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hans deckmyn

KU Leuven @ Kulak, Laboratory for Thrombosis Research, Faculty Member

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Papers by hans deckmyn

Preparation and characterization of large-format macroporous cryogel disks for use in affinity chromatography and biotechnological applications

Analytical and Bioanalytical Chemistry, Oct 3, 2018

We have prepared and evaluated larger format phage-bound epoxy-cryogel columns in order to increa... more We have prepared and evaluated larger format phage-bound epoxy-cryogel columns in order to increase the yield of bound target. Freezing thermograms showed that larger column formats (2,5 cm-5 cm diameter) are not usable due to irregular polymerization phenomena. Preparing thin discs of 0,5 cm height with similar diameter proved to be an excellent alternative. Discs could be stacked and run in a chromatographic set up. In this way we could increase the matrix volume, ligand binding capacity and finally the yield of bound target. By increasing the column volume about 7 fold, we observed a twelve fold increase of ligand density and a 7 fold increase in the yield of protein recovery in a column where phages were attached without spacer and a 10 to 34 fold increase in a spacer column, depending on the spacer used.

Inhibition of Thrombin-Activatable Fibrinolysis Inhibitor and Plasminogen Activator Inhibitor-1 Reduces Ischemic Brain Damage in Mice

Stroke, Sep 1, 2016

Background and Purpose-Cerebral ischemia and reperfusion is associated with activation of the coa... more Background and Purpose-Cerebral ischemia and reperfusion is associated with activation of the coagulation cascade and fibrin deposition in cerebral microvessels. Both thrombin-activatable fibrinolysis inhibitor (TAFI) and plasminogen activator inhibitor-1 (PAI-1) attenuate fibrinolysis and are therefore attractive targets for the treatment of ischemic stroke. Methods-TAFI and PAI-1 were inhibited by monoclonal antibodies in a mouse model of transient middle cerebral artery occlusion. Twenty-four hours after stroke, mice were neurologically scored, cerebral thrombotic burden was assessed, and brain infarct sizes were calculated. Results-Inhibition of TAFI or PAI-1 significantly decreased cerebral infarct sizes by 50% 24 hours after stroke. This reduction in cerebral damage was associated with a significant decrease in fibrin(ogen) deposition in the ischemic brain. Concurrently, functional recovery of the animals was improved. Interestingly, combined targeting of TAFI and PAI-1 using low, and by themselves inactive, doses of antibodies improved cerebral blood flow and reduced cerebral fibrin(ogen) deposition and infarct sizes by 50%. When dual treatment was delayed to 1 hour after the start of reperfusion, it still reduced brain injury; however, this was not statistically significant. Conclusions-Targeting of PAI-1 and TAFI is protective in an ischemic stroke model by attenuating fibrin(ogen) deposition, thereby improving reperfusion. Combined inhibition has a co-operative effect that could become useful in ischemic stroke therapy.

Child-onset thrombotic thrombocytopenic purpura caused by p.R498C and p.G259PfsX133 mutations in ADAMTS13

European Journal of Haematology, Jun 25, 2018

or visit the DOI to the publisher's website. • The final author version and the galley proof are ... more or visit the DOI to the publisher's website. • The final author version and the galley proof are versions of the publication after peer review. • The final published version features the final layout of the paper including the volume, issue and page numbers. Copyright and moral rights for the publications made accessible in the public portal are retained by the authors and/or other copyright owners and it is a condition of accessing publications that users recognise and abide by the legal requirements associated with these rights. • Users may download and print one copy of any publication from the public portal for the purpose of private study or research. • You may not further distribute the material or use it for any profit-making activity or commercial gain • You may freely distribute the URL identifying the publication in the public portal. If the publication is distributed under the terms of Article 25fa of the Dutch Copyright Act, indicated by the "Taverne" license above, please follow below link for the End User

Differences in von Willebrand factor function in type 2A von Willebrand disease and left ventricular assist device‐induced acquired von Willebrand syndrome

