This Article
Right arrow Extract Freely available
Right arrow Full Text (PDF) Free
Right arrow Letters to the Editor: Submit a response
Right arrow Alert me when this article is cited
Right arrow Alert me when Letters to the Editor are posted
Right arrow Alert me if a correction is posted
Services
Right arrow E-mail this article to a friend
Right arrow Similar articles in this journal
Right arrow Similar articles in PubMed
Right arrow Alert me to new issues of the journal
Right arrow Add to My File Cabinet
Right arrow Download to citation manager
Right arrow Rights and Permissions
Citing Articles
Right arrow Citing Articles via Google Scholar
Google Scholar
Right arrow Articles by MIYAUCHI, Y.
Right arrow Articles by YOSHIOKA, A.
Right arrow Search for Related Content
PubMed
Right arrow PubMed Citation
Right arrow Articles by MIYAUCHI, Y.
Right arrow Articles by YOSHIOKA, A.
Social Bookmarking
Add to CiteULike   Add to Connotea   Add to Del.icio.us   Add to Facebook   Add to Technorati   Add to Twitter  
What's this?
The Journal of Bone and Joint Surgery 78:1409-14 (1996)
© 1996 The Journal of Bone and Joint Surgery, Inc.

Operative Treatment of Intramedullary Hematoma Associated with Congenital Deficiency of {alpha}2-Plasmin Inhibitor. A Report of Three Cases*

YOSHIZUMI MIYAUCHI, M.D.{dagger}, YOSHIO MII, M.D.{dagger}, MAKOTO AOKI, M.D.{dagger}, SUSUMU TAMAI, M.D.{dagger}, YUKIHIRO TAKAHASHI, M.D.{dagger} and AKIRA YOSHIOKA, M.D.{dagger}, KASHIHARA CITY, NARA, JAPAN

Investigation performed at the Departments of Orthopedic Surgery and Pediatrics, Nara Medical University, Kashihara City, Nara


   Introduction
Top
 Introduction
Case Reports
 Discussion
 References
 
Congenital deficiency of {alpha}2-plasmin inhibitor is a very rare disease that is associated with severe bleeding problems. To our knowledge, the condition was first reported in 1978 by Koie et al., who described a twenty-five-year-old man who had symptoms similar to those of severe hemophilia. Since then, the cases of at least eight patients, from six families, who had homozygous deficiency have been reported3,7,8,10,12,17. The main symptoms were umbilical bleeding, bleeding in the central nervous system, epistaxis, bleeding gums, hemothorax, hypermenorrhea, hemarthrosis, and excessive loss of blood after minor trauma. These patients often needed to be hospitalized for long periods because of the tendency for severe bleeding that had begun in early childhood and was clinically similar to hemophilia. The episodes of bleeding were thought to be characterized by hemostatic plugs that had formed normally but disappeared rapidly because of unrestrained fibrinolysis. Thus, routine laboratory studies revealed no important abnormality of coagulation or platelet function except the shortened times of lysis of whole blood and euglobulin. The diagnosis usually was made on the basis of assay of the level of antigen or the activity of {alpha}2-plasmin inhibitor.

We first reported15 multiple intramedullary hematomas, a form of bleeding, in 1991. This condition developed in the long bones of three sisters who had a congenital deficiency of {alpha}2-plasmin inhibitor. The episodes of bleeding in these sisters were described in that report15 and in a previous one17. The long-term clinical features of the lesions and the results of successful operative treatment are described in the present report.

The concentration of {alpha}2-plasmin inhibitor in the plasma of these patients was assayed with functional and immunological methods14, and it was found to be severely deficient17. The genetic abnormality was shown to be a frame-shift mutation, leading to elongation of the deduced amino-acid sequence13. After the establishment of the diagnosis, the hemorrhagic symptoms, except for the intramedullary hematomas, were successfully treated with tranexamic acid administered orally or intravenously, or both. The lesions were treated with one of two operative methods in conjunction with perioperative intravenous administration of tranexamic acid (forty milligrams per kilogram of body weight per day). One of the sisters was managed with conventional curettage and insertion of a hydroxyapatite implant in the left femur, while the lesions in the right radius were filled with a mixture of fibrin glue and tranexamic acid (250 milligrams per milliliter). The other two sisters were managed with the latter procedure only.


