clinical aspects of congenital factor vii deficiency

13
Clinical Aspects of Congenital Factor VII Deficiency* VICTOR J. MARDER, M.D. and N. RAPHAEL SHULMAN, M.D. Bethesda, Maryland S INCE the first description of “idiopathic hypoprothrombinemia” by Rhoads and Fitz-Hugh in 1941 [7], many case reports have appeared in the literature describing congenital coagulation disorders that involve primarily a prolongation of the one-stage prothrombin time. The reports by Owren (factor v deficiency) [Z], Alexander et al. (factor VII deficiency) [3], Telfer et al. [4] and Hougie et al. (factor x deficiency) [5,6] have elucidated those congenital syndromes other than hypoprothrombinemia that are associated with a long prothrombin time. As the laboratory tests necessary to differentiate these congenital syndromes have evolved, two and even three reports of the same case have sometimes appeared, each time with a revised diagnosis [5,7-741. In addition, many reports describing factor VII deficiency [75-481 have been shown by retrospective analysis to be reporting deficiencies of a different factor or to contain insufficient information to rule out this possibility. Applying the necessary criteria, fifty-one cases of isolated marked congenital factor VII deficiency have been found in the world literature [3,49-871. The reported data relating to congenital factor VII deficiency are summarized and compared with the results obtained in the present study. METHODS Laboratory tests were performed as indicated in Table I. The anticoagulant used was 0.1 part 40 per cent sodium citrate per 9.9 parts whole blood. A modified one-stage assay [82,83], based on the degree of correction of the long one-stage time of plasma congenitally deficient in factor VII, was used to determine the factor VII levels. The factor VII level of the test plasma was calculated from a standard correction curve obtained by diluting the normal plasma in the factor VII-deficient plasma. The normal plasma that was assigned a value of 100 per cent factor VII was obtained from a donor whose plasma factor VII level was closest to the average value of samples from twenty random donors. The normal range of factor VII concentration was found to be from TABLE I COAGULATION TEST RESULTS Test Reference Normal Case 29 Case 30 Factor VII assay (a) Clotting time (min.) Bleeding time (min.) One-stage prothrombin time (sec.) Russell’s viper venom time (sec.) Platelet count (lO*/cu. mm.) Thromboplastin generation (serum) (sec.) Two-stage prothrombin assay (units/ml.) 60-Minute prothrombin consumption (X) Fibrinogen (mg. %) Anticoagulant Keller et al. [82], Owren, Aas [83] Lee, White [84] Ivy et al. [85] Quick [86] Fullerton [87] Brecher, Cronkite [88] Biggs, Douglas [S!J] Warner et al. [go], Ware, Seegers [97] de Vries et al. [!Z?] Cullen, van Slyke [93] Conley et al. [94], Margolius et al. [95] 75-125 6-12 3-7 12-15 9-12 150-250 10-13 200-300 92-l 00 200-300 <O.l 12 5 80-100 * 9.9 200 12 206 100 282 Negative <0.5 11 6 49-72 * 9.2 178 10.6 200 95 290 Negative - - - - * Prolonged one-stage prothrombin time corrected by addition of normal serum. * From the Clinical Hematology Branch, National Institute of Arthritis and Metabolic Diseases, National Insti- tutes of Health, Bethesda, Maryland. Manuscript received October 22, 1963. 182 AMERICAN JOURNAL OP MEDICINE

Upload: victor-j-marder

Post on 18-Oct-2016

236 views

Category:

Documents


17 download

TRANSCRIPT

Clinical Aspects of Congenital Factor VII

Deficiency*

VICTOR J. MARDER, M.D. and N. RAPHAEL SHULMAN, M.D.

Bethesda, Maryland

S INCE the first description of “idiopathic

hypoprothrombinemia” by Rhoads and Fitz-Hugh in 1941 [7], many case reports have appeared in the literature describing congenital coagulation disorders that involve primarily a prolongation of the one-stage prothrombin time. The reports by Owren (factor v deficiency) [Z], Alexander et al. (factor VII deficiency) [3], Telfer et al. [4] and Hougie et al. (factor x deficiency) [5,6] have elucidated those congenital syndromes other than hypoprothrombinemia that are associated with a long prothrombin time. As the laboratory tests necessary to differentiate these congenital syndromes have evolved, two and even three reports of the same case have sometimes appeared, each time with a revised diagnosis [5,7-741. In addition, many reports describing factor VII deficiency [75-481 have been shown by retrospective analysis to be reporting deficiencies of a different factor or to contain insufficient information to rule out this possibility. Applying the necessary criteria,

fifty-one cases of isolated marked congenital factor VII deficiency have been found in the world literature [3,49-871. The reported data relating to congenital factor VII deficiency are summarized and compared with the results obtained in the present study.

METHODS

Laboratory tests were performed as indicated in Table I. The anticoagulant used was 0.1 part 40 per cent sodium citrate per 9.9 parts whole blood. A modified one-stage assay [82,83], based on the degree of correction of the long one-stage time of plasma congenitally deficient in factor VII, was used to determine the factor VII levels. The factor VII level of the test plasma was calculated from a standard correction curve obtained by diluting the normal plasma in the factor VII-deficient plasma. The normal plasma that was assigned a value of 100 per cent factor VII was obtained from a donor whose plasma factor VII level was closest to the average value of samples from twenty random donors. The normal range of factor VII concentration was found to be from

TABLE I COAGULATION TEST RESULTS

Test Reference Normal Case 29 Case 30

Factor VII assay (a) Clotting time (min.) Bleeding time (min.) One-stage prothrombin time (sec.) Russell’s viper venom time (sec.) Platelet count (lO*/cu. mm.) Thromboplastin generation (serum) (sec.) Two-stage prothrombin assay (units/ml.) 60-Minute prothrombin consumption (X) Fibrinogen (mg. %) Anticoagulant

Keller et al. [82], Owren, Aas [83] Lee, White [84] Ivy et al. [85] Quick [86] Fullerton [87] Brecher, Cronkite [88] Biggs, Douglas [S!J] Warner et al. [go], Ware, Seegers [97] de Vries et al. [!Z?] Cullen, van Slyke [93] Conley et al. [94], Margolius et al. [95]

75-125 6-12 3-7

12-15 9-12

150-250 10-13

200-300 92-l 00

200-300

<O.l 12

5 80-100 *

9.9 200

12 206 100 282 Negative

<0.5 11

6 49-72 *

9.2 178

10.6 200

95 290 Negative

-

-

- -

* Prolonged one-stage prothrombin time corrected by addition of normal serum.

* From the Clinical Hematology Branch, National Institute of Arthritis and Metabolic Diseases, National Insti- tutes of Health, Bethesda, Maryland. Manuscript received October 22, 1963.

182 AMERICAN JOURNAL OP MEDICINE

Congenital Factor VII Deficiency-Murder, Shulman 183

75 to 200 per cent. In assaying a plasma sample, duplicate determinations were performed, using two dilutions that gave prothrombin time values in an accurate part of the standard curve. The average per cent deviation of four such determinations from their respective mean values was * 12.

CASE REPORTS

(:ASE 29 (Table III). A five year old, full blooded Savajo Indian girl (A. N.) was first seen at the U. S. Public Health Service Indian Hospital in Tuba City, Arizona, at the age of twelve months because of pronounced epistaxis and gingival bleeding. Pre- liminary coagulation studies showed a normal bleed- ing time, clotting time and platelet count but an abnormal prothrombin time.* Results of liver func- tion tests were normal. A tentative diagnosis of factor VII deficiency was made 1591, and the patient was treated with plasma, whole blood, orally administered vitamin K and iron. Because of repeated bleeding from mucous membranes, occasionally severe enough to cause tarry stools, the patient was transferred to the Clinical Center, National Institutes of Health, in October 1958 at the age of twenty-three months.

