 2 ), PGD 2 , and PGF 2␣ . AA infusion caused a progressive drop of mean arterial pressure (MAP), cardiac arrest, and death in wild-type (WT) mice but did not induce shock in TXAS ؊/؊ mice or in WT and TXAS ؊/؊ mice treated with antagonist to the thromboxane-prostanoid (TP) receptor. The TXAS ؊/؊ mice were able to maintain normal MAP upon AA insult when TP was present but were unable to do so when TP was blocked by an antagonist, suggesting a role of endoperoxide accumulation in influencing MAP. We conclude that TXAS is not essential for thrombopoiesis and lymphocyte differentiation. Its deficiency causes a mild hemostatic defect and protects mice against arachidonate-induced shock and death. The TXAS-deleted mice will be valuable for investigating the roles of arachidonate metabolic shunt in various pathophysiologic processes. IntroductionThromboxane A 2 synthase (TXAS) is a 60-kDa transmembrane protein that is distributed in platelets, monocytes, and several other cell types. [1][2][3][4][5] It belongs to the large cytochrome p450 (CYP) family. 6 It is considered to be an atypical CYP as it does not possess mono-oxygenase activity. It is an isomerase catalyzing the conversion of prostaglandin H 2 (PGH 2 ) to thromboxane A 2 (TXA 2 ), HHT (l2-L-hydroxy-5, 8,10-heptadecatrienoic acid), and malondialdehyde (MDA). TXA 2 is a potent stimulator of platelet activation and aggregation and vascular constriction. 7 These actions of TXA 2 have been demonstrated to be mediated by binding to a G-proteincoupled-specific receptor, the thromboxane-prostanoid (TP) receptor. 8 The cellular and tissue distribution of TP receptors is closely correlated with that of TXAS. 9 Since TXA 2 has an extremely short half-life and acts as an autocoid, the concordant tissue distribution between TXAS and TP facilitates the rapid actions of TXA 2 . TXA 2 plays a major role in hemostasis, thrombosis, vasoconstriction, and vascular cell proliferation. Patients whose platelets are defective in producing TXA 2 have a bleeding disorder, whereas overproduction of TXA 2 is associated with diverse vascular events including acute coronary syndrome, ischemic stroke, pulmonary hypertension, abnormal renal hemodynamics, and preeclampsia. [10][11][12][13][14][15][16][17][18] The important role of TXA 2 in hemostasis and vascular disorders is further supported by the defects observed in TP-deleted mice generated by gene targeting. TP Ϫ/Ϫ mice have normal embryogenesis, postnatal growth, and ferti...

show abstract

Section: Discussionmentioning

confidence: 99%

mentioning

confidence: 99%

TXAS-deleted mice exhibit normal thrombopoiesis, defective hemostasis, and resistance to arachidonate-induced death

Lin²,

Huang³

et al. 2004

Blood

View full text Add to dashboard Cite

show abstract

“…impaired liberation of arachidonic acid, cyclooxygenase deficiency, TXA2 synthase deficiency) have been described who show platelet function abnormalities as has been observed in storage pool disease (see below) [63,64].…”

Section: Hereditary Defects In Phospholipase C-β2 Activation In Ca 2mentioning

confidence: 95%

Inherited and Acquired Disorders of Platelet Function

Jurk

Kehrel²

2007

Transfus Med Hemother

View full text Add to dashboard Cite

Platelet function defects are caused by rare congenital or, more frequently, by acquired disorders. They may lead to bleeding or thrombotic tendencies despite of normal platelet counts. The corresponding symptoms are often quite heterogeneous. A disorder of platelet function is suspected on the basis of case and family history, physical examination and platelet function tests. The so far primary screen of platelet dysfunctions, the bleeding time, is neither very sensitive nor specific and depends very much on the skills of the person that performs the test. Therefore, other general and in addition more specialised laboratory tests have to be performed for diagnosing an isolated platelet abnormality or in most cases combined platelet function defects. An approach to diagnosing a platelet disorder is presented, which supports the high significance of flow cytometry in platelet function analysis. Furthermore, we like to elucidate that in most cases a platelet-mediated haemostatic disorder cannot be characterised by just a single function defect, but rather by a combination of platelet functional abnormalities. Detailed knowledge of the platelet disorder is necessary for adequate therapeutical management of the individual patient, including the control of the underlying disease in acquired disorders, transfusion of platelets and administration of haemostatic drugs.

show abstract

“…Its actions are completely opposite to those of prostacyclin (PGI 2 ) [14]. Its role in vascular homeostasis has been postulated and supported by the finding that patients whose platelets were unresponsive to TXA 2 displayed hemostatic defects [87,156,197,198] and that a deficiency of platelet TXA 2 production [111,194] or mutations of the TXA 2 receptor gene led to bleeding disorders [72]. TXA 2 also stimulates mitogenesis and hypertrophy of vascular smooth muscle cells [2,64].…”

Section: Thromboxane Synthasementioning

confidence: 99%

“…The mutant receptor expressed in Chinese hamster ovary cells showed decreased agonistinduced second messenger formation despite its normal ligand binding affinity. Previous reports on defective platelet response to PGG 2 need to be reinvestigated to elucidate the molecular basis of possible receptor or TXA 2 S defect [111,194]. Furthermore, possible mutation of the TXA 2 R of patients having defective response to TXA 2 is also worth studying to provide the structural basis of receptor defect [87,156,197,198].…”

Section: Pathophysiologymentioning

confidence: 99%

Thromboxanes: Synthase and Receptors

Shen

Tai

1998

J Biomed Sci

View full text Add to dashboard Cite

Thromboxane A₂ is a biologically potent arachidonate metabolite through the cyclooxygenase pathway. It induces platelet aggregation and smooth muscle contraction and may promote mitogenesis and apoptosis of other cells. Its roles in physiological and pathological conditions have been widely documented. The enzyme that catalyzes its synthesis, thromboxane A₂ synthase, and the receptors that mediate its actions, thromboxane A₂ receptors, are the two key components critical for the functioning of this potent autacoid. Recent molecular biological studies have revealed the structure-function relationship and gene organizations of these proteins as well as genetic and epigenetic factors modulating their gene expression. Future investigation should shed light on detailed molecular signaling events specifying thromboxane A₂ actions, and the genetic underpinning of the enzyme and the receptors in health and disease.

show abstract

Severe Bleeding Associated With Defective Thromboxane Synthetase

Cited by 42 publications

References 7 publications

TXAS-deleted mice exhibit normal thrombopoiesis, defective hemostasis, and resistance to arachidonate-induced death

TXAS-deleted mice exhibit normal thrombopoiesis, defective hemostasis, and resistance to arachidonate-induced death

Inherited and Acquired Disorders of Platelet Function

Thromboxanes: Synthase and Receptors

Contact Info

Product

Resources

About