Hemophilia

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Hemophilia

  1. 1. ASIA-PACIFIC JOURNAL OF ONCOLOGY & HEMATOLOGY ORIGINAL RESEARCHManagement of Ocular Posterior Segment Hemorrhagesin Patients With HemophiliaTeng-Yi Wang1, Chi-Ting Horng2, Yeu-Chin Chen3, Yung-Hsiang Chang1, Ke-Hung Chien1, Da-Wen Lu1, Jiann-Torng Chen1 andMing-Ling Tsai1,4Affiliations: : 1Department of Ophthalmology, Tri-Service General Hospital, Taipei, Taiwan; 2Department of Ophthalmology,Kaohsiung Armed Force General Hospital, Kaohsiung, Taiwan; 3Division of Hematology-Oncology, Department of Internal Medicine,Tri-Service General Hospital, Taipei, Taiwan; 4Department of Ophthalmology, Veterans General Hospital, Taichung, TaiwanSubmission date: 10th May 2009, Revision date: 15th June 2009, Acceptance date: 1st July 2009 A B S T R A C T Hemophilia is a bleeding disorder characterized by a deficiency of clotting factors. This disease can have a profoundand debilitating effect on the gastrointestinal, neurologic, and musculoskeletal systems. Ophthalmologists may encounterpatients with hemophilia and ocular hemorrhages ranging from subconjunctival hemorrhages to ocular posterior segmenthemorrhages that may lead to significant visual impairment. The role of the ophthalmologist in the care of a hemophiliapatient usually consists of controlling the bleeding source and establishing a clear optic medium to restore visual acuity.Factor replacement therapy is essential for gaining rapid control of bleeding diatheses in these patients. Furthermore,surgical intervention may be necessary to remove residual hemorrhages and recover vision. In this study, we analyzed theavailable reports on ocular posterior segment hemorrhages developing in patients with hemophilia, focusing on patientcharacteristics, mechanisms, and treatments. Keywords: hemophilia, retinal hemorrhage, disc hemorrhage, ocular surgery Correspondence: Ming-Ling Tsai, M.D., Ph.D., Department of Ophthalmology, Tri-Service General Hospital, No.325, Sec. 2, Chenggong Rd, Taipei 114, Taiwan, Republic of China. Tel: +886-9-68392245; fax: +886-2-28388737; e-mail:doc30845@yahoo.com.twINTRODUCTION therapy rapidly led to medical and social improvements, Hemophilia is an unusual bleeding disorder caused by with a decrease in the frequency of hemorrhages andan acquired or hereditary deficiency of clotting factors considerably improved life expectancy of patients within the blood. Acquired hemophilia, much rarer than the hemophilia. However, there are still case reports show-hereditary type, is a rare autoimmune bleeding disorder, ing that ocular hemorrhages such as subconjunctival,resulting from the presence of autoantibodies directed macular, and optic disc hemorrhages occur in hemo-against coagulation factors. The etiology of the disor- philiacs. Of these conditions, ocular posterior segmentder remains obscure, although approximately half of all hemorrhages (retina, choroids, optic nerve, etc) alwayscases are associated with underlying conditions, such as draw the attention of ophthalmologists and hematolo-lupus and rheumatoid arthritis. Hereditary hemophilia gists because they can lead to significant visual impair-is an X-linked genetic bleeding disease caused by a defi- ment. Therefore, it is necessary to improve our under-ciency of coagulation factor VIII (hemophilia A) and fac- standing of the diagnosis and management of patientstor IX (hemophilia B), or an autosomal recessively inher- with ocular posterior segment hemorrhages associatedited factor XI deficiency (hemophilia C). Because of the with hemophilia. Moreover, ocular surgical interventionhereditary pattern of hemophilia, patients are almost may be necessary when surgical conditions developedinvariably male, while women can be carriers of the dis- secondary to posterior segment hemorrhages such asease. Before the introduction of clotting factor replace- glaucoma, cataract, and vitreous hemorrhages.ment therapy, the mean life expectancy of patients with In this investigation, we analyzed the previous reportshemophilia was commonly less than 30 years, and pa- describing the characteristics of ocular posterior seg-tients mostly died of intracranial or other hemorrhages. ment hemorrhages developing in patients with hemo- Since the 1960s, a series of coagulation factor prepa- philia. In addition, we also reviewed the characteristicsrations including cryoprecipitates, plasma-derived fac- of hemophilia patients who underwent ocular surgery,tors, and recombinant factors have been available for because ocular posterior segment hemorrhages maythe treatment of hemophilia. This factor replacement lead to many conditions that require ocular surgery.APJOH 2009; 1: (3). September 2009 1 www.slm-oncology.com