The family history revealed that the patient’s mother was the step-daughter, as well as the wife, of the patient’s father. (Fig. 1.) One sister and two half-brothers had severe epistaxis and joint bleeding almost from birth and died before the age of two years. Neither of the parents nor any other family members had a bleeding tendency. Of interest was the presence of albinism in three half siblings, one of whom died of hemorrhage in childhood.

On admission, the patient appeared healthy except for the presence of dried blood in the nasal cavity and numerous ecchymoses in various stages of evolution. Routine blood counts were normal except for a slight anemia. Results of liver function tests and urinalysis were normal. Pertinent coagulation data, listed in ‘fable I, confirmed the diagnosis of factor VII deficiency.

Hemorrhagic manifestations in this patient con- sisted of spontaneous ecchymoses, epistaxis, gingival bleeding and hemarthroses, and were usually accompanied by listlessness and irritability. Two noteworthy hemorrhagic complications occurred during the three and a half years of observation. At tbventy-eight months of age, without antecedent trauma, the patient had sudden pain, tenderness and fullness in the left upper quadrant of the abdomen and was thought to have a splenic hematoma. She recovered quickly after a plasma infusion. At thirty- seven months of age the patient had a spontaneous cerebrovascular accident, manifest as seizures and hemiparesis on the right side. A lumbar puncture revealed grossly bloody fluid, xanthochromia and crenated red blood cells, and electroencephalogram showed a pattern consistent with a left temporal

* Lovelace Clinic, Albuquerque, New Mexico.

VOL. 37, AUGUST 1964

r

co. I f

I

00 ’ PROBABLE NORMAL t DECEASED

an PROBABLE HETEROZYGOTE * ALBlNlSM

l = PROBABLE HOMOZYGOTE {_-j;;--j NOT TESTED

FIG. 1. Pedigree of patient (Case 29). The numbers indicate the plasma factor VII Ievels in per cent of normal. Levels above 75 per cent are considered within the normal range (see text). The patient’s two half-brothers and one sister, who had severe hemorrhagic symptoms leading to death before two years of age, were not tested but are considered homozygous for a defective gene controlling factor VII. The other five dead siblings had no history of abnormal bleeding.

hemorrhage. She was treated with plasma and Dilantin”* and made a rapid, complete recovery.

It was found that infusions of approximately 250 ml. of plasma were immediately effective in con- trolling all types of hemorrhage, with beneficial effects lasting for three to four days. If prophylactic plasma infusions were given every three to four days, the patient could be kept free of hemorrhagic episodes for months at a time. Prolongation of the interval between plasma infusions to five or six days regularly resulted in the entire spectrum of bleeding mentioned. The patient was still susceptible to abnormal hemor- rhage after trauma, and at the age of five years she had a large traumatic right periorbital hematoma which resolved after an additional infusion of plasma.

Intensive intravenous vitamin Kt therapy with Hykinone@ (6 mg. per kg. per day for nine days), Synkavitea (6 mg. per kg. per day for six days) and

* Dilantin, diphenylhydantoin, Parke-Davis & CO., Detroit, Michigan.

t Hykinone, menadione sodium disultite, Abbott Laboratories, North Chicago, Illinois; Synkavite, menadiol sodium diphosphate, Hoffmann-La Roche Inc., Nutley, New Jersey; Mephyton, vitamin K1 emul- sion (phytonadione), Merck & Co., Rahway, New Jersey.

184 Congenital Factor VII Deficiency-Marder, Shulman

TABLE IX

SURVIVAL OF FACTOR VII REPORTED

1N THE LITERATURE

Hitzig, Zollinger

WI Frick [7041* Caen et al. [a91 Haag et al. 1491

Loeliger et al. [lo21

RODS et al. [64] Hjort et al. [103] Present paper

Half-Life (min.) Vita- min K Half-

Reap- cou- pear-

Plasma Serum

concen-

Infusions Infu- trate mar’n ance

sions Infusions Treat- Time ment (min.)

115-135 _. 57 330-360 240-360 240-360 . . . (I) 11-17 ::: I :::

(2) 90-110 1) 70-115 125-205 250-375 420-600

2) 250-375 190 330

..I “’ 290-320 300 .., (1) 35 280 280

(2) 300

NOTE: When two decay components are identified, these are labelled

(1) and (2). *Assay system did not distinguish factor x from factor VII. Both

factors were reduced in the coumarin-treated subject receiving the plasma infusions.

Mephyton@ (70 mg. per kg. per day for two days) had no effect on the clinical course or laboratory findings. A factor VII concentrate* used by Hoag et al. [49] for survival studies was also found to provide effective prophylactic therapy. This preparation contained up to eighty times the factor VII content found in plasma, and infusions of only 3 to 10 ml. of concentrate every three to four days were sufficient for effective prophylactic therapy. Prophylactic treatment by plasma infusions over a two year period permitted the patient to participate in normal physical activities with only an occasional increase in therapy necessitated by significant trauma. The patient left our care at the age of five and a half years.

CASE 30. A thirty-nine year old Caucasian male hospital orderly (R. K.) was admitted to the Clinical Center, National Institutes of Health, in July 1963 for evaluation of his bleeding tendency. The patient’s first hemorrhagic symptoms, at three years of age, consisted of bouts of prolonged epistaxis often requiring hospitalization for replacement trans- fusion. Subcutaneous hemorrhages were frequent and occasionally appeared in joint areas. These peri- articular ecchymoses caused severe pain on motion and necessitated immobilization for one to two weeks but did not result in permanent joint deformity or limitation of motion.

At the age of nineteen the patient underwent an appendectomy at the Allentown, Pennsylvania, General Hospital. According to history and available

* Kindly supplied by Dr. Paul Aggeler, San Francisco Medical Center, San Francisco, California.

68 51 67 FIG. 2. Pedigree of patient (Case 30). Symbols described in Figure 1. Patient’s only sibling died of hemorrhage at six years of age.

hospital records, no transfusions were administered before or during the operation, and there was no abnormal operative or postoperative bleeding. The patient has had several dental extractions, each preceded by an infusion of plasma, with normal hemostasis after each procedure.

At age thirty the patient first noted gross hematuria associated with back pain, Intravenous and retro- grade pyelography and cystoscopy at the Gnaden- Huetten Hospital in Lehighton, Pennsylvania, failed to demonstrate an underlying cause for this bleeding. He has continued to have intermittent gross and microscopic hematuria to the present time. In June 1963 the patient had gross rectal hemorrhage and was found to have proctitis, with “freshly healed bleeding sites” on sigmoidoscopic examination. Therapeutic trials of vitamin K have proved ineffective in chang- ing the one-stage prothrombin time or in controlling hemorrhage of any type.

There is no history of bleeding in the patient’s parents or grandparents, but a sister died at six years of age after a severe bout of epistaxis and gingival bleeding. (Fig. 2.)

On admission, the physical examination revealed no abnormalities except for a small hematoma on the left thigh and grossly carious teeth. Laboratory data (Table I) demonstrated a pure factor VII deficiency. In addition, mixture of this patient’s plasma with that of the patient described in Case 29 did not result in shortening of the long one-stage prothrombin time, proving an identical deficiency in both .patients. Liver function chemistries were normal.

The patient had an unremarkable hospital course with no episodes of spontaneous bleeding. Intravenous pyelography again failed to demonstrate an under- lying cause for the intermittent hematuria of the previous nine years. After a 60 minute infusion of 19 ml. plasma per kg., he underwent dental extraction of two molars, extensive dental repair and gingival prophylaxis, with no abnormal postoperative bleed- ing. His plasma factor VII level rose from a preopera- tive level of less than 0.5 per cent of normal to a level

AMERICAN JOURNAL OF MEDICINE

Congenital Factor VI I Deficiency-Adder, Shulman 185

of 24 per cent at the time of surgery. He was dis- charged home in good condition.