Research and practice in thrombosis and haemostasis, Oct 1, 2018

Background: Patients with von Willebrand disease (VWD) type 2A or acquired von Willebrand syndrom... more Background: Patients with von Willebrand disease (VWD) type 2A or acquired von Willebrand syndrome (aVWS) as a consequence of implantation of left ventricular assist devices (LVAD) are both characterized by a loss of von Willebrand factor (VWF) function. Loss of VWF function is however more severe in VWD type 2A than in LVAD patients. Objectives: To compare VWF function in patients with VWD type 2A and LVAD-induced aVWS to highlight the differences in VWF activity and to stress the importance of VWF multimer analysis for correct diagnosis of aVWS in LVAD patients. Patients/Methods: Plasma samples from nine VWD type 2A, nine LVAD patients, and 20 healthy donors (HD) were analyzed for VWF function (VWF:CB/VWF:Ag and VWF:RCo/VWF:Ag) and loss of high molecular weight (HMW) VWF multimers. Results: A severely impaired VWF function was indeed confirmed in all VWD 2A patients. HMW VWF multimers were severely reduced compared to HD (0% [0, 12.29] vs 34.19% [31.68, 38.88] for HD, P < 0.001) and this loss was reflected by VWF:CB/VWF:Ag and VWF:RCo/VWF:Ag ratios <0.7. In contrast, VWF function was less affected in LVAD patients. Although HMW VWF multimers were reduced in all

Deletion of GARP on mouse regulatory T cells is not sufficient to inhibit the growth of transplanted tumors

Cellular Immunology, Oct 1, 2018

GARP is a transmembrane protein that presents latent TGF-β1 on the surface of regulatory T cells ... more GARP is a transmembrane protein that presents latent TGF-β1 on the surface of regulatory T cells (Tregs). Neutralizing anti-GARP monoclonal antibodies that prevent the release of active TGF-β1 inhibit the immunosuppressive activity of human Tregs in vivo. In this study, we investigated the contribution of GARP on mouse Tregs to immunosuppression in experimental tumors. Unexpectedly, conditional knockout (KO) mice challenged orthotopically with GL261 tumor cells or subcutaneously with MC38 colon carcinoma cells did not show prolonged survival or delayed tumor growth. Also, the suppressive function of KO Tregs was similar to that of WT Tregs in the T cell transfer model in allogeneic, immunodeficient mice. In conclusion, garp deletion in mouse Tregs is not sufficient to impair their immunosuppressive activity in vivo.

Sickle cell disease and COVID‐19: Atypical presentations and favorable outcomes

eJHaem, 2020

COVID-19 pandemic has already claimed several lives. Individuals with underlying health condition... more COVID-19 pandemic has already claimed several lives. Individuals with underlying health conditions including sickle cell disease (SCD) are considered to be at higher risk of complications from the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). Here, we report our experience with three patients with severe SS SCD, all originating from Congo that contracted COVID-19 infection (Table ). All three devel-Obesity No No No Hydroxyurea Yes low Compliance Yes Yes Aspirin Yes No No Regular exchange therapy Yes No No Deferasirox No No Yes COVID -19 diagnosis PCR PCR PCR Lung lesion at entry Unilateral ground glass Mild typical COVID lesion Pneumomediastin ; no lung lesion Length of PCR positivity > 30 days Respiratory symptoms Cough Cough None Others symptoms Abdominal pain, weight loss Leg ulcer Dehydration after vomiting Deep venous thrombosis No No localized DVT catheter site 11 days after ET Renal insufficiency No Yes but already basal Acute and reversible Intensive care No No No Exchange therapy Regular, one during COVID 2 during COVID 1 ( suspected DHTR) Hydroxychloroquin No 400 mg x 2/d then 200 mg x2/d 5 d

The ISTH bleeding assessment tool as predictor of bleeding events in inherited platelet disorders: Communication from the ISTH SSC Subcommittee on Platelet Physiology

Journal of Thrombosis and Haemostasis, 2021

Background: The ISTH Bleeding Assessment Tool (ISTH-BAT) has been validated for clinical screenin... more Background: The ISTH Bleeding Assessment Tool (ISTH-BAT) has been validated for clinical screening of suspected von Willebrand disease (VWD) and for bleeding prediction. Recently it has been validated for subjects with inherited platelet disorders (IPD) (BAT-VAL study). Objectives: To determine whether the ISTH-BAT bleeding score (BS) predicts subsequent bleeding events requiring treatment in IPD patients.

