Hemophilia A and High Titer Inhibitors
C.A. Petrescu, M. S¸erban, P. T¸epeneu, W. Schramm, R. Ba˘det¸i and B. Popescu
Introduction
Hemophilic pseudotumours (PTs ), first described by Fernandez de Valderrama and Matthews [7], are rare complications of bleedings: 1-2% of patients in a large study over 25 years [1]; 1.89% in a study on 212 patients from Romania, aged between 0- 25 years, followed for 11 years [15]. PTs develop after repeated, unresolved muscu- lar hematomas, or subperiosteal hemorrhages [5, 16, 17]. The distinct clinical fea- tures of PTs are progressive enlargement, with destruction of the adjacent structu- res (bones, vessels, nerves) compressed by, or included within the PT. Pathologically, the PTs are blood collection in different states of organization, with a liquid or solid content, having one or more cavities; PTs are surrounded by a fibrous capsule with very rich blood supply, usually originating from more than one artery; calcificati- ons, and ossification of the capsule, inflammatory cells, many histiocytes containing copious amounts of siderin may be seen [2, 4, 16].
Objectives, Patients
The study aims to analyze the characteristics (favoring factors, locations, imagistic aspects, evolution) and to evaluate the results of the medical and surgical approach- es in a rare case of multiple consecutive distal PTs appeared in a single patient. The patient (G.E.) with severe familial hemophilia A (factor VIII:C <0.2%) was diag- nosed at 9 months of age (1990), and treated in the IIIrdPediatric Clinic, and re- spectively, in the Pediatric Surgical and Orthopedic Clinic Timis¸oara.Very high titre inhibitors were first diagnosed in 1998, and persisted at high levels (>10 BU). No treatment for immune tolerance induction (ITI) was applied. The molecular defect is not known. Inhibitors were absent in a patient’s affected cousin, with only a few exposures to FVIII.
The patient developed five consecutive distal PTs with different locations, be- tween his ages of 8-13 years. The conservative measures were inefficient (progressi- ve bone destruction, infection, hemorrhage), and radical surgical interventions were necessary in order to save the patient’s life. Replacement therapy with rFVIIa, and aPCC was used. An antiangiogenic treatment with Interferon alpha (IFNa) was applied for eight months, apparently with good results.
I. Scharrer/W. Schramm (Ed.)
34thHemophilia Symposium Hamburg 2003
” Springer Medizin Verlag Heidelberg 2005
by x-ray, ultrasounds, CT, and MRI investigations; the epiphyseal, or the epiphyso- metaphysary distal PTs usually have multiple cavities, while the diaphyseal, or diaphyso-methaphysary PTs have a single cavity [2, 16, 17].
Multiple PTs were extremely rare described [8]. The presented patient is the single one in our experience with this type of complication. The PTs appeared con- secutively, between the patients’ age of 8-13 years, being located at the both foots, the left knee, and the right shank.
The patient G.E. was diagnosed at the age of 9 months (1990) presenting a mus- cular hematoma after intramuscularly injection, and severe anemia. It’s important to underline that the familial care was inadequate (low socio-economic level, alco- holic father with advanced tuberculosis, unemployed, two brothers at school ages, mother working all days long), the patient being admitted many times with multi- ple muscular hematomas, advanced hemarthroses of the knees, opened wounds, gingival, lingual, and pharyngeal hemorrhages, epistaxis, epicranial hematomas, frequently with severe anemia or hemorrhagic shock. Chronic arthropathy of the knees and ankles developed in time. The replacement treatment with plasma, cryo- precipitate, and erythrocyte concentrate in his first two years of life was compli- cated with HCV infection (donors screening for HCV was introduced in our trans- fusions center in 1992), but he remained HIV negative (donors screening for HIV was introduced in our transfusions center in 1990); between 1992-1997 he was treated only with factor VIII concentrates, with good clinical response, although one surgical intervention for an infected hematoma, performed in 1995 under FVIII concentrate coverage, was complicated by severe hemorrhage. The psychological disturbances, repeated urinary tract infections with E.coli, and Proteus spp., pulmo- nary tuberculosis (contact with father), and multiple dental problems complicated the patient’s state.