OBSERVATIONS AND COMMENTS

Laboratory Diagnosis. Hemorrhage associated with a prolonged one-stage prothrombin time can be seen in the following groups of disorders:

Congenital dejciencies: These disorders are usually isolated, involving a lack of factor I

(fibrinogen), factor II (prothrombin), factor v (labile factor, AC globulin, proaccelerin), factor VII (stable factor, SPCA, proconvertin) or factor x (Stuart-Prower factor).

Acquired dejciencies: These abnormalities are usually multiple, involve one or several of the factors listed above and occur usually in asso- ciation with liver disease, after treatment with coumarin drugs, with vitamin K deficiency, or during acute defibrinating syndromes. Occa- sionally an isolated deficiency may be acquired, e.g., involving factor x [96,97].

clnticoagulants: Anticoagulants are seen in sys- temic lupus erythematosus [95] after administra- tion of heparin or following fibrinolysis [98]. The presence of an anticoagulant can be ruled out by failure of the test plasma to prolong the recalcification time [94] or prothrombin time [95] of normal plasma. There are no confirmed studies to indicate that a pure factor VII inhibitor exists.

Differentiation of the isolated congenital deficiencies can be achieved in the following manner: Hypofibrinogenemia which is severe enough to prolong the prothrombin time is usually detectable by inspection of the whole blood or plasma clot and can be confirmed by quantitative fibrin measurement (e.g., clottable nitrogen) [93]. A diagnosis of prothrombin deficiency is made most reliably by a two-stage assay [90,97] using normal human serum as a source of accelerator in the test. Of the three remaining possible deficiencies (factors v, VII and x), only factor v activity is absent in serum and lost during prolonged storage of plasma. Therefore, correction of the prolonged one- stage prothrombin time of pathologic plasma by normal serum rules out a deficiency of factor v.

If these studies fail to identify the deficiency, the diagnosis rests between factor VII deficiency and factor x deficiency. The use of Russell’s viper venom instead of the usual tissue thrombo- plastin in the one-stage prothrombin time is useful in distinguishing these two deficiencies. With factor vrr-deficient plasma, the Russell’s

VOL. 37, AUGUST 1964

viper venom time is normal, whereas with plasma deficient in factor x (as well as pro- thrombin or factor v) the Russell’s viper venom time is prolonged. In addition, serum deficient in factor x is abnormal in the thromboplastin generation test [89] whereas serum deficient in factor VII is normal in this test. Availability of plasma from patients with known deficiencies allows verification of specific abnormalities by correction experiments. When multiple de- ficiencies exist, these correction tests may be the only reliable means of diagnosis.

Genetic Studies. The pedigree of the patient described in Case 29 is shown in Figure 1. Essentially, these are two separate family trees, each with a common paternal ancestor. There was no inconsistency in this pedigree on the basis of red cell phenotypes of fifteen antigens. The patient’s father and his first wife (the patient’s maternal grandmother) both have reduced levels of factor VII. The appearance of albinism in three of their offspring suggests consanguinity, but this cannot be verified historically. The patient’s mother (step-daughter and second wife of the patient’s father) has a normal plasma factor VII level. Despite the difference in factor VII levels between the hus- band’s two wives, the two sets of ten offspring are similar in incidence of clinically apparent hemorrhagic diathesis and measurable reduction of plasma factor VII. There is a history of severe hemorrhagic symptoms in four of the twenty total offspring, three of whom died of secondary effects of blood loss before the age of two.

The only sibling of the patient described in Case 30 (Fig. 2) died of hemorrhage at six years of age and probably also had severe factor VII deficiency. The patient’s wife has a normal factor VII level, but all three children have reduced plasma factor VII levels. None of the children has had a bleeding or bruising tendency.

The laboratory studies reported in the literature on family members of factor VII-

deficient patients are extensive ancl have led to a variety of conclusions regarding the expression and inheritance of the abnormal gene. The following is a summary of the genetic findings in these and the present studies: I(lj There is general agreement that the gene is autosomal and that consanguinity of the parents is frequent. (2) Despite considerable variation in laboratory technics, three general ranges of plasma factor VII are differentiated in the families of the

86 Congenital Factor VII Deficiency-Mder, Shdman

H 10 ML. R-AWA/KG 1 I 0 5 IO 15 20

HOURS Fro. 3. Correction of long one-stage prothrombin time in Case 29 after infusion of fresh frozen plasma. Pro- thrombin time returned to preinfusion levels less than 24 hours after the infusion. Patient weighed 16 kg. at time of infusion.

propositii: normal (75 to 200 per cent), reduced or intermediate (25 to 75 per cent) and low (0 to 25 per cent). Abnormal bleeding occurs only in the group with low factor vu levels, with a single exception [90]. (3) The parents and the children of the propositii usually have inter- mediate levels of factor VII, with five notable exceptions in which the levels are normal. None of the parents or children of the propositii have a documented hemorrhagic diathesis, and in only one family do these relatives have factor VII levels below 25 per cent [57]. (4) In three families (including the present Case 29) one parent of the propositus has a normal, rather than reduced factor VII level [68,76], and in another family both paternal grandparents have

normal levels [a]. In a fifth family, some persons with normal levels have children with intermediate factor VII levels [54].

These observations indicate that the gene or genes controlling factor VII is autosomal but neither completely dominant nor completely recessive. The abnormality leading to factor VII

deficiency can be thought of as resulting from an “incomplete” or “defective” gene. The “bleeders” probably are homozygous for the abnormal gene. Consistent with this possibility is the fact that four of the twenty children of the father of the patient in Case 29 had severe hemorrhagic manifestations. As in hemophilia [NJ, the “carrier” often has a reduced level of the clotting factor. However, some carriers have

I I I 1 I I I

? A - l0 ML. RAShfA/KG,

\ \

B - 07 ML. cLwczN?RATE/KG~

C -02h4L. COMFA’?RATE/KG

FIG. 4. Factor VII decay curves obtained in Case 29 following infusions of plasma and a plasma concentrate. Plasma factor VII levels are plotted on a logarithmic scale. Infusion times were 3 hours for A, 10 minutes for B and 3 minutes for C. The two decay components are best illustrated in curve B. The dotted part of curve A was drawn to fit the calculated half-time of the first decay component [700,707].

normal levels and can be identified only if they

have a severely affected offspring. Survival of Factor VII in Vivo. The half-life of

factor VII is short, as reflected in the return of the one-stage prothrombin time to pretreatment values in less than 24 hours after a large plasma infusion. (Fig. 3.) Quantitative decay rates of factor VII can be measured after infusions of normal plasma, serum or factor vn concentrates into recipients lacking the factor or into normal persons who have received coumarin-type drugs.

In our patients, a two-component decay curve was seen following rapid infusions of a con- centrate, but only a single decay component was noted after plasma infusions. (Fig. 4 and 5.) The two-component curve probably repre- sents primarily an initial rapid diffusion of the factor into the extravascular space, followed by a slower phase of metabolism and back diffusion. The single decay slope obtained after the plasma infusions was not statistically different from the second decay component following concentrate infusions [7Oa, 7071. The half-lives of the two components, calculated from the fitted slopes

[7@ 7071, are 35 minutes and 300 minutes, respectively. The early decay phase is apparent

AMERICAN JOURNAL OF MEDICINE

Congenital Factor VII Deficiency-Murder, Shulman 187

I I I I I I __

0 4 8 I2 16 zo 24

TIME (HOURS)

FIG. 5. Factor VII decay curve following infusion of 19 ml. plasma per kg. in Case 30. Infusion time was 30 minutes; patient’s weight was 80 kg. Observed half-time agreed with results obtained in Case 29, despite a fivefold difference in body weight and a striking clinical disparity between the two patients.

only after rapid infusions of concentrate. Since a prolonged plasma infusion obscures this early phase, most studies reported in the literature measure only the second decay component. The half-life of factor VII after administration of Coumadin@* to a normal volunteer (Fig. 6) and the half-reappearance time after intra- venous administration of vitamin li, are both approximately 280 minutes. In Table II, our results are compared with other reported results.

