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
1From the 1 Haemostasis and Thrombosis Research Unit, the 2Dept. of Surgery, and the 3Dept. 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.
Ι
II
III
IV
Fig. l Pedigrcc of family A. Π = male; O = fcmalc; O = sex unknown; l" l = history of artcrial thrombosis; ' = history of vcnous throm-bocmbolism; 1Ί = dcccased; l = invcstigatcd; 01 = hctcrozygous for hcrcditary protcin S deficiency; \ = propositus
ύ
0 ü
a t
II
πι __ _ _
1 2 3 4 5
Fig. 2 Pedigrcc of family B. Symbols: see Fig. l
Results
Case Reports and Family Results
In the group of 37 consecutive patients with peripheral arterial occlusions presenting before the age of 45, three patients (8%) were protein S dcficicnt. Family investigations were then carried out. The rcsults of the measurement of protein S, protein C, factor II and factor X antigen have been listed in Tables l, 2 and 3. The medical historics of the threc patients and the results of the fcfamily studies are the following:
Patient A (III-2 in Fig. 1) had the first complaints of claudica-tion at the age of 39, which were slowly progressive in the following year. He smokcd about 10 cigarettes a day, was healthy, and hypertcnsion and diabetes mellitus were absent. Angiography showed an occlusion of the right superficial femoral artery and a venous femoropopliteal bypass was pcrformed. Five years later he was frce of Symptoms with normal Doppier ankle/arm indices. When he entered the study, a serum cholesterol level was measured of 8.9 mmol/1. Further investigations showed that he had a type Ilb hypcrlipoproteinemia. In his family (family A, Fig. 1) II-5 and I-la had dicd of a myocardial infarction before the age of 50. II-6 had suffered from recurrent superficial thrombo-phlebitis, with the first episode after dclivery at the age of 35. She survivcd two myocardial infarctions at 68 and 69 years of age, but died recently, presumably of a third myocardial infarction. I-2a was said to have had deep venous thrombosis after childbirth. II-8 who has non-insulin depcndent diabetes mellitus, has recently suffered from an arterial occlusion in a leg. He could not participate in the study. No other family members had suffered episodcs of venous thromboembolism or arterial occlusion. Only the asymptomatic sister of the propositus (ΠΙ-3) was found to be heterozygous for protein S deficiency. In this family serum cholesterol levels were measured. The serum cholesterol level was
high (9.6 mmol/1) in II-6, but normal (i. e. less than 6.5 mmol/1) in the other participants.
Patient B (II-2 in Fig. 2) had her first Symptoms of claudication at the age of 39. She smoked 15 cigarettes a day and was treated for hypertension. Her medical history further included pulmonary embolisms of unknown origin at the age of 35 and seropositive rheumatoid arthritis since age 26. She had had several surgical operations without complications. Angiography showed an occlu-sion of the right, and a significant Stenosis of the left common iliac artery. An aortobifemoral bypass was implanted and she stopped
Table l Family A: results of laboratory studies Pedigrcc numbcr II-5a II-6 111-2* III-3 IV-3 IV-4 IV-5 IV-6 Sex F F M F F M F F Age (ycars) 70 76 44 35 20 18 12 8 PS-ag 116 97 30 65 87 106 114 87 PC-ag 118 154 54 117 123 79 87 87 Fll-ag 123 123 54 138 111 118 102 108
FX-ag OAC def 118 154 43 + + 152 - + 140 106 102 102
F = female, M = male; OAC = oral anticoagulation; def = protcin S dcficient; * propositus.
Table 2 Family B: rcsults of laboratory studies Pedigrec number 1-6 II-l II-2* II-3 III-l ΙΠ-2 III-3 III-4 Sex M M F M F M M M Age (years) 64 45 43 39 19 17 20 17 PS-ag 102 11 66 27 86 45 55 49 PC-ag 200 33 100 74 82 87 115 110 FTI-ag 138 32 145 63 74 120 92 92
FX-ag OAC def
118 37 + + 120 - + 45 + + 60 80 - + 80 - + 95 - +
F = female, M = Male; OAC = oral anticoagulation; def = protein S deficicnt; * the propositus.
