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Occult hemophilia as a cause of postoperative and postpartum hemorrhage
Occult hemophilia as a cause of postoperative and postpartum hemorrhage With special reference to factor VII deficiency
HAROLD S. MORGAN, M.D. JON T. WILLIAMS, M.D. Lincoln, Nebraska
Methods
0 c c u L T hemophilia, the term suggested by Aggeler 1 to designate the mild congenital blood coagulation defects, has been adopted by us as best describing the status of a group of 7 patients whom we have studied during the past year. In adopting this term, we have broadened it to include deficiencies in factors V and VII and the Stuart-Prower factor, as well as defects in AHF, PTA, and PTC. It is our purpose to show that, in its unrecognized state, occult hemophilia can be a dangerous condition leading to severe postoperative or postpartum hemorrhage, but that, if the condition is recognized, appropriate measures may be adopted that will protect or treat the patient. Of the 7 cases to be reported, 4 are concerned with mild defects in the serum accelerator factor VII and one each in the PTA, PTC (Christmas disease) , and StuartPrower factors. (We are indebted to the members of the Staff of the Department of Obstetrics and Gynecology of the Lincoln General Hospital for the privilege of including their patients in this report.)
The following laboratory tests were used to detect the faulty coagulation mechanism in the patients studied: I. Platelet count by the indirect method of Dameshek. 2 2. Coagulation time of Lee and White." 3. Thromboplastin time (the one-stage prothrombin time of Quick1 ) . 4. Factor V determination (labile factor). 5. Factor VII determination (stable factor). 6. Qualitative prothrombin. These latter three by the method of Biggs and Macfarlane.5 7. Thromboplastin generation test (TGT) of Biggs and Douglas6 in which Asolectin suspension was substituted for a platelet suspension for the AHF (factor VIII), PTC (factor IX or Christmas disease), and PTA (factor X) activity. 8. Russell viper venom test of Hjort and co-workers 7 for the combined activity of platelets, prothrombin, factor V. and StuartPrower factor. Case reports Case 1. A 39-year-old gravida iv, para iv, was admitted to the hospital for the correction of relaxation of the pelvic floor with prolapse. There was a previous history of tonsillectomy and laparotomy for ovarian cyst without unduf' bleeding. Vaginal hysterectomy was performed on Sept. 4, 1960. Twelve hours after operation
From the Departments of Obstetrics and Gynecolof?y and Internal ..Medicine, Lincoln General Hospital. Presented by invitation at the Seventy-second Annual Meeting of the American Association of Obstetricians and Gynecologists, Hot Springs, Virginia, Sept. 7-9, 1961.
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Volume 83 Nutl::lber 8
there were signs and symptoms of intra-abdominal bleeding, and laparotomy disclosed approximately 1,200 c.c. of intraperitoneal blood. Bleeding in the infundibulopelvic area and from the vaginal cuff was brought under control. Two units of fibrinogen and transfusions to replace blood loss were given. Intermittent vaginal bleeding continued. A hemorrhagic diathesis was suspected and laboratory studies demonstrated a normal coagulation time. Platelets were 360,000. The prothrombin time was 55 per cent of normal. Tests for factor V were normal. The thromboplastin generation test was normal (ruling out deficiencies in AHF, PTC, and PTA). The Russell viper venon1 test ruled out a Stuart-Provver factor deficiency. Qualitative tests for factor VII demonstrated a full correction of the patient's prothrombin time to 12 seconds or 100 per cent. Treatment with serum from clotted blood was instituted for the factor VII deficiency. Bleeding was controlled for 5 days but recurred in the form of massive hemorrhage on the sixth day following treatment. Shock ensued and it was thought necessary to re-explore the abdomen. Generalized oozing from all cut surfaces was noted and approximately 500 c.c. of blood was rf'moved from the pelvic cavity. Immediate serum therapy was reinstituted as well as whole blood replacement. The advent of shock had complicated the hemorrhagic condition, resulting in a prolonged stormy course. A total of 1,500 c.c. of serum and 11,500 c.c. of whole blood was used in the treatment of this patient. She was dismissed on the fifty-first hospital day in good condition. Case 2. A 38-year-old gravida iv, para iv, was admitted with the diagnosis of prolapse of the uterus. There was no history of unusual bleeding, except for a postpartum hemorrhage with retained secundines. Vaginal hysterectomy with repair of a cystocele and rectocele was performed on Oct. 20, 1960. Eleven days after operation she developed severe bleeding of the vaginal cuff which was controlled by suturing from below. Coagulation studies at this time demonstrated a platelet count of 163,000 and coagulation time of 6 minutes, 10 seconds. The prothrombin time was 12.8 seconds (96 per cent of normal). Factors V and VII were normal. The patient received one transfusion of whole blood and was dismissed apparently in good condition.
