ze~.chri~
Bltit ,so.
Blut 38, 119-125 (1979)
9 Springer-Verlag 1979
Congenital Factor VII Deficiency A Report of Four New Cases
R. Zirnmerrnann 1, G. Ehlers 1, W. Ehlers I, H. von Voss 3, U. G6beP and U. Wahn z l Medizinische Universitgtsklinik Heidelberg, Bergheimerstral3e 58, D-6900 Heidelberg 1, Federal Republic of Germany UniversitS.tskinderklinik Heidelberg, D-6900 Heidelberg, Federal Republic of Germany Universit~.tskinderklinik B, Dtisseldorf, D-4000 Diisseldorf, Federal Republic of Germany
Kongenitaler Faktor VII-Mangel Ein Berieht fiber vier neue F/ille Zusammenfassung. Vier neue Ffille mit angeborenem homozygoten und zehn Patienten rnit heterozygotem Faktor VII-Mangel werden beschrieben. Bei den homozygoten Ffillen war die Faktor VII-Aktivit/it auf < 1%, 3 %, 8 % und 10 % der N o r m vermindert. Schweregrad und H/iufigkeit der hfimorrhagischen Erscheinungen entsprachen dabei dem Ausmal3 der Faktor VII-Erniedrigung. Bei dem Patienten rnit schwerern Faktor VII-Mangel ( < 1%) wurde wegen rezidivierender Hfimarthrosen rnit Einschr/inkung der Gelenkfunktion eine Heimselbstbehandlung eingeleitet. Diese wird seit 1 89 Jahren mit einer Dosis yon 20 E/kg K G Prothrombinkomplex und neuerdings mit Faktor VII-Konzentrat in Abst/inden von etwa drei Wochen ohne Nebenreaktionen durchgeftihrt. Zwei Brfider (Faktor VII 8 % und 10 %) erreichten ein hohes Alter von fiber 70 Jahren. Trotz Substitution karn es nach einer Appendektornie zu einer Nachblutung, w~ihrend eine Achillessehnenoperation und eine Oberschenkelamputation ohne Substitution komplikationslos verliefen. Es wird vorgeschlagen, bei Patienten mit isoliertem Faktor VII-Mangel < 10 % bei operativen Eingriffen eine Mindest-Faktor VII-Konzentration yon 10-15% fiber einen Zeitraurn von drei Tagen aufrechtzuerhalten. Schliisselw6rter: Faktor VII - Hypoproconvertinemia - Faktor VII Substitutions-Therapie - Prothrornbinkomplex - Faktor VlI-Konzentration - Heirnselbstbehandlung - Operative Eingriffe
Summary. Four new cases with congenital homozygous factor VII deficiency are described. Factor VII levels were reduced to < 1%, 3%, 8% and 10%, respectively. The incidence and severity of bleeding symptoms were well correlated with the measured factor VII activity. In the severe case of factor VII Offprint requests to: Dr. Rainer Zimmermann (address see above) 0006-5242/79/0038/0119/$1.40
120
R. Zimmermann et al. deficiency ( < 1 ~ ) a home treatment program was started because of severe recurrent hemarthroses. This entailed transfusions of 20 U/kg body weight prothrombin complex or factor VII concentrate in case of acute bleeding approximately every three weeks. These transfusions have been carried out successfully without any problems. In contradiction, two brothers with hypoproconvertinemia (factor VII 8 ~ and 10~, respectively) reached an age of more than 70 years. Despite replacement therapy postoperative bleeding followed one appendectomy, whereas no postoperative bleeding followed patients requiring Achilles tendon lengthening and an above knee amputation and only slight bleeding followed a tonsillectomy. Based on our experience we suggest that in patients with factor VII deficiency of less than 10~, when undergoing surgery, should be maintained a minimal factor VII activity of 1 0 - 1 5 ~ during the first three postoperative days. Key words: Factor VII - Hypoproconvertinemia - Factor VII substitution therapy - Prothrombin complex - Factor VII concentrate - Home treatment Surgery
The existence of a new clotting factor termed "proconvertin", "serum prothrombin conversion accelerator" and finally factor VII was postulated in 1948 by Owen [21] and one year later by de Vries [28] and Alexander [1]. Proconvertin participates in the extrinsic pathway of blood coagulation and converts factor X to factor X a in the presence of tissue factor, phospholipid and calcium. However, evidence exists that the factor VII activity can be increased by the factors X a [24], XIIa [17], fragments of factor XII [25] and by storage at 0-4 ~ C due to the action of kallikrein [7]. Factor VII occurs in plasma as a single chain glycoprotein with a molecular weight of about 59,000, whereas that of the serum form is estimated to be 45,000 [8, 15,24]. The first case of congenital deficiency of proconvertin was described in 1951 by Alexander [2]. Due to methodical problems patients were widely reported as suffering from hypoproconvertinemia, but had later to be classified as a deficiency of Stuart-Prower factor, which was discovered in 1956 [3,22]. About 80 patients with homozygous factor VII deficiency have since been reported. The inheritance is autosomal recessive [5, 31]. Immunologic examinations have shown that in most of the cases "cross reacting material" (CRM) with proconvertin was not demonstrable by means of an inhibitor neutralization assay [20]. However, patients with normal or moderately reduced amount of CRM were described [4,6,9,10,20]. In the following report four new cases with homozygous factor VII deficiencies of different degrees of severity will be described. In contrast to one patient who was referred to a home treatment program because of serious bleeding tendency, two brothers reached an age of more than seventy years without dangerous hemorrhage.
