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Clinical and laboratory studies of plasma thromboplastin antecedent deficiency (PTA)
Clinical
and Laboratory
Thromboplastin JOHN A.
Antecedent CAVINS,
M.D. and ROBERT
Columbus,
U
Studies of Plasma
recently the term hemophilia denoted an hereditary disorder of blood coagulation appearing clinically in males and transmitted by females apparently unaffected by this disease. However, Pavlovsky [7], mixing the plasmas of two patients with hemophilia showed mutual correction of their coagulation defects, thus demonstrating that hemophilia was not a single disease. Refinements of technic, such as the thromboplastin generation test of Biggs and McFarlane [2], subsequently have shown that the original hemophilia actually consists of at least five distinct coagulation defects. One of the defects of plasma thromboplastin generation, plasma thromboplastin antecedent (PTA), described originally by Rosenthal, Dreskin and Rosenthal [&5j, was found not to be sex-linked in its passage and therefore present not only in males but transmitted as an autosomal dominant independent of sex linkage. The disease as originally described by Rosenthal and co-workers was that of a mild, familial coagulation disease, occurring in males and females, and exhibiting bleeding principally after trauma or operations. Coagulation times were prolonged; prothrombin consumption was abnormal, correction being accomplished by the addition of normal serum, normal plasma, BaSOd-absorbed normal serum, and mixtures of serum from the patient plus normal serum. These observations have also been confirmed using the thromboplastin generation test. The prothrombin times were normal. It was also noted that PTA activity increased when serum or plasma was kept at room temperature or in the frozen state; this caused some difficulty in reproducing results when samples were sent to other laboratories. Soulier, Wartelle and Mensche [S] commented in this connection on the relationship between the Hageman and PTA factors. Their conclusions were that the Hageman factor is NTIL
Deficiency (PTA)* L.
WALL,
M.D.
Ohio first activated by glass and subsequently activates the PTA factor in the presence of calcium. They therefore place PTA and Hageman factors in the very initial states of coagulation. The present investigation was prompted by an opportunity to study several members (two generations) in a family with PTA deficiency. In addition, we have gathered data concerning five other patients who were not related with this deficiency seen by us over the past two years. METHODS
The patients in question were studied by means of the following tests: (1) Lee and White coagulation time [7]; (2) plasma recalcification coagulation time; (3) prothrombin time, the one-stage method of Quick with control time of twelve seconds [8]; (4) the thromboplastin generation tests as outlined by Biggs and MacFarlane with substitutions in this system as described [Z]; (5) thromboelastography, utilizing the Haemoscope; t and (6) partial thromboplastin time [9]. CASE
HISTORIES
The family previously mentioned first came to our attention when one member (W. B.) was seen with menorrhagia. A second’patient was seen recently for persistent, severe epistaxis. Careful evaluation of seven additional members of the family was carried out. CASE I. W. B., a seventeen year old girl,’ was admitted to Ohio State University Hospital on January 23, 1959, for profuse menorrhagia of twenty days’ duration. No other symptoms were noted. The onset of menses had been at the age of thirteen with no previous irregularity or excessive flow. She had had occasional epistaxis in the past, the last episode taking place seven years previously. Her hemoglobin on admission was 7.8 gm. per cent. The remainder of the blood count was as follows: white blood cells 11,600 per cu. mm., red blood cells 3,150,OOO per cu. mm., reticulocytes 3.4 per cent, platelets 875,700 per cu.
t Haemoscope from the Haemoscope Corporation, Albertson, New York.
* From the College of Medicine, The Ohio State University, Columbus, Ohio. This investigation was supported in part by U.S. Public Health Service Research Grant C-2472 444
(Hematology).
AMERICAN
JOUR”AL
OF
MEDICINE
Plasma Thromboplastin
Antecedent
mm. The results of coagulation studies were as indicated in Table I.The impression was that of PTA deficiency and treatment consisted of the administration of whole stored blood. On January 29, 1959, she was discharged improved, with no further bleeding, and has done well since. CASE II. S. B., JR., a thirteen year old boy, was admitted to Ohio State University Hospital for severe epistaxis of one day’s duration. He gave a history of severe recurrent epistaxis since the age of two years, requiring occasional hospitalization for transfusion. The last severe epistaxis had taken place one year previously. On admission to the hospital a unit of blood was being infused. Hemoglobin was 6.9 gm. per cent, and white blood cells 11,750 per cu. mm. Two additional units of fresh blood were given. Initial coagulation studies were invalid because of the blood already administered, but later studies showed the characteristics of PTA deficiency. (Table I.) He was discharged asymptomatic May 17, 1959. His hemoglobin at the time of discharge was 11.5 gm. per cent. CASE III. X, a female child, died of severe epistaxis at fourteen months of age. She was not available for study. CASE IV. S. H. B., a fifteen year old girl, gave no history of bleeding tendency. Her menses were normal.