The decay of autologous factor VII in normal subjects [ 702,704] (or persons with hemophilia) [703] after coumarin treatment is identical with that seen after infusions of factor VII into subjects congenitally deficient in factor VII. This suggests that factor VII is not utilized more rapidly in patients with congenital factor VII deficiency

* Coumadin, warfarin sodium, Endo Laboratories Inc., Richmond Hill, New York.

VOL. 37, AUGUST 1964

t , I I I I

6 12 18 24 30 36 TIME AFTER COUMADIN (HOURS)

FIG. 6. Decay of factor VII and prothrombin after intra- venous administration of Coumadin (300 mg.) to a normal subject. Observed half-lives were 5 hours for factor VII and 30 hours for prothrombin. The half- reappearance time of factor VII (Table II) was measured after intravenous administration of vitamin K,, when the plasma level had dropped below 1 per cent of normal.

than in normal subjects. In addition, the sur- vival of plasma factor VII is the same as that of serum factor vn [64,X72] or concentrate factor VII (Fig. 4), suggesting that there is no difference in factor VII from these sources.

Clinical Course. The clinical findings in the fifty-two case studies of proved severe congenital factor VII deficiency are summarized in Table III. There were thirty-one female and twenty-one male subjects in forty-four families. The diag- nosis was established before fifteen years of age in 46 per cent of the cases, in many of which severe hemorrhage had occurred in the first week of life. There were four deaths, three before the age of two years; two resulted from intra- cranial hemorrhage. In addition, seven untested siblings of the patients in the reported cases died of “hemorrhage,” six in infancy, and pre- sumably had factor VII deficiency.

There was a wide variation in hemorrhagic manifestations from patient to patient, as demonstrated by comparison of the two cases presented herein. One patient (Case 30) showed no bleeding tendency until three years of age and since then has led a relatively normal

Congenital Fat tor VII Deficiency----Mar&r, Shulman

TABLE III

REPORTED CASES OF PROVED CONGENITAL FACTOR VII DEFICIENCY

Case No.

Reference Patient, Age (yr.1 and Sex

-

1

-_

One-Stage ‘rothrombin Time (sec.)

I Ackroyd I681 R. H., 52,M 42-70

2 Alexander et al. 191 3 Berker et al. (7.81 4 Brinkhous et al. [6’71 5 Briister 1761

R.,4,F 70 H.,35,F 36 R. S.,32,M 60 . ..l.F 91-114

6 Burmeister 1681 7 Caen et al. 1691 8 Cl&n, Loeliger [701 Q Cl&on, Loeliger I701

10 Cl&on, Loeliger I701

9,F ti. L.,l2,F S. H.,S.F A. W.,37,M H. W.,39,F

107-240 53 Q&l10 90-110 9&110

11 Dann et al. [n]

12 de Luca, Santangelo 177 13 Discha, Benfield 1791 14 Dische, Benfield [731

15 Gleuck, Sutherland 1801

16 Hicks I741 17 Hiteig, Zollinger [81]

18 Hitzig, Zollinger [8f]

.65,F 46

Z. L.,2,M 27 G. H.,38,F 55-111 R. L.,37,M 6(tlO5

L. E.,2,M 25-35

. ..16.F 105 A. B.,I,F 60-207

P. B.,l,M ‘Very long”

19 Haag et al. I4Sl Bi. C.,6,M 20 Haag et al. [49] Bo. C.,8,M

21 Hoag et al. [491 22 Haag et al. [e91

1 Jenkins (501 39-70

23 Jiirgens (5fl 24 Koch et al. [581 25 Kowalski et al. [5Y 26 Kupfer et al. [541

27 28 29

30 31

Inxiye, Orlovs [751 Marciniak6wna (551 Present paper

Present pape1 Miller [561

M. R.,ll,F N. C.,23.M R. H.,49,M

14,M A. P.,5,F H. D.,34,M C. R.,4,F

M.,20,F F

A. N.,5,F

R. K.,BQ,M M. P.,2,M

90 50 48-113 35-57

37 “Long” 80-90

49-72 45-51

32 Owren (67,681 Am. M.,38,M

33 Owren [58] J. D.,46,F

34 Owren [68] B. S.,48,F

55-60

55-60

29 Painter, Ellett (691 A. N.,3,F 67

31 Painter, Ellett [69] M. P.,l,M 79

35 Pitney 1601 36 Quick et al. [6fl 37 Quick et al. [6’11 38 Rabiner et al. (791

39 Uk, Waltner [&?I 40 Rerakovic, Pleho 1631

.32,F M. P.,3,F H. S.,53,F

<l,F

I. H.,l6,F . ..lB.M

89 70 2645 41

46103 28

-

T -

(

Hemorrhagic Manifestations

-

-2 5

G -

-

_

+ -

- - - -

+

- - -

-

- -

-

-

_

-

I _ - _ + _

_ - -

-

_ _ _ _ - -

-

-

.I 2 “, P i _ _

r _ _ r - + + -t - - + -

- _ _ + + _ - _

- + _ _ _ _ 5 - + - -

_ a .s 1 .E ,o I 0 -

t

+

+ _

_ _ - - _

t

- - -

-

i

+

+

+

+ + _

_

_

+ _

_

-

_

+

_

r I _ -

-

.F? 8

$ P

_

+ _ _

_ _ - - _

-

+ _ _

_

- -

-

-

- - + -

t

-

- -

_

_

_

_

_

_ -

r - - -

-

7 4 2

3 -

-

+ -

+ -

- - - - -

-

- _ -

_

I +

-

- _ _ - - _ _ _ _

- _ _

-

-. - - - - - -

-

i > E Fz -

t

: + -

+ -

z - - + + - - - _ -

_ _ _ 5 - +

I

t t + _ t t +

- -

_

s 2 -2 _

t

_

;

;

t

t

_

i

t

_ t

_

t

z t t

_ _ _

_

E ;

3 2 _

_

_ _

_

-t

_

2 2 $ k 3 x ;: 5 _

t

_ _

::

I t

_

I t _ t

T t

_

_

_

_ t t

: -

Plasma Factor vn % normal

5

3

Q

10 1

<O.l <O.l <o. 1

3040 <2 <2

6-12

1

3-7 2-6

1 4

12 13-18 8 @25

<O.l

10.5 5-12

3

2-3

l-3

14 14

3-15

Comments

-

A; I?

8 :! Fi

3 3 * 9 --

- -

- -

f-

+-

- - - - - -

- -

- - - -

- -

- -

- -

- - - - - -

- -

-t

- -

- -

-t

- -

- -

- - -+

-+

- - - -

-

i

i ,

g

-

2 .z .z 2 .5 ‘6 L7w --

+t

+$ ++ -t - - - - - - - -

-t

7; _ -

Ii -t -t

_L+

++ -t

$1 tt ++

z: -t -t -t tt tt - - - - - - - - t- -+ -

Case previously reported by Jenkins [501

Also had osteogenesis imperfecta

Sister of patient in Case 9, died of tuberculosis (hemoptysis)

Sister died of uterine hemorrhage at age 18

Brother of patient in Case 13

Only Negro described with this deficiency

Bloody pleural effusion% unknown etiology

Brother of patient in Case 17, died at 18 mo., un- known cawe

..I Brother of patient in Case

19 . . .