Table 3 Family C: results of laboratory studies Pedigrec numbcr II-6 II-9 III-l III-2 III-3 III-5 1II-6 III-8 III-9 111-12 111-13 111-14 111-15 111-16* 111-17 111-18 IV-26 IV-27 Sex M M M M F F M M M M F F M M F M M F Age (ycars) 62 72 61 47 45 51 41 41 58 51 36 34 29 45 32 21 11 7 PS-ag 134 79 126 127 103 117 111 101 118 127 111 95 96 19 93 96 35 36 PC-ag 94 48 94 108 120 125 125 102 120 108 108 108 96 68 100 84 75 75 Fll-ag 128 67 87 138 103 132 96 96 102 120 128 96 103 47 110 90 71 81
FX-ag OAC def
118 61 + -94 123 130 123 118 103 114 168 123 130 123 29 + + 118 104 77 - + 81 - +
F = female, M = male; OAC = oral anticoagulation; def = protcin S dcficicnt; * propositus.
Pedigiec of family C Symbols scc Fig l
smokmg Foui years later she was frec of Symptoms and the ^Dopple! ankle/aim indices wcre normal When she entered the
study, a serum cholesteiol level of 6 2 mmol/1 was measuied In her family (family B, Fig 2), 1-2 was repoitcd to have suffeied fiom a deep venous thrombosis at the age of 19 after immobihzation dunng a pneumoma Only one of his brotheis (1-6) was able to participate m the study At the age of 62, this man had icceived anticoagulant therapy foi an axillary vein thrombosis followmg abdominal surgery Il-f and II-3 had suffered from spontaneous deep venous thiombosis at the age of 30 None of the family membeis had had Symptoms of artenal occlusive disease II-l and 11-3 weie found to be hcterozygous foi protcin S deficiency, äs wcie III 3, III-4 and III-2
Patient C (111-16 in Fig 3) had claudication when he was 35 yeais of age Hc smoked 25 cigarettes a day and had always been hcalthy before A few months eaihei he had suffeied from a deep venous thiombosis in the left leg aftei immobilization for what was thought to be a tendimtis, and he leceivcd coumann theiapy smce Angiogiaphy showed an occlusion of the aorta with an extensive collateral circulation An aoitobifemoial bypass was performed and f year later hc was ftee of Symptoms At the Start of the study a serum cholesterol level of 8 l mmol/1 was mea-ksured In his family (family C, Fig 3) 11-10 had suffered fiom pulmonary embolisms m the year before he died of lungcancer He also had had a myocaidial mfarction before the age of 65 Of his gencration, only two relatives were still alivc at the time of the mvcstigation The first was II 6, who had a myocardial mtaiction at the age of 60 One month aftei the study he died after a second mfaiction, aged 62 The second was II-9, who at 56 refused to icccive surgeiy foi artenal occlusive disease in a leg and who had a myocardial mfaiction at the age of 70, while on oral anticoagu-lant theiapy II-l died of myocardial mfaiction at age 66 II-2 suffeied from a stroke at the age of 42 and died followmg vascular surgery foi an acute aitcnal occlusion in a leg at the age of 54 II-4 suffered a fatal stroke at age 50 Hei son (ΙΠ-4) died of a heait
attack dunng a soccermatch, 33 yeais old II-7 had had non-insuhn dcpendent diabetes melhtus, he died in his sleep at the age of 66, aftei havmg chestpam the previous cvemng Some ycars caiher a medical cxammation had revealed that hc had suffered a silent myocaidial mfaiction II 8 had a heart attack at the age of 65 His cldcst son (ΠΙ-9) suffered from an occlusion of the left aitcua cciebn mcdia at age 57 111-12 received surgery because of an aitenal occlusion m the leg when he was 20 yeais old He was fice of Symptoms smce Of all family mcmbers participating, only two children of the piopositus (IV 26 and IV-27) weie found to bc heterozygous foi protein S deficiency The serum cholesterol
100
β ϋ ^-^jj —g
10 20 30 40 50
age (years}
70 80
Fig 4 Litctablc venous thrombocmbohsm thiombosis hee surviva] iclated to the piobabihty of betng heteiozygous foi heieditaiy protein S deficiency, -D- 0 to 12 5% piobabihty to bc heteiozygous (n = 52), -Δ- 12 5 to 50% piobabihty (n = 25), -O- 100% piobabihty (n = 12, piobands mcluded)
100 t*·
10 20 30 40 50
age (years)
70 80
Fig 5 Lifetablc aitcnal thiombosis thrombosis fiee suivival rclated to the piobabihty ot bcmg hcterozygous foi heieditaiy piotcm S deficiency, -D- 0 to 12 5% piobabihty to bc heteiozygous (n = 52) -Δ- 12 5 to 50% piobabihty (n = 25) -O- 100% piobabihty (n = 9, piobands ex-cludcd)