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She was readmitted 24 hours later with severe vaginal hemorrhage. Coagulation studies were repeated. The prothrombin time was 14.2 seconds (58 per cent). The addition of factor V and prothrombin did not correct this. Factor VII corrected to 12 seconds ( 100 per cent of normal). The thromboplastin generation test . ... HF, P'TC, or PI"'..~ deshovred no apparent . A ficiency. The Russell viper venom test ruled out a Stuart-Prower factor deficiency. These results indicated a factor VII defect. Intravenous serum was administered which rapidly controlled the bleeding. Additional serum was given at increasing intervals in order to forestall further bleeding. Whole blood and packed blood cells \vere used for replacement. When the patient was discharged, she was in good condition. Case 3. A 48-year-old gravida iii, para iii, with a diagnosis of uterine fibroids and relaxation of the pelvic floor, was admitted on Feb. 23, 1961. There was a history of prolonged bleeding after tonsillectomy and severe hemorrhage requiring transfusions after each of her 3 deliveries. Coagulation studies revealed a platelet count of 250,000 a coagulation time of 27 minutes, 45 seconds, and a prothrombin time of 13.8 seconds ( 60 per cent). Factor V was normal. Addition of factor VII corrected the prothrombin time to 12.4 seconds ( 100 per cent). The Russell viper venom test was negative. The thromboplastin generation test demonstrated no apparent AHF, PTA, or PTC deficiency. These tests indicated a factor VII deficiency. In view of the preoperative diagnosis one unit of serum was administered intravenously on the day before operation. Vaginal hysterectomy was accomplished with a surprisingly small blood loss. The field was dry at all times. One unit of serum was administered on the third postoperative day and the patient was dismissed on the eighth day in good condition. Case 4. A 13-year-old girl who had continued to bleed profusely since the onset of catamenia, 3 weeks prior to admission, was seen in borderline shock. There was a history of frequent epistaxis ii1 early childhood; a sister had had excessive vaginal bleeding at age 17. Coagulation studies demonstrated a hemoglobin level of 6.4 Gm. or 40 per cent. The platelets were 195,000. The coagulation time was 8 minutes, 38 seconds. The prothrombin time was 14 seconds ( 60 per cent of normal). Ad-
1048 Morgan and Williams
clition of factor VII corrected to 12.2 seconds or 100 per cent. With this information it was considered most probable that the defect was in factor VII. She was given 3 units of serum. Bleeding was under control in approximately 15 minutes after administration of the first unit of serum. A transfusion of 1,500 c.c. of whole blood was given as replacement and she was dismissed with a prothrombin time of 12.4 seconds (100 per cent). We were unable to obtain further studies. Case 5. A 25-year-old para ii, gravida iii, with a history of immediate postpartum hemorrhage in 1956 and a postpartum hemorrhage on the fifth day in 1957 requiring two transfusions, was suspected of having a coagulation defect. Accordingly, she was studied in the thirty-fourth week of pregnancy. Platelets were adequate on the peripheral blood smear. The prothrombin time was 14 seconds ( 65 per cent of normal). Factor V was normal. The addition of factor VII corrected to 6 seconds ( 100 per cent plus) (control 12 seconds) . The coagulation time was 12 minutes, 30 seconds. The thromboplastin generation test was negative for AHF, PTC, or PTA deficit. The Russell viper venom time was prolonged to 26 seconds, indicating a Stuart-Prower deficit. The patient received 1 unit of serum at the first indication of labor. Delivery and puerperium were uncomplicated. Case 6. A 26-year-old nulliparous patient was admitted with a diagnosis of bilateral ovarian cystic disease. There was a history of irregular menstruation with menorrhagia. The past history disclosed episodes of spontaneous epistaxis and bleeding after tonsillectomy and following operation on a toe. Coagulation studies showed a platelet count of 256,000, a coagulation time of 18 minutes, and a prothrombin time of 13.1 seconds ( 13 second control). Tests for factors V and VII were negative. Thromboplastin generation tests indicated a PTA deficiency. In view of the increased hazard in this patient, it was decided that elective operation was contraindicated. Case 7. A 46-year-old gravida iii, para iii, was admitted with a diagnosis of fibroid tumors of the uterus, menometrorrhagia, and severe anemia of long duration. In 1950 she had a cesarean section and was vague as to undue blood loss following this operation. The anemia had been present since the onset of catamenia. In 1955 it had been ascertained that she had a
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April !5, !9h2 OhsL & U.yne:<:
prothrombin time of 18 seconds, or 35 per cent of normal, but testing revealed no deficiendcs in the qualitative prothrombin nor in factors V and VII. Two months later the prothrombin time was 14 seconds, or 65 per cent of normaL In January, 1957, the test was repeated and was found to be 13 seconds, or 95 per cent of normal. Upon admission and prior to operation coagulation studies demonstrated the platclt~ls at 250,000, and a coagulation time of 10 min· utes, 2U seconds. The prothrombin time was H:.l seconds (54 per cent of a 12 second control). The addition of factor V failed to correct the prothrombin time. The addition of factor VTI gave a partial correction of the total prothrombin time to 13 seconds. The thromboplastin generation test indicated a PTC deficiency (Christmas disease). She received serum before ,, curettage and before hysterectomy. The operative field was dry at the time of closure and all bleeding points in the laparotomy wound were controlled. Twenty-four hours later, hemorrhage from the abdominal wound was noted and became increasingly severe. However, the administration of one additional unit of serum controlled the bleeding within a short time. Her course was uneventfui thereafter. Comment
This group of patients, demonstrating a variety of coagulation defects, may well be categorized as having occult hemophilia. These individuals ordinarily do not have gross hematuria, hemarthroses, or gastrointestinal bleeding as do patients with true hemophilia. Nor do they develop severe hemorrhages until blood loss from trauma or surgical procedures depletes the coagulation factor involved to a critical level. As Miale 8 and others believe, many of the coagulation factors may not exist as individual chemical entities. Some of these substances may be breakdown products of prothrombin with differing characteristics and actions in the coagulation mechanism. What we regard today as factor VII may actually be some other substance, but, regardless of terminology, the fact remains that a serum factor deficit of a very mild degree can result in serious hemorrhage. We were able to detect a deficit in this substance or activity only by testing for factor VII.