   Case Reports
Top
 Introduction
 Case Reports
Discussion
 References
 
CASE 1. In 1989, a fifteen-year-old girl had sudden severe pain in the left thigh and was unable to walk. She had noted intermittent mild pain for the previous two years, but she had no history of trauma. The patient had no family history of symptoms that suggested a tendency for bleeding, except for those in her sisters (described in the present report).

On physical examination, the patient had local tenderness in the thigh but no swelling. The pain was worse with attempted motion of the knee and hip. Radiographs showed intramedullary lesions of uniform density with a so-called ground-glass appearance similar to that of fibrous dysplasia. The lesions extended from the intertrochanteric region to the diaphysis of the left femur (Fig. 1-A). Bone scintigraphy with technetium-99m revealed an area of increased uptake in the cortex but a relative decrease of activity in the intramedullary area. Preoperative magnetic resonance imaging with a short spin-echo (repetition time, 800 milliseconds; echo time, twenty milliseconds) showed two continuous intramedullary lesions that had a homogeneous high-intensity signal in the left femur (Fig. 1-B). Long-spin-echo images (repetition time, 2000 milliseconds; echo time, eighty milliseconds), however, revealed that the signal intensities of the individual lesions were heterogeneous and the anterior side of the cavity had a higher-intensity signal (Fig. 1-C).



View larger version (68K):
[in this window]
[in a new window]
  		Figs. 1-A through 1-E: Case 1. Fig. 1-A: Radiograph of the left femur, revealing three intramedullary cyst-like lesions (arrows) with slight expansion and thinning of the cortex.

 


View larger version (138K):
[in this window]
[in a new window]
  		Fig. 1-B: Magnetic resonance image of the left femur, made preoperatively with a short spin-echo (repetition time, 800 milliseconds; echo time, twenty milliseconds), showing two continuous intramedullary lesions (arrowheads) with a homogeneous high-intensity signal.

 


View larger version (130K):
[in this window]
[in a new window]
  		Fig. 1-C: Long-spin-echo image (repetition time, 2000 milliseconds; echo time, eighty milliseconds) of the left femur, showing the signal intensities of the three intramedullary lesions (arrows) to be heterogenous. The anterior side of the cavity has a high-intensity signal, and the posterior side has a relatively low-intensity signal.

 
The level of {alpha}2-plasmin inhibitor was very low (Table I), and it was found to be low in both of the patient's parents as well. The pattern was attributed to a congenital heterozygous deficiency of the {alpha}2-plasmin inhibitor.


View this table:
[in this window]
[in a new window]
  		TABLE I HEMOSTATIC DATA ON THE PATIENTS

 
On June 29, 1989, the lesions were curetted and hydroxyapatite implants were inserted to prevent pathological fractures. Tranexamic acid (twenty milligrams per kilogram of body weight per day) was administered intravenously from the day before the operation until the thirteenth day postoperatively. At the operation, there were no remarkable findings in the subcutaneous tissue, muscle, or periosteum; however, there was a slight bulging of the cortex of the left femur. When a small hole was made in the cortex, fluid containing membranous tissue and approximately thirty milliliters of old blood welled out. Tranexamic acid was not detected in the fluid. (The short-term clinical course and hemostatic data were described in a previous report15.)

Histopathological study revealed an old blood clot surrounded by fibrous tissue; non-specific granulation and reactive bone formation were seen as a host reaction. No other specific or characteristic abnormalities were recognized.

Postoperatively, the wound healed uneventfully. However, diffuse swelling of the left thigh appeared a few days after the operation in conjunction with a decrease in the level of hemoglobin and the hematocrit from 125 grams per liter and 0.39, respectively, on June 1, 1989, to eighty-eight grams per liter and 0.28 seven days after the operation, despite the administration of whole blood on the day of the operation. The internal bleeding was successfully controlled with the intravenous administration of tranexamic acid (forty milligrams per kilogram of body weight per day) for two weeks and a transfusion of 200 milliliters of fresh whole blood.