  2. 2. Asia-Pacific Journal of Oncology & HematologyTable 1. Demographics of Patients With Ocular Hemorrhages Associated With Hemophilia in the Literature Case no. 1 2 3 Authors Hon et al Maguluri et al Wang et al Age (years) 80 52 13 Ocular findings Visual acuity 6/60 20/Hand motion 6/6 Posterior Macular hemorrhage Hyphema segment Vitreous hemorrhage Disc hemorrhages Laboratory findings PT (s) and normal range 12.2 (11.2–13.2) 11.3 (10–13) n/a PTT (s) and normal range 86.2 (27.6–37.6) 45.1 (24–35) n/a Factor status VIII inhibitor VIII 11% VIII 1.9% Inhibitor status Present, 57 BU None None Diagnosis Acquired hemophilia A Mild hemophilia A Moderate hemophilia A Macular hemorrhage, Choroidal hemorrhage, Hemorrhagic complications choroidal hemorrhage with Disc hemorrhages retinal detachment acute angle closure glaucoma Mechanisms Spontaneous After surgery Spontaneous Treatments Aspiration of hyphema, Ocular management None vitrectomy, lensectomy, None enucleation For intraocular pressure reduction: acetazolamide, mannitol, pilocarpine For hemorrhages: Perioperative rFVIII Infusion of factor VIII Medical therapy prednisolone 40 mg daily, infusion for enucleation concentrates: 21000 U in total factor VIII concentrate For laser peripheral iridec- tomy: rFVIIa Loss of vision, enucleation Died of intracranial Prognosis without bleeding Visual acuity: 6/6 hemorrhage complicationsBU, Bethesda units; rFVIIa, activated recombinant factor VII; rFVIII, Recombinant factor VIII.METHODS RESULTS We searched PubMed and Medline databases using We identified 45 references through electronic andkeywords including hemorrhage, hemophilia, vitreous, manual searches. After reading the titles and abstracts,retina, choroids, optic disc, ocular surgery, ocular poste- we excluded 23 irrelevant references and selected 22 forrior segment, and related terms. We excluded patients further assessment. Only 21 references met the crite-with ocular posterior segment hemorrhages resulting ria. Because some previous treatments such as cryopre- cipitate would not be used nowadays by a hematologist,from other systemic diseases such as diabetes mellitus, only cases that had been documented for more than 10hypertension, and vessel embolization. Patients with years were listed in the references [4-7, 9]. In this in-prior ocular diseases such as optic disc edema, papillitis, vestigation, all of the relevant data are shown in Ta-ischemic optic neuropathy, drusen, and juxtapapillary ble 1, which documents the features of ocular posteriorsubretinal neovascular membranes were also excluded. segment hemorrhage in patients with hemophilia, andMedical and ocular history, systemic condition, ocular Table 2, which summarizes the characteristics of hemo-examinations, and ancillary testing were reviewed ret- philia patients who underwent ocular surgery. Moreo-rospectively for each patient. ver, these selected cases are described below.APJOH 2009; 1: (3). September 2009 2 www.slm-oncology.com