Volume 83 Number 8
In our experience the history has been of the greatest importance in leading to the detection of persons with these mild defects. All patients in our series had a history of some abnormal bleeding v:ith the exception of Case 2. In this instance, not only was the history of no help, but the initial laboratory studies were within normal range. It has been noted by Steffanini9 that during periods of normal vascular integrity in persons with mild coagulation defects the laboratory studies may be within normal limits and that the lack of history of bleeding and essentially normal tests make the diagnosis of a hemorrhagic diathesis impossible in some instances. In Case 1 the history of bleeding following the extraction of teeth in the earlier years was not obtained preoperatively and the patient's previous obstetric and surgical experiences without bleeding problems led to a feeling of complacency relative to her forthcoming operation. It was only during the period of convalescence and under close questioning that the story of prolonged bleeding after the extraction of teeth was obtained. Incidentally, this patient's cousin, a woman of 50, likewise is now known to have a factor VII deficiency. In Case 3, in which the diagnosis of factor VII deficiency was made preoperatively and serum administration was carried out both pre- and postoperatively, no difficulty with bleeding was encountered. On the contrary, the blood loss during the operative procedure was so slight as to cause particular comment to be made in the operative record. In Case 4, although initial studies pointed to a factor VII deficit, a complete study including TGT and the Russell viper venom test was not obtainable. However, the rather dramatic cessation of bleeding following the administration of serum (within 15 minutes) is of interest. The suggestion of Friedman 10 as well as that of Seaman and Benson 11 that any of the coagulation defects may produce aberrations in the menstrual cycle is borne out. The defect may even result in death as reported by Brink and Kingsley. 12 In Case 5, wherein occult hemophilia was suspected from the previous history in a
Occult hemophilia
1049
near-term gravida, laboratory studies confirmed the impression and proved a StuartPrower deficit. Studies by many investigators in the past have demonstrated repeatedly that, in the third trimester of a norma! pregnancy, all coagulation factors are within the range of high normal or elevated, with the possible exception of prothrombin, which may be lowered mildly. In this patient the low thromboplastin time became even greater in significance. In this one case, at least, we find ourselves at variance with the suggestions of Broady and Finch 13 that there is an improvement in Stuart-Prower factor deficiency during pregnancy. Case 6, an instance of PTA deficiency, illustrates again a history suggestive of occult hemophilia. Because of the experience of others, elective operation was indefinitely postponed. The condition found in Case 7, Christmas disease, is considered a rare entity in the female; one of the few reports in the literature of this condition is that by Radman.14 During the process of coagulation of whole blood, the serum factors are increased in amount many times over the concentration in whole blood or plasma. Therefore, serum from clotted blood was used as the treatment of choice in these patients because each one treated had a serum factor deficit. It is well to note that in Case 2 one transfusion of whole blood did not prevent subsequent severe bleeding. We have not been able to find any references in the literature to mild deficiencies of factor VII as a cause of abnormal bleeding, although one of us15 has previously reported a series of such cases in college athletes following trauma. We feel that testing has been inadequate since a prothrombin time of 50 per cent or greater has been routinely considered as normal in the past. However, when more complete coagulation studies including the TGT and Russell viper venom test are carried out, we believe the mild factor VII deficiencies will be pinpointed as a heretofore unrecognized cause of postoperative or postpartum hemorrhage.
1050 Morgan and Williams
Am.
Conclusions 1. A careful history with reference to any undue bleeding following trauma, unexplained menometrorrhagia, or postpartum hemorrhage is essential. 2. Suspect cases must be subjected to adequate laboratory testing. 3. A deficit in factor VII, little suspected
REFERENCES I. Aggeler, P. M.: Am.
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6: 23, 1953. 7. Hjort, P., Rappaport, S. 1., and Owren, P. A.: J. Lab. & Olin. Med. 46: 89, 1955. 8. Miale, ]. B.: Laboratory Medicine-Hema-
April 15,
196~
Obst. & Gynec.
in the past, is often the cause of severe postoperative or postpartum hemorrhage. 4. Serum when indicated should be utilized before and after any traumatic procedures resulting in blood loss. 5. More than meticulous care must be taken during operations to minimize blood loss in patients with mild coagulation defects.
J. Med. 30: 84, 1961.
2. Dameshek, W.: Arch. Int. Med. 50: 579, 1932. 3. Lee, R. I., and White, P. D.: Am. J. M. Sc. 145: 495, 1913. 4. Quick, A. J.: J. Bioi. Chern. 109: 73, 1935. 5. Biggs, R., and Macfarlane, R. G.: Human Blood Coagulation and Its Disorders, Oxford, 1953, Blackwell Scientific Publications, p. 352.
J.
9.
10. 11. 12. 13. 1 A
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tology, St. Louis, 1958, The C. V. Mosby Company, p. 548. Steffanini: Personal communication. Friedman, I. A., et al.: J. A. M. A. 175: 370, 1961. Seaman, A. J., and Benson, R. C.: AM J. 0BST. & GYNEC. 79: 1, 1960. Brink, A. J., and Kingsley, C. S.: Quart. J. Med. 21: 1952. Broady, J. 1., and Finch, S. C.: New England ]. Med. 263: 996, 1960.
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79: 1, 1960. 15. Williams, J. T.: Paper read at Annual Session, Nebraska State Medical Association, April 27, 1960.