Two years after the operation, the patient had no symptoms in the left thigh, but she had moderate pain in both forearms despite the intermittent oral administration of tranexamic acid (twenty milligrams per kilogram of body weight per day). Radiographs revealed that lesions that were similar to those found previously in the femur had developed in the radius bilaterally and in the left fibula.

On August 1, 1991, a small hole, two millimeters in diameter, was made in the distal part of the lesion in the right radius, a fine tube was inserted, and fluid was aspirated. A mixture of fibrin glue (Tisseel; Immuno AG, Vienna, Austria) and tranexamic acid (250 milligrams per milliliter) was instilled into the lesion. Tranexamic acid (forty milligrams per kilogram of body weight per day) was administered intravenously, beginning four hours before the operation and continuing until seven days after the operation.

In August 1993, four years after the operation on the left femur and two years after the operation on the right radius, radiographs of the femur showed apparent incorporation of the hydroxyapatite implants and healing of the fenestrated cortex (Figs. 1-D and 1-E). The patient had no symptoms in the right forearm, and radiographs revealed normal findings. However, the patient had headaches and general fatigue. No objective neurological abnormality was found, and the symptoms were attributed to the use of tranexamic acid. Tranexamic acid was not administered constantly because of these symptoms.



View larger version (60K):
[in this window]
[in a new window]
  		Anteroposterior and lateral radiographs of the left femur, made four years after the operation on the lesion, showing good union of the fenestrated cortex and incorporation of the hydroxyapatite. The lesions did not recur.

 


View larger version (53K):
[in this window]
[in a new window]
  		Anteroposterior and lateral radiographs of the left femur, made four years after the operation on the lesion, showing good union of the fenestrated cortex and incorporation of the hydroxyapatite. The lesions did not recur.

 
CASE 2. In June 1989, the twelve-year-old sister of the first patient (Case 1) reported that for two years she had had pain without swelling in both forearms whenever she played volleyball. (A brief clinical history was described in our previous report15.) Radiographs made in August 1989 revealed intramedullary lesions of uniform density in the radius bilaterally. When the patient had pain in a forearm, she took 250 milligrams of tranexamic acid orally once or twice a day for a few days, and this was initially effective in relieving the symptoms. Radiographs made in 1988 had revealed an asymptomatic lesion in the metaphysis of the right femur that had not been evident one year before.

On July 23, 1990, an operation was performed on the right radius because the patient had reported a gradual increase in pain with motion and intermittent spontaneous pain in the right forearm despite the use of the tranexamic acid. A small hole, two millimeters in diameter, was made in the distal part of the lesion. A fine tube was inserted, and one milliliter of dark red fluid was aspirated. Tranexamic acid and tumor cells were not found in the fluid. A mixture of fibrin glue and tranexamic acid (250 milligrams per milliliter) was instilled into the lesion. Perioperatively, the patient had intravenous administration of tranexamic acid (forty milligrams per kilogram of body weight per day). One year after the operation, the patient had no pain in the right forearm and the lesion (except for the distal part, which had not been filled completely with the fibrin glue) appeared to be healed radiographically.

On August 1, 1991, the same operation was performed on the left radius. At that time, a three-millimeter-diameter hole was made at the level of the distal part of the lesion and a mixture of fibrin glue, tranexamic acid (250 milligrams per milliliter), and contrast medium (60 per cent Urografin; Schering, Berlin, Germany) was instilled into the cavity (Fig. 2-A). On August 12, 1993, the patient had no symptoms in either forearm and the proximal part of the right radius and the distal part of the left radius appeared normal on radiographs (Fig. 2-B). The pain in the left forearm occasionally recurred, but this was eliminated by the oral administration of 250 milligrams of tranexamic acid once or twice a day for a few days.