Congenital Factor VII Deficiency
121
Case Reports Case I
A fourteen-year-old boy with no family history of hemorrhagic diathesis and with a normal anteand perinatal history had clinical signs of cerebral palsy. Because of equinus deformities of both feet a lengthening of the Achilles tendons was carried out. Despite no substitution of factor VII there was no evidence of postoperative bleeding. A factor VII deficiency was diagnosed in 1969 after manifestation of the first hemorrhagic symptoms at six years of age (factor VII < 1%). They consisted of prolonged epistaxis, subcutaneous hemorrhages and occasional bleeding into finger, knee and ankle joints. A phimosis was dilated without any hemorrhagic complications. In 1969, despite two transfusions of 1000 U of ACC 76 an appendectomy was followed by melena and hematuria and required transfusions of blood. Later on bleeding from the gums around carious teeth and epistaxis was observed. Repeated hemorrhages every two to four weeks into both elbow joints led to a loss of extension and pronation. Due to the progessively reduced range of movement it was decided to start a program of therapy at home. After a training period, the home treatment was performed well and reliably for 11A years by the patient when acute bleeding occured. A dose of 1000 U prothrombin complex was substituted after onset of bleeding and was sufficient to control the hemorrhage (body weight 53 kg). For the last few months the fourteenyear-old boy has given himself 1000 U factor VII concentrate (Immuno GMBH, Heidelberg) at each joint bleeding. Up to now the home replacement therapy has been tolerated well. Case I I
A sixteen-year-old boy with family history of allergic diathesis and normal ante- and perinatal history was observed as having recurrent epistaxis in infancy. In 1971, a tonsillectomy was followed by a moderate postoperative hemorrhage involving a slight reduction of hemoglobin. An injury from glass splinters led to prolonged bleeding from multiple cuts. Before an appendectomy in September 1973, a routine coagulation analysis demonstrated a prolonged prothrombin time of 36%. 300 U prothrombin complex was given prior and during the operation and further at 6-hourly intervals for three days (body weight 35 kg). There was no excessive bleeding, neither during nor after surgery. On further investigation of the prolonged protfirombin time, a liver disease was excluded and the tentative diagnosis of factor VII deficiency confirmed (factor VII 3 %). Case III
A 71-year-old man. Family history and childhood history could not be recalled completely; but a serious hemorrhagic diathesis could not be ascertained. At 27 years of age, while playing football the patient knocked against the goal post with his left knee. After a year's clinical treatment due to recurrent trouble in the knee joint the left knee finally stiffened in the flexion position. A later fall on this joint led to an above knee amputation. In 1973, 1974, and 1975 he was admitted to hospital because of repeated severe epistaxis and an atrophic gastritis. A liver disease could be excluded. The coagulation analysis demonstrated a hypoproconvertinemia (factor VII 8%). Replacement therapy was not necessary. Case I V
While examining the family of case III factor VII deficiency was established in the 76-year-old brother (factor VII 10%). No severe bleeds were reported in the history. Five members of this family (3 females and 2 males) showed a partial factor VII deficiency; but only one daughter gave a history of recurrent slight epistaxis (factor VII 54 %).
Methods The factor VII activity was assayed according to Koller [16] using a human factor VII-deficient plasma, the factors VIII and IX using commercial reagents (Merz and Dade Company, Miinchen). Concentration of the factors II, V, X, the Stypven clotting time and the thrombin time were determined by means of reagents from the Behringwerke, Marburg/Lahn and the Normotest according to Owren [23]. The prothrombin time, the activated partial thromboplastin time, thrombelastography, concentration of fibrinogen, the Mielke-bleeding time and the platelet count were performed as reported previously [30].
