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Journal of Neurosurgical Sciences 1999 March;43(1):45-51

Copyright © 1999 EDIZIONI MINERVA MEDICA

language: English

Association of elevated levels of prothrombin fragment 1+2 and Arg506 to Gln mutation in patients with a history of ischemic stroke

De Lucia D. 1, Papa M. L. 3, Ammendola F. 1, Pezzella S. 1, Del Giudice V. 1, Marotta R. 1, Renis V. 1, Di Mauro C. 1, Maisto G. 1, Masi S. 1, Nina P. 2, Franco A. 2, Schisano G. 2

1 Institute of General Pathology and Oncology, II University of Naples, Italy; 2 Neurosurgery Division, Nuovo Pellegrini Hospital, Naples, Italy; 3 Thrombosis and Haemophilia Center, Nuovo Pellegrini Hospital, Naples, Italy


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Back­ground. ­Recent find­ings ­have indi­cat­ed ­the asso­ci­a­tion ­between ­APC-resis­tance ­and cereb­ro­vas­cu­lar dis­ease. ­These ­reports prompt­ed us to inves­ti­gate wheth­er resis­tance to ­APC ­could be ­found in ­patients suf­fer­ing ­from ­stroke.
Meth­ods. There­fore, we stud­ied ­APC-resis­tance in 50 ­young ­adults (≤45 ­yrs) ­with a his­to­ry of ischem­ic ­stroke. ­Eleven ­out of fif­ty cereb­ro­vas­cu­lar sub­jects ­showed ­APC-resis­tance, ­while 2 ­had PC defi­cien­cy ­and 3 PS defi­cen­cy. No defi­cien­cies in ­the anti­co­ag­u­lant pro­tein AT ­III ­and in fibrin­o­lyt­ic pro­teins ­were ­found. ­The fam­i­ly his­to­ry dem­on­strat­ed a dis­tri­bu­tion of ­APC-resis­tance com­pat­ible ­with dom­i­nant auto­so­mal inher­i­tance. ­The plas­ma con­cen­tra­tion of pro­throm­bin frag­ment 1+2 (F1+2), ­which is a mark­er of hyper­coa­gu­lable ­states, ­was ­also meas­ured in pat­ients ­and fam­i­ly mem­bers of resist­ant sub­jects (n=38).
­Results. ­DNA anal­y­sis ­showed fac­tor V R506Q muta­tion (Leid­en muta­tion) in 11 ­patients ­and ­their rala­tives ­with ­poor ­response to acti­vat­ed pro­tein C detect­ed by ­APTT ­tests. Of 11 inves­ti­gat­ed sub­jects ­with ­APC-resis­tance, 9 ­were het­er­o­zy­gotes ­and 2, ­with ­the low­est ­APC-­ratio val­ues, ­were homo­zy­gotes ­for fac­tor V muta­tion. ­Among 38 rel­a­tives, 22 ­showed a ­poor ­response to ­APC ­and accord­ing to ­the ­APC-­ratio val­ues, 18 ­were het­er­o­zy­gotes ­and 4 homo­zy­gotes ­for FV Leid­en muta­tion. ­The muta­tion, in het­er­o­zy­gous ­form, ­was ­also ­found in 2% of ­our nor­mal pop­u­la­tion (n=100). ­The plas­ma con­cen­tra­tion of F1+2 ­was sig­nif­i­cant­ly high­er ­both in 11 indi­vid­u­als car­ry­ing ­the FV:Q506 muta­tion ­and in 39 ­patients with­out ­APC-resis­tance com­pared to ­that ­found in ­the con­trol ­group. How­ev­er, ­the ­patients ­with FV:Q506 mutation ­showed ­the high­est val­ues in F1+2. In ­the stud­ied fam­i­ly mem­bers F1+2 plas­ma lev­els ­were with­in nor­mal val­ues.
Con­clu­sions. ­Our find­ings indi­cate a pos­sible involve­ment of ­APC-resis­tance in ­the path­o­gen­e­sis of cere­bral throm­bo­sis in ­young ­adults ­and ­agree ­with ­the hypoth­e­sis ­that indi­vid­u­als ­with ­APC-resis­tance ­have an imbal­ance ­between ­pro- ­and ­anti-coag­u­lant forc­es lead­ing to ­increased throm­bin gen­er­a­tion ­and a hyper­coa­gu­lable ­state.

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