View larger version (62K):
[in this window]
[in a new window]
  		Figs. 2-A and 2-B: Case 2. Fig. 2-A: Intraoperative radiograph of the left radius, made on August 1, 1991, showing a three-millimeter hole that was made into the distal part of the cavity of the lesion. A fine tube was inserted, and the lesion was aspirated. A mixture of fibrin glue, tranexamic acid (250 milligrams per milliliter), and contrast medium was instilled into the cavity.

 


View larger version (57K):
[in this window]
[in a new window]
  		Fig. 2-B: Radiograph, made on August 12, 1993, showing the structure of the left radius, which was normal except for the most proximal part (arrowheads).

 
CASE 3. In August 1989, the nine-year-old sister of the other two patients had an episode of hemarthrosis of the right knee after she had fallen and bruised the knee. The patient was hospitalized, the limb was immobilized in an above-the-knee cast for three weeks, and tranexamic acid (1000 milligrams a day) was administered orally for two months. The pain resolved after the limb had been in the cast for two weeks, but clinically the effusion did not subside completely until six weeks after the injury. Because of the family history, radiographs of the long bones were made at the time of the injury; no lesions were observed.

In July 1990, radiographs revealed an asymptomatic intramedullary cystic lesion without marginal sclerosis in the distal part of the metaphysis of the right humerus. The lesion had uniform density, was eccentric, and apparently had been penetrated by the nutrient artery of the shaft. Clinically, however, the patient had no local pain, swelling, or tenderness in the arm. In January 1993, severe pain had developed in the right arm and by August 12, 1993, the lesion had increased substantially in size despite the intermittent oral administration of tranexamic acid (twenty milligrams per kilogram of body weight per day). As in the second patient (Case 2), a mixture of fibrin glue and tranexamic acid (250 milligrams per milliliter) was instilled into the lesion.


   Discussion
Top
 Introduction
 Case Reports
 Discussion
References
 
Regulation of the fibrinolytic system is essential for the maintenance of hemostasis, which is achieved with a balance between the activation and inhibition of plasminogen into plasmin. In 1976, it was discovered that {alpha}2-plasmin inhibitor is the major inhibitor of plasmin in plasma5,14 and, in 1978, Koie et al. reported on a patient who had a congenital deficiency of {alpha}2-plasmin inhibitor associated with a severe bleeding disorder. In 1987, an associated abnormal molecule, called {alpha}2-plasmin inhibitor Enschede, was found9. The mode of inheritance is autosomal recessive3,8. Clinically, recurrent bleeding from a wound hours after trauma or an operation is typical and closely resembles the pattern in congenital deficiency of clotting factor XIII, as previously described2.

The intramedullary hematomas associated with the congenital deficiency of {alpha}2-plasmin inhibitor in our three patients occurred early in the second decade of life. Multiple lesions developed only in the long bones, and there was no swelling of the surrounding soft tissue. The initial stage may develop in connection with the main nutrient vessel of a long bone. The lesions may grow slowly and concentrically and cause thinning of the cortex (Fig. 1-A), and growth of the lesion may be associated with the growth of the bone. The lesions were painful, presumably as a result of the high intramedullary pressure. In the large lesions, areas of high and low signal intensity, suggesting a mixture of fresh and old blood, can be visualized with use of long-spin-echo magnetic resonance imaging (Fig. 1-C).

In our first patient (Case 1), none of the tranexamic acid that had been administered intravenously was found in the lesion. Therefore, we believe that direct administration of tranexamic acid into the lesion is essential for healing. We have not studied the release of tranexamic acid from the fibrin or fibrin-tranexamic acid compound. Release of the drug from the fibrin clot is probably by simple diffusion and therefore largely dependent on the concentration gradient between the clot and its environment. Because a fibrin clot is a matrix with relatively large pores, only a small amount of tranexamic acid would be incorporated. However, tranexamic acid that has been incorporated into a fibrin clot is retained for a longer period of time than is tranexamic acid that has been directly instilled into an intramedullary hematoma. Thus, we used intralesional administration of tranexamic acid mixed with fibrin glue.