CASE v. S. K. B., a twelve year old girl, gave a vague history of epistaxis with trauma but with no other bleeding tendency. CASE VI. K. B., a five year old girl, had no bleeding tendency. CASES VII and VIII. P. B., a three year old male infant, and B. B., a two year old male infant, likewise had no history of abnormal bleeding. CASE IX. R. B. (mother of the eight children, Cases I to VIII) had no history of abnormal bleeding. There had been no difficulty at the time of menses, trauma, childbirth or operation. CASE x. S. B., Sr. (father of the eight children, Cases I to VIII) had no history of abnormal bleeding. One year previously he had had a traumatic subdural hematoma requiring multiple trephinings. Comments: As can be seen from Figure 1 there are six persons with a history of bleeding in this family over the past two generations. The lineage apparently follows the ancestry of the mother (R. B.), and males and females have been affected with equal severity and incidence. Some exhibit epistaxis, menorrhagia, or posttraumatic bleeding of moderate severity, one (a fourteen month old infant) died of unconSEPTEMBER
1960
Deficiency-Cauins,
Wall
445
446
Plasma Thromboplastin
DIED AGE 14 MON.
W.B
Antecedent
S.K.B
SHB.
Deficiency-Cumins,
K.B
S.B.JR.
W’ZZ
l?B.
B.B.
d $ P.T.A. DEFICIENT d ? NEGATIV E FOR P.T.A DEFICIENCY FIG. 1. Family tree of family B. The parents, S. B., Sr. and R. B., and seven siblings were studied by coagulation tests. Other relatives were not available for testing.
trolled epistaxis, another (S. B. Jr.) had a hemoglobin of 6.9 gm. per cent after bleeding in less than twenty-four hours after trauma to the nose. The coagulation data (Table I) show widespread involvement of all seven siblings by the PTA defect. Coagulation times were prolonged in all and the thromboplastin generation test revealed a corresponding defect in all but one case. This defect was corrected by normal serum, Al(OH)s absorbed plasma, BaSOi-absorbed serum, or a mixture of normal serum and the patient’s serum. In the. aforementioned subject (S. H. B.) the thromboplastin generation test revealed no abnormalities; however, she did not correct the deficiency in one of her siblings (S. B. Jr.), thus demonstrating involvement by the disease. R. B. (the mother) showed a moderately prolonged coagulation time with an abnormal thromboplastin generation time which was corrected as noted. However, she exhibited no clinical bleeding. The father (S. B. Sr.) was entirely normal in regard to his coagulation tests. We conclude, therefore, that the mother (R. B.) is the means of transmission of the defect to the seven children. This is corroborated by the genetic background of the family, which reveals three persons with clinical bleeding, all related to R. B. The prothrombin times were uniformly normal, the plasma recalcification times were highly variable, from normal to moderately
prolonged. Thromboelastography did not add significantly to the study. It thus appears that the deficiency (PTA) is transmitted as an autosomal dominant with in-
I
I
I
2
3
4
5
6
INCUBATION TIME IN MINUTES
FIG. 2. Thromboplastin generation Tests on patient P. B. (a) Patient’s system; (b) normal serum 1 :5 substituted for patient’s serum; (c) normal plasma absorbed with Al(OH)s substituted for patient’s plasma; (d) 0.15 ml. normal serum absorbed with BaSOl 1 :5 plus 0.15 ml. patient serum substituted for patient serum 1 : 5; (e) 0.15 ml. normal serum 1 :20 plus 0.15 ml. patient serum 1 :5substituted for patient serum; (f) plasma from PTC deficient patient substituted for patient plasma; (g) patient’s plasma plus serum from unrelated PTA deficient patient (M. F.) showing lack of correction; (h) patient’s serum plus plasma from AHG deficient patient; patient’s platelets used in all generation tests. AMERICAN
JOURNAL
OF
MEDICINE
Plasma Thromboplastin
Antecedent Deficiency-Cumins, Wall