Discussion DR. RoBERT A. Ross, Chapel Hill, North Carolina. The authors have presented the case reports of 7 patients who had the clinical problem of bleeding which in their opinion was due to one of several blood factor deficiencies. The title "occult hemophilia" is used and this could be considered a point of disagreement by the investigators in this field who use the term "hemophilia" to mean factor VIII or AHF deficiency. The authors give 8 tests that are used in their study. We comment that we have found the coagulation time of little use in mild defects. We prefer the partial thromboplastin time (PTT) to the thromboplastin generation test ( TG T), believing it to be quicker and better. Commercial partial thromboplastin is now available. Postoperative vaginal cuff bleeding, as in Case 1, is a crisis most have experienced. It is difficult to see how a 55 per cent ( 2 seconds greater than control) factor VII determined 12 hours after operation could cause this much trouble. At the first postoperative laparotomy bleeding points were controlled, 2 units of fibrinogen given, and blood replacement accom-
plished. Later serum from clotted blood was given. Five days later further hemorrhage required a second postoperative laparotomy. We probably would have relied upon fresh whole blood following the first postoperative laparotomy. There is no mention of fibrinolysis investigation or bleeding time. A total of 1,500 c.c. of serum and 11,500 c.c. of whole blood was given. Thrombin is in serum and thrombin can do harm when injected. Could the serum have contributed to the need for blood? Serum will accelerate in vitro tests, but there is little evidence that this occurs in vivo. In Case 2 the patient had vaginal hysterectomy and repair and on the eleventh postoperative day there was severe bleeding, which was controlled by suturing. One whole blood transfusion was given. Twenty-four hours later the patient had another severe bleeding episode. Prothrombin time was 14.2 seconds (58 per cent). The addition of factor V and prothrombin did not correct this figure. Factor VII corrected to 12 seconds ( 100 per cent). The authors state, "these results indicated a factor VII defect." True, but they do not necessarily proVf• that this was the cause of bleeding.
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Cases 3, 4, and 5 all had somewhat prolonged prothrombin time corrected by using factor VII. Case 4, the 13-year-old with excessive bleeding from the onset of catamenia 3 months previously, had only 6.4 Gm. of hemoglobin. We share in the hope that she returns for further study. Case 6 is one of PT.A.. deficiency. This is a condition rarely encountered in the South, with the characteristic of unusually long clotting time. One would like to know if the Hageman trait was excluded. Case 7 is PTC deficiency disease, but the degree was not stated. The question of liver function occurs since prothrombin time should be normal in uncomplicated PTC deficiency. In several of the cases where an abnormal prothrombin time was noted, no mention was made of the blood counts. Abnormal prothrombin time occurs in anemic patients if standard amounts of anticoagulant solution are used. with normal hematocrit the plasma-anticoagulant ratio is 4.5:1 and with low hematocrit this rate may be as much as 7:1. In testing these bloods one must determine the optimal amounts of calcium. In this paper one of the major diagnostic points is the correction of the slightly abnormal prothrombin time by the addition of factor VII. It would be helpful if it were stated how this material was prepared or how much was added. It was shown many years ago that a serum factor (other than thrombin) will shorten the prothrombin time of normal plasma as well as plasma deficient in any of the known coagulation factors. If enough of this material is added one will get a very short prothrombin time as did the authors in their Case 5. The shortening of prothrombin time by the addition of factor VII is not sufficient evidence to diagnose a factor VII deficiency. The coexistence of a slight deficit of some factor and bleeding does not necessarily imply a cause-and-effect relationship. We control severe bleeding by elevating the levels from zero to 50 per cent of normal even during operation. We do emphasize our reliance on fresh whole blood and plasma in the management of patients with bleeding problems. This in no way minimizes the need for anticipating emergencies. Tn the interest of a more complete discussion we may outline our own routine practices, 4 relatively simple, rapidly performed studies: 1. Fibrinogen estimation is perhaps the most
1051
obvious in obstetric problems. In our laboratory, the preferred method is by conversion of fibrinogen to fibrin by topical thrombin foiiowed by colorimetric estimation of nitrogen content. 2. We use the Brecher-Cronkite method of platelet counting, but the various indirect methods should be adequate for clinical purposes. 3. The partial thromboplastin time is useful in detecting deficiencies of the factors involved in the first stage of coagulation (i.e., AHF, PTC, factor V, Hageman factor, plasma thromboplastin antecedent [PTA], and the Stuan factor). 4. The Quick one-stage prothrombin time will detect clinically important deficiencies of pro-
thrombin, Stuart factor, factor V, and SPCA, but minimal changes in these factors may not be apparent in the Quick prothrombin time. Clinically important changes, however, would certainly be evident. Specific assays may be dom· for any of the above factors should the screening test results be abnormaL It should be emphasized that multiple deficiencies can and do occur.
DR. WILLIAMS* (Closing). In our attempt to avoid lengthiness, we have apparently sacrificed some degree of clarity. We must also admit that we have not contributed to the simplification of nomenclature by the use of the term "occult hemophilia." However, there seems to be no general agreement on just what hemophilia is. As to the use of "factor X" for PTA, there ha' been disagreement here also, but we have followed the nomenclature adopted by the Internatienal Committee of Hematology Nom('nclature. We do not share the confidence that Dr. Ross has in bleeding time determinations. Numerous tests by the Ivy technique in the past in similar cases have been routinely unrewarding. We have also found the coagulation time to b<' of no help in these cases. It is true that in the past little evidence has been presented that the use of intravenous serum accelerates the clotting phenomenon. It is for this reason among others that this paper was presented. Clinically, there can be no question of the efficacy of this treatment. In almost everv case bleeding was apparently controlled within 15 to 20 minutes after the administration of the serum. This has also been noted in 11 other cases following operations for various conditions. *By invitation.
1052 Morgan and Williams
Aprill5, 1962 .\~~
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The use of serum in such cases is also advocated by Steffanini and Miale. In our hands it has been much more effective than whole blood or plasma. It is important to note that the effect of the serum lasts only 5 or 6 days, and at the end of that time hemorrhage may recur requiring further treatment. Blood counts were omitted in several insta..r1ccs because we felt that they did not contribute to any better understanding of the coagulation defect involved. Since the Hageman trait never
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results in abnormal bleeding, specific tests for this were not performed. The preparation of matenal for factor v 11 testing was by the method of Biggs and Macfarlane, 5 and 0.1 mi. of the material was used. We realize it is difficult to comprehend that a 50 or 60 per cent thromboplastin time may be responsible for continued hemorrhage in rnild factor VII deficiencies. We can only restate that these people have a lower reservoir of this substance upon which to draw in emergencies.