Although the association of pseudotumor (subperiosteal hematoma) with hemophilia has been described1,6, we are not aware of any report of a patient with a bleeding disorder who had an intramedullary hematoma. The clinical features of a pseudotumor are different than those of an intramedullary hematoma. A pseudotumor in a patient who has hemophilia usually is formed by traumatic intramuscular or subperiosteal bleeding. Even when it is advanced and large, a pseudotumor that involves bone has irregular, multiple lytic areas with marginal sclerosis and sometimes calcification in the soft tissue that can be seen on radiographs. Histologically, the cysts contain old blood clots with necrotic tissue as well as some collagenous fibers and are surrounded by a thick fibrous wall in which macrophages phagocytose hemosiderin, lipoid substances, and foreign-body giant cells1. However, as we are unaware of a report on the initial stage of a pseudotumor involving bone, it is possible that the changes that we describe in the present report represent the end stage of a pseudotumor, such as that associated with hemophilia.

Although the exact cause of hematomas associated with a congenital deficiency of {alpha}2-plasmin inhibitor is unclear, we speculate that these lesions have high intramedullary pressure that resembles a characteristic of simple bone cysts4. The location of the lesion may be related to the main nutrient vessels of a long bone. Major trauma did not appear to play an important role in the formation of these hematomas.

To our knowledge, except in reports of bleeding after minor trauma or a dental extraction, the treatment of postoperative bleeding in a patient with a congenital deficiency of {alpha}2-plasmin inhibitor has been described only once7. The patient in that report had profuse bleeding during removal of suprapatellar and infrapatellar cysts and resumption of bleeding eight hours after initial hemostasis. Administration of aminocaproic acid, another anti-plasmin reagent, was used to control the bleeding. In our patients, continuous intravenous administration of tranexamic acid (forty milligrams per kilogram of body weight per day) perioperatively was effective. The total antifibrinolytic activity, the euglobulin lysis time, the fibrin-degradation product, and the level of fibrinogen in the plasma of each patient were found to be within a normal range. Clinically, the bleeding was successfully controlled without massive loss of blood.


   Footnotes
 
*No benefits in any form have been received or will be received from a commercial party related directly or indirectly to the subject of this article. No funds were received in support of this study.

{dagger}Departments of Orthopedic Surgery (Y. Miyauchi, Y. Mii, M. A., and S. T.) and Pediatrics (Y. T. and A. Y.), Nara Medical University, 840 Shijyo-cho, Kashihara City, Nara, Japan. Please address requests for reprints to Dr. Miyauchi.


   References
Top
 Introduction
 Case Reports
 Discussion
 References
 

  1. Abell, J. M., Jr., and |and |Bailey, R. W.: Hemophiliac pseudotumor. Two cases occuring in siblings. Arch. Surg., 81: 569-581, 1960.

  2. Aoki, N.: Genetic abnormalities of the fibrinolytic system. Sem. Thromb. and Hemost., 10: 42-50, 1984.

  3. Aoki, N.; Saito, H.; Kamiya, T.; Koie, K.; Sakata, Y.; and |and |Kobakura, M.: Congenital deficiency of alpha2-plasmin inhibitor associated with severe hemorrhagic tendency. J. Clin. Invest., 63: 877-884, 1979.

  4. Cohen, J.: Etiology of simple bone cyst. J. Bone and Joint Surg., 52-A: 1493-1497, Oct. 1970.[Free Full Text]

  5. Collen, D.: Identification and some properties of a new fast-reacting plasmin inhibitor in human plasma. European J. Biochem., 69: 209-216, 1976.[Medline]

  6. Fernandez De Valderrama J. A., and |and |Matthews, J. M.: The haemophilic pseudotumour or haemophilic subperiosteal haematoma. J. Bone and Joint Surg., 47-B(2): 256-265, 1965.

  7. Kettle, P., and |and |Mayne, E. E.: A bleeding disorder due to deficiency of alpha2-antiplasmin. J. Clin. Pathol., 38: 428-429, 1985.[Abstract/Free Full Text]

  8. Kluft, C.; Vellenga, E.; and |and |Brommer E. J.: Homozygous alpha2-antiplasmin deficiency. Lancet, 2: 206, 1979.[Medline]

  9. Kluft, C.; Nieuwenhuis, H. K.; Rijken, D. C.; Groeneveld, E.; Wijngaards, G.; van Berkel, W.; Dooijewaard, G.; and |and |Sixma, J. J.: Alpha2-antiplasmin Enschede: dysfunctional alpha2-antiplasmin molecule associated with an autosomal recessive hemorrhagic disorder. J. Clin. Invest., 80: 1391-1400, 1987.