Rereported by Ackroyd 1661

Cephalohematoma at birth

Previously reported by Painter, Ellett I591

. Brother died of hemor- rhage in infancy, re- reoorted bv Painter, Eilett (691

Raeported by Vow Waaler [651

Rereparted by Voes, Waaler I651

Sister of patient in Case 32, rereported by Voss, Waler I651

One of present case studies, 3 sibs died of hemorrhage

Hopi Indian, previously reported by Miller I661

Died at 3 mo. of intra- cranial hemorrhage

Sister died of hemorrhage

AMERICAN JOURNAL OF MEDICINE

Congenital Factor VII Deficiency-Mar&r, S/&man 189

TABLE III (Contind) REPORTED CASES OF PROVED CONGENlTAL FACTOR VII DEFICIENCY

7- T -

1 1 (

-

Hemorrhagic Manifestations

_ _

3

iz 21

-s rz _ - - t

- : - + -

+

z + - -

- T

a

2 - + - -

I - - - _

-

- - _ -

-

.4! 3 -2 Lo

: -

-

-

_

- - _

-

+

-

-

- - -

-

_ a ,s J .c s 2 a _

-

-

-

- _ _

_

_

-

_ _ - -

-

2 z 5 ::

t

_

_ _

_

_

_

_

-

7 g 2

3 - - + +

_ _ - - - -

-

_ - - _ -

- _

7 & .E _

t

_

_

_

- _

.‘D 2 P w" _ -

_

_

t _ +

t

t

+

t

+

I - -

T _

2 z b 8 -

-

-

-

_

_

-

-

-

_

- _ _

-

--

R% 3 B 52 3 & 9

_ -

-+

- -

- - - -

-+

- -

- -

- -

- -

-

Patient. One-Stage Ago (rr.1 ‘rothrombir and Sex rime (sec.)

Plasma Factor VII % normal)

CW No.

--

41

42

43

Roes et al. 1641

van Creveld et al. [71]

van Creveld et al. [7f]

44 vos, Wsaler l&5] 45 voss, Waaler [65] 32 voss. Wsaler [65]

46 voss. Waaler [I%]

33 voss, Waaler [66]

34 Vow, Waaler [65]

47 48

voss. Waaler 1661 voss. Waaler (651

49 Voss, Waaler [66] 50 voss. Waaler (651 51 Voss, Waaler 1661 52 Vofis, Waaler [SS]

-

Comments

2 $

s_; g .z e2 -__

+!-

-+ - - -+

-+

-+

-+

-+

-+ -+ 1;

J. W. R.,64,M

..<l,F

<l.F

74-84

59-125

55

55-&l

55-60

0 4-4

o-4

0

<3 <3 <3

<3

<3

<3

<3 <3

3.5 <3 <3 <3

Also had dystmghic myo- tonis

Died of intracranial hemorrhage at 5 wk.

Sister of patient in Case 41. third sister died of intracranial hemorrhage at 2 In,.

Previously reported by Owen [67,681

Brother of patient in Case 31

~wiously reported by Owren IS81

Sister of patient in Case 32, previously reported by Oaren 1581

Brother of p;rtient in Case

46

S. K.,IO,F E. K.,ZO,F Am. M.,44,M

P. M.,43,M

J. D..62,F

B. S.,56,F

Mag. U..ZB,M Mal. U.,23,M

K. H.,65,F B. N.,ZS.F T. T.,Il,F P. J.,15,M

NOTE: + = present; - = absent; = no information available.

existence (steady job for fifteen years, married and the father of three) except for bothersome episodes of epistaxis and subcutaneous hemor- rhage. The other patient (Case 29) had con- tinuous manifestations of hemorrhage since infancy, and without prophylactic treatment was confined to a hospital bed for much of her first three years of life. Despite this difference in clinical severity of disease, the plasma factor VII level of both patients was almost identical (less than 0.5 per cent).

Bleeding attributable to factor VII deficiency (Table III) was manifest mainly as epistaxis, easy bruising, intra- or periarticular hemorrhage, and gingival bleeding associated with tooth eruption or extraction. Some infants were first noted to have a hemorrhagic diathesis when bleeding occurred from the umbilical stump. Intracranial hemorrhage was a frequent cause of death but, interestingly, three patients (Cases 29, 33 and 36) recovered completely from a spontaneous cerebrovascular accident, two with- out plasma therapy.

Of the seventeen severely deficient female patients who were over eleven years of age,

VOL. 37, AUGUST 1964

twelve had severe menorrhagia, necessitating curettage or hysterectomy in six. One patient had severe hemorrhage after each of three deliveries (Case 13), and another had eight deliveries which “usually required blood transfusions postpartum” (Case 35). However, two patients (Cases 33 and 49) with three deliveries each, and one patient with two deliveries (Case 37) did not have abnormal postpartum bleeding and received no pre- or postpartum plasma therapy.

Blood in the gastrointestinal tract was uncom- mon without concomitant epistaxis or gingival bleeding. Renal or pulmonary bleeding was rare and usually attributable to lesions that cause hemorrhage in normal persons. Excessive bleeding from lacerations was noted in only six patients, and surgical procedures were generally tolerated well as described below.

Treatment. Surgical management: Bleeding after routine dental extractions was common if plasma was not infused but did not occur if the patient was treated with plasma before the extraction. (Tables III and IV.) There was no abnormal bleeding in four major surgical pro- cedures in which the patients received plasma

190 Congenital Factor VII Deficiency-Murder, Shulman

TABLE Iv OPERATIONS REPORTED ON PATIENTS WITH PROVED

CONGENITAL FACTOR VII DEFICIENCY

Case *

1 2 3 8 9 9

10 11 11 13 16 16 16 16 24 27 27 30 30 35 37

37

Operation

Clot removal, ankle Laparotomy Tonsillectomy Dental extraction Tonsillectomy Herniotomy Hysterectomy Hysterectomy Laparotomy Hysterectomy Herniorrhaphy Herniorrhaphy Appendectomy Uterine curettage Tonsillectomy Appendectomy Uterine curettage Appendectomy Dental extractions Dental extraction “Gynecologic oper-

ation” Excision, vaginal

cyst

Pre- opera-

tive Trans- fusion

- -

+

+ - -

+ - -

- -

+ - -

:: -

-

-

Hemor- rhage

-

+

T - - - - - 13 + - - _ - - 3 +

-

2-

Post- opera-

tive Trans- fusion

1; - -

+

:; -

+ - - -

+ -

-t -t

+ +

+

NOTE: + = yes; - = no. * Cases numbered according to Table III. t Details not available; patient presumed not to have

received transfusions. $ Slight bleeding after removal of clips; no transfusion

necessary.

infusions before or immediately after operation. However, even without plasma transfusion only five of fourteen major surgical procedures resulted in abnormal bleeding necessitating replacement transfusion, and there was no mortality attributable to uncontrollable surgical or postsurgical bleeding.

Similar observations have been made on pa- tients with factor VII deficiency as a result of receiving coumarin drugs [705,706]. At the time of surgery, the prothrombin time was in the therapeutic range (15 to 30 per cent of normal) and probably reflected factor VII levels of less than 5 per cent of normal [1O4]. These patients did not have abnormal operative or postopera- tive bleeding.

Thus, it appears that sufficient plasma therapy to produce a factor VII level of 10 to 20 per cent at the time of major surgery and on each of

several days postoperatively, will assure normal hemostasis. An additional infusion probably should be given at the time of removal of sutures

[741. Management of s@ontaneous and traumatic

hemorrhage: Therapeutic attempts have been made with oral and parenteral vitamin K therapy and with infusions of serum, plasma or plasma concentrates. With one exception [.%?I, administration of vitamin K has uniformly failed to improve the clinical status or increase the factor VII blood level of patients with heredi- tary decreases in factor VII. The fact that massive amounts of synthetic and natural vitamin K did not produce observable clinical benefit or measurable laboratory improvement in Case 29 confirms this. On the other hand, plasma, serum or concentrate infusions have generally been suc- cessful in controlling all types of hemorrhage.