Selective inhibition of TGF-β1 produced by GARP-expressing Tregs overcomes resistance to PD-1/PD-L1 blockade in cancer

Nature Communications, 2020

TGF-β1, β2 and β3 bind a common receptor to exert vastly diverse effects in cancer, supporting ei... more TGF-β1, β2 and β3 bind a common receptor to exert vastly diverse effects in cancer, supporting either tumor progression by favoring metastases and inhibiting anti-tumor immunity, or tumor suppression by inhibiting malignant cell proliferation. Global TGF-β inhibition thus bears the risk of undesired tumor-promoting effects. We show that selective blockade of TGF-β1 production by Tregs with antibodies against GARP:TGF-β1 complexes induces regressions of mouse tumors otherwise resistant to anti-PD-1 immunotherapy. Effects of combined GARP:TGF-β1/PD-1 blockade are immune-mediated, do not require FcγR-dependent functions and increase effector functions of anti-tumor CD8+T cells without augmenting immune cell infiltration or depleting Tregs within tumors. We find GARP-expressing Tregs and evidence that they produce TGF-β1 in one third of human melanoma metastases. Our results suggest that anti-GARP:TGF-β1 mAbs, by selectively blocking a single TGF-β isoform emanating from a restricted ce...

Open ADAMTS13, induced by antibodies, is a biomarker for subclinical immune-mediated thrombotic thrombocytopenic purpura

Blood, 2020

Recently, we showed that during the acute phase of immune-mediated thrombotic thrombocytopenic pu... more Recently, we showed that during the acute phase of immune-mediated thrombotic thrombocytopenic purpura (iTTP), ADAMTS13 circulates in an open conformation. Although the cause of this conformational change in acute iTTP remains elusive, ADAMTS13 is mainly closed in iTTP patients (i) in remission with an ADAMTS13 activity >50% and undetectable anti-ADAMTS13 autoantibodies, and (ii) after rituximab treatment, suggesting a role for anti-ADAMTS13 autoantibodies. Therefore, IgGs from 18 acute iTTP patients were purified and added to closed ADAMTS13 in healthy donor plasma. This resulted in open ADAMTS13 in 14/18 (78%) samples, proving that indeed anti-ADAMTS13 autoantibodies can induce an open ADAMTS13 conformation. To further elucidate the conformation of ADAMTS13 in iTTP patients, we studied a novel iTTP patient cohort (n=197) that also included plasma samples of iTTP patients in remission where ADAMTS13 activity was <50%. The open ADAMTS13 conformation was not only found during a...

Dual Effect of Fluoride on Endothelial Prostacyclin Production

XIth International Congress on Thrombosis and Haemostasis, 1987

The effects of fluoride at mM concentrations on prostacyclin (PGI2) production by human umbilical... more The effects of fluoride at mM concentrations on prostacyclin (PGI2) production by human umbilical vein endothelial cells in culture were investigated. At lower concentrations, with a peak activity around 20-30 mM, sodium fluoride (NaF) caused a slow rise in PGI2 release reaching a maximum of 6 to 8 × control values after 1 hour. With increasing concentrations, the NaF-induced PGI2 production progressively decreased to almost control levels at 100 mM. Preincubation of the cells with 100 mM NaF inhibited thrombin— and A23187-stimulated PGI2 production by 46 % and 64 % respectively. The response to NaF was not significantly enhanced by AlCl3 nor was it inhibited by pertussis toxin.The dual, stimulatory and inhibitory, effect of NaF on endothelial PGI2 production as well as its slow mode of action resemble the stimulus-response pattern observed in platelets upon exposure to NaF as it has previously been described by our grcup. Therefore, NaF might be an interesting tool for the investig...

Anti-ADAMTS13 Autoantibodies against Cryptic Epitopes in Immune-Mediated Thrombotic Thrombocytopenic Purpura

Thrombosis and Haemostasis, 2018

Immune-mediated thrombotic thrombocytopenic purpura (iTTP) is characterized by severe ADAMTS13 (a... more Immune-mediated thrombotic thrombocytopenic purpura (iTTP) is characterized by severe ADAMTS13 (a disintegrin and metalloprotease with thrombospondin type 1 repeats, member 13) deficiency, the presence of anti-ADAMTS13 autoantibodies and an open ADAMTS13 conformation with a cryptic epitope in the spacer domain exposed. A detailed knowledge of anti-ADAMTS13 autoantibodies will help identifying pathogenic antibodies and elucidating the cause of ADAMTS13 deficiency. We aimed at cloning anti-ADAMTS13 autoantibodies from iTTP patients to study their epitopes and inhibitory characteristics. We sorted anti-ADAMTS13 autoantibody expressing B cells from peripheral blood mononuclear cells of 13 iTTP patients to isolate anti-ADAMTS13 autoantibody sequences. Ninety-six B cell clones producing anti-ADAMTS13 autoantibodies were identified from which 30 immunoglobulin M (IgM) and 5 IgG sequences were obtained. For this study, we only cloned, expressed and purified the five IgG antibodies. In vitro...