levels in the family were under 6.5 mmol/1, cxcept in II-9 (6.7 mmol/1), III-5 (6.6 mmol/1), 111-13 (7.8 mmol/1) and IV-9 (7.1 mmol/1).
After dividing all family mcmbers into three groups according to the probability that they were heterozygous for hereditary protein S deficiency we drew up life tables with regard to the occurrence of venous and arterial thrombosic events. After the age of 40, venous thrombotic events occurred more often in heterozygotes than in persons with a 50% or Icss probability of being heterozygous for the deficiency (Fig. 4). The occurrence of arterial thrombosis did not incrcase with the probability of having the deficiency (Fig. 5).
Discussion
Since 1980 the role of protein S äs cofactor of activated protein C has been reported in several papcrs (2-4). Activated protein C inhibits the blood coagulation cascadc by inactivating factors Va and Villa (22, 23). It accclerates clot lysis äs well (4, 24). Protein S is an esscntial cofactor for the expression of both
«
perties of protein C (3, 4). In plasma protein S is present in a ; form and bound in a complex with C4b-binding protein; only the free from acts äs a cofactor for activated protein C (25).In several publications the association between familial throm-bophilia and hereditary protein C deficiency was reported (5-7, 26, 27). The same association for hereditary protein S deficiency and venous thrombophilia was demonstrated (8-10). It was cstablished that, in families with venous thrombophilia and protein S deficiency, heterozygotes for the deficiency tend to develop venous thrombosis more often and at a younger age than non-deficient family members (10).
In the literature several patients with arterial thrombosis and protein S deficiency have been reported (8-18). The type of study and the crilcria on which the diagnosis protein S deficiency was based showed considerable Variation.
Schwarz et al. (9), Coller et al. (11), Mannucci et al. (12), Israels et al. (13) and Girolami et al. (14) all presented a case of a patient with arterial thrombosis at a young age with a hereditary protein S deficiency. No Information was given on the selection procedurc of the probands. The diagnosis was based on the finding of low total protein S levels (9, 12, 14) or on the presence
«
ow free protein S levels with normal total protein S levels (11, . Family investigations revealed heterozygous relatives, somc of whom had suffered from venous thromboembolic events (9, 11, 12, 14). No Information was given about a possiblc family history of arterial thrombosis.Von Feiten et al. (15), Thommcn et al. (16), Schäfer et al. (17), and Chancellor (28) screened groups of patients with arterial thrombosis for protein S deficiency and othcr deficiencies. The inclusion criteria of these studies were not always clearly defined. The patients initially reported by von Feiten et al. were included in the 33 patients with arterial cerebral thrombosis studied by Schäfer et al. In total ninc patients were reported to have a protein S deficiency, defined äs low total protein S levels with low free protein S levels, which was familial in four cases. Four other patients had low free protein S levels but normal total protein S levels, and this type of deficiency was a found to be familial in one casc. Thommen et al. (16) investigated scven patients with arterial thrombosis, and reported one patient with low free protein S levels and low (calculated) total protein S levels, a phenotype also found in an asymptomatic sister of the patient. Other patients were described with low free protein S levels and various outcomes in the calculation of total protein S and the mcasurement of C4b-BP-bound protein S, but in none of those cases a hereditary dcfect was proven. In the thrce reports the
Information about the occurrence of venous and arterial throm-bosis in the families is incomplete. Chancellor et al. (28) measured total and free protein S antigen levels and found no protein S deficiencies in a study in 38 consecutive patients with unexplained non-hemorrhagic cerebral infarctions.
