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Rivista di Angiologia

Official Journal of the International Union of Angiology, the International Union of Phlebology and the Central European Vascular Forum
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International Angiology 1999 June;18(2):163-70


lingua: Inglese

Mech­a­nisms under­ly­ing ­increased plate­let reac­tiv­ity in ­patients with periph­er­al arte­ri­al dis­ease. Pre­lim­i­nary ­results

Reininger C. B., Boeger C. A., Steckmeier B., Spannagl M., Scweiberer L.

From the Chi­rur­gis­che Kli­nik und Mediz­i­nis­che Kli­nik des Klin­ik­um Innes­tadt, LMU ­München, Ger­ma­ny


Back­ground. In periph­er­al arte­ri­al dis­ease (PAD) ath­ero­scler­o­sis is dis­sem­i­nat­ed and throm­bo­sis risk is high. We have not only shown the plate­lets of PAD ­patients to by hyper­reac­tive and aspi­rin resist­ant, but have recent­ly ver­i­fied them to be hyper­sen­si­tive to hep­ar­in as well. In the ­present study we have begun to clar­i­fy the mechan­isms under­ly­ing these reg­u­lar­ly ­observed clin­i­cal find­ings.
Meth­ods. Plate­let func­tion was test­ed with con­ven­tion­al, ADP-­primed aggre­ga­tion and with stag­na­tion point flow adhe­sio-aggre­gom­e­try (SPAA). SPAA per­mits real time, quan­ti­ta­tive assess­ment of plate­let adhe­sion and aggre­ga­tion under bio­log­i­cal­ly rel­e­vant flow con­di­tions. The plate­lets from a ­female ­patient with con­gen­i­tal afib­ri­nog­e­ne­mia, were ana­lyzed ­before and after intra­ve­nous fibrino­gen sub­sti­tu­tion. In 14 PAD ­patients and 14 con­trols, plate­let reac­tiv­ity was ­assessed ­before and after incu­ba­tion with the two plate­let mem­brane gly­co­pro­tein (GP)-IIb/IIIa inhib­i­tors Ro 43-8857 and 7E3. Last­ly, experi­ments were per­formed ­before and after addi­tion of plas­ma ali­quots stem­ming from 4 PAD ­patients to plate­let rich plas­ma and to solu­tions of gel-fil­tered plate­lets (GFP) stem­ming from 4 ­healthy vol­un­teers. ­Before fibrino­gen sub­sti­tu­tion, the plate­lets of the afib­ri­nog­e­nem­ic ­patient were ­unable to ­adhere in the SPAA-­system and max­i­mal ADP-­primed aggreg­abil­ity was below 10%. After sub­sti­tu­tion, nor­mal plate­let adhe­sion was meas­ured and ­primed aggre­ga­tion ­increased three-fold. Mean base­line adhe­sion in the ­patient col­lec­tive was twice that com­pared to con­trols (p<0.001). SPAA-meas­ured, spon­ta­ne­ous aggre­ga­tion was ­observed in ten ­patients and in none of the con­trols (p<0.001).
­Results. Both SPAA-meas­ured and ­primed aggre­ga­tion were abol­ished at the low­est sub­strate con­cen­tra­tions (0.1 μM Ro 43-8857, 1 μg/ml 7E3). At these con­cen­tra­tions adhe­sion was ­reduced by 65% and 40% (respec­tive­ly) in ­patients, and by 55% and 25% in con­trols. Total abo­li­tion of adhe­sion in both ­groups was seen with 0.5 μM Ro 43-8857 and 10 μg/ml 7E3. Plate­let ­response to inhib­i­to­ry agent was sim­i­lar in ­patients and con­trols, as were the dif­fer­enc­es in dose-­response ­between aggre­ga­tion and adhe­sion. Upon addi­tion of ­patient plas­ma to vol­un­teer PRP, the plate­lets of all 4 ­healthy indi­vid­u­als aggre­gat­ed spon­ta­ne­ous­ly and the mean adhe­siv­ity in the group rose three-fold. The over­all abil­ity of the GFP to ­adhere when re-added to their own plas­ma was ­decreased, where­as, in the pres­ence of ­patient plas­ma, adhe­sion ­increased sig­nif­i­cant­ly.
Con­clu­sions. On the basis of these find­ings we con­clude that: 1) SPAA meas­ures and quan­ti­fies plate­let inter­ac­tions with both fluid-phase (aggre­ga­tion) and immo­bi­lized (adhe­sion) fibrino­gen, 2) these reac­tions are medi­at­ed by the GP, IIb/IIIa recep­tor com­plex 3) the bind­ing affin­ity, meta­bol­ic path­ways and sig­nal trans­duc­tion under­ly­ing plate­let adhe­sion dif­fer from those ­involved in aggre­ga­tion (pos­sibly reflect­ing their var­y­ing roles in hemo­sta­sis), 4) the func­tion­al­ly nor­mal plate­lets of ­patients with PAD are ­primed in vivo by a cir­cu­lat­ing plas­ma con­stit­u­ent, which leads to ­enhanced recruit­ment of acti­vat­ed GP, IIb/IIIa onto the plate­let sur­face and, there­by, to an over­all ­increase in reac­tiv­ity.

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