Anti-ADAMTS13 Antibodies and a Novel Heterozygous p.R1177Q Mutation in a Case of Pregnancy-Onset Immune-Mediated Thrombotic Thrombocytopenic Purpura

TH Open, 2018

In this study, we investigated a case of pregnancy-onset thrombotic thrombocytopenic purpura (TTP... more In this study, we investigated a case of pregnancy-onset thrombotic thrombocytopenic purpura (TTP). The patient had severely decreased ADAMTS13 (a disintegrin and metalloprotease with thrombospondin type 1 motif, member 13) activity levels during acute phase and the presence of inhibitory anti-ADAMTS13 autoantibodies was demonstrated, which led to the diagnosis of immune-mediated TTP. However, ADAMTS13 activity was only mildly restored during remission, although inhibitory anti-ADAMTS13 antibodies were no longer detected. We hypothesized that genetic abnormalities could account for this discrepancy between ADAMTS13 activity and antigen. Genetic analysis revealed the presence of two heterozygous substitutions on the same allele: a single nucleotide polymorphism (SNP) c.2699C > T (p.A900V), located in the beginning of the T5 domain, and a mutation c.3530G > A (p.R1177Q) located in the third linker region of ADAMTS13. In vitro testing of those substitutions by expression of recom...

An open conformation of ADAMTS‐13 is a hallmark of acute acquired thrombotic thrombocytopenic purpura

Journal of Thrombosis and Haemostasis, 2018

• Conformational changes in ADAMTS-13 are part of its mode-of-action. • The murine anti-ADAMTS-13... more • Conformational changes in ADAMTS-13 are part of its mode-of-action. • The murine anti-ADAMTS-13 antibody 1C4 discriminates between folded and open ADAMTS-13. • ADAMTS-13 conformation is open in acute acquired thrombotic thrombocytopenic purpura (TTP). • Our study forms an important basis to fully elucidate the pathophysiology of TTP. Summary. Background: Acquired thrombotic thrombocytopenic purpura (aTTP) is an autoimmune disorder characterized by absent ADAMTS-13 activity and the presence of anti-ADAMTS-13 autoantibodies. Recently, it was shown that ADAMTS-13 adopts a folded or an open conformation. Objectives: As conformational changes in self-antigens play a role in the pathophysiology of different autoimmune diseases, we hypothesized that the conformation of ADAMTS-13 changes during acute aTTP. Methods: Antibodies recognizing cryptic epitopes in the spacer domain were generated. Next, the conformation of ADAMTS-13 in 40 healthy donors (HDs), 99 aTTP patients (63 in the acute phase versus 36 in remission), 12 hemolytic-uremic syndrome (HUS) patients and 63 sepsis patients was determined with ELISA. Results: The antibody 1C4 recognizes a cryptic epitope in ADAMTS-13. Therefore, we were able to discriminate between a folded and an open ADAMTS-13 conformation. We showed that ADAMTS-13 in HDs does not bind to 1C4, indicating that ADAMTS-13 circulates in a folded conformation. Similar results were obtained for HUS and sepsis patients. In contrast, ADAMTS-13 of acute aTTP patients bound to 1C4 in 92% of the cases, whereas, in most cases, this binding was abolished during remission, showing that the conformation of ADAMTS-13 is open during an acute aTTP episode. Conclusions: Our study shows that, besides absent ADAMTS-13 activity and the presence of anti-ADAMTS-13 autoantibodies, an open ADAMTS-13 conformation is also a hallmark of acute aTTP. Demonstrating this altered ADAMTS-13 conformation in acute aTTP will help to further unravel the pathophysiology of aTTP and lead to improved therapy and diagnosis.