In July 1998, the patient (8 years old) was admitted presenting a tumoral mass of the left heel, intense pain, with obvious signs of infection, and the imminence of spontaneous rupture. The problem has been neglected, the patient being previously taken care in a related family (Moldavia) for two months. The x-ray showed destruc- tion of the calcaneus (Fig. 1-A), and the presence of a distal PT was not recognized, the case being initially interpreted as osteomyelitis. The surgical intervention (eva- cuation) under FVIII concentrate coverage and antibiotics was complicated by severe hemorrhage; repeated evacuations, application of local hemostatics and anti-
biotics, selective arterial ligature, were inefficient, with extensive foot bone destruc- tion, extension of the infection, and repeated life-threatening hemorrhages. About 140,000 IU of FVIII concentrate were administered in that period. After the diagno- sis of very high titer inhibitors, no FVIII concentrates were administered. Although the presence of a left heel PT was accepted, and amputation was considered neces- sary in order to save the patient’s life, the shortage of bypassing agents imposed the temporization of the radical surgery. Amputation from the medium left shank level (Fig. 1-B) was performed in September 1998, under rFVIIa (2,940 kIU) and FEIBA (21,000 IU) coverage, in good conditions. However, post-surgical infection with extensive soft tissues destruction appeared (S.aureus, P.aeruginosa), and remodel- ling of the amputated fragment was necessary (October 1998).
A second right heel PT destructing the calcaneus was diagnosed in May 1999 (Fig. 2-A). Local trauma (vicious sitting position after amputation, with persistent Fig. 1. A. Left heel PT destructing the calcaneus; B. Amputated fragment showing massive bone and tissues destruction
Fig. 2. A. Right heel PT with calcaneus destruction; B. Good result after complete excision;
appearance of the third PT
pressure on the right heel, insufficient home care, psychological disturbances with auto-aggression), and severe secondary osteoporosis were most probably favoring factors. Repeated episodes of infection and rebleeding, associated with intense pain, only responding to opioids, were treated with antibiotics and bypassing agents, but the medical treatment didn’t stop the progression of the PT. After two months of evolution, a minimal surgical intervention was performed (percutaneous evacuati- on, drainage, local hemostatic agents) but rebleeding appeared in a short time. In September 1999, a radical surgical cure was performed, with complete excision after selective arterial ligature, curettage of the residual cavity, and application of local hemostatic agents, under rFVIIa coverage (8,280 kIU), with good results (Fig. 2-B).
A third PT at the dorsum of the right foot appeared in October 1999 (Fig. 1-B);
the same pattern of undulant evolution, with periods of partial remissions, and periods of rapid enlargement with severe pain was noted. Progressive destruction the right astragalus (Fig. 3-A), and repeated episodes of infections appeared (Fig. 3-B). Because of the shortage of bypassing agents (inhibitors were still at very high levels), the surgery was postponed; medical conservative methods were applied for seven months, with no long-term result. The PT was evacuated in May 2000 with temporary results, with a consumption of 5,760 kIU rFVIIa. In February 2001 the evolution was complicated by a fulminating hemorrhage (vascular erosion determined by the progression of the PT). Repeated evacuations, drainage, local hemostatic agents were not efficient, and in May 2001 a second amputation from the inferior right shank level was performed. The by-passing agent consumption in this period was 9,700 KIU of rFVIIa, respectively 26,300 IU of FEIBA.
Beginning with September 2002, intense pain and progressive growth of the left knee, and the radiological aspect, raised the suspicion of another PT development (Fig. 4-A). The presence of the fourth PT of the left knee was confirmed by the MRI investigation showing a PT with multiple cavities, with femoral and tibial destruc- tion (Fig. 4-B).