Recently, Sie et al. (18) reported on six patients with protein S deficiency and arterial thrombosis at a young age, identified among 23 symptomatic heterozygotes from 17 families. The diagnosis was based on a low total protein S level, or on a normal total protein S with a low free protein S antigen level. It is not clcar on which criteria the families had been selected and the total numbcr of heterozygotes in these families is unknown. In three of the six patients a hereditary deficiency was not proven or not reported. A positive family history for venous thrombosis was present in three cases, familial arterial thrombosis was not reported.
Only one report on hereditary protein S deficiency in patients selected on the basis of venous thrombophilia gives Information about the occurrence of arterial thrombosis in the families studied: Engesser et al. (10) interviewed 72 heterozygotes in 12 protein S deficient families. Twenty-five of these persons were more than 50 years old at the time of the interview (personal communication) and none of them had had Symptoms of arterial disease.
We carried out a study in the department of vascular surgery in 37 consecutive patients with symptomatic arterial occlusive dis-ease before the age of 45. Three proved to be heterozygous for hereditary protein S deficiency (8%). The prevalence of hered-itary protein S deficiency in the gcneral population is unknown, in patients with venous thrombophilia it is reported to be between 2 and 8% (29-31). The fact that we find a similar prevalence in the group of patients with arterial thrombosis suggests that the defect may be a risk factor for arterial thrombosis äs it is for venous thrombosis. However, since the defect is hereditary, an associa-tion between deficiency and Symptoms should then also be evident in family studies.
To investigate whether or not a relation between protein S deficiency and Symptoms of arterial thrombosis was present in the families of the three patients with the deficiency, we divided all family members into three groups according to the probability that they were heterozygous. Life table analysis demonstrated a clear relation between the occurrence of venous thrombosis and a heterozygous state for hereditary protein S deficiency (Fig. 4). This corroborates previous findings in a study of 12 families with hereditary protein S deficiency (10). The result is all the more of interest since, in contrast to the previous study, venous throm-bophilia was not a selection criterion in our study.
On the other hand, the occurrence of arterial thrombosis did not incrcase with the probability of having the deficiency (Fig. 5). However, in this exercise we did not include the three probands since their Symptoms were the reason why they were included in the study. Group 3 thus consists of only nine individuals with a 100% probability to be heterozygous. The fact that they were on average younger (mean age 26.7 years, ränge 8 to 52 years) than the members in the other two groups (mean age 37.1 years, ränge 0 to 78 years) might cxplain why no correlation between protein S deficiency and arterial thrombosis was found.
None of the patients in our study had a deficiency of protein C or antithrombin III. This suggests that there might bc a special relation between protein S deficiency and the development of arterial thrombi. A direct effect may bc possible, äs both endothelial cells and platelets are sites of protein S synthesis and action in vivo (32). A high serum cholesterol may be a potentiat-ing factor.
defect is a nsk factor for the development of venous thrombosis, and it seems to be associated with the occurrence of artenal thrombosis äs well An open eye for this possibility m the approach of mdividual patients, and more extensive family and epidemiologic studies may help to determme whethei or not hereditary protem S deficiency is mdeed a nsk factor for the development of artenal occlusive disease and thrombosis
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»
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»
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Received Februaiy 7, 1990 Accepted aftcr rcvision May 2, 1990
