Thrombosis and Haemostasis - © F. K. Schattauer Verlagsgesellschaft mbH (Stuttgart) 64 (2) 206-210 (1990) Hereditary Protein S Deficiency in Young Adults with Arterial Occlusive Disease C. F. Allaart 1 , D. C. Aronson 2 , Th. Ruys 2 , F. R. Rosendaal 3 , J. H. van Bockel 2 , R. M. Bertina 1 , and E. Briet 1 From the 1 Haemostasis and Thrombosis Research Unit, the 2 Dept. of Surgery, and the 3 Dept. of Clinical Epidemiology, University Hospital Leiden, The Netherlands Summary Protein S is the vitamin K dcpendent cofactor of activatcd protcin C. 1t has an important rolc m the regulation of blood coagulation and fibrinolysis. Heieditary protein S deficiency is associated with familial venous thrombophilia. Smce a few patients with artenal occlusions have been rcported to be Protein S deficient, it is speculated that hereditary protein S deficiency may bc also a risk factor for the dcvelopmcnt of arterial thrombosis. In a group of 37 consecutive patients with arlerial occiusive disease presenting before the age of 45, three patients werc found hcteiozygous for hereditaiy protein S deficiency. None of the patients had a protein C deficiency or an antithrom- bin III deficiency. Family investigations showed a clear associa- tion between the hereditary deficiency and venous thrombosis, but a rclation between the deficiency and ai terial thrombosis was less obvious. A revicw of pievious literature on patients with arterial thrombosis and protein S deficiency revealed that more extensive studies arc needcd to demonstrate whcthei or not hereditaiy piotein S deficiency is a risk factoi foi the dcvelop- mcnt of arterial thrombosis. Introduction Protein S is a vitamin K depcndent plasma protein that was discovcred in 1977 (1). Smce 1980, cvidence for its role äs an essential cofactor of activatcd protein C has been rcported in sevcral papcrs, wherc its importancc in the expression of both the kinticoagulant and the profibrinolytic activity of activatcd pro- tcin C was demonstrated (2-4). After the first casc leports of patients with familial venous thiombophilia due to hereditary protein C deficiency (5-7), it was pointed out in subscquent papers that this syndromc could also be causcd by hereditary protein S deticiency (8-10). Moreover, some invcstigators have reported the presence of hereditaiy protcin S deficiency in young patients with manifesta- tions of ai terial thrombosis (11-18). To comparc the prcvalence of piotein S deficiency in patients with ai terial thrombosis with the reported prevalence in patients with venous thrombophilia, we screencd 37 consecutive patients with arterial occlusion presenting before the age of 45. In the familics of the patients with a hereditaiy deficiency we invcsti- gated whether the defect was associated with Symptoms of arterial thrombosis, venous thrombosis or both. In this papcr we prcsent the icsults of thcse studies and discuss possible lelations between piotein S deficiency and the occurrencc of venous and arterial thrombosis. Coirespondcncc to Di C F Allaalt, Haemostasis and Thiombosis Rcscaich Unit, Umvcisity Hospital Leiden, Building t, C2-R, PO Box 9600, 2300 RC Leiden, The Ncthcilands Patients and Methods Wc camed out a study m the department of vasculai surgeiy in the Umveisity Hospital Leiden, with the puipose to detect disoiders m the icgulation of coagulation and hbrinolysis, fat raetabolism and methionm metabohsm m patients with aitenal occlusions in the lowci cxtiemities picscntmg before the age of 45 Patients with vascular occlusions caused by tiauma, pophtcal cntrapmcnt 01 adventitial cystic disease weie excludcd ftom the study Thirty-sevcn consecutive patients who had been ticatcd at the department of vasculai suigeiy between the years 1978 and 1987 weic invitcd to the outpatient chnic and all agieed to paiticipatc in the study The diagnosis was based on the patient's histoiy, the physical exammation, the Dopplei picssuie mdices at the ankle levcl, and if available the angiogiaphic findmgs When surgeiy was pcifoimed, the mtia-opcrativc obseivations and the histologic exammation of the spcci- mcn obtamcd dunng suigeiy confirmed the diagnosis The lesions wcre equally distnbutcd between aoitic-ihac and femoio-distal rcgions, äs could be seen on the angiograms All laboiatoiy methods and outcomcs of the completc study have been published m dctail (19) To detect an isolated protein S deficiency venous blood was collected in 1/10 volume of 0 11 M tusodium citrate Platclet free plasma was obtamed by centntugmg the platclct poor plasma for 30 mm at 20,000 x g at 4° C Total piotein S antigcn was mcasured with an EL1SA, iccently dcvcloppcd in oui laboiatoiy (20) and based on the same pimciples earhei applicd in the immunoiadiometnc assay (21) Piotein C antigcn, factoi II antigcn, and tactor X antigen weie mcasured by electio-immunoassay (6) Fiom the thiec patients wheie a Iow plasma levcl piotcm S was found (scc below) a second plasma sample was obtamcd to conlnm the iirst lesults The results of the second analysis confnmed that all thiec patients had an isolated protcin S deficiency The diagnosis was based on the followmg cntciia a total protcin S-antigcn levcl below the lowci limit of the noimal ränge found in healthy contiols (67—125%, n = 45) 01, for patients on oial anticoagulanl therapy, a total protein S-antigcn Icvel below the lowei limit of the lange found in a icfcicnce gioup ot patients icccivmg coumann thciapy (33-74%, n = 93) Othei vitamin K-dcpcndent factoi s had to be withm the normal lange äs found m the contiols with 01 without coumann theiapy (21) Subsequently, all available iclatives ot the probands wcrc mvestigatcd, usmg the samc methods and cntciia In family A and C, with a positive family history toi arteual thrombosis, cholcsteiol levels in serum werc measuicd äs well The mcdical histoiy of all paiticipatmg family membcrs was taken and mfoimation about theu deccased iclatives was also obtamed Wc classified all tamily membcis into thiec gioups accordmg to the piobabil- ity lhat they weic hcteiozygous for heieditary piotein S deficiency This classification was based on the laboiatoiy results of the paiticipatmg family mcmbeis and the position m thc pedigrec of those who couldn't paiticipate Individuais with a documented piotein S deficiency have a 100% piobability to be hetciozygous, those with normal protein S levels have a 0% piobability When thcir protein S levels aic unknown, cach paient of a known hetciozygotc has a 50% piobability to be hcteiozygous foi thc deficiency äs well, aunts and uncles have a 25% probabihty and so on Gioup l includes tamily membcrs with a less than 12 5% probabihty to be helciozygous, gioup 2 icpresents all of those with a probabihty between 12.5% and 50%, and mdividuals with a 100% piobability to bc hcteiozygous aic m gioup 3 Wc diew up hfe tablcs foi the occurrence of venous thiombosis and aitenal thiombosis. 206