complete penetrance and variable expressivity. Our incidence is somewhat higher than reported by other authors, but is consistent with the heredity pattern postulated. Of interest is the fact that, regardless of the severity of the defect in this family group, all were easily controlled by the administration of fresh or stored blood. In one patient (S. B. Jr.) the coagulation defect was corrected by the administration of 250 cc. of stored blood and all bleeding stopped after two units more were given. Five more examples of PTA deficiency have been found in our laboratory over the past two years. The same methods were employed as in the previous cases. (Table I.) CASE I. M. F., a forty-two;year old white woman, had a history of marked hematoma of the left side of the face after a tooth extraction. Her past history showed numerous episodes of bleeding at times of trauma or surgery. The menses had been normal. Her family history revealed several bleeders on her maternal side, her mother died of profuse hemorrhage at the time of a delivery. The blood count was normal with adequate platelets and hemoglobin. CASE II. B. F., a thirty-three year old white woman, had a history of menorrhagia of nine years’ duration, and excessive bleeding from minor cuts. She had undergone surgery without difficulty on one occasion, but had severe bleeding on another and also at the time of tooth extractions. One brother gave a history of severe epistaxis. CASE III. D. R., a nineteen year old white girl, was seen for hemorrhage after tooth extractions. Examination and complete blood count were within normal limits. Her family history showed three “bleeders” on the maternal side, one having died from traumatic bleeding of an extremity. CASE IV. D. S. was a six year old white boy with no clinical bleeding. Examination and complete blood count were within normal limits. Coagulation studies revealed a deficiency of PTA. It is of interest that he underwent surgery for an inguinal herniorrhaphy in the past without difficulty.
CASE v. W. F., an eight year old white girl, presented with a history of frequent spontaneous and traumatic epistaxis. It had been noted that she bruised easily. She had several teeth extracted for infection without sequelae.
COMMENTS With the development of the modern concept of plasma thromboplastin, the original hemophilia has been subdivided into several groups, SEPTEMBER
1960
each lacking a specific thromboplastin factor. Classic hemophilia lacks antihemophiliac globulin (AHG), which being quite labile can be supplied only by the administration of fresh blood or fresh frozen plasma. Christmas disease lacks plasma thromboplastin component (PTC). This is a stable factor and can be given as stored blood or plasma. The Hageman factor is essential for glass activation, but a deficiency of it does not cause a bleeding tendency. The Stuart factor has a dual role in the formation of plasma thromboplastin and prothrombin conversion to thrombin, and thus can be identified by coagulation studies. PTA is the remaining factor of significance. It has been shown to be active in plasma and serum, and to be present after BaS04 absorption, thus delineating it from both AHG and PTC. As initially described, PTA deficiency was thought to be the rarest and the mildest of the hemophilioid states. Frick [70] stated in 1954 that of fifty-five cases of hemophilia restudied, four had PTA deficiency, an incidence of only 7.3 per cent. Ratnoff [77] stated in 1958 that of 105 families reported by three groups, only six were deficient in PTA. He adds, however, that difficulties in performing coagulation studies may have been a factor in this low incidence, many being considered to have PTC deficiency. It is obvious from the preceding case reports that this entity cannot be considered uniformly mild, but that it can on occasion be as lethal as any other coagulation disorder, and should be treated as vigorously as classic hemophilia or Christmas disease. We would agree with the postulated mode of inheritance as an autosomal dominant, but emphasize the variable expressivity and incomplete penetrance. The therapeutic importance of distinguishing AHG, PTC, PTA and Hageman defects lies in the type of material needed to correct the defect clinically. The thromboplastin generation test with the various admixture experiments gives clues as to what is actually required to stop bleeding and correct the coagulation time. Thus hemophilia requires fresh blood or plasma, while PTC and PTA deficiencies can be corrected by stored blood or plasma. This could be of critical importance if the available supply of fresh material is low. SUMMARY Fourteen patients reviewed, including
with PTA deficiency are a family with six bleeders
Plasma Thromboplastin
Antecedent
in the past two generations. Data are presented which show that the bleeding tendency in this disorder is often mild, as hitherto emphasized, but may also be of moderate or severe degree. Heredity appears to be by an autosomal dominant gene with variable expressivity and incomplete penetrance. Acknowledgment: We wish to acknowledge the technical assistance of Miss Delma Moore, R.N., M.T.