  3. 3. Management of Ocular Posterior Segment Hemorrhages in Patients With HemophiliaTable 2. Demographics of Hemophilia Patients Scheduled for Ophthalmic Surgery in the Literature Case no. 1 2 3 4 5 6 7 Authors Jijina et al Jijina et al Jijina et al Jijina et al Jijina et al Biron-An- Pekçelen dréani et al et al Age (years) 60 8 9 75 56 40 36 Ocular Cataract Trabeculec- Hyphema Cataract Cataract Cataract Cataract surgery extraction tomy aspiration, extraction extraction extraction extraction vitrectomy Laboratory findings Factor status VIII 9.5% IX <1% VIII 32% IX 26% VIII 12% VIII 1% VIII <1% Inhibitor None None None None None Present: Present: status OD 3.5 BU >600 BU OS 1.8 BU Diagnosis Mild hemo- Severe he- Mild hemo- Hemophilia Mild hemo- Acquired Acquired philia A mophilia B philia A B philia A hemophilia hemophilia A A Preventive Preop: 2000 Preop: 1800 Preop: Preop: 3000 Preop: OD: 150 IU/ Preop: 90 treatment U factor U factor IX DDAVP U factor IX DDAVP and kg of Auto- μg/kg (7.2 VIII concen- concentrate and factor Postop: ep- 3000 U of plex (total mg) of trate raised Postop: VIII 1800 silon amino factor VIII 12000 IU) rFVIIa and factor level 4800 U in U raised caproic acid raised factor OS: 90 μg/ tranexamic to 80% total factor level 1 g q8 h for level to 62% kg (8.1 mg) acid 20 mg/ Postop: to 15% for 10 days Postop: of rFVIIa kg q8 h 1000 U q8 aspiration factor VIII preopera- Postop: 90 h for 48 h of hyphema; 3000 U, tively; total μg/kg of (total 7000 factor VIII DDAVP 0.3 48.6 mg rFVIIa q12 U) 1500 U for μg/kg qod h twice vitrectomy for 4 times, Postop: and epsilon DDAVP 0.3 amino μg/kg qd for caproic acid 3 days for 1 g q8 h for aspiration 10 days of hyphema; 750 U factor VIII qd for 5 days for vitrectomy Total 6750 U of factor VIIIBU, Bethesda units; DDAVP, desmopressin; OD, right eye; OS, left eye; rFVIIa, activated recombinant factor VII.Patients With Hemophilia relatively less common in these cases. One of the threeand Intraocular Hemorrhage cases completely lost vision, whereas one recovered to The demographic characteristics of the three patients normal vision. One patient died of intracranial hemor-with hemophilia complicated with intraocular hemor- rhage. In the early years, cryoprecipitates and epsilonrhage are shown in Table 1. The age range was wide, amino caproic acids were used for hemostasis before andfrom 13 to 80 years of age. Ocular posterior segment during operations. With the advent of new coagulationhemorrhages may develop in both hereditary and ac- products, factor concentrates and recombinant factorsquired hemophilia. All levels of severity of hemophilia have remained among the mainstream treatments. Inwere associated with posterior segment hemorrhages. cases where factor inhibitors were present, steroidsOne of the three patients had hemorrhages after sur- were also added to the treatment formula to optimizegery and trauma, while in two of the other patients, it the treatment outcome.had occurred spontaneously. Two of the three patients Case 1. Hon et al [1] reported a rare case of nontrau-had choroidal detachment with hemorrhage and poor matic macular hemorrhage. The patient initially pre-visual outcome. Disc and macular hemorrhages were sented with monocular blindness due to gross macularwww.slm-oncology.com 3 APJOH 2009; 1: (3). September 2009
  4. 4. Asia-Pacific Journal of Oncology & Hematologyhemorrhage, and returned because of painful loss of vi- Jijina et al [8] carried out ophthalmic surgery in fivesion. A choroidal hemorrhagic detachment detected by patients (cases 1 to 5) during the period between 1994ultrasound B scan resulted in secondary glaucoma that and 2000. The surgeries performed included cataractdid not respond to medical therapy. The laboratory ex- extraction with intraocular lens implantation, trab-aminations later revealed the diagnosis of acquired fac- eculectomy, vitrectomy, and hyphema aspiration. Thesetor VIII inhibitor. Despite treatment with prednisolone, patients received factor VIII or IX before and after thefactor VIII concentrates and laser iridotomy, the patient operations with or without addition of desmopressindied of a sudden cerebral hemorrhage. (DDAVP).Case 2. Maguluri et al [2] described an undiagnosed Case 1. The preoperative factor VIII level was increasedhemophilia patient with delayed suprachoroidal hemor- from 9.5% to 80% with the use of 2000 units of factorrhage after head injury. The patient had hyphema and VIII concentrate. A total of 7000 units of factor VIII wasvitreous hemorrhage and received an anterior cham- used for the cataract extraction procedure, and no post-ber washout, but the hyphema recurred together with operative complications were