122
R. Zimmermann et al.
Table 1. Coagulation analysis of the three families with congenital homozygous (cases I-IV) and heterozygous factor VII deficiency. Concentrations of the coagulation factors VII, II, IX, X, the prothrombin time (PT), Normotest (NT), activated partial thromboplastin time (APPT) and the bleeding time (B.T.) Patient
PT (%)
NT (%)
case I father mother sister case II father mother case III case IV daughter daughter son grandchild grandchild
12 85 53 76 32 100 100 37 25 95 100 75 75 110
< 10 66 42 65 32 70 54 36 39 67 64 62 56 74
normal values
70-130
70-130
Factors VII
II
100 100 100 100 > 100 100 100 100 > 100
IX (%) 66 100 100 92 > 100 > 100 > 100 > 100 100 > 100 > 100 100 > 100 > t00 70-120
X
APTT (sec.)
B.T. (sec.)
100 100 100 98 85 > 100 100 > 100 100 > 100 > 100 100 > 100 > 100
40 42 41 38 41 39 46 37 35 37 32 34 35 39
225 165 190 270 274 285 210 400 295 290 280 285 510 445
35-50
-360
Results The essential d a t a of the c o a g u l a t i o n analysis are shown in T a b l e 1. The f o u r patients with h o m o z y g o u s h y p o p r o c o n v e r t i n e m i a d e m o n s t r a t e d isolated r e d u c t i o n s of the factor V I I with concentrations o f < 1%, 3%, 8 % a n d 10%, respectively. A d d i t i o n a l l y p e r f o r m e d tests such as Stypven clotting time, t h r o m b o p l a s t i n generation test, factor V, factor VIII, t h r o m b e l a s t o g r a p h y , platelet count, fibrinogen c o n c e n t r a t i o n a n d the t h r o m b i n time were normal. D u e to clinical and in s o m e cases histological e x a m i n a t i o n s it was possible to exclude a liver disease in all patients.
Discussion I n h o m o z y g o u s h y p o p r o c o n v e r t i n e m i a factor VII level is generally reduced to less t h a n 10%. M o s t o f the patients d e m o n s t r a t e a lifelong bleeding tendency [2,11, 19,221. The h e m o r r h a g i c s y m p t o m s can a l r e a d y be manifest in the n e w b o r n (neonatal type) with umbilical, gastrointestinal a n d cerebral bleeding or later, e.g., after p u b e r t y (juvenile type) [22]. Epistaxis, h e m a r t h r o s e s a n d gastrointestinal bleeding are m o r e c o m m o n in males, whereas in females m e n o r r h a g i a is the p r e d o m i n a n t s y m p t o m [5,19,22]. C o m p a r i n g the r e p o r t e d cases o f congenital f a c t o r V I I deficiency the incidence a n d the degree o f severity o f bleeding s y m p t o m s v a r y widely a n d do n o t show any relation to the established factor V I I activity [11,19].
Congenital Factor VII Deficiency
123
These discrepancies can be based on the genetic and biochemical heterogeneity of hypoproconvertinemia [10] or on the differences in laboratory tests and their interpretations [19, 27]. Our four patients with homozygous factor VII deficiency demonstrated a relationship between hemorrhagic diathesis and factor VII activity. The boy with a factor VII level of < 1 ~ displayed the most serious bleeding symptoms with development of joint deformities, which are rarely seen in hypoproconvertinemia [11,27]. Patient 1[ (factor VII 3 ~ ) and the 71-year-old man (case III, factor VII 8 ~ ) showed recurrent epistaxis, while the fourth patient (factor VII 10 ~) reached the age of 76 years without manifest bleeding. These observations support the suggestion of Strauss [27] that only patients with a factor VII level of less than 3 demonstrate an evident bleeding tendency, provided the real factor VII activity is evaluated by using a human or animal factor VII deficient plasma. Patients with factor VII activity of more than 3 ~ bleed less often and can apparently reach an old age. The replacement therapy of hypoproconvertinemia can be performed with whole blood, plasma [2, 19,22,27] or prothrombin complex [9,31]. Since 1975 a purified commercial factor VII concentrate is available [12,26]. In our cases II and III (factor VII 3 ~ and 8%, respectively) replacement therapy was rarely necessary, while the 76-year-old man (factor VII 10 %) never had to be substituted. In the severe case (patient I, factor VII < 1 ~) a continuous substitution therapy was required and has been carried out by home treatment without any side-effects or other problems. In case of acute bleeding the patient transfuses 1000 U factor VII concentrate, thus attaining a factor VII level of 15-20~. Literature values of factor VII levels necessary to achieve hemostasis vary widely from 5-20 ~ [11, 18, 19, 27]. According to our experience a therapy with 20 U factor VII concentrate/kg body weight might represent an effective therapeutic regimen. In the exceptional serious case of hypoproconvertinemia a prophylactic therapy [19, 26, 31] or a home treatment may be indicated. The management of patients with congenital factor VII deficiency undergoing surgery is very controversially. Operations successfully carried out with and without transfusion of factor VII containing material have been reported [5, 19, 27,29]. In our patients despite replacement therapy postoperative bleeding followed one appendectomy, whereas no postoperative bleeding followed patients requiring Achilles tendon lengthening and an above knee amputation and only slight bleeding followed a tonsillectomy. Based on this experience it is our opinion that a bleeding prophylaxis should be carried out in all operations, if the spontaneous factor VII level is assayed at less than 10 ~. A factor VII activity of at least 10-15 ~ should be attained during the first three postoperative days. Because of the short half-life of factor VII of 2 to 6 h [13,14] such a concentration canbe achieved by transfusion of factor VII concentrate or preparations containing factor VII 10-15 U/kg body weight at 6-hourly intervals [12,26]. However, one must also consider that patients suffering from severe hypoproconvertinemia are not protected against thromboembolic complications [11].
