Haematologica 2004;89: supplement no. 8 - Supplements ...

4Educational Sessionsclinical relevance, different studies indicate that thisphenomenon may account for recurrent vascularthrombotic events,, during long-term follow-up, butad hoc clinical studies are necessary to understandthe exact role that aspirin resistance has in theatherotrombotic compliances. In conclusion at themoment several questions, regarding aspirin resistance,are open; in the future study this phenomenomusing appropriate methods will clarify most ofthem, expecially mechanisms and clinical relevance,and the Italian “Gruppo di Studio delle Piastrine” ishighly involved in the matter.HEMORRHAGIC SYNDROMESTHE HEMOSTATIC BALANCE: REVISITED THROUGH NATURALLYOCCURRING MODELSMannucci PMCentro Emofilia e Trombosi Angelo Bianchi Bonomi,Dipartimento di Medicina Interna e Dermatologia,IRCCS Ospedale Maggiore e Università di Milano, ItalyIt has been postulated more than 50 years ago thathemostasis is ensured by a balance between prohemostaticand anti-hemostatic factors, and thatthe derangement of this balance may lead to bleedingor thrombosis. Recent evidence obtained throughthe study of natural clinical models has providedimportant contributions to validate the existence ofa balance between hemostatic and antihemostaticmechanisms. The presence of thrombophilic mutationsor phenotypes attenuates hemorrhagic phenotypes.For instance, women carrying factor V Leidenbleed less at parturition than non-carriers, carriers ofboth sexes have less blood losses than non-carriersduring cardiac surgery and have less frequentlyintracranial bleeding; patients with hemophilia andother congenital coagulation defects have a lesssevere hemorrhagic phenotype when they also carrythrombophilic mutations. On the other plate ofthe balance, there are data indicating that patientswith hemophilia and obligatory hemophilia carrierswith reduced levels of factor VIII suffer less frequentlyfrom myocardial infarction than the normalpopulation. This is due to their decreased tendencyto form coronary thrombi, whereas they have no lessatherosclerosis than controls. The same observation(lack of protection from atherosclerosis, protectionfrom thrombosis) was made in carriers of such prototypicdefects of platelet adhesion and aggregationas severe von Willebrand disease and Glanzmannthrombasthenia. On the whole, it seems that the tendencyto bleeding or thrombosis may be attenuatedand/or modified by the coexistence of inheritedthrombophilic abnormalities.PATIENT STUDIES PROVIDING NEW INSIGHTS IN PLATELETPHYSIOLOGYVan Geet C, Freson K, Vermylen JCenter for Molecular and Vascular Biology, Universityof Leuven, BelgiumIn this era of “evidence-based”medicine, pathophysiologyoften takes second seat to epidemiology.Yet the history of thrombosis and haemostasis hascontinuously demonstrated that the careful study ofunusual patients with congenital disorders can providemajor insights into important physiologicalprocesses. Examples are the discovery of the clottingfactors, the elucidation of the cause of thrombasthemia,the familial thrombophilias, etc. Suchpathophysiological studies are now markedly aidedby the increased knowledge of the human genome,allowing identification of the genetic basis of thedisturbance and reproduction of the anomaly in animalmodels. A recent example* is the study of tworelated patients with mental retardation, a bleedingtendency, reduced platelet aggregation and a mildthrombocytopenia. Partial trisomy 18 p in thesepatients led to the search for possibly involved genesin this area. The patients indeed had three copies ofthe pituitary adenylate cyclase-activating polypeptide(PACAP) gene, increased PACAP mRNA levels infibroblasts, and elevated PACAP concentrations inplasma. The PACAP receptor in platelets is coupled toadenylyl cyclase activation; accordingly, increasedbasal cAMP levels were found in patients' platelets,providing a basis for the reduced aggregation.Megakaryocyte-specific transgenic overexpressionof PACAP in mice increased PACAP release fromplatelets, reduced platelet activation, and prolongedthe tail bleeding time. In contrast, the PACAP antagonistPACAP (6-38) or a monoclonal PACAP antibodyenhanced the collagen-induced aggregation of normalhuman platelets, and in PACAP knockout mice,an increased sensitivity toward collagen was found.Injection of antibody to PACAP in normal miceinduced marked thrombocytosis, indicating thatPACAP has a dampening role on thrombocytopoiesis.These findings suggest a potential role for PACAPinhibitors in managing bleeding problems.*J Cancer Inst, 2004,113;905-912.haematologica vol. 89(suppl. n. 8):september 2004