noted.choroidal detachment and suprachoroidal hemorrhage. Case 2. The preoperative level of factor IX was <1%.Accordingly, he received pars plana lensectomy and vit- Preoperative use of 1800 units of factor IX resulted inrectomy, but the bleeding persisted, resulting in a dis- 100% correction. The trabeculectomy was successfullyorganized retinal anatomy with poor visual outcome. performed, and a total of 4800 units of factor IX wasThe hematology service was then consulted because of used.the persistent bleeding despite surgical intervention,and laboratory evaluation revealed a factor VIII level of Case 3. The patient underwent aspiration of hyphema11%. With perioperative recombinant factor VIII infu- owing to trauma. The preoperative level of factor VIIIsion, enucleation for pain relief was performed without was 32%. He received DDAVP and 1800 units of factor ,complications. VIII.Case 3. Wang et al [3] reported a 13-year-old boy with Case 4. The preoperative level of factor IX was 26%.known hemophilia A who suffered a black shadow in The patient underwent trabeculectomy and bilateralfront of his left eye. Vision was 6/6 in both eyes. Fun- cataract extraction with intraocular lens implantationdal examination revealed disc hemorrhages of the left followed by a single postoperative injection of 3000 unitseye. Laboratory examination showed a factor VIII ac- of factor IX concentrate together with oral epsilon ami-tivity of 1.9%. The hematologists treated him with re- no caproic acid.combinant factor VIII concentrate for 8 weeks, approxi- Case 5. Cataract surgery was performed under the cov-mately 21000 units in total. His vision remained 6/6 at 3 er of a preoperative infusion of DDAVP and factor VIIImonth follow-up, and the hemorrhage was significantly concentrate. A total of 6000 international units (IU) ofabsorbed. factor VIII was used.Ocular Surgery in Hemophilia Patients In general, major operations such as vitrectomy and trabeculectomy require a longer duration of postopera- In Table 2, we summarize the patient characteristics, tive infusion of factors. Preoperative factors infusedelective surgeries performed, and preventive treatments range from 1500 units to 3000 units, and postoperativefor 7 hemophilia patients that are reported in the litera- factors from 3000 to 7000 units. The basal levels of fac-ture. tor VIII ranged from 9.5% to 32%, and of factor IX from Again, the age range was wide (8 years to 75 years of less than 1% to 26%.age). All levels of severity of hemophilia were encoun-tered in ophthalmic surgery. Early cases received whole Use of recombinant FVIIa in acquired hemo-blood, cryoprecipitates, porcine antihemophilic globulin, philia (cases 6 and 7)and epsilon amino caproic acid for preventive treatment Recombinant FVIIa (rFVIIa) has been implicated inbefore surgery with acceptable results [4–7]. Most of bleeding prevention in ophthalmic surgery, especiallythe surgeries carried out in hemophilia patients were in cases where factor inhibitors are present. In cases ofcataract extractions (five cases), which are classified as acquired hemophilia with the presence of inhibitors, pr-anterior segment surgeries. Only one posterior segment eoperative preventive measures other than factor con-surgery (vitrectomy) was known to have been performedin a hemophilia patient. In hereditary hemophilia cases centrates have been used [9–11].(cases 1 to 5), the calculated preoperative factor levels Case 6. Biron-Andréani et al [10] describe a 40-year-oldachieved by factor treatment were between 80% and patient with factor VIII inhibitor. The preoperative level150%, whereas acquired hemophilia patients (cases 6 of factor VIII was below 1 IU/dL with an inhibitor titerand 7) requiring ophthalmic surgeries were given Auto- of 1.8 Bethesda units. rFVIIa was given immediatelyplex (prothrombin complex concentrate) or activated re- before the surgery to control bleeding by binding to ac-combinant factor VII (rFVIIa) to provide adequate coag- tivated platelets, thereby increasing thrombin genera-ulation. Only well described cases are presented below. tion. The cataract surgery was done under peribulbarAPJOH 2009; 1: (3). September 2009 4 www.slm-oncology.com