124
R. Zimmermann et al.
References 1. Alexander, B., de Vries, A., Goldstein, R., Landwehr, G. : Prothrombin conversion accelerator in serum. Science 109, 544 (1949) 2. Alexander, B., Goldstein, R., Landwehr, G., Cook, C.D.: Congenital SPCA deficiency: a hitherto unrecognized coagulation defect with hemorrhage rectified by serum and serum fractions. J. Clin. Invest. 30, 596 (1951) 3. Bachmann, F., Duckert, F., Geiger, M., Baer, P., Koller, F. : Differentiation of the factor VII complex. Studies on the Stuart-Prower factor. Thrombos. Diathes. Haemorrhag. 1, 169 (1957) 4. Bri~t, E., Loeliger, E.A., van Tilburg, N.H., Veltkamp, J. J. : Molecular variant of factor VII. Thrombos. Diathes. Haemorrhag. 35, 289 (1976) 5. Cleton, F.J., Loeliger, E.A. : Two typical hereditary charts of congenital factor VII deficiency. Thrombos. Diathes. Haemorrhag. 5, 87 (1961) 6. Denson, K.W.E., Conard, J., Samama, M.: Genetic variants of factor VII. Lancet I, 1234 (1972) 7. Gjonmess, H. : Cold promoted activation of factor VII. II. Identification of the activator. Thrombos. Diathes. Haemorrhag. 28, 169 (1972) 8. Gladhaug, A., Prydz, H. : Purification of the coagulation factor VII and X fi'om human serum. Some properties of factor VII. Biochim. Biophys. Acta 215, 105 (1970) 9. GlaBner, K., Schneider, W., Fr6hlich, C.: Die angeborene Faktor VII-Mangelaktivit~it. Dtsch. Med. Wochenschr. 98, 1969 (1973) 10. Goodnight, S.H., Feinstein, D.I., Osterud, B., Rapaport, S. I. : Factor VII antibody-neutralization material in hereditary and acquired factor VII deficiency. Blood 38, 1 (1971) 11. Hall, C.A., Rapaport, S.I., Ames, S.B., Degroot, J.A. : A clinical and family study of hereditary proconvertin (factor VII) deficiency. Am. J. Med. 37, 172 (1964) 12. I-Ieene, D.L. : Zur Anwendung eines Faktor VII-Konzentrates bei angeborenem ProconvertinMangel. In: 6. H/imophilie-Symposium, Hamburg, Landbeck, G., Marx, R. (eds.), p. 181. Heidelberg: Immuno GmbH 1976 13. Hitzig, W.H., Zollinger, W. : Kongenitaler Faktor VII-Mangel. Familienuntersuchung und physiologische Studien fiber den Faktor VII. Helv. Paediatr. Acta 13, 189 (1958) 14. Hoag, M.S., Aggeler, P.M., Fowell, A.H. : Disappearence rate of concentrated proconvertin extracts in congenital and acquired hypoproconvertinemia. J. Clin. Invest. 39, 554 (1960) 15. Kisiel, W., Davie, E.W. : Isolation and characterisation of bovine factor VII. Biochemistry 14, 4928 (1975) 16. Koller, F., Loeliger, A., Duckert, F. : Experiments on a new clotting factor (factor VII). Acta Haematol. 6, 1 (1951) 17. Laake, K., Osterud, B. : Activation of purified plasma factor VII by human plasmin, plasma kallikrein and activated components of the human intrinsic blood coagulation system. Thromb. Res. 5, 759 (1974) 18. Lasch, H.G., Heene, D., Mueller-Eckardt, C. : Pathophysiologie und Klinik der h~tmorrhagischen Diathesen. In: Klinische H/imatologie. Begemann, H., Rastetter, J., Kaboth, W. (eds.), S. 703. Stuttgart: Thieme 1970 19. Marder, V.J., Shulman, N.R.: Clinical aspects of congenital factor VII deficiency. Am. J. Med. 37, 182 (1964) 20. Mazzucconi, M.G., Mandelli, F., Mariani, G., Bri6t, E., Veltkamp, J.J.: A CRM-positive variant of factor VII deficiency and the detection of heterozygotes with the assay of factor-like antigen. Br. J. Haematol. 36, 127 (1977) 21. Owen, C.A., Bollmann, J.L.: Prothrombin conversion factor of dicoumarol plasma. Proc. Soc. Exp. Biol. Med. 67, 231 (1948) 22. Owen, C.A., Amundson, M.A., Thompson, J.H., Spittel, J.A., Bowie, E.J.W., Stillwell, G.G., Hewlett, J.S., Mills, S.D., Sauer, W.G., Gage, R.P. : Congenital deficiency of factor VII (hypoproconvertinemia) Am. J. Med. 37, 71 (1964) 23. Owren, P.A., Strandli, O.K. : Normotest. Farmakoterapi 1, 14 (1969) 24. Radcliffe, R., Nemerson, Y. : Activation and control of factor VII by activated factor X and thrombin. Biol. Chem. 250, 388 (1975) 25. Radcliffe, R., Bagdasarian, A., Colman, R., Nemerson, Y. : Activation of bovine factor VII by Hageman factor fragments. Blood 50, 611 (1977)