  10. Koie, K.; Kamiya, T.; Ogata, K.; and |and |Takamatsu, J.: Alpha2-plasmin-inhibitor deficiency (Miyasato disease). Lancet, 2: 1334-1336, 1978.[Medline]

  11. Laurell, C.-B.: Quantitative estimation of protein by electrophoresis in agarose gel containing antibodies. Analyt. Biochem., 15: 45-52, 1966.

  12. Miles, L. A.; Plow, E. F.; Donnelly, K. J.; Hougie, C.; and |and |Griffin, J. H.: A bleeding disorder due to deficiency of alpha2-antiplasmin. Blood, 59: 1246-1257, 1982.[Abstract/Free Full Text]

  13. Miura, O.; Hirosawa, S.; Kato, A.; and |and |Aoki, N.: Molecular basis for congenital deficiency of alpha2-plasmin inhibitor. A frameshift mutation leading to elongation of the deduced amino acid sequence. J. Clin. Invest., 83: 1598-1604, 1989.

  14. Moroi, M., and |and |Aoki, N.: Isolation and characterization of alpha2-plasmin inhibitor from human plasma. A novel proteinase inhibitor which inhibits activator-induced clot lysis. J. Biol. Chem., 251: 5956-5965, 1976.[Abstract/Free Full Text]

  15. Takahashi, Y.; Tanaka, T.; Nakajima, N.; Yoshioka, A.; Fukui, H.; Miyauchi, Y.; Mii, Y.; and |and |Tamai, S.: Intramedullary multiple hematomas in siblings with congenital alpha-2-plasmin inhibitor deficiency: orthopedic surgery with protection by tranexamic acid. Haemostasis, 21: 321-327, 1991.[Medline]

  16. Tsukada, S.: Studies on {alpha}2-plasmin inhibitor. I. Preparation of {alpha}2-plasmin inhibitor ({alpha}2PI) deficient plasma by immunoadsorption and specific assay for {alpha}2PI activities. J. Nara Med. Assn., 35: 25-34, 1984.

  17. Yoshioka, A.; Kamitsuji, H.; Takase, T.; Iida, Y.; Tsukada, S.; Mikami, S.; and |and |Fukui, H.: Congenital deficiency of {alpha}2-plasmin inhibitor in three sisters. Haemostasis, 11: 176-184, 1982.[Medline]


Add to CiteULike CiteULike   Add to Connotea Connotea   Add to Del.icio.us Del.icio.us   Add to Facebook Facebook   Add to Technorati Technorati   Add to Twitter Twitter    What's this?



This Article
Right arrow Extract Freely available
Right arrow Full Text (PDF) Free
Right arrow Letters to the Editor: Submit a response
Right arrow Alert me when this article is cited
Right arrow Alert me when Letters to the Editor are posted
Right arrow Alert me if a correction is posted
Services
Right arrow E-mail this article to a friend
Right arrow Similar articles in this journal
Right arrow Similar articles in PubMed
Right arrow Alert me to new issues of the journal
Right arrow Add to My File Cabinet
Right arrow Download to citation manager
Right arrow Rights and Permissions
Citing Articles
Right arrow Citing Articles via Google Scholar
Google Scholar
Right arrow Articles by MIYAUCHI, Y.
Right arrow Articles by YOSHIOKA, A.
Right arrow Search for Related Content
PubMed
Right arrow PubMed Citation
Right arrow Articles by MIYAUCHI, Y.
Right arrow Articles by YOSHIOKA, A.
Social Bookmarking
Add to CiteULike   Add to Connotea   Add to Del.icio.us   Add to Facebook   Add to Technorati   Add to Twitter  
What's this?