  5. 5. Management of Ocular Posterior Segment Hemorrhages in Patients With HemophiliaFigure 1. (A) Normal appearance of optic disc, vessels, and macular area on fundus. (B) Examination using optical coherence tomog-raphy can produce cross-sectional images in vivo and provide the thickness of the maculaanesthesia without bleeding or postoperative complica- translates an optical image into neural impulses, andtions. sends these to the brain via the optic nerve. The maculaCase 7. Pekçelen et al [11] performed a cataract extrac- is located roughly in the center of the retina, temporaltion under topical anesthesia in a 36-year-old patient to the optic nerve (Figure 1A). It is a highly sensitivewith hemophilia A and inhibitor. They used less rFVIIa part of the retina, responsible for detailed central vision.than did Biron-Andréani et al because of the different In this investigation, two of three patients developedtype of anesthesia. hemorrhages located at the choroid that required enu- cleation. The suprachoroidal space is normally a virtualDISCUSSION space situated between the choroid and the sclera. The choroid is firmly attached to the sclera at the ampullae As shown in Table 1, we found that only three cases of of the vortex veins, and the posterior ciliary arteries liehemophilia developed ocular posterior segment hemor- within this space and are encased by collagenous tissue.rhages. All had a deficiency of coagulation factor VIII, Previous studies reported that trauma-induced hypot-which resulted from either hereditary hemophilia (fac- ony appears to be the major precipitating factor, result-tor levels ranging from 1.9% to 11%) or acquired factor ing in stretching of the long or a short posterior ciliaryVIII inhibitor. We also observed that the acquired type artery. When a deficiency of coagulation occurs, the re-commonly occurred in old age, whereas the hereditary sult is an extravasation of blood from the stretched ves-type occurred at a young age. These hemorrhages may sels, and suprachoroidal hemorrhage develops.be caused by trauma, or can occur spontaneously. Thecases with poor visual acuity mentioned above remind Controversy still exists regarding the best course ofus of the importance of laboratory examinations for treatment for these patients. Although the introductionevaluation of coagulation status in patients with hem- of perfluorocarbon liquids as a surgical adjunct duringorrhagic events. The success of treatment for patients vitrectomy may assist in the prevention of suprachoroi-with hemophilia relies on accurate diagnosis, coopera- dal hemorrhage, the visual outcomes remain disap-tion with the hematologists, and appropriate coagula- pointing. The macula is also a site at risk of bleeding intion products. Delay in diagnosis and treatment of ocu- patients with hemophilia. It may develop vascular ab-lar posterior segment hemorrhages often results in loss normalities which could result from ocular or systemicof vision, and sometimes even death. conditions including age-related macular degeneration, high myopia, diabetic retinopathy, and uncontrolled hy- In our investigation, we observed that ocular posterior pertension. Moreover, vitreous may gradually shrinksegment hemorrhages in these patients commonly de- and separate from the macula with age. The vascularveloped at the macula, disc, and suprachoroidal space.The ocular posterior segment consists of the vitreous abnormalities and vascular stretching effect may lead tobody, retina, choroid, posterior sclera and optic nerve. macular hemorrhage, especially in patients with bloodThe retina is a thin disc-shaped layer of light-sensitive coagulation diseases [12].tissue on the back wall of the eye. The outer retina is Kokame et al [13] suggested that the optic disc is an-supplied by the choroid, which is supplied by the various other potential bleeding site in the ocular posterior seg-ciliary arteries. The inner retina is supplied by the cen- ment because the vitreoretinal dragging of retinal andtral retinal artery and related branch vessels. The retina choroidal tissues over and around the elevated edge maywww.slm-oncology.com 5 APJOH 2009; 1: (3). September 2009