Congenital Factor VII Deficiency
125
26. Schimpf, K., Zimmermann, K. : Rehabilitation unter Substitution mit einem neuen Faktor VII-Konzentrat bei einem Patienten mit schwerem Faktor VII-Mangel. In: 6. HS.mophilieSymposium, Hamburg. Landbeck, G., Marx, R. (eds.), p. 175. Heidelberg: Immuno GrnbH 1976 27. Strauss, H. S. : Surgery in patients with congenital factor VII deficiency (congenital hypoproconvertinemia). Experience with one case and review of the literature. Blood 25, 325 (1965) 28. de Vries, A., Alexander, B., Goldstein, R. : A factor in serum which accelerates the conversion of prothrombin to thrombin. I. Its determination and some physiological and biochemical properties. Blood 4, 247 (1949) 29. Yorke, A.Y., Mant, M. J. : Factor VII deficiency and surgery. Is preoperative replacement therapy necessary? JAMA 238, 424 (1977) 30. Zimmermann, R., Hoffrichter, A., Walter, E., Ehlers, W., Andrassy, K., Lang, P.D., Schlierf, G., Weber, E., Barth, P.: Orale Antikoagulation und Thrombocytenfunktion bei hypolipfimischer Behandlung mit einem neuen Clofibrat-Analog (BM 15075). Dtsch. Med. Wochenschr. 102, 509 (1977) 31. Zollinger, W.: Familienuntersuchung beim kongenitalen Faktor VII-Mangel. Archiv der Julius-Klaus-Stiftung 38, 1 (1963)
Received May 8, 1978
Bltit ,so.
Blut 38, 119-125 (1979)
9 Springer-Verlag 1979
Congenital Factor VII Deficiency A Report of Four New Cases
R. Zirnmerrnann 1, G. Ehlers 1, W. Ehlers I, H. von Voss 3, U. G6beP and U. Wahn z l Medizinische Universitgtsklinik Heidelberg, Bergheimerstral3e 58, D-6900 Heidelberg 1, Federal Republic of Germany UniversitS.tskinderklinik Heidelberg, D-6900 Heidelberg, Federal Republic of Germany Universit~.tskinderklinik B, Dtisseldorf, D-4000 Diisseldorf, Federal Republic of Germany
Kongenitaler Faktor VII-Mangel Ein Berieht fiber vier neue F/ille Zusammenfassung. Vier neue Ffille mit angeborenem homozygoten und zehn Patienten rnit heterozygotem Faktor VII-Mangel werden beschrieben. Bei den homozygoten Ffillen war die Faktor VII-Aktivit/it auf < 1%, 3 %, 8 % und 10 % der N o r m vermindert. Schweregrad und H/iufigkeit der hfimorrhagischen Erscheinungen entsprachen dabei dem Ausmal3 der Faktor VII-Erniedrigung. Bei dem Patienten rnit schwerern Faktor VII-Mangel ( < 1%) wurde wegen rezidivierender Hfimarthrosen rnit Einschr/inkung der Gelenkfunktion eine Heimselbstbehandlung eingeleitet. Diese wird seit 1 89 Jahren mit einer Dosis yon 20 E/kg K G Prothrombinkomplex und neuerdings mit Faktor VII-Konzentrat in Abst/inden von etwa drei Wochen ohne Nebenreaktionen durchgeftihrt. Zwei Brfider (Faktor VII 8 % und 10 %) erreichten ein hohes Alter von fiber 70 Jahren. Trotz Substitution karn es nach einer Appendektornie zu einer Nachblutung, w~ihrend eine Achillessehnenoperation und eine Oberschenkelamputation ohne Substitution komplikationslos verliefen. Es wird vorgeschlagen, bei Patienten mit isoliertem Faktor VII-Mangel < 10 % bei operativen Eingriffen eine Mindest-Faktor VII-Konzentration yon 10-15% fiber einen Zeitraurn von drei Tagen aufrechtzuerhalten. Schliisselw6rter: Faktor VII - Hypoproconvertinemia - Faktor VII Substitutions-Therapie - Prothrornbinkomplex - Faktor VlI-Konzentration - Heirnselbstbehandlung - Operative Eingriffe