HAROLD S. MORGAN, M.D. JON T. WILLIAMS, M.D. Lincoln, Nebraska
Methods
0 c c u L T hemophilia, the term suggested by Aggeler 1 to designate the mild congenital blood coagulation defects, has been adopted by us as best describing the status of a group of 7 patients whom we have studied during the past year. In adopting this term, we have broadened it to include deficiencies in factors V and VII and the Stuart-Prower factor, as well as defects in AHF, PTA, and PTC. It is our purpose to show that, in its unrecognized state, occult hemophilia can be a dangerous condition leading to severe postoperative or postpartum hemorrhage, but that, if the condition is recognized, appropriate measures may be adopted that will protect or treat the patient. Of the 7 cases to be reported, 4 are concerned with mild defects in the serum accelerator factor VII and one each in the PTA, PTC (Christmas disease) , and StuartPrower factors. (We are indebted to the members of the Staff of the Department of Obstetrics and Gynecology of the Lincoln General Hospital for the privilege of including their patients in this report.)
The following laboratory tests were used to detect the faulty coagulation mechanism in the patients studied: I. Platelet count by the indirect method of Dameshek. 2 2. Coagulation time of Lee and White." 3. Thromboplastin time (the one-stage prothrombin time of Quick1 ) . 4. Factor V determination (labile factor). 5. Factor VII determination (stable factor). 6. Qualitative prothrombin. These latter three by the method of Biggs and Macfarlane.5 7. Thromboplastin generation test (TGT) of Biggs and Douglas6 in which Asolectin suspension was substituted for a platelet suspension for the AHF (factor VIII), PTC (factor IX or Christmas disease), and PTA (factor X) activity. 8. Russell viper venom test of Hjort and co-workers 7 for the combined activity of platelets, prothrombin, factor V. and StuartPrower factor. Case reports Case 1. A 39-year-old gravida iv, para iv, was admitted to the hospital for the correction of relaxation of the pelvic floor with prolapse. There was a previous history of tonsillectomy and laparotomy for ovarian cyst without unduf' bleeding. Vaginal hysterectomy was performed on Sept. 4, 1960. Twelve hours after operation
From the Departments of Obstetrics and Gynecolof?y and Internal ..Medicine, Lincoln General Hospital. Presented by invitation at the Seventy-second Annual Meeting of the American Association of Obstetricians and Gynecologists, Hot Springs, Virginia, Sept. 7-9, 1961.
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Volume 83 Nutl::lber 8
there were signs and symptoms of intra-abdominal bleeding, and laparotomy disclosed approximately 1,200 c.c. of intraperitoneal blood. Bleeding in the infundibulopelvic area and from the vaginal cuff was brought under control. Two units of fibrinogen and transfusions to replace blood loss were given. Intermittent vaginal bleeding continued. A hemorrhagic diathesis was suspected and laboratory studies demonstrated a normal coagulation time. Platelets were 360,000. The prothrombin time was 55 per cent of normal. Tests for factor V were normal. The thromboplastin generation test was normal (ruling out deficiencies in AHF, PTC, and PTA). The Russell viper venon1 test ruled out a Stuart-Provver factor deficiency. Qualitative tests for factor VII demonstrated a full correction of the patient's prothrombin time to 12 seconds or 100 per cent. Treatment with serum from clotted blood was instituted for the factor VII deficiency. Bleeding was controlled for 5 days but recurred in the form of massive hemorrhage on the sixth day following treatment. Shock ensued and it was thought necessary to re-explore the abdomen. Generalized oozing from all cut surfaces was noted and approximately 500 c.c. of blood was rf'moved from the pelvic cavity. Immediate serum therapy was reinstituted as well as whole blood replacement. The advent of shock had complicated the hemorrhagic condition, resulting in a prolonged stormy course. A total of 1,500 c.c. of serum and 11,500 c.c. of whole blood was used in the treatment of this patient. She was dismissed on the fifty-first hospital day in good condition. Case 2. A 38-year-old gravida iv, para iv, was admitted with the diagnosis of prolapse of the uterus. There was no history of unusual bleeding, except for a postpartum hemorrhage with retained secundines. Vaginal hysterectomy with repair of a cystocele and rectocele was performed on Oct. 20, 1960. Eleven days after operation she developed severe bleeding of the vaginal cuff which was controlled by suturing from below. Coagulation studies at this time demonstrated a platelet count of 163,000 and coagulation time of 6 minutes, 10 seconds. The prothrombin time was 12.8 seconds (96 per cent of normal). Factors V and VII were normal. The patient received one transfusion of whole blood and was dismissed apparently in good condition.