  6. 6. Asia-Pacific Journal of Oncology & HematologyFigure 2. Absorption of optic disc hemorrhage after treatment with factor VIII concentrates in a boy with hemophilia Aput the capillaries at risk for bleeding. Sibony et al [14] A, the PTT can be normal under conditions of stress,proposed that discs with a compressed or tilted shape which can result in failure to diagnose the condition.have a high risk of developing peripapillary hemorrhag- Thus, if there is a family history of hemophilia A, it mayes. Compressed optic discs may compromise vessel circu- be prudent to directly measure the factor VIII level in alation. Tilted optic discs may change the optic vessel di- patient with ocular hemorrhages, as a factor VIII defi-rection into the retina along an acutely angled pathway. ciency alters the course of management.When vitreous traction occurs, vessels running out of The diagnosis of hemophilia with inhibitors and ac-these discs may be stretched or compressed, predispos- quired hemophilia is suggested when a patient with he-ing to hemorrhages. Previous studies also report that mophilia begins to lose his or her hemostatic response tomyopic eyes have thinner and more distensible sclera, factor supplementation, and when a bleeding tendencyand that the discs may also suffer a stretching effect. develops in a previously healthy person repetitively. The These observations may partly explain why, in our pre- possibility of this diagnosis is further increased when avious case of a 13-year-old boy with moderate hemophil- patient has a prolonged PTT and measurably decreasedia A, spontaneous peripapillary hemorrhage occurred factor VIII levels.when the coagulation factor level was low (1.9%) [3]. As shown in Table 2, we analyzed ophthalmic surgeryThe patient had a spontaneous optic disc hemorrhage in seven previously reported cases with known hemo-with peripapillary retinal and subretinal hemorrhages philia. Most of the surgeries were cataract extractionin his left eye (Figure 2). The hemorrhages resolved af- through avascular cornea. About 40 years ago, Ruben-ter the administration of factor VIII concentrate. stein et al [15] reported four hemophilia patients with The diagnosis of ocular posterior segment hemorrhage postoperative ocular hemorrhages with poor visual out-is made by an ophthalmologist after dilated fundoscopic come. These authors suggested that surgery should beexamination. Sonography is applied to detect posterior avoided whenever possible in people with hemophilia.segment hemorrhages when opacities occur in the ante- However, there have been successful cataract extrac-rior segment, such as corneal lesions and cataract. Opti- tions performed with adequate preoperative prepara-cal coherence tomography (Figure 1B) is also used to tions including whole blood transfusion, use of steroids,evaluate retinal thickness, and to identify microscopic antihemophilic globulin, and epsilon amino caproic acidretinal hemorrhages. A differential diagnosis of ocular [4, 5]. Nowadays, ophthalmic surgery on a known he-posterior segment hemorrhage depends on a detailed mophiliac with preventive antihemophilic treatmentsystemic survey of the underlying medical and ocular (factor concentrates and rFVIIa) and improved surgicalconditions such as diabetes mellitus, hypertension, and techniques often results in a good surgical outcome.glaucoma. In cases with hemophilia and prior systemic The management principles of ocular posterior seg-diseases, the absence of pathological changes of the fun- ment hemorrhages in patients with congenital hemo-dus in previous assessments and in the other eye should philia include stabilization of the bleeding tendencyprompt suspicion of a bleeding diathesis. Most of the pa- and management of hemorrhages. Stabilization of thetients with ocular trauma were not diagnosed as hemo- bleeding tendency has improved tremendously over thephiliacs until uncontrolled postoperative hemorrhages years because of the ready availability of high purityor delayed spontaneous hemorrhages led to laboratory plasma-derived recombinant factor concentrates andtests of prothrombin time (PT), partial thromboplastin other medications. Previous studies suggest keeping thetime (PTT), and factor evaluation that resulted in the factor VIII activity level above 30% and the factor IXdiagnosis of hemophilia. However, in mild hemophiliaAPJOH 2009; 1: (3). September 2009 6 www.slm-oncology.com