Observations in Case 29 showed that plasma factor VII levels of 15 to 20 per cent were ade- quate to stop spontaneous bleeding promptly, and beneficial results were sometimes seen with levels of only 6 per cent. It is of interest that in nine of the fifty-two reported cases of factor VII

deficiency there were baseline levels of about 10 per cent or more, and yet hemorrhagic manifestations were evident, some as severe as those seen in cases of apparent complete de- ficiencies (Cases 5, 6, 12, 24, 26, 31, 37, 38 and 39). This discrepancy could be explained by a variation in the level of factor VII at which different patients bleed or by differences in laboratory technics and interpretations. Never- theless, it is apparent that spontaneous hemor- rhage, as well as operative bleeding, was not difficult to control in patients with factor VII

deficiency, despite the fact that factor VII was

relatively short-lived in the circulation. Prophylactic management: Several investigators

previously have attempted prophylactic treat- ment schedules for spontaneous hemorrhage and reported varying results. Hitzig and Zol- linger [81] noted clinical remissions lasting five to fourteen days after infusions of a plasma extract, and Koch et al. [52] gave three injections of this extract in a six month period and reported a reduced number of episodes of epistaxis. However, Kupfer et al. [54] found that the frequency of ecchymoses was not decreased after infusions of the same extract every two weeks, and Miller [56] stated in 1959 that “prophy- lactic therapy with plasma or blood fractions is not practicable at the present time.”

AMERICAN JOURNAL OF MEDICINE

Congenital Factor VII Deficiency--Mar&r, Shulman 191

Prophylactic therapy obviously is not neces- sary in all patients with factor VII deficiency, for many do not have frequent or continuous in- capacitating hemorrhage. Prophylactic infusions of plasma (10 to 15 ml. per kg.) were given in Case 29 every three to four days and prevented otherwise invariable spontaneous hemorrhage over a two year period. Delay of the infusion by one to two days resulted in the appearance of severe epistaxis, ecchymoses and the other symptoms as described previously. A plasma concentrate, used in amounts proportional to the in vitro titer, e.g., 0.1 to 0.15 ml. per kg. for a concentrate with 100 times the activity of normal plasma, was also effective in controlling hemorrhage. Some of the poor results of “prophylactic” treatment reported in the liter- ature may be due to the prolonged interval between infusions, since beneficial effects ap- peared to last only two to four days. Thus far we have not detected “tolerance” or reduced therapeutic effect of the infusions nor have we been able to detect the presence of an anti- coagulant against factor VII in the patient’s plasma by in vitro testing.

SUMMARY

The reported cases of severe, isolated con- genital factor VII deficiency are reviewed and compared with the present studies. In all, fifty-two cases fulfill the necessary diagnostic criteria.

The deficiency appears to be due to a “defec- tive” autosomal gene, full clinical expression of hemorrhagic symptoms appearing only in the homozygous subject. The decay of transfused factor VII has two components, with respective half-lives of 35 and 300 minutes. Treatment of factor VII-deficient patients with plasma or plasma extracts is effective in controlling all types of spontaneous hemorrhage and in pre- venting hemorrhage associated with major surgical procedures. A successful course of long- term prophylactic plasma therapy is described.

Acknowledgment: We wish to express our appre- ciation to Dr. Mones Berman of the National Institute of Arthritis and Metabolic Diseases, Bethesda, Maryland, for assistance with mathe- matical analyses of the data.

REFERENCES

1. KHOADS, J. E. and FITZ-HUGH, T., JR. Idiopathic hypoprothrombinemia-an apparently -unre- corded condition. Am. J. M. SC.. 202: 662. 1941.

2. OWREN, P. A. Parahaemophilia: Haemorrhagic

VOL. 37. AUGUST 1964

diathesis due to absence of a previously unknown clotting factor. Lancet, 1: 446, 1947.

3. ALEXANDER, B., GOLDSTEIN, R., LANDWENR, G. and COOK, C. D. Congenital SPCA deficiency: a hitherto unrecognized coagulation defect with hemorrhage rectified by serum and serum frac- tions. J. Clin. Invest., 30: 596, 1951.

4. TELFER, T. P., DENSON, K. W. and WRIGHT, D. R. A “new” coagulation defect. &it. J. Z-laemat., 2: 308, 1956.

5. HOUCIE, C., BARROW, E. M. and GRAHAM, J. B. Stuart clotting defect. I. Segregation of an hereditary hemorrhagic state from the hetero- geneous group heretofore called “Stable factor” (SPCA, proconvertin, factor VII) deficiency. J. Clin. Znoest., 36: 485, 1957.

6. GRAHAM, J. B., BARROW, E. M. and HOUGIE, C. Stuart clotting defect. II. Genetic aspects of a “new” hemorrhagic state. J. Clin. Znucst., 36: 497, 1957.

7. HAOEN, P. S. and LYATSON, C. J. Idiopathic (familial) hypoprothrombinemia. J. Lab. G? Clin. Med., 33: 542, 1948.

8. FRICK, P. G. and HAGEN, P. S. Congenital familial deficiency of the stable prothrombin conversion factor; restudy of case originally reported as “idiopathic hypoprothrombinemia.” J. Lab. tY Clin. Med., 42: 212, 1953.

9. GONYEA, L. M. and KRIVIT, W. Congenital coagulation deficiency of Stuart factor activity. J. Lab. &f Clin. Med., 51: 398, 1958.

10. LEWIS, J. H., FRESH, J. W. and FERGUSON, J. H. Congenital hypoproconvertinemia. f’roc. SOL. &per. Biol. & Med., 84: 651, 1953.

11. CHEVALLIER, P., BERNARD, J., FIEHRER, A., BILSKI-PASQUIER, G., SAMAMA, M. and CERF, M. Deux cas d’hypoconvertinemie familiale. Sang, 26: 650, 1955.

12. CHEVALLIER, P., BERNARD, J., BILSKI-PASQUIER, G., DE GROUCHY, J. and SAMAMA, M. IXficience congenitale et familiale en facteur Stuart. A propos de deux cas personneIs initialement consider& comme hypoconvertin6mie cong&i- tale. Sang, 30: 525, 1959.

13. VAN BELLE, C. J. Parahemophilia. Thesis, Utrecht, 1952.

14. Roos, J., VAN ARKEL, C., VERLOOP, M. C. and JORDAN, F. L. J. A “new” family with Stuart- Prower deficiency. Thromb. t-t Diath. Haemorrh., 3: 59, 1959.

15. LAURIN, J. G. Les hypoconvertintmies congtnitales htmorragipares. Union r&d. Canada, 83: 157, 1954.

16. MERAB, A., TALEB, N. and MASSOUD, E. Syndrome hemophilique chez une jeune fille dQ h un deficit en proconvertine (facteur VII). Reo. med. moyen Orient, 15: 273, 1958.

17. PAVERO, A. and CAVIGLIA, E. Sindrome emorragica premestruale da deficit di proconvertina. Arch. Maragliano pat. e clin., 13: 995, 1957.

18. STEIN, 1-I. B. and ABRAHAMS, 0. I,. Combined mild PTC (plasma thromboplastin component) and factor VII deficiencies. South African .J. M. SC., 21: 13, 1956.

19. VERSTRAETE, M., VERMYLEN, C. and VANDEN- BROUCKE, J. Hemophilia B associated with a

192 Congenital Factor VII Deficiency-Mar&r, Shulman

decreased factor VII activity. Am. J. M. SC., 243: 20, 1962.

20. DE VRIES, S. I., KETTENBORG, H. K. and VAN DER POL, E. T. Haemorrhagic diathesis due to a deficiency of factor VII (hypoproconvertinaemia). Acta haemat., 14: 43, 1955.

21. WURZEL, H. A., ROTH, K. and ZUBROW, S. Mild familial hypoproconvertinemia. J. Lab. G? Clin. Med., 44: 403, 1954.

22. BELL, W. N. and ALTON, H. G. Christmas disease associated with factor VII deficiency. Case report with family survey. Bit. M. J., I: 330, 1955.

23. GRIEG, H. B. W. and TATTERSALL, J. C. Evidence for the existence of a third serum clotting factor. Brit. J. Haemat., 2: 421, 1956.

24. SOULIER, J. P., ALAGILLE, D., MARTIN, C. and BUHOT, S. Un cas d’hypoconvertintmie con- g&nitale. Sang, 26: 660, 1955.

25. STEPANOVIC, S., MILOSAULJEVIC, A. and STE- PANOVIC, R. Deux cas d’hypoconvertin6mie congtnitale. Sang, 26: 315, 1955.