Deficiency-Cuuins,
Wall
deficiency; clinical, coagulation, therapeutic and hereditary aspects of a new hemophilia-like disease.
Blood, 10: 120, 1955. 5. ROSENTHAL,R. L. Hemophilia
and hemophilia-like diseases caused by deficiencies in plasma thromboplastin factors. Am. J. Med., 17: 57, 1954. 6. SOULIER, J. P., WARTELLE, O., MENACHE, D. Hageman trait and PTA deficiency-the role of contact of blood with glass. Brit. J. Haemat., 5: 121,
1959. 7. LEE, R. I. and WHITE, P. D. A clinical study of the coagulation of blood. Am. J. M. SC., 145: 495, 1913. 8. QUICK, A. J. Hemorrhagic Diseases and the Physiol;g;;zz;smostasis. Springfield, Ill., 1942. Charles
REFERENCES 1. PAVLOVSKY,A. Contribution to the pathogenesis of hemophilia. Blood, 2: 185,, 1947. 2. BICOS, R. and MCFARLANE, R. G. Human Blood Coagulation and Its Disorders. Springfield, Ill., 1953. Charles C Thomas: 3. ROSENTHAL,R. L., DRESKIN,0. H. and ROSENTHAL, N. New hemophilia-like disease caused by deficiency of a third plasma thromboplastin factor.
Proc. Sot. Exper. Biol. B Med., 82: 171, 1953. 4. ROSENTHAL,R. L., DRESK~N,0. H. and ROSENTHAL, N.
Plasma
thromboplastin
antecedent
(PTA)
9. RODMAN, N. F., BARROW, E. M. and GRAHAM, J. B. Diagnosis and control of the hemophilioid states with the nartial thrombonlastin time (PTT) test.
Am. J. Clk. Path., 29: 52J, 1958. . ’ 10. FRICK, P. G. The relative incidence of anti-hemophilic globulin (AHG), plasma thromboplastin component (PTC), and plasma thromboplastin antecedent (PTA) deficiency-a study of 55 cases.
J. Lab. &’ Clin. Med., 43: 860, 1954. 11. RATNOFF, 0. D. Hereditary Defects in Clotting Mechanisms, Advances in Internal Medicine, 9: 107. Chicago, 1959. Yearbook Publishers.
AMERICAN
JOURNAL
OF MEDICINE
and Laboratory
Thromboplastin JOHN A.
Antecedent CAVINS,
M.D. and ROBERT
Columbus,
U
Studies of Plasma
recently the term hemophilia denoted an hereditary disorder of blood coagulation appearing clinically in males and transmitted by females apparently unaffected by this disease. However, Pavlovsky [7], mixing the plasmas of two patients with hemophilia showed mutual correction of their coagulation defects, thus demonstrating that hemophilia was not a single disease. Refinements of technic, such as the thromboplastin generation test of Biggs and McFarlane [2], subsequently have shown that the original hemophilia actually consists of at least five distinct coagulation defects. One of the defects of plasma thromboplastin generation, plasma thromboplastin antecedent (PTA), described originally by Rosenthal, Dreskin and Rosenthal [&5j, was found not to be sex-linked in its passage and therefore present not only in males but transmitted as an autosomal dominant independent of sex linkage. The disease as originally described by Rosenthal and co-workers was that of a mild, familial coagulation disease, occurring in males and females, and exhibiting bleeding principally after trauma or operations. Coagulation times were prolonged; prothrombin consumption was abnormal, correction being accomplished by the addition of normal serum, normal plasma, BaSOd-absorbed normal serum, and mixtures of serum from the patient plus normal serum. These observations have also been confirmed using the thromboplastin generation test. The prothrombin times were normal. It was also noted that PTA activity increased when serum or plasma was kept at room temperature or in the frozen state; this caused some difficulty in reproducing results when samples were sent to other laboratories. Soulier, Wartelle and Mensche [S] commented in this connection on the relationship between the Hageman and PTA factors. Their conclusions were that the Hageman factor is NTIL
Deficiency (PTA)* L.
WALL,
M.D.