Summary. Four new cases with congenital homozygous factor VII deficiency are described. Factor VII levels were reduced to < 1%, 3%, 8% and 10%, respectively. The incidence and severity of bleeding symptoms were well correlated with the measured factor VII activity. In the severe case of factor VII Offprint requests to: Dr. Rainer Zimmermann (address see above) 0006-5242/79/0038/0119/$1.40
120
R. Zimmermann et al. deficiency ( < 1 ~ ) a home treatment program was started because of severe recurrent hemarthroses. This entailed transfusions of 20 U/kg body weight prothrombin complex or factor VII concentrate in case of acute bleeding approximately every three weeks. These transfusions have been carried out successfully without any problems. In contradiction, two brothers with hypoproconvertinemia (factor VII 8 ~ and 10~, respectively) reached an age of more than 70 years. Despite replacement therapy postoperative bleeding followed one appendectomy, whereas no postoperative bleeding followed patients requiring Achilles tendon lengthening and an above knee amputation and only slight bleeding followed a tonsillectomy. Based on our experience we suggest that in patients with factor VII deficiency of less than 10~, when undergoing surgery, should be maintained a minimal factor VII activity of 1 0 - 1 5 ~ during the first three postoperative days. Key words: Factor VII - Hypoproconvertinemia - Factor VII substitution therapy - Prothrombin complex - Factor VII concentrate - Home treatment Surgery
The existence of a new clotting factor termed "proconvertin", "serum prothrombin conversion accelerator" and finally factor VII was postulated in 1948 by Owen [21] and one year later by de Vries [28] and Alexander [1]. Proconvertin participates in the extrinsic pathway of blood coagulation and converts factor X to factor X a in the presence of tissue factor, phospholipid and calcium. However, evidence exists that the factor VII activity can be increased by the factors X a [24], XIIa [17], fragments of factor XII [25] and by storage at 0-4 ~ C due to the action of kallikrein [7]. Factor VII occurs in plasma as a single chain glycoprotein with a molecular weight of about 59,000, whereas that of the serum form is estimated to be 45,000 [8, 15,24]. The first case of congenital deficiency of proconvertin was described in 1951 by Alexander [2]. Due to methodical problems patients were widely reported as suffering from hypoproconvertinemia, but had later to be classified as a deficiency of Stuart-Prower factor, which was discovered in 1956 [3,22]. About 80 patients with homozygous factor VII deficiency have since been reported. The inheritance is autosomal recessive [5, 31]. Immunologic examinations have shown that in most of the cases "cross reacting material" (CRM) with proconvertin was not demonstrable by means of an inhibitor neutralization assay [20]. However, patients with normal or moderately reduced amount of CRM were described [4,6,9,10,20]. In the following report four new cases with homozygous factor VII deficiencies of different degrees of severity will be described. In contrast to one patient who was referred to a home treatment program because of serious bleeding tendency, two brothers reached an age of more than seventy years without dangerous hemorrhage.