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She was readmitted 24 hours later with severe vaginal hemorrhage. Coagulation studies were repeated. The prothrombin time was 14.2 seconds (58 per cent). The addition of factor V and prothrombin did not correct this. Factor VII corrected to 12 seconds ( 100 per cent of normal). The thromboplastin generation test . ... HF, P'TC, or PI"'..~ deshovred no apparent . A ficiency. The Russell viper venom test ruled out a Stuart-Prower factor deficiency. These results indicated a factor VII defect. Intravenous serum was administered which rapidly controlled the bleeding. Additional serum was given at increasing intervals in order to forestall further bleeding. Whole blood and packed blood cells \vere used for replacement. When the patient was discharged, she was in good condition. Case 3. A 48-year-old gravida iii, para iii, with a diagnosis of uterine fibroids and relaxation of the pelvic floor, was admitted on Feb. 23, 1961. There was a history of prolonged bleeding after tonsillectomy and severe hemorrhage requiring transfusions after each of her 3 deliveries. Coagulation studies revealed a platelet count of 250,000 a coagulation time of 27 minutes, 45 seconds, and a prothrombin time of 13.8 seconds ( 60 per cent). Factor V was normal. Addition of factor VII corrected the prothrombin time to 12.4 seconds ( 100 per cent). The Russell viper venom test was negative. The thromboplastin generation test demonstrated no apparent AHF, PTA, or PTC deficiency. These tests indicated a factor VII deficiency. In view of the preoperative diagnosis one unit of serum was administered intravenously on the day before operation. Vaginal hysterectomy was accomplished with a surprisingly small blood loss. The field was dry at all times. One unit of serum was administered on the third postoperative day and the patient was dismissed on the eighth day in good condition. Case 4. A 13-year-old girl who had continued to bleed profusely since the onset of catamenia, 3 weeks prior to admission, was seen in borderline shock. There was a history of frequent epistaxis ii1 early childhood; a sister had had excessive vaginal bleeding at age 17. Coagulation studies demonstrated a hemoglobin level of 6.4 Gm. or 40 per cent. The platelets were 195,000. The coagulation time was 8 minutes, 38 seconds. The prothrombin time was 14 seconds ( 60 per cent of normal). Ad-
1048 Morgan and Williams
clition of factor VII corrected to 12.2 seconds or 100 per cent. With this information it was considered most probable that the defect was in factor VII. She was given 3 units of serum. Bleeding was under control in approximately 15 minutes after administration of the first unit of serum. A transfusion of 1,500 c.c. of whole blood was given as replacement and she was dismissed with a prothrombin time of 12.4 seconds (100 per cent). We were unable to obtain further studies. Case 5. A 25-year-old para ii, gravida iii, with a history of immediate postpartum hemorrhage in 1956 and a postpartum hemorrhage on the fifth day in 1957 requiring two transfusions, was suspected of having a coagulation defect. Accordingly, she was studied in the thirty-fourth week of pregnancy. Platelets were adequate on the peripheral blood smear. The prothrombin time was 14 seconds ( 65 per cent of normal). Factor V was normal. The addition of factor VII corrected to 6 seconds ( 100 per cent plus) (control 12 seconds) . The coagulation time was 12 minutes, 30 seconds. The thromboplastin generation test was negative for AHF, PTC, or PTA deficit. The Russell viper venom time was prolonged to 26 seconds, indicating a Stuart-Prower deficit. The patient received 1 unit of serum at the first indication of labor. Delivery and puerperium were uncomplicated. Case 6. A 26-year-old nulliparous patient was admitted with a diagnosis of bilateral ovarian cystic disease. There was a history of irregular menstruation with menorrhagia. The past history disclosed episodes of spontaneous epistaxis and bleeding after tonsillectomy and following operation on a toe. Coagulation studies showed a platelet count of 256,000, a coagulation time of 18 minutes, and a prothrombin time of 13.1 seconds ( 13 second control). Tests for factors V and VII were negative. Thromboplastin generation tests indicated a PTA deficiency. In view of the increased hazard in this patient, it was decided that elective operation was contraindicated. Case 7. A 46-year-old gravida iii, para iii, was admitted with a diagnosis of fibroid tumors of the uterus, menometrorrhagia, and severe anemia of long duration. In 1950 she had a cesarean section and was vague as to undue blood loss following this operation. The anemia had been present since the onset of catamenia. In 1955 it had been ascertained that she had a
\Ill.
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April !5, !9h2 OhsL & U.yne:<:
prothrombin time of 18 seconds, or 35 per cent of normal, but testing revealed no deficiendcs in the qualitative prothrombin nor in factors V and VII. Two months later the prothrombin time was 14 seconds, or 65 per cent of normaL In January, 1957, the test was repeated and was found to be 13 seconds, or 95 per cent of normal. Upon admission and prior to operation coagulation studies demonstrated the platclt~ls at 250,000, and a coagulation time of 10 min· utes, 2U seconds. The prothrombin time was H:.l seconds (54 per cent of a 12 second control). The addition of factor V failed to correct the prothrombin time. The addition of factor VTI gave a partial correction of the total prothrombin time to 13 seconds. The thromboplastin generation test indicated a PTC deficiency (Christmas disease). She received serum before ,, curettage and before hysterectomy. The operative field was dry at the time of closure and all bleeding points in the laparotomy wound were controlled. Twenty-four hours later, hemorrhage from the abdominal wound was noted and became increasingly severe. However, the administration of one additional unit of serum controlled the bleeding within a short time. Her course was uneventfui thereafter. Comment
This group of patients, demonstrating a variety of coagulation defects, may well be categorized as having occult hemophilia. These individuals ordinarily do not have gross hematuria, hemarthroses, or gastrointestinal bleeding as do patients with true hemophilia. Nor do they develop severe hemorrhages until blood loss from trauma or surgical procedures depletes the coagulation factor involved to a critical level. As Miale 8 and others believe, many of the coagulation factors may not exist as individual chemical entities. Some of these substances may be breakdown products of prothrombin with differing characteristics and actions in the coagulation mechanism. What we regard today as factor VII may actually be some other substance, but, regardless of terminology, the fact remains that a serum factor deficit of a very mild degree can result in serious hemorrhage. We were able to detect a deficit in this substance or activity only by testing for factor VII.