Ohio first activated by glass and subsequently activates the PTA factor in the presence of calcium. They therefore place PTA and Hageman factors in the very initial states of coagulation. The present investigation was prompted by an opportunity to study several members (two generations) in a family with PTA deficiency. In addition, we have gathered data concerning five other patients who were not related with this deficiency seen by us over the past two years. METHODS
The patients in question were studied by means of the following tests: (1) Lee and White coagulation time [7]; (2) plasma recalcification coagulation time; (3) prothrombin time, the one-stage method of Quick with control time of twelve seconds [8]; (4) the thromboplastin generation tests as outlined by Biggs and MacFarlane with substitutions in this system as described [Z]; (5) thromboelastography, utilizing the Haemoscope; t and (6) partial thromboplastin time [9]. CASE
HISTORIES
The family previously mentioned first came to our attention when one member (W. B.) was seen with menorrhagia. A second’patient was seen recently for persistent, severe epistaxis. Careful evaluation of seven additional members of the family was carried out. CASE I. W. B., a seventeen year old girl,’ was admitted to Ohio State University Hospital on January 23, 1959, for profuse menorrhagia of twenty days’ duration. No other symptoms were noted. The onset of menses had been at the age of thirteen with no previous irregularity or excessive flow. She had had occasional epistaxis in the past, the last episode taking place seven years previously. Her hemoglobin on admission was 7.8 gm. per cent. The remainder of the blood count was as follows: white blood cells 11,600 per cu. mm., red blood cells 3,150,OOO per cu. mm., reticulocytes 3.4 per cent, platelets 875,700 per cu.
t Haemoscope from the Haemoscope Corporation, Albertson, New York.
* From the College of Medicine, The Ohio State University, Columbus, Ohio. This investigation was supported in part by U.S. Public Health Service Research Grant C-2472 444
(Hematology).
AMERICAN
JOUR”AL
OF
MEDICINE
Plasma Thromboplastin
Antecedent
mm. The results of coagulation studies were as indicated in Table I.The impression was that of PTA deficiency and treatment consisted of the administration of whole stored blood. On January 29, 1959, she was discharged improved, with no further bleeding, and has done well since. CASE II. S. B., JR., a thirteen year old boy, was admitted to Ohio State University Hospital for severe epistaxis of one day’s duration. He gave a history of severe recurrent epistaxis since the age of two years, requiring occasional hospitalization for transfusion. The last severe epistaxis had taken place one year previously. On admission to the hospital a unit of blood was being infused. Hemoglobin was 6.9 gm. per cent, and white blood cells 11,750 per cu. mm. Two additional units of fresh blood were given. Initial coagulation studies were invalid because of the blood already administered, but later studies showed the characteristics of PTA deficiency. (Table I.) He was discharged asymptomatic May 17, 1959. His hemoglobin at the time of discharge was 11.5 gm. per cent. CASE III. X, a female child, died of severe epistaxis at fourteen months of age. She was not available for study. CASE IV. S. H. B., a fifteen year old girl, gave no history of bleeding tendency. Her menses were normal.
CASE v. S. K. B., a twelve year old girl, gave a vague history of epistaxis with trauma but with no other bleeding tendency. CASE VI. K. B., a five year old girl, had no bleeding tendency. CASES VII and VIII. P. B., a three year old male infant, and B. B., a two year old male infant, likewise had no history of abnormal bleeding. CASE IX. R. B. (mother of the eight children, Cases I to VIII) had no history of abnormal bleeding. There had been no difficulty at the time of menses, trauma, childbirth or operation. CASE x. S. B., Sr. (father of the eight children, Cases I to VIII) had no history of abnormal bleeding. One year previously he had had a traumatic subdural hematoma requiring multiple trephinings. Comments: As can be seen from Figure 1 there are six persons with a history of bleeding in this family over the past two generations. The lineage apparently follows the ancestry of the mother (R. B.), and males and females have been affected with equal severity and incidence. Some exhibit epistaxis, menorrhagia, or posttraumatic bleeding of moderate severity, one (a fourteen month old infant) died of unconSEPTEMBER
1960
Deficiency-Cauins,
Wall
445
446
Plasma Thromboplastin
DIED AGE 14 MON.
W.B
Antecedent
S.K.B
SHB.
Deficiency-Cumins,
K.B
S.B.JR.
W’ZZ
l?B.