Congenital Factor VII Deficiency
121
Case Reports Case I
A fourteen-year-old boy with no family history of hemorrhagic diathesis and with a normal anteand perinatal history had clinical signs of cerebral palsy. Because of equinus deformities of both feet a lengthening of the Achilles tendons was carried out. Despite no substitution of factor VII there was no evidence of postoperative bleeding. A factor VII deficiency was diagnosed in 1969 after manifestation of the first hemorrhagic symptoms at six years of age (factor VII < 1%). They consisted of prolonged epistaxis, subcutaneous hemorrhages and occasional bleeding into finger, knee and ankle joints. A phimosis was dilated without any hemorrhagic complications. In 1969, despite two transfusions of 1000 U of ACC 76 an appendectomy was followed by melena and hematuria and required transfusions of blood. Later on bleeding from the gums around carious teeth and epistaxis was observed. Repeated hemorrhages every two to four weeks into both elbow joints led to a loss of extension and pronation. Due to the progessively reduced range of movement it was decided to start a program of therapy at home. After a training period, the home treatment was performed well and reliably for 11A years by the patient when acute bleeding occured. A dose of 1000 U prothrombin complex was substituted after onset of bleeding and was sufficient to control the hemorrhage (body weight 53 kg). For the last few months the fourteenyear-old boy has given himself 1000 U factor VII concentrate (Immuno GMBH, Heidelberg) at each joint bleeding. Up to now the home replacement therapy has been tolerated well. Case I I
A sixteen-year-old boy with family history of allergic diathesis and normal ante- and perinatal history was observed as having recurrent epistaxis in infancy. In 1971, a tonsillectomy was followed by a moderate postoperative hemorrhage involving a slight reduction of hemoglobin. An injury from glass splinters led to prolonged bleeding from multiple cuts. Before an appendectomy in September 1973, a routine coagulation analysis demonstrated a prolonged prothrombin time of 36%. 300 U prothrombin complex was given prior and during the operation and further at 6-hourly intervals for three days (body weight 35 kg). There was no excessive bleeding, neither during nor after surgery. On further investigation of the prolonged protfirombin time, a liver disease was excluded and the tentative diagnosis of factor VII deficiency confirmed (factor VII 3 %). Case III
A 71-year-old man. Family history and childhood history could not be recalled completely; but a serious hemorrhagic diathesis could not be ascertained. At 27 years of age, while playing football the patient knocked against the goal post with his left knee. After a year's clinical treatment due to recurrent trouble in the knee joint the left knee finally stiffened in the flexion position. A later fall on this joint led to an above knee amputation. In 1973, 1974, and 1975 he was admitted to hospital because of repeated severe epistaxis and an atrophic gastritis. A liver disease could be excluded. The coagulation analysis demonstrated a hypoproconvertinemia (factor VII 8%). Replacement therapy was not necessary. Case I V
While examining the family of case III factor VII deficiency was established in the 76-year-old brother (factor VII 10%). No severe bleeds were reported in the history. Five members of this family (3 females and 2 males) showed a partial factor VII deficiency; but only one daughter gave a history of recurrent slight epistaxis (factor VII 54 %).
Methods The factor VII activity was assayed according to Koller [16] using a human factor VII-deficient plasma, the factors VIII and IX using commercial reagents (Merz and Dade Company, Miinchen). Concentration of the factors II, V, X, the Stypven clotting time and the thrombin time were determined by means of reagents from the Behringwerke, Marburg/Lahn and the Normotest according to Owren [23]. The prothrombin time, the activated partial thromboplastin time, thrombelastography, concentration of fibrinogen, the Mielke-bleeding time and the platelet count were performed as reported previously [30].
122
R. Zimmermann et al.
Table 1. Coagulation analysis of the three families with congenital homozygous (cases I-IV) and heterozygous factor VII deficiency. Concentrations of the coagulation factors VII, II, IX, X, the prothrombin time (PT), Normotest (NT), activated partial thromboplastin time (APPT) and the bleeding time (B.T.) Patient
PT (%)
NT (%)
case I father mother sister case II father mother case III case IV daughter daughter son grandchild grandchild
12 85 53 76 32 100 100 37 25 95 100 75 75 110
< 10 66 42 65 32 70 54 36 39 67 64 62 56 74
normal values
70-130
70-130
Factors VII
II
100 100 100 100 > 100 100 100 100 > 100
IX (%) 66 100 100 92 > 100 > 100 > 100 > 100 100 > 100 > 100 100 > 100 > t00 70-120
X
APTT (sec.)
B.T. (sec.)
100 100 100 98 85 > 100 100 > 100 100 > 100 > 100 100 > 100 > 100
40 42 41 38 41 39 46 37 35 37 32 34 35 39
225 165 190 270 274 285 210 400 295 290 280 285 510 445
35-50
-360
Results The essential d a t a of the c o a g u l a t i o n analysis are shown in T a b l e 1. The f o u r patients with h o m o z y g o u s h y p o p r o c o n v e r t i n e m i a d e m o n s t r a t e d isolated r e d u c t i o n s of the factor V I I with concentrations o f < 1%, 3%, 8 % a n d 10%, respectively. A d d i t i o n a l l y p e r f o r m e d tests such as Stypven clotting time, t h r o m b o p l a s t i n generation test, factor V, factor VIII, t h r o m b e l a s t o g r a p h y , platelet count, fibrinogen c o n c e n t r a t i o n a n d the t h r o m b i n time were normal. D u e to clinical and in s o m e cases histological e x a m i n a t i o n s it was possible to exclude a liver disease in all patients.
Discussion I n h o m o z y g o u s h y p o p r o c o n v e r t i n e m i a factor VII level is generally reduced to less t h a n 10%. M o s t o f the patients d e m o n s t r a t e a lifelong bleeding tendency [2,11, 19,221. The h e m o r r h a g i c s y m p t o m s can a l r e a d y be manifest in the n e w b o r n (neonatal type) with umbilical, gastrointestinal a n d cerebral bleeding or later, e.g., after p u b e r t y (juvenile type) [22]. Epistaxis, h e m a r t h r o s e s a n d gastrointestinal bleeding are m o r e c o m m o n in males, whereas in females m e n o r r h a g i a is the p r e d o m i n a n t s y m p t o m [5,19,22]. C o m p a r i n g the r e p o r t e d cases o f congenital f a c t o r V I I deficiency the incidence a n d the degree o f severity o f bleeding s y m p t o m s v a r y widely a n d do n o t show any relation to the established factor V I I activity [11,19].