26. GILLOT, F., SENDRA, L., GRIGUER, P., LEGEAIS, G. and AKOUN, P. L’hypoconvertinemie constitu- tionnelle. (A propos d’une observation familiale avec transmission genetique a caractere domi- nant.) Arch. Frank. @d&t., 15: 507, 1958.

27. HULE, V., SABAC&, J. and SAXL, 0. Ein Fall von angeborenem Mange1 von Faktor VII (SPCA- mangel, Hypoproconvertinaemia congenita). He&t. paediat. acta, 10: 419, 1955.

28. HBRDER, M.-H. Kongenitaler, familiarer Faktor vn-mange1 mit zudtzlichem Defekt in der Thromboplastinbildung. Acta haemat., 19: 30, 1958.

29. LONG, L. A., LETENDRE, P. and COLPRON, G. Hypoproconvertintmie congenitale. Acta hat-mat., 13: 242, 1955.

30. BEAUMONT, J. L. and BERNARD, J. Syndrome htmorrhagique congenital (dfi au dtfaut du facteur de coagulation rtcemment isole sous le nom de facteur VII, convertine, SPCA). Actn med. scan&au., 145: 200, 1953.

31. RAFFI, A., GRIGUER, P., TRICOIRE, J. and BOINEAU, N. Hypoconvertintmie congtnitale. Observation famihare. Song, 28: 605, 1957.

32. CHOREMIS, C., PADIATELLIS, C., TSEVRENIS, I., HADJIDIMITRIOU, E., PRIOVOLOS, I. and MAN- DALAKI, T. A propos d’un cas d’hypoprocon- vertintmie congenitale. Helvet. paediat. acta, 11: 301, 1956.

33. BIGGS, R. Some observations on the blood of patients with “factor VII” deficiency. Brit. J. Haemat., 2: 412, 1956.

34, BARNETT, C. P. Hemorrhagic diathesis due to factor VII deficiency. Arch. Znt. Med., 99: 280, 1357.

35. NEWCOMB, T., MATTER, M., CONROY, L., DE- MARSH, Q, B. and FINCH, C. A. Congenital hemorrhagic diathesis of the prothrombin com- plex. Am. J. Med., 20: 798, 1956.

36. SERAPINI, U. M. and PERICOLI, F. Die angeborene familiare Hypoprokonvertinamie. B1ut, 3: 135, 1957.

37. SCHULTZE, H. E. and SCHWICK, G.: Uber eine neuartige hamorrhagische Diathese. II. Mit- teilung. Blut, 3: 233, 1957.

38. GODAL, H. C., MADSEN, K. and NISSEN-MEYER, R. Thrombo-embolism in patients with total pro- convertin (factor VII) deficiency. A report on two cases. Acta med. scandinav., 171: 325, 1962.

39. AVOGADRO, D. P. Le ipoconvertinemie congenite e familiari. Acta medica patavina, 15: 1, 1956.

40. VANACORE, C. and PELLO, F. Studio sulla conver- sione protrombinica in un case di “ipoprocon- vertinemia congenita” (deficit VII o SPCA). Riv. Emoter. Immunoemat., 5: 183, 1958.

41. LOPEZ-BOTET, E. and VILAR, R. DOS cases de parahemofilia por carencia de factor v y VII de Owren. Rev. c&n. espafi., 58: 220, 1955.

42. DAVIDOVI~, S. Slucaj hipokonvertinemije. Voj. San. Pregled, 13: 76, 1956.

43. KOVACS, E., RANKY, E., KERTESZ, E. and NOLL, K. Idiopathias familiaris hypoconvertinaemia (Izolalt VII faktor Hi&y). Orvosi Hetilup, 96: 378, 1955.

44. DYK, T. Hypoconvertinaemia constituionalis. Polskie Arch. Med. Wewnet, 28: 225, 1958.

45. TVETEN, H. T. Hemartrose ved hypoproconver- tinemi. Nord. med., 59: 565, 1958.

46. SOARES, A. D. and PARREIRA, F. Hipoprocon- vertinemia idiopltica. Nota so bre urn case clinico. J. Med. (Porto), 33: 61, 1957.

47. GALBRAITH, P. A. A case report of idiopathic factor seven deficiency. M. Services J. Canad., 15: 445, 1959.

48. HANIOTIS, N. L. and ZENTOUKIS, I. Hypoprocon- vertinemia (or definite hemorrhagic diathesis). Hellen. latrike, 30: 1341, 1961.

49. HOAG, M. S., AGGELER, P. M. and FOWELL, A. H. Disappearance rate of concentrated procon- vertin extracts in congenital and acquired hypo- proconvertinemia. J. Clin. Invest., 39: 554, 1960.

50. JENKINS, J. S. Haemorrhagic diathesis due to deficiency of factor VII. J. Clin. Path., 7: 29, 1954.

51. J~~RGENS, .I. Kongenitaler Factor VII (SPCA)- mange1 als Ursache einer hlmophiheartigen hamorrhagischen Diathese. Acta haemat., 16: 181, 1956.

52. KOCH, F., SCHULTZE, H. E., SCHWICK, G. and BELLER, F. K. Beobachtungen bei angeborenem Faktor vn-mange1 (Hypokonvertinamie). Ztschr. Kinderh., 76: 208, 1955.

53. KOWALSKI, E., LATALLO, Z. and NIEWIAROWSKI, S. The function of factor VII in blood coagulation and hemostasis. Acta Physiol. Polonica, 9: 295, 1958.

54. KUPFER, H. G., HANNA, B. L. and KINNE, D. R. Congenital factor VII deficiency with normal Stuart activity: clinical, genetic and experimental observations. Blood, 15: 146, 1960.

55. MARCINIAK~WNA, E. Porbwnanie dwdch przypadbw niedoboru prodonwertyny. PoJtepy Hig. Med. Dosw., 13: 307, 1959.

56. MILLER, S. P. Congenital deficiency of procon- vertin: a clinical and laboratory report. Blood, 14: 1322, 1959.

57. OWREN, P. A. New clotting factors. In: Transac- tions of the Fifth Conference on Blood Clotting and Allied Problems, p. 92. New York, 1952. Josiah Macy, Jr. Foundation.

58. OWREN, P. A. Prothrombin and accessory factors. Am. J. Med., 14: 201, 1953.

AMERICAN JOURNAL OF MEDICINE

Congenital Factor VI I Deficiency-Murder, Shulman

59. PAINTER, S. L. and ELLETT, R. Hemophilia (AHG deficiency) and factor VII (stable factor) de- ficiency in the American Indian. Report of four cases. Rocky Mountain M. J,, 57: 65, 1960.

60. PITNEY, W. R. Congenital deficiency of factor VII. Australasian Ann. Med., 7: 15, 1958.

61. QUICK, A. J., PISCIOTTA, A. V. and HUSSEY, C. V. Congenital hypoprothrombinemic states. Arch. Znt. Med., 95: 2, 1955.

62. RAK, K. and WALTNER, K. iiber einen Fall kongenitaler Hypoprokonvertinamie (Faktor VII- Mangel). Thromb. et Diath. Haemorrh., 3: 418, 1959.

63. REZAKOVIC, D. and PLEHO, A. Un cas d’hypo- convertintmie congtnitale. Sang, 31: 857, 1960.

64. Roes, J., VAN ARKEI., C., KEUTER, E. J. W. and BALLIEUX, R. E. Blood coagulation as a con- tinuous process. II. The turnover rate of pro- convertin. Acta med. scandinau., 168: 477, 1960.

65. Voss, D. and WAALER, B. A. Congenital hypo- proconvertinemia. A report on 12 cases with total deficiency and 19 cases with partial de- ficiency. Thromb. et Diath. Haemorrh., 3: 375, 1959.