Taken into account the history of this patient, and the previous unsatisfactory results in treating his PTs, leading to amputation of both legs, we’ve decided to try an alternative therapeutic approach. The idea of an antiangiogenic treatment was Fig. 3. A. Right foot PT destructing the astragalus; B. Infection and rebleeding of the PT
based on the successful use of interferon alpha (IFNa) in children’s angiomatous diseases (hemangiomas, angioblastomas) [7, 12, 13]. In fact, PTs can be considered vascular tumors. The very rich vascular supply of the capsule [23], usually origina- ting from more than one artery, and the progressive fibrosis, characteristic features of PTs, suggests an endothelial and fibroblastic proliferation. This is most probably the result of the »toxic« effect of iron; iron deposits in the capsule of PTs, and of the presence of histiocytes with large amounts of hemosiderin were described [4, 10, 16]. It was clearly shown that iron has a proinflammatory role [3, 10, 20], through formation of radical oxygen species (ROS) that produce tissue damage [10] and induce endothelial and fibroblastic proliferation [14, 19].
The use of IFNa, in a daily regimen of 3 millions IU/m2/day, seemed to have good effects: the rapid (in a few days) disappearance of the previously very intense pain (only responding to opioids), suggesting no bleeding, and stopping of the PT progression. We’ve continued the treatment for six months (November 2003-April 2004). After the IFNa treatment interruption (April-June 2004), an unexpectedly rapid »rebound effect« was noted (intense pain, rapid growing of the PT – 4 cm in diameter in one month); this »rebound effect« was also described in case of heman- gioma treatment with IFNa [1].
In April 2004, a fifth PT of the right shank producing tibial diaphyseal destruc- tion (Fig. 5-A), with a multilocular structure (Fig. 5-B) was diagnosed; this time the Fig. 4. A. Left knee PT with femoral and tibial destruction; B. PT with multiple cavities
on of the both PTs was considered to be the only right option (August 2004). A total
Fig. 5. A. Right shank PT; B. Tibial diaphyseal destruction; C: Multilocular PT
amount of 12,060 kIU of rFVIIa, and respectively 420,000 IU of FEIBA was consu- med with these last two PTs.
Multiple PTs of the limbs were extremely rarely described [8]. The chronology of events in our patient could be probably explained by some particular favoring factors:
– the severe secondary osteoporosis (x-ray, osteodensitometry) induced by the long-term immobilization, favoring intraosseous hemorrhage, even after minor trauma;
– the vicious positions adopted by the patient, mainly in time of sitting; the secon- dary psychological disorders (dysphoria with auto-aggression, anxiety, conversi- on disorders) favoring multiple trauma;
– the persistent high titer inhibitors (ITI was considered to be most probably inef- ficient, tacking into account the inhibitors level and the late moment of interven- tion); because of the bypassing agents shortage, prophylaxis was not possible, and on demand treatment was assured only at minimal levels in case of bleeding episodes; except for the first PT, radical surgery (amputation) was performed in good conditions;
– the secondary immunodeficiency (previous treatment with low/intermediate purity products [15], infection with HCV [15]), favoring the infection of PTs, the infectious complications after surgery;
– the associated health problems (chronic hepatitis with HCV, pulmonary tuber- culosis, repeated urinary tract infections);
– the insufficient home care (three brothers at school ages, unemployed father with advanced tuberculosis, and alcoholism).
Conclusions
The described PTs had the characteristics of distal PTs, appeared most probably after intraosseous hemorrhage. The presented case of multiple distal PTs is extre- mely rare. The most important factors favoring the apparition of multiple PTs were:
high inhibitors level, shortage of bypassing agents, and severe osteoporosis. The spontaneous evolution of PTs was characterized by repeated episodes of hemor- rhage and infection, and progressive growth. The conservative surgical approach (evacuation, drainage) was almost always inefficient. PTs could be solved only by complete excision/amputation. Alternative approaches to radical surgery, in patients with distal PTs and inhibitors merit to be discussed (antiangiogenic thera- py, long-term therapy with bypassing agents, early conservative surgery – percuta- neous management).
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