Volume 83 Number 8
In our experience the history has been of the greatest importance in leading to the detection of persons with these mild defects. All patients in our series had a history of some abnormal bleeding v:ith the exception of Case 2. In this instance, not only was the history of no help, but the initial laboratory studies were within normal range. It has been noted by Steffanini9 that during periods of normal vascular integrity in persons with mild coagulation defects the laboratory studies may be within normal limits and that the lack of history of bleeding and essentially normal tests make the diagnosis of a hemorrhagic diathesis impossible in some instances. In Case 1 the history of bleeding following the extraction of teeth in the earlier years was not obtained preoperatively and the patient's previous obstetric and surgical experiences without bleeding problems led to a feeling of complacency relative to her forthcoming operation. It was only during the period of convalescence and under close questioning that the story of prolonged bleeding after the extraction of teeth was obtained. Incidentally, this patient's cousin, a woman of 50, likewise is now known to have a factor VII deficiency. In Case 3, in which the diagnosis of factor VII deficiency was made preoperatively and serum administration was carried out both pre- and postoperatively, no difficulty with bleeding was encountered. On the contrary, the blood loss during the operative procedure was so slight as to cause particular comment to be made in the operative record. In Case 4, although initial studies pointed to a factor VII deficit, a complete study including TGT and the Russell viper venom test was not obtainable. However, the rather dramatic cessation of bleeding following the administration of serum (within 15 minutes) is of interest. The suggestion of Friedman 10 as well as that of Seaman and Benson 11 that any of the coagulation defects may produce aberrations in the menstrual cycle is borne out. The defect may even result in death as reported by Brink and Kingsley. 12 In Case 5, wherein occult hemophilia was suspected from the previous history in a
Occult hemophilia
1049
near-term gravida, laboratory studies confirmed the impression and proved a StuartPrower deficit. Studies by many investigators in the past have demonstrated repeatedly that, in the third trimester of a norma! pregnancy, all coagulation factors are within the range of high normal or elevated, with the possible exception of prothrombin, which may be lowered mildly. In this patient the low thromboplastin time became even greater in significance. In this one case, at least, we find ourselves at variance with the suggestions of Broady and Finch 13 that there is an improvement in Stuart-Prower factor deficiency during pregnancy. Case 6, an instance of PTA deficiency, illustrates again a history suggestive of occult hemophilia. Because of the experience of others, elective operation was indefinitely postponed. The condition found in Case 7, Christmas disease, is considered a rare entity in the female; one of the few reports in the literature of this condition is that by Radman.14 During the process of coagulation of whole blood, the serum factors are increased in amount many times over the concentration in whole blood or plasma. Therefore, serum from clotted blood was used as the treatment of choice in these patients because each one treated had a serum factor deficit. It is well to note that in Case 2 one transfusion of whole blood did not prevent subsequent severe bleeding. We have not been able to find any references in the literature to mild deficiencies of factor VII as a cause of abnormal bleeding, although one of us15 has previously reported a series of such cases in college athletes following trauma. We feel that testing has been inadequate since a prothrombin time of 50 per cent or greater has been routinely considered as normal in the past. However, when more complete coagulation studies including the TGT and Russell viper venom test are carried out, we believe the mild factor VII deficiencies will be pinpointed as a heretofore unrecognized cause of postoperative or postpartum hemorrhage.
1050 Morgan and Williams
Am.
Conclusions 1. A careful history with reference to any undue bleeding following trauma, unexplained menometrorrhagia, or postpartum hemorrhage is essential. 2. Suspect cases must be subjected to adequate laboratory testing. 3. A deficit in factor VII, little suspected
REFERENCES I. Aggeler, P. M.: Am.
C.
v.
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6: 23, 1953. 7. Hjort, P., Rappaport, S. 1., and Owren, P. A.: J. Lab. & Olin. Med. 46: 89, 1955. 8. Miale, ]. B.: Laboratory Medicine-Hema-
April 15,
196~
Obst. & Gynec.
in the past, is often the cause of severe postoperative or postpartum hemorrhage. 4. Serum when indicated should be utilized before and after any traumatic procedures resulting in blood loss. 5. More than meticulous care must be taken during operations to minimize blood loss in patients with mild coagulation defects.
J. Med. 30: 84, 1961.
2. Dameshek, W.: Arch. Int. Med. 50: 579, 1932. 3. Lee, R. I., and White, P. D.: Am. J. M. Sc. 145: 495, 1913. 4. Quick, A. J.: J. Bioi. Chern. 109: 73, 1935. 5. Biggs, R., and Macfarlane, R. G.: Human Blood Coagulation and Its Disorders, Oxford, 1953, Blackwell Scientific Publications, p. 352.
J.
9.
10. 11. 12. 13. 1 A
1"1' •
tology, St. Louis, 1958, The C. V. Mosby Company, p. 548. Steffanini: Personal communication. Friedman, I. A., et al.: J. A. M. A. 175: 370, 1961. Seaman, A. J., and Benson, R. C.: AM J. 0BST. & GYNEC. 79: 1, 1960. Brink, A. J., and Kingsley, C. S.: Quart. J. Med. 21: 1952. Broady, J. 1., and Finch, S. C.: New England ]. Med. 263: 996, 1960.
n
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79: 1, 1960. 15. Williams, J. T.: Paper read at Annual Session, Nebraska State Medical Association, April 27, 1960.
