Inherited factor VII deficiency and surgery: clinical data are the best criteria to predict the risk of bleeding

Authors


Dr Muriel Giansily Blaizot, Laboratoire d'Hématologie, CHU de Montpellier, 80 avenue Augustin Fliche, 34295 Montpellier Cedex, France. E-mail: m-giansily@chu-montpellier.fr

Abstract

Summary. Inherited factor VII (FVII) deficiency is a rare autosomal disorder characterized by a weak relationship between FVII activity (FVII:C) and operative bleeding risk. We report a retrospective study of 17 patients with a FVII:C below 0·1 IU/ml, in whom surgery was performed without any replacement therapy. Clinical and biological data were analysed to establish predictive criteria for bleeding tendency. We found that systematic preoperative replacement therapy may not be necessary for ‘minor’ surgical procedures, for patients suffering from inherited FVII deficiency, unless the clinical history includes severe haemorrhagic symptoms such as haemarthrosis, severe haematomas (even of soft tissue) or abundant epistaxis.

Factor VII (FVII) is a vitamin-K-dependent plasma glycoprotein that plays a pivotal role in the initiation of blood coagulation in vivo. Inherited FVII deficiency is a rare autosomal recessive disorder (Cooper et al, 1997) that is characterized by a weak relationship between FVII coagulant activity (FVII:C) and operative bleeding risk (Triplett et al, 1985). Therefore, treatment strategies remain to be defined for patients with low FVII:C levels and either mild bleeding phenotypes or no bleeding history. Only a few patients with FVII:C below 0·1 IU/ml who underwent surgery without replacement therapy have been described (Mariani & Mazzucconi, 1983; Peyvandi et al, 1997). The largest series ever published described nine cases (Yorke & Mant, 1977). Here, we report a retrospective study of 17 patients with severe inherited FVII deficiency who underwent haemostatic challenges without replacement therapy. The clinical and biological data were evaluated in order to help to provide guidelines relative to infusion therapy in severe inherited FVII deficiency.

Patients and methods

Patients.  Seventeen patients, 6 males and 11 females, aged 6–81 years, attending 10 haemostasis disorders centres were included. Two patients were sisters (patients 5 and 16). The criteria for inclusion were a FVII:C level < 0·1 IU/ml and a history of haemorrhagic challenge without replacement therapy. This study was approved by the Ethics Committee of Montpellier University Hospital.

Laboratory assays.  Plasmas collected in 0·129 mol/l trisodium citrate tubes were dispatched frozen in dry ice from each centre to our laboratory. FVII:C and FVII antigen (FVII:Ag) levels were determined using a recombinant human thromboplastin assay (Instrumentation-Laboratory, Lexington, USA) and an enzyme-linked immunosorbent assay, Asserachrom FVIIag (Diagnostica Stago, Asnière-sur-Seine, France) respectively. Activated partial thromboplastin time (APTT) clotting assays were performed for all patients. Ristocetin cofactor activity was determined for patients with a bleeding clinical phenotype. The FVII genotype was characterized for each patient as previously described (Giansily Blaizot et al, 2001).

Results

Clinical data

The 17 patients investigated in this study were classified into two clinical groups (Table I). Group A (n = 4) comprised patients with no bleeding history, whereas group B (n = 13) consisted of patients presenting with bleeding symptoms including menorrhagia, epistaxis and either spontaneous or traumatic haematoma. None of the B group patients had experienced a bleeding event such as haemarthrosis or large muscle haematoma requiring occasional or periodic replacement therapy. The distribution and severity of each symptom are reported in Table I.

Table I.  Clinical, biological and genetic data of the 17 patients.

Laboratory
number

Sex/age
(years)

FVII:C
(IU/ml)

FVII
Ag

Clinical
group


Haematoma


Epistaxis


Menorrhagia
Haemostatic
challenge without
substitutive therapy

Diagnosis
known

Bleeding
outcomes


FVII genotypes
 
  • *

    Antifibrinolytic drugs were used during the surgical procedure.

  • Y, yes; N, no; R, the bleeding outcome revealed the diagnosis of FVII deficiency; wt, wild-type nucleotide sequence of the nine exons of the FVII gene; FVII:C, FVII coagulant activity; FVIIAg, FVII antigen levels. Menorrhagia was considered to exist when the menstrual blood loss appeared to be at least as abundant as 80 ml for the whole period and clotting plugs were present (Higham et al, 1990). It was defined as severe when the menstrual losses led to the use of combined oestrogen–progestogen medications or to iron deficiency according to the criteria of Lak et al (2000). Epistaxis was considered as recurrent when it occurred more than six times a year or recurred despite cauterization procedures. It was qualified as abundant when it induced iron-deficient anaemia or required blood-replacement treatment. Each haematoma was reported whatever the circumstances and the localization.