66. ACKROYD, J. F. The function of factor VII. hit. J. Haemat., 2: 397, 1956.

67. BRINKHOUS, K. M., LANGDELL, R. D., PENICK, G. D., GRAHAM, J. B. and WAGNER, R. H. Newer approaches to the study of hemophilia and hemophilioid states. J. A. M. A., 154: 481, 1954.

68. BURMEISTER, A. Zur Differentialdiagnose des angeborenen Faktor vn-Mangels. Xtschr. Kinderh., 81: 88, 1958.

69. CAEN? J., YANOTTI, S., VARANGOT, J. and BERNARD, J. Etude d’un cas d’hypoproconvertinemie vraie congtnitale. Sang, 30: 535, 1959.

70. CLETON, F. J. and LOELIGER, E. A. Two typical hereditary charts of congenital factor VII de- ficiency. Thromb. et Diath. Haemorrh., 5: 87, 1960.

71. VAN CREVELD, S., VEDER, H. A. and BLANS, M. M. Hypoproconvertinemie congtnitale. Sang, 28: 23, 1957,

72. DANN, H. A., FISHER, H. W., BURNETT, L. and BRIGGS, D. Congenital serum prothrombin con- version accelerator (SPCA) deficiency. Ann. Znt. Med.. 49: 459, 1958.

73. DISCIIE, F. E. and BENFIELD, V. Congenital factor VII deficiency. Haematological and genetic aspects. Acta Haemat., 21: 257, 1959.

74. HICKS, N. D. A coagulation disorder due to a factor vn-like defect. M. J. Australia, 2: 331, 1955.

75. LORIYE, Y. I. and ORLOVA, L. D. Hemorrhagic diathesis caused by deficiency of factor VII (proconvertin). Probl. Gematol., 6: 163, 1961.

76. BREWSTER, H. Angeborener Faktor VII-Mange1 in Kombination mit Osteopsathyrosis idiopathica typ Lobstein. Monatsschr. Kinderh., 107: 237, 1959.

77. DE LUCA, R. and SANTANGELO, G. Rilievi clinici e genetici su due casi di ipoproconvertinemia. Haematologica, 44: 765, 1959.

78. BERKER, F., ULUTIN, 0. N. and KARACA, M. Kongenital hipoprokonvertinemi. ‘Tiirk tib Gem. met., 24: 318, 1958.

79. RABINER, S. F., WINICK, M. and SMITH, C. H. Con- genital deficiency of factor VII associated with

VOL. 37, AUGUST 1964

hemorrhagic disease of the newborn. Pediatrics, 25: 101, 1960.

80. GLEUCK, H. I. and SUTHERLAND, J. M. Inherited factor-vn defect in a Negro family. Pediatrics, 27: 204, 1961.

81. HITZIG, W. H. and ZOLLINGER, W. Kongenitaler Faktor-vn-Mangel. Familienuntersuchung und physiologische Studien tiber den Faktor VII. Neluet. paediat. acta, 13: 189, 1958.

82. KOLLER, F., LOELIGER, A. and DUCKERT, F. Experiments of a new clotting factor (factor VII). Acta haemat., 6: 1, 1951.

83, OWREN, P. A. and AAs, K. The control ofDicumaro1 therapy and the quantitative determination of prothrombin and proconvertin. Scarandinao. J. Cfin. @ Lab. Znoest., 3: 201, 1951.

84. LEE, R. I. and WHITE, P. D. A clinical study of the coagulation time of blood. Am. J. ,VZ. SC., 145: 495,1913.

85. IVY, A. C., SHAPIRO, P. F. and MELNICK, P. The bleeding tendency in jaundice. &rg. Gynec. @ Obst., 60: 781, 1935.

86. QUICK, A. J. On various properties of thromboplas- tin (aqueous tissue extracts). Am. J. Physiol., 114: 282, 1935.

87. FULLERTON, H. W. Estimation of prothrombin. A simplified method. Lancet, 239: 195, 1940.

88. BRECHER, G. and CRONKITE, E. P. Morphology and enumeration of human blood platelets. PTOC. Sac. Exper. Biol. & Med., 78: 796, 1951.

89. BIGGS, R. and DOUGLAS, A. S. The thromboplastin generation test. J. Clin. Path., 6: 23, 1953.

90. WARNER, E. D., BRINKHOUS, K. M. and SMITH, H. P. A quantitative study on blood clotting: prothrombin fluctuations under experimental conditions. Am. J. Physiol., 114: 667, 1936.

91. WARE, A. G. and SEEGERS, W. H. Two-stage pro- cedure for the quantitative determination of prothrombin concentration. Am. J. Cfin. Path., 19: 471, 1949.

92. DE VRIES, A., HERZ, N. and HEIMAN-HOLLANDER, E. Observations on prothrombin consumption during clotting of normal blood in glass. Acta med. scandinau., 138: 219, 1950.

93. CULLEN, G. E. and VAN SLYKE, D. D. Determina- tion of the fibrin, globulin, and albumin nitrogen of blood plasma. J. Biol. Chem., 41: 587, 1920.

94. CONLEY, C. L., HARTMANN, R. C. and MORSE, W. I., II. Circulating anticoagulants: a technique for their detection and clinical studies. Bull. Johns Hopkins Hosp., 84: 255, 1949.

95. MARGOLIUS, A., JR., JACKSON, D. P. and RATNOFF, 0. D. Circulating anticoagulants: a study of 40 cases and a review of the literature. .Vedicine, 40: 145, 1961.

96. KORSAN-BENGTSEN, K., HJORT, P. F. and YGGE, J. Acquired factor x deficiency in a patient with amyloidosis. Thromb. et. LIiath. Haemorrh., 7: 558, 1962.

97. HOWELL, M. Acquired factor x deficiency asso- ciated with systematized amyloidosis--a report of a case. Blood, 21: 739, 1963.

98. FLETCHER, A. P., ALKJAERSIG, N. and SHERRY, S. Pathogenesis of the coagulation defect develop- ing during pathological plasma proteolytic (“fibrinolytic”) states. 1. The significance of

Congenital Factor VII Deficiency-Murder, Shulman

fibrinogen proteolysis and circulating fibrinogen breakdown products. J. C&r. Invest., 41: 896, 1962.

99. PITNEY, W. R. and ARNOLD, B. J. Plasma anti- haemophilic factor (AHF) concentrations in families of patients with haemorrhagic states. Brit. J. Hat-mat., 5: 184, 1959.

100. BERMAN, M., SHAHN, E. and WEISS, M. F. The routine fitting of kinetic data to models. A mathematical formalism for digital computers. Biophys. J., 2: 275, 1962.

101. BERMAN, M., WEISS, M. F. and SHAHN, E. Some formal approaches to the analysis of kinetic data in terms of linear compartmental systems. Biophys. J., 2: 289, 1962.

102. LOELIGER, E. A., ESCH, B., CLETON, F. J., BOOIJ, H. L. and MATTERN, M. J. On the metabolism of factor VII. In: Proceedings of the Seventh Congress of the European Society of Haema-

tology, London, 1959, part 2, p. 764. Basel, 1960. S. Karger.

103. HJORT, P. F., EGEBERG, 0. and MIKKELSEN, S. Turnover of prothrombin, factor VII and factor IX in a patient with hemophilia A. Scandinav. J. Clin. B Lab. Invest., 13: 668, 1961.

104. FRICK, P. G. Studies on the turnover rate of stable prothrombin conversion factor in man. Acta haemat., 19: 20, 1958.

105. SEVITT, S. and GALLAGHER, N. G. Prevention of venous thrombosis and pulmonary embolism in injured patients. A trial of anticoagulant pro- phylaxis with phenindione in middle-aged and elderly patients with fractured necks of femur. Lancet, 2: 981, 1959.

106. RUSTAD, H. and MYHRE, E. Surgery during anti- coagulant treatment. The risk of increased bleed- ing in patients on oral anticoagulant treatment. Acta med. scandinav., 173: 115, 1963.

AMERICAN JOURNAL OF MEDICINE