Discussion DR. RoBERT A. Ross, Chapel Hill, North Carolina. The authors have presented the case reports of 7 patients who had the clinical problem of bleeding which in their opinion was due to one of several blood factor deficiencies. The title "occult hemophilia" is used and this could be considered a point of disagreement by the investigators in this field who use the term "hemophilia" to mean factor VIII or AHF deficiency. The authors give 8 tests that are used in their study. We comment that we have found the coagulation time of little use in mild defects. We prefer the partial thromboplastin time (PTT) to the thromboplastin generation test ( TG T), believing it to be quicker and better. Commercial partial thromboplastin is now available. Postoperative vaginal cuff bleeding, as in Case 1, is a crisis most have experienced. It is difficult to see how a 55 per cent ( 2 seconds greater than control) factor VII determined 12 hours after operation could cause this much trouble. At the first postoperative laparotomy bleeding points were controlled, 2 units of fibrinogen given, and blood replacement accom-
plished. Later serum from clotted blood was given. Five days later further hemorrhage required a second postoperative laparotomy. We probably would have relied upon fresh whole blood following the first postoperative laparotomy. There is no mention of fibrinolysis investigation or bleeding time. A total of 1,500 c.c. of serum and 11,500 c.c. of whole blood was given. Thrombin is in serum and thrombin can do harm when injected. Could the serum have contributed to the need for blood? Serum will accelerate in vitro tests, but there is little evidence that this occurs in vivo. In Case 2 the patient had vaginal hysterectomy and repair and on the eleventh postoperative day there was severe bleeding, which was controlled by suturing. One whole blood transfusion was given. Twenty-four hours later the patient had another severe bleeding episode. Prothrombin time was 14.2 seconds (58 per cent). The addition of factor V and prothrombin did not correct this figure. Factor VII corrected to 12 seconds ( 100 per cent). The authors state, "these results indicated a factor VII defect." True, but they do not necessarily proVf• that this was the cause of bleeding.
Occult hemophilia
Volume 83 Number 8
Cases 3, 4, and 5 all had somewhat prolonged prothrombin time corrected by using factor VII. Case 4, the 13-year-old with excessive bleeding from the onset of catamenia 3 months previously, had only 6.4 Gm. of hemoglobin. We share in the hope that she returns for further study. Case 6 is one of PT.A.. deficiency. This is a condition rarely encountered in the South, with the characteristic of unusually long clotting time. One would like to know if the Hageman trait was excluded. Case 7 is PTC deficiency disease, but the degree was not stated. The question of liver function occurs since prothrombin time should be normal in uncomplicated PTC deficiency. In several of the cases where an abnormal prothrombin time was noted, no mention was made of the blood counts. Abnormal prothrombin time occurs in anemic patients if standard amounts of anticoagulant solution are used. with normal hematocrit the plasma-anticoagulant ratio is 4.5:1 and with low hematocrit this rate may be as much as 7:1. In testing these bloods one must determine the optimal amounts of calcium. In this paper one of the major diagnostic points is the correction of the slightly abnormal prothrombin time by the addition of factor VII. It would be helpful if it were stated how this material was prepared or how much was added. It was shown many years ago that a serum factor (other than thrombin) will shorten the prothrombin time of normal plasma as well as plasma deficient in any of the known coagulation factors. If enough of this material is added one will get a very short prothrombin time as did the authors in their Case 5. The shortening of prothrombin time by the addition of factor VII is not sufficient evidence to diagnose a factor VII deficiency. The coexistence of a slight deficit of some factor and bleeding does not necessarily imply a cause-and-effect relationship. We control severe bleeding by elevating the levels from zero to 50 per cent of normal even during operation. We do emphasize our reliance on fresh whole blood and plasma in the management of patients with bleeding problems. This in no way minimizes the need for anticipating emergencies. Tn the interest of a more complete discussion we may outline our own routine practices, 4 relatively simple, rapidly performed studies: 1. Fibrinogen estimation is perhaps the most
1051
obvious in obstetric problems. In our laboratory, the preferred method is by conversion of fibrinogen to fibrin by topical thrombin foiiowed by colorimetric estimation of nitrogen content. 2. We use the Brecher-Cronkite method of platelet counting, but the various indirect methods should be adequate for clinical purposes. 3. The partial thromboplastin time is useful in detecting deficiencies of the factors involved in the first stage of coagulation (i.e., AHF, PTC, factor V, Hageman factor, plasma thromboplastin antecedent [PTA], and the Stuan factor). 4. The Quick one-stage prothrombin time will detect clinically important deficiencies of pro-
thrombin, Stuart factor, factor V, and SPCA, but minimal changes in these factors may not be apparent in the Quick prothrombin time. Clinically important changes, however, would certainly be evident. Specific assays may be dom· for any of the above factors should the screening test results be abnormaL It should be emphasized that multiple deficiencies can and do occur.
DR. WILLIAMS* (Closing). In our attempt to avoid lengthiness, we have apparently sacrificed some degree of clarity. We must also admit that we have not contributed to the simplification of nomenclature by the use of the term "occult hemophilia." However, there seems to be no general agreement on just what hemophilia is. As to the use of "factor X" for PTA, there ha' been disagreement here also, but we have followed the nomenclature adopted by the Internatienal Committee of Hematology Nom('nclature. We do not share the confidence that Dr. Ross has in bleeding time determinations. Numerous tests by the Ivy technique in the past in similar cases have been routinely unrewarding. We have also found the coagulation time to b<' of no help in these cases. It is true that in the past little evidence has been presented that the use of intravenous serum accelerates the clotting phenomenon. It is for this reason among others that this paper was presented. Clinically, there can be no question of the efficacy of this treatment. In almost everv case bleeding was apparently controlled within 15 to 20 minutes after the administration of the serum. This has also been noted in 11 other cases following operations for various conditions. *By invitation.
1052 Morgan and Williams
Aprill5, 1962 .\~~
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The use of serum in such cases is also advocated by Steffanini and Miale. In our hands it has been much more effective than whole blood or plasma. It is important to note that the effect of the serum lasts only 5 or 6 days, and at the end of that time hemorrhage may recur requiring further treatment. Blood counts were omitted in several insta..r1ccs because we felt that they did not contribute to any better understanding of the coagulation defect involved. Since the Hageman trait never
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results in abnormal bleeding, specific tests for this were not performed. The preparation of matenal for factor v 11 testing was by the method of Biggs and Macfarlane, 5 and 0.1 mi. of the material was used. We realize it is difficult to comprehend that a 50 or 60 per cent thromboplastin time may be responsible for continued hemorrhage in rnild factor VII deficiencies. We can only restate that these people have a lower reservoir of this substance upon which to draw in emergencies.