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These discrepancies can be based on the genetic and biochemical heterogeneity of hypoproconvertinemia [10] or on the differences in laboratory tests and their interpretations [19, 27]. Our four patients with homozygous factor VII deficiency demonstrated a relationship between hemorrhagic diathesis and factor VII activity. The boy with a factor VII level of < 1 ~ displayed the most serious bleeding symptoms with development of joint deformities, which are rarely seen in hypoproconvertinemia [11,27]. Patient 1[ (factor VII 3 ~ ) and the 71-year-old man (case III, factor VII 8 ~ ) showed recurrent epistaxis, while the fourth patient (factor VII 10 ~) reached the age of 76 years without manifest bleeding. These observations support the suggestion of Strauss [27] that only patients with a factor VII level of less than 3 demonstrate an evident bleeding tendency, provided the real factor VII activity is evaluated by using a human or animal factor VII deficient plasma. Patients with factor VII activity of more than 3 ~ bleed less often and can apparently reach an old age. The replacement therapy of hypoproconvertinemia can be performed with whole blood, plasma [2, 19,22,27] or prothrombin complex [9,31]. Since 1975 a purified commercial factor VII concentrate is available [12,26]. In our cases II and III (factor VII 3 ~ and 8%, respectively) replacement therapy was rarely necessary, while the 76-year-old man (factor VII 10 %) never had to be substituted. In the severe case (patient I, factor VII < 1 ~) a continuous substitution therapy was required and has been carried out by home treatment without any side-effects or other problems. In case of acute bleeding the patient transfuses 1000 U factor VII concentrate, thus attaining a factor VII level of 15-20~. Literature values of factor VII levels necessary to achieve hemostasis vary widely from 5-20 ~ [11, 18, 19, 27]. According to our experience a therapy with 20 U factor VII concentrate/kg body weight might represent an effective therapeutic regimen. In the exceptional serious case of hypoproconvertinemia a prophylactic therapy [19, 26, 31] or a home treatment may be indicated. The management of patients with congenital factor VII deficiency undergoing surgery is very controversially. Operations successfully carried out with and without transfusion of factor VII containing material have been reported [5, 19, 27,29]. In our patients despite replacement therapy postoperative bleeding followed one appendectomy, whereas no postoperative bleeding followed patients requiring Achilles tendon lengthening and an above knee amputation and only slight bleeding followed a tonsillectomy. Based on this experience it is our opinion that a bleeding prophylaxis should be carried out in all operations, if the spontaneous factor VII level is assayed at less than 10 ~. A factor VII activity of at least 10-15 ~ should be attained during the first three postoperative days. Because of the short half-life of factor VII of 2 to 6 h [13,14] such a concentration canbe achieved by transfusion of factor VII concentrate or preparations containing factor VII 10-15 U/kg body weight at 6-hourly intervals [12,26]. However, one must also consider that patients suffering from severe hypoproconvertinemia are not protected against thromboembolic complications [11].
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26. Schimpf, K., Zimmermann, K. : Rehabilitation unter Substitution mit einem neuen Faktor VII-Konzentrat bei einem Patienten mit schwerem Faktor VII-Mangel. In: 6. HS.mophilieSymposium, Hamburg. Landbeck, G., Marx, R. (eds.), p. 175. Heidelberg: Immuno GrnbH 1976 27. Strauss, H. S. : Surgery in patients with congenital factor VII deficiency (congenital hypoproconvertinemia). Experience with one case and review of the literature. Blood 25, 325 (1965) 28. de Vries, A., Alexander, B., Goldstein, R. : A factor in serum which accelerates the conversion of prothrombin to thrombin. I. Its determination and some physiological and biochemical properties. Blood 4, 247 (1949) 29. Yorke, A.Y., Mant, M. J. : Factor VII deficiency and surgery. Is preoperative replacement therapy necessary? JAMA 238, 424 (1977) 30. Zimmermann, R., Hoffrichter, A., Walter, E., Ehlers, W., Andrassy, K., Lang, P.D., Schlierf, G., Weber, E., Barth, P.: Orale Antikoagulation und Thrombocytenfunktion bei hypolipfimischer Behandlung mit einem neuen Clofibrat-Analog (BM 15075). Dtsch. Med. Wochenschr. 102, 509 (1977) 31. Zollinger, W.: Familienuntersuchung beim kongenitalen Faktor VII-Mangel. Archiv der Julius-Klaus-Stiftung 38, 1 (1963)
Received May 8, 1978