Deletion of GARP on mouse regulatory T cells is not sufficient to inhibit the growth of transplanted tumors

Cellular immunology, 2018

GARP is a transmembrane protein that presents latent TGF-β1 on the surface of regulatory T cells ... more GARP is a transmembrane protein that presents latent TGF-β1 on the surface of regulatory T cells (Tregs). Neutralizing anti-GARP monoclonal antibodies that prevent the release of active TGF-β1, inhibit the immunosuppressive activity of human Tregs in vivo. In this study, we investigated the contribution of GARP on mouse Tregs to immunosuppression in experimental tumors. Unexpectedly, Foxp3 conditional garp knockout (KO) mice challenged orthotopically with GL261 tumor cells or subcutaneously with MC38 colon carcinoma cells did not show prolonged survival or delayed tumor growth. Also, the suppressive function of KO Tregs was similar to that of wild type Tregs in the T cell transfer model in allogeneic, immunodeficient mice. In conclusion, garp deletion in mouse Tregs is not sufficient to impair their immunosuppressive activity in vivo.

Long-Term Prevention of Congenital Thrombotic Thrombocytopenic Purpura in ADAMTS13 Knockout Mice by Sleeping Beauty Transposon-Mediated Gene Therapy

Arteriosclerosis, thrombosis, and vascular biology, 2017

Severe deficiency in the von Willebrand factor-cleaving protease ADAMTS13 (a disintegrin and meta... more Severe deficiency in the von Willebrand factor-cleaving protease ADAMTS13 (a disintegrin and metalloproteinase with thrombospondin type 1 motif, member 13) because of mutations in the ADAMTS13 gene can lead to acute episodes of congenital thrombotic thrombocytopenic purpura (TTP), requiring prompt treatment. Current treatment consists of therapeutic or prophylactic infusions of fresh frozen plasma. However, lifelong treatment with plasma products is a stressful therapy for TTP patients. Here, we describe the use of the nonviral sleeping beauty (SB) transposon system as a gene therapeutic approach to realize lifelong expression of ADAMTS13 and subsequent protection against congenital TTP. We demonstrated that hydrodynamic tail vein injection of the SB100X system expressing murine ADAMTS13 in Adamts13(-/-) mice resulted in long-term expression of supraphysiological levels of transgene ADAMTS13 over a period of 25 weeks. Stably expressed ADAMTS13 efficiently removed the prothrombotic u...

The A/T1381 polymorphism in the A1-domain of von Willebrand factor influences the affinity of von Willebrand factor for platelet glycoprotein Ibα

Thrombosis and Haemostasis, 2007

SummaryMany polymorphisms in vonWillebrand factor (VWF) have been reported and their association ... more SummaryMany polymorphisms in vonWillebrand factor (VWF) have been reported and their association with VWF plasma levels or cardiovascular diseases has been investigated. The aim of this study was to examine whether the amino acid polymorphis mA/T1381 in the VWF A1-domain would affect VWF binding to platelet GPIbα. Sixty-one normal individuals were genotyped at the A/T1381 locus. Twenty-one A/A1381 homozygotes, 30 A/T1381 heterozygotes and 10 T/T1381 homozygotes were identified. Remarkably, when compared to VWF of A/T1381 and A/A1381 individuals, VWF of individuals carrying the T/T1381 variant showed an increased affinity for its platelet receptor GPIbα under static conditions, as reflected by an increased sensitivity to low concentrations of ristocetin or botrocetin. In addition, also the rVWF-T1381 demonstrated a higher affinity for GPIbα than rVWF-A1381. Interestingly, this enhanced affinity of the T/T variant over the A/T and A/A variant was, however, too subtle to affect platele...

Platelet adhesion to collagen

Thrombosis Research, 2011

Platelets play a central role in maintaining hemostasis mainly by binding to subendothelial colla... more Platelets play a central role in maintaining hemostasis mainly by binding to subendothelial collagen exposed upon vascular injury, thereby initiating thrombus formation. Platelets can bind directly to the exposed collagen through two major receptors i.e. the integrin a2b1 and glycoprotein (GP) VI. However, under high shear conditions the GPIb-V-IX receptor complex and its main ligand von Willebrand Factor are additionally needed for firm platelet adhesion to the vessel wall. In this review, we summarize the current knowledge on the individual roles and structure-function relationships of these main platelet adhesion receptors.