1F/810·0648%BSoft tissueRecurrentYVaginal delivery
Tooth extraction
N
N
Y
Y
294 Ala→Val294 Ala→Val
/delC11125
2F/46< 0·018%BSoft tissueYYTonsillectomyNY100 Gln→Arg97 Gly→Cys
3M/14< 0·0147%BNRecurrent,
abundant
/CircumcisionRY327 Met→Ile327 Met→Ile
4F/230·0776%BNRecurrent,
abundant
YTonsillectomy
Vaginal delivery
N
R
N
Y
298 Met→Ile298 Met→Ile
5F/23< 0·0158%BSoft tissueNYAdenoidectomy
Tooth extraction*
N
Y
Y
N
10543del15bp310 Cys→Phe
6F/510·0262%BNYSevereTonsillectomy
2 caesarian deliveries
Tooth extraction
N
N
N
N
N
N
64+5G→A179 Gly→Arg
7M/730·0323%BNRecurrent/Tooth extractionNN304 Arg→Gln180 Gly→Arg
8F/52< 0·019%BNNSevereTooth extraction*YNdelC11125/
294 Ala→Val
13 Leu→Gln
9F/150·025%BNRecurrentYTonsillectomy
Adenoidectomy
N
N
N
N
1 Met→Valwt
10M/330·0217%BNY/Tooth extraction*YN277 Arg→Cys28 Arg→Gly
11M/74< 0·01< 1%BNY/Tooth extraction*
Tonsillectomy
N
N
N
N
359 Thr→Met359 Thr→Met
12F/330·0340%BNRecurrentSevereAppendicectomy
Vaginal delivery
N
N
N
N
298 Met→Ile364 Trp→Stop
13F/250·1105%BNYNUterus curettingYN304 Arg→Gln304 Arg→Gln
14F/62< 0·01 64%ANNN3 vaginal deliveriesNN331 Gly→Ser100 Gln→Arg
15M/60·07 25%ANN/Important skin injuryNN191 Ala→Thr191 Ala→Thr
16F/20< 0·01 56%ANNNTooth extraction*YN10543del15bp310 Cys→Phe
17M/80·01  2%ANN/Adenoidectomy
Circumcision
Y
Y
N
N
wtwt

Twenty-nine surgical procedures or haemostatic challenges were registered (Table II). No postoperative bleeding was reported in the asymptomatic group whereas six complicated episodes occurred for five patients from group B. Of these, only the circumcision procedure (patient 3) led to severe haemorrhaging requiring blood transfusion. Only 1/8 dental extractions led to excessive bleeding, but the patient had taken aspirin shortly before the procedure.

Table II.  Prevalence of bleeding outcomes of haemostatic challenges performed without replacement therapy.
Haemostatic
challenges

n
Bleeding
outcomes
  1. The clinical distribution between groups A and B is indicated in parentheses. ‘A’ refers to group A patients whereas ‘B’ refers to group B patients.

Tooth extraction 8 (1A−7B)1 (B)
Tonsillectomy 5 (5B)1 (B)
Adenoidectomy 3 (1A−2B)1 (B)
Childbirth: vaginal delivery 6 (3A−3B)2 (B)
Childbirth: caesarean section 2 (2B)0
Uterus curetting 1 (B)0
Major skin injury 1 (A)0
Circumcision 2 (1A−1B)1 (B)
Appendicectomy 1 (B)0
Total29 (7A−22B)6 (B)

Biological data

Genetic heterogeneity did not enable the identification of a specific FVII mutation or genotype in the bleeding group (Table I). Moreover, there was no relationship between FVII:C levels and bleeding tendency. The cross-reacting material (CRM) and CRM+ biological phenotypes, which were based upon the absence or presence of a discrepancy between FVII activity and FVII antigen values, respectively (Triplett et al, 1985), were equally distributed in both groups.

Discussion

In this study, we retrospectively analysed 29 haemostatic challenges carried out without replacement treatment on 17 patients with inherited FVII deficiency (FVII:C < 0·1 IU/ml). Only six cases, corresponding to five patients, were complicated with excessive bleeding, one of which, a circumcision procedure, required blood transfusion. With regard to the very low FVII:C values measured in vitro, it may sound paradoxical that the majority of the probands did not experience any surgical bleeding. Previously published studies have also reported few uncomplicated procedures, other than dental extractions, which were performed without any replacement therapy: three patients with a FVII:C level < 0·01 IU/ml and recurrent epistaxis (Peyvandi et al, 1997), and seven patients with FVII:C < 0·1 IU/ml (Yorke & Mant, 1977). This finding is consistent with the hypothesis that only trace amounts of activated FVII are required to trigger the coagulation cascade in vivo (Lawson et al, 1994). Conventional clotting assays might not be sensitive enough to detect this residual FVII procoagulant activity.

On the other hand, as most of the procedures are located in surgical areas with high fibrinolytic activity, the use of antifibrinolytic drugs, especially for dental extractions, might contribute to the good management of these types of surgery. In addition, the physiological rise of FVII in both zymogen and activity state during pregnancy (De Moerloose et al, 1998; Wright et al, 1998) might explain why the delivery of some babies did not lead to excessive bleeding outcomes.

In agreement with literature data, neither clotting assays nor the FVII genotypes were predictive for the bleeding tendency (Triplett et al, 1985; Cooper et al, 1997). Even in family members possessing the same FVII mutations, one girl with a clinical history of epistaxis and haematoma bled after tonsillectomy, whereas her previously asymptomatic sister did not experience any post-surgical bleeding. Other unknown gene products or environmental factors might influence the activity or the turnover of the FVII molecule.

In our series, clinical data appeared to be the best predictive parameters of bleeding risk. In the asymptomatic group, none of the four patients had excessive bleeding after surgery. Among the five patients who bled after surgery, three suffered from soft tissue haematoma and the remainder experienced abundant epistaxis. Therefore, the previous occurrence of soft tissue haematoma or a history of abundant epistaxis defined by blood losses leading to iron deficiency or requiring hospitalization must prompt surgeons to give a replacement therapy prior to surgery. In contrast, recurrent epistaxis or menorrhagia, even severe, did not seem to be associated with a higher bleeding risk. Thus, this study strongly supports the view that ‘minor’ surgical procedures such as dental extraction, ear–nose–throat or genital tract surgery could be performed without replacement therapy on patients with FVII:C values < 0·1 IU/ml, and mild to absent bleeding phenotypes, when the clinical history is well defined. FVII concentrates or recombinant activated FVII (NovoSevenTM) infusions (Mariani et al, 1999) must be available in case of bleeding during surgery, but should not be systematically used as a preventive therapy.

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