B.B.
d $ P.T.A. DEFICIENT d ? NEGATIV E FOR P.T.A DEFICIENCY FIG. 1. Family tree of family B. The parents, S. B., Sr. and R. B., and seven siblings were studied by coagulation tests. Other relatives were not available for testing.
trolled epistaxis, another (S. B. Jr.) had a hemoglobin of 6.9 gm. per cent after bleeding in less than twenty-four hours after trauma to the nose. The coagulation data (Table I) show widespread involvement of all seven siblings by the PTA defect. Coagulation times were prolonged in all and the thromboplastin generation test revealed a corresponding defect in all but one case. This defect was corrected by normal serum, Al(OH)s absorbed plasma, BaSOi-absorbed serum, or a mixture of normal serum and the patient’s serum. In the. aforementioned subject (S. H. B.) the thromboplastin generation test revealed no abnormalities; however, she did not correct the deficiency in one of her siblings (S. B. Jr.), thus demonstrating involvement by the disease. R. B. (the mother) showed a moderately prolonged coagulation time with an abnormal thromboplastin generation time which was corrected as noted. However, she exhibited no clinical bleeding. The father (S. B. Sr.) was entirely normal in regard to his coagulation tests. We conclude, therefore, that the mother (R. B.) is the means of transmission of the defect to the seven children. This is corroborated by the genetic background of the family, which reveals three persons with clinical bleeding, all related to R. B. The prothrombin times were uniformly normal, the plasma recalcification times were highly variable, from normal to moderately
prolonged. Thromboelastography did not add significantly to the study. It thus appears that the deficiency (PTA) is transmitted as an autosomal dominant with in-
I
I
I
2
3
4
5
6
INCUBATION TIME IN MINUTES
FIG. 2. Thromboplastin generation Tests on patient P. B. (a) Patient’s system; (b) normal serum 1 :5 substituted for patient’s serum; (c) normal plasma absorbed with Al(OH)s substituted for patient’s plasma; (d) 0.15 ml. normal serum absorbed with BaSOl 1 :5 plus 0.15 ml. patient serum substituted for patient serum 1 : 5; (e) 0.15 ml. normal serum 1 :20 plus 0.15 ml. patient serum 1 :5substituted for patient serum; (f) plasma from PTC deficient patient substituted for patient plasma; (g) patient’s plasma plus serum from unrelated PTA deficient patient (M. F.) showing lack of correction; (h) patient’s serum plus plasma from AHG deficient patient; patient’s platelets used in all generation tests. AMERICAN
JOURNAL
OF
MEDICINE
Plasma Thromboplastin
Antecedent Deficiency-Cumins, Wall
complete penetrance and variable expressivity. Our incidence is somewhat higher than reported by other authors, but is consistent with the heredity pattern postulated. Of interest is the fact that, regardless of the severity of the defect in this family group, all were easily controlled by the administration of fresh or stored blood. In one patient (S. B. Jr.) the coagulation defect was corrected by the administration of 250 cc. of stored blood and all bleeding stopped after two units more were given. Five more examples of PTA deficiency have been found in our laboratory over the past two years. The same methods were employed as in the previous cases. (Table I.) CASE I. M. F., a forty-two;year old white woman, had a history of marked hematoma of the left side of the face after a tooth extraction. Her past history showed numerous episodes of bleeding at times of trauma or surgery. The menses had been normal. Her family history revealed several bleeders on her maternal side, her mother died of profuse hemorrhage at the time of a delivery. The blood count was normal with adequate platelets and hemoglobin. CASE II. B. F., a thirty-three year old white woman, had a history of menorrhagia of nine years’ duration, and excessive bleeding from minor cuts. She had undergone surgery without difficulty on one occasion, but had severe bleeding on another and also at the time of tooth extractions. One brother gave a history of severe epistaxis. CASE III. D. R., a nineteen year old white girl, was seen for hemorrhage after tooth extractions. Examination and complete blood count were within normal limits. Her family history showed three “bleeders” on the maternal side, one having died from traumatic bleeding of an extremity. CASE IV. D. S. was a six year old white boy with no clinical bleeding. Examination and complete blood count were within normal limits. Coagulation studies revealed a deficiency of PTA. It is of interest that he underwent surgery for an inguinal herniorrhaphy in the past without difficulty.
CASE v. W. F., an eight year old white girl, presented with a history of frequent spontaneous and traumatic epistaxis. It had been noted that she bruised easily. She had several teeth extracted for infection without sequelae.