Characterization of Murine Anti-Glycoprotein Ib Monoclonal Antibodies That Differentiate between Shear-Induced and Ristocetin/Botrocetin-Induced Glycoprotein Ib-von Willebrand Factor Interaction

Pathophysiology of Haemostasis and Thrombosis, 2000

Platelet adhesion to vascular subendothelium under conditions of high shear stress is mediated by... more Platelet adhesion to vascular subendothelium under conditions of high shear stress is mediated by the platelet glycoprotein (GP) Ib-von Willebrand Factor (vWF) interaction. The aim of this study was to characterize the murine monoclonal antibodies (MoAbs) 27A10 and 28E6, both raised against purified GPIb. The MoAb 27A10 is a potent inhibitor of shear-induced platelet adhesion to collagen type I in a flow chamber at shear rates of 1,300 and 2,700 s–1. 20 μg/ml of MoAb 27A10, furthermore, could completely block shear-induced aggregation in a modified Couette viscometer at shear rates of 1,000 and 4,000 s–1. On the other hand, MoAb 27A10 had a negligible effect on botrocetin-induced GPIb-vWF binding and is only a poor inhibitor of the ristocetin-dependent interaction. In contrast, MoAb 28E6 did abolish both the ristocetin- and botrocetin-induced GPIb-vWF binding, whereas it did not block the shear-induced interaction. Thus, we identify here two anti-GPIb MoAbs 27A10 and 28E6 that eithe...

The Novel S527F Mutation in the Integrin β3 Chain Induces a High Affinity αIIbβ3 Receptor by Hindering Adoption of the Bent Conformation

Journal of Biological Chemistry, 2009

Three heterozygous mutations were identified in the genes encoding platelet integrin receptor ␣II... more Three heterozygous mutations were identified in the genes encoding platelet integrin receptor ␣IIb␤3 in a patient with an ill defined platelet disorder: one in the ␤3 gene (S527F) and two in the ␣IIb gene (R512W and L841M). Five stable Chinese hamster ovary cell lines were constructed expressing recombinant ␣IIb␤3 receptors bearing the individual R512W, L841M, or S527F mutation; both the R512W and L841M mutations; or all three mutations. All receptors were expressed on the cell surface, and mutations R512W and L841M had no effect on integrin function. Interestingly, the ␤3 S527F mutation produced a constitutively active receptor. Indeed, both fibrinogen and the ligand-mimetic antibody PAC-1 bound to non-activated ␣IIb␤3 receptors carrying the S527F mutation, indicating that the conformation of this receptor was altered and corresponded to the high affinity ligand binding state. In addition, the conformational change induced by S527F was evident from basal antiligand-induced binding site antibody binding to the receptor. A molecular model bearing this mutation was constructed based on the crystal structure of ␣IIb␤3 and revealed that the S527F mutation, situated in the third integrin epidermal growth factor-like (I-EGF3) domain, hindered the ␣IIb␤3 receptor from adopting a wild type-like bent conformation. Movement of I-EGF3 into a cleft in the bent conformation may be hampered both by steric hindrance between Phe 527 in ␤3 and the calf-1 domain in ␣IIb and by decreased flexibility between I-EGF2 and I-EGF3.

Effects of thromboxane A2 on lymphocyte proliferation

Cellular Immunology, 1985

The main cyclooxygenasedependent arachidonic acid derivatives produced by monocytes and macrophag... more The main cyclooxygenasedependent arachidonic acid derivatives produced by monocytes and macrophages have been shown to be thromboxane A2 and prostaglandin E2. The immunomodulatory effects of thromboxane A2 were examined using a specific thromboxane synthase inhibitor (dazoxiben), a thromboxane A2 analog (U46619), and a thromboxane A2 receptor blocker (BM13.177). Dazoxiben inhibited lymphocyte proliferation in response to mitogens (PHA and OKT3), but also reoriented cyclic endoperoxide metabolism towards the production of prostaglandin E2. Prostaglandin E2 has been shown previously to inhibit mitogeninduced lymphocyte proliferation. U466 19, a stable thromboxane A2 analog, slightly enhanced lymphocyte responses to mitogens in the presence of dazoxiben and in the presence of a cyclooxygenase inhibitor (indomethacin). This occurred at concentrations of U46619 which are probably supraphysiological in view of the short half-life of natural thromboxane AZ. Finally, the thromboxane A2 receptor blocker BM13.177 did not have any effect on mitogeninduced lymphocyte proliferation. It is concluded that thromboxane A2 has no or minimal modulatory effects on lymphocyte proliferative responses to mitogens and that the effect of thromboxane A2 synthase inhibition is rather due to reorientation of cyclic endoperoxide metabolism, resulting in increased prostaglandin E2 production. 8 1985 Academic PIW, IN.