COMMENTS With the development of the modern concept of plasma thromboplastin, the original hemophilia has been subdivided into several groups, SEPTEMBER
1960
each lacking a specific thromboplastin factor. Classic hemophilia lacks antihemophiliac globulin (AHG), which being quite labile can be supplied only by the administration of fresh blood or fresh frozen plasma. Christmas disease lacks plasma thromboplastin component (PTC). This is a stable factor and can be given as stored blood or plasma. The Hageman factor is essential for glass activation, but a deficiency of it does not cause a bleeding tendency. The Stuart factor has a dual role in the formation of plasma thromboplastin and prothrombin conversion to thrombin, and thus can be identified by coagulation studies. PTA is the remaining factor of significance. It has been shown to be active in plasma and serum, and to be present after BaS04 absorption, thus delineating it from both AHG and PTC. As initially described, PTA deficiency was thought to be the rarest and the mildest of the hemophilioid states. Frick [70] stated in 1954 that of fifty-five cases of hemophilia restudied, four had PTA deficiency, an incidence of only 7.3 per cent. Ratnoff [77] stated in 1958 that of 105 families reported by three groups, only six were deficient in PTA. He adds, however, that difficulties in performing coagulation studies may have been a factor in this low incidence, many being considered to have PTC deficiency. It is obvious from the preceding case reports that this entity cannot be considered uniformly mild, but that it can on occasion be as lethal as any other coagulation disorder, and should be treated as vigorously as classic hemophilia or Christmas disease. We would agree with the postulated mode of inheritance as an autosomal dominant, but emphasize the variable expressivity and incomplete penetrance. The therapeutic importance of distinguishing AHG, PTC, PTA and Hageman defects lies in the type of material needed to correct the defect clinically. The thromboplastin generation test with the various admixture experiments gives clues as to what is actually required to stop bleeding and correct the coagulation time. Thus hemophilia requires fresh blood or plasma, while PTC and PTA deficiencies can be corrected by stored blood or plasma. This could be of critical importance if the available supply of fresh material is low. SUMMARY Fourteen patients reviewed, including
with PTA deficiency are a family with six bleeders
Plasma Thromboplastin
Antecedent
in the past two generations. Data are presented which show that the bleeding tendency in this disorder is often mild, as hitherto emphasized, but may also be of moderate or severe degree. Heredity appears to be by an autosomal dominant gene with variable expressivity and incomplete penetrance. Acknowledgment: We wish to acknowledge the technical assistance of Miss Delma Moore, R.N., M.T.
Deficiency-Cuuins,
Wall
deficiency; clinical, coagulation, therapeutic and hereditary aspects of a new hemophilia-like disease.
Blood, 10: 120, 1955. 5. ROSENTHAL,R. L. Hemophilia
and hemophilia-like diseases caused by deficiencies in plasma thromboplastin factors. Am. J. Med., 17: 57, 1954. 6. SOULIER, J. P., WARTELLE, O., MENACHE, D. Hageman trait and PTA deficiency-the role of contact of blood with glass. Brit. J. Haemat., 5: 121,
1959. 7. LEE, R. I. and WHITE, P. D. A clinical study of the coagulation of blood. Am. J. M. SC., 145: 495, 1913. 8. QUICK, A. J. Hemorrhagic Diseases and the Physiol;g;;zz;smostasis. Springfield, Ill., 1942. Charles
REFERENCES 1. PAVLOVSKY,A. Contribution to the pathogenesis of hemophilia. Blood, 2: 185,, 1947. 2. BICOS, R. and MCFARLANE, R. G. Human Blood Coagulation and Its Disorders. Springfield, Ill., 1953. Charles C Thomas: 3. ROSENTHAL,R. L., DRESKIN,0. H. and ROSENTHAL, N. New hemophilia-like disease caused by deficiency of a third plasma thromboplastin factor.
Proc. Sot. Exper. Biol. B Med., 82: 171, 1953. 4. ROSENTHAL,R. L., DRESK~N,0. H. and ROSENTHAL, N.
Plasma
thromboplastin
antecedent
(PTA)
9. RODMAN, N. F., BARROW, E. M. and GRAHAM, J. B. Diagnosis and control of the hemophilioid states with the nartial thrombonlastin time (PTT) test.
Am. J. Clk. Path., 29: 52J, 1958. . ’ 10. FRICK, P. G. The relative incidence of anti-hemophilic globulin (AHG), plasma thromboplastin component (PTC), and plasma thromboplastin antecedent (PTA) deficiency-a study of 55 cases.
J. Lab. &’ Clin. Med., 43: 860, 1954. 11. RATNOFF, 0. D. Hereditary Defects in Clotting Mechanisms, Advances in Internal Medicine, 9: 107. Chicago, 1959. Yearbook Publishers.
AMERICAN
JOURNAL
OF MEDICINE