  7. 7. Management of Ocular Posterior Segment Hemorrhages in Patients With Hemophiliaactivity level above 20% for mild hemorrhages (such as tality from hemorrhages. Treatment of acquired hemo-early hemarthrosis, epistaxis and gingival bleeding); the philia involves three aspects to achieve proper coagu-factor VIII activity level above 50% and the factor IX lation status, including elevation of circulating FVIIIactivity level above 40% for major hemorrhages; and the level, supplementing of bypassing agents, and eradica-factor VIII activity level above 80% to 90% and the fac- tion of inhibitor. However, human FVIII concentrate istor IX activity level above 60% to 80% for life-threaten- usually an inadequate hemostatic therapy unless theing bleeding episodes (such as major trauma or surgery inhibitor titer is low, less than 5 BU/mL. Thus, the useand intracranial hemorrhages) [16]. However, there are of bypassing agents and strategies to raise the level ofno definitive guidelines with regard to handle intraocu- circulating FVII is required. Bypassing agents are cur-lar hemorrhages in patients with congenital hemophilia. rently the most used approach and both recombinantIt is reasonable to keep hemostatic levels of the deficient factor VIIa (rFVIIa) and factor eight inhibitor bypassingfactor above 60% until the process potentially triggering activity (FEIBA) have been demonstrated to be effectivebleeding is well under control. If bleeding does not re- in the treatment of acquired hemophilia. The eradica-solve despite adequate treatment, clotting factor levels tion of inhibitor may also be achieved with immuno-should be monitored and inhibitors should be checked to suppressive agents including corticosteroids, cytotoxicdetermine whether the level is unexpectedly low. drugs, and anti-CD20 monoclonal antibody. Although Variations in responses related to patient or product about 25% of patients will achieve remission spontane-parameters make determinations of factor levels impor- ously without immunosuppressive treatment, patientstant. These determinations should be performed imme- still remain at risk of severe or life-threatening bleedingdiately after infusions and continued thereafter to en- until the inhibitor is eradicated. Therefore, the choice ofsure an adequate response and maintenance levels. For the most appropriate therapeutic strategy will dependdosage calculations, the general guidelines suggest that on patient characteristics and the site and severity offor factor VIII, 1 unit/kg increases factor VIII plasma the bleed [18].levels by 2%. The reaction half-life is 8 to 12 h. In addi-tion, administration of DDAVP can raise the factor VIII The protocol for prevention of surgical bleeding in pa-level sufficiently high in patients with mild hemophilia tients with acquired hemophilia has also been hamperedA. Antifibrinolytic drugs (e.g. tranexamic acid, epsilon by the lack of prospective studies due to the rare na-amino caproic acid) are effective as adjunct treatments ture of this disorder. Lak et al reported that hemostasisto decrease the use of coagulation products. could be controlled in 5 out of 7 operation procedures by administering immunosuppressor and coagulation by- Some hemorrhages absorb spontaneously when the passing agents (rFVIIa, NovoSeven, and aPCC; FEIBA).bleeding tendency is stabilized. Surgical intervention Moreover, the protocol for administration of rFVIIamay be necessary if hemorrhages persist or related com-plications such as glaucoma, cataract, or vitreous hem- was suggested at a dose of 90 μg/kg intravenously (IV),orrhage develop. Ophthalmic intervention in congeni- 2 hourly for 12 doses (24 h) and 4 hourly for 8 dosestal hemophiliacs has been reported to have reasonable (32 h). It was followed by 90 μg/kg 4 to 6 hourly untiloutcomes under adequate preventative cover. However, the bleeding resolved and the wound healed (range 8 hthere is no consensus of opinion regarding the minimum to 12 days treatment). They observed that there weresafe factor levels during surgery and in the postoperative no intraoperative bleeds in the 7 procedures and onlyperiod. According to guidelines provided by the World 2 patients required blood transfusions. The efficacy ofFederation of Hemophilia, the dosage and duration of rFVIIa therapy in that study was also revealed by dem-clotting factor concentrate coverage vary. For hemo- onstrating a shortening of the PT and by the increasedphilia A, the desired preoperative level is 80% to 100%, level of FVII activity [19].while for hemophilia B a 60% to 80% level is desirable. Dealing with ocular hemorrhages in patients with he-The desirable postoperative levels for hemophilia A are mophilia remains a challenge for both hematologists60% to 80% for 1 to 3 days, 40% to 60% for 4 to 6 days, and ophthalmologists. Accurate diagnosis and promptand 30% to 50% for 7 to 14 days. The desirable postop- treatment are necessary. Furthermore, further investi-erative levels for hemophilia B are 40% to 60% for 1 to gation is essential to identify the appropriate protocol to3 days, 30% to 50% for 4 to 6 days, and 20% to 40% for 7 handle ocular posterior ocular segment hemorrhages into 14 days [17]. Previous studies reported that for gen- patients with hemophilia.eral surgery, preoperative factor levels should be raisedto 80% to 100% of normal, and levels of >50% main- Disclosure: The authors have no financial interests to dis-tained for 7 to 10 days [8]. Furthermore, the eyeball is close related to the contents of this article.a delicate structure and as transparency of the media is ACKNOWLEDGMENTS: This study was supported by Na-an absolute requirement for good visual recovery, every tional Science Council grant NSC-91-2314-B-016-080; theattempt should be made to ensure adequate hemostasis. Research & Development Fund of the Tri-Service General Bleeding in acquired hemophilia needs aggressive Hospital (TSGH-C97-69; TSGH-C98-69), and the Chen-Hantreatment, since there is significant morbidity and mor- Foundation.www.slm-oncology.com 7 APJOH 2009; 1: (3). September 2009
  8. 8. Asia-Pacific Journal of Oncology & HematologyREFERENCES1. Hon C, Liu H, Chan J. Acquired factor VIII inhibitor presenting as macular haemorrhage. Haemophilia. 2005;11:164–166.2. Maguluri S, Bueno CL, Fuller IB, Eagle RC, Spell DW. Delayed suprachoroidal hemorrhage and factor VIII deficiency. Am J Ophthalmol. 2005;139:195–197.3. Wang TY, Horng CT, Cheng SN, Li CH, Chen JT, Tsai ML. Optic disc hemorrhages in a patient with hemophilia A. Int J Hematol. 2008;87:550–552.4. Degrosz I, Borbely L, Szabados D, Rado JP Successful extraction . of complicated cataract in a patient suffering from haemophilia B. Acta Ophthalmol. 1965;43:574–578.5. Osterlind G, Nilsson IM. Extraction of cataract in a patient with severe haemophilia A. Acta Ophthalmol. 1968;46:176–181.6. Strauss L, Ramsell TG. Successful cataract extraction in a severe haemophiliac. Br J Ophthalmol. 1968;52:242–244.7. Rothkoff L, Biedner B, Shoham K. Bilateral cataract: extraction in classic haemophilia with retrobulbar anaesthesia and periph- eral iridectomy. Br J Ophthalmol. 1977;61:765–766.8. Jijina F, Ghosh K, Madkaikar M, Mohanty D. Ophthalmic surgery in haemophilia. Haemophilia. 2001;7:464–467.9. Tourbaf KD, Dunlap BE, Ambrus JL, Rodman DJ, Atwal AJ. The use of FEIBA (factor eight inhibitor bypassing activity) in cataract extraction in hemophilia A patient with inhibitor. J Med. 1982;13:399–410.10. Biron-Andréani C, Dupeyron G, Mainemer M, Schved JF. Suc- cessful use of recombinant factor VIIa in a haemophiliac with inhibitor undergoing cataract surgery. Blood Coagul Fibrinolysis. 2001;4:215–216.11. Pekçelen Y, Yavuz AS, Namli S, Gücükoglu A. Short-course use of recombinant factor VIIa in a haemophilia patient with inhibi- tor undergoing cataract surgeries. Blood Coagul Fibrinolysis. 2005;16:445–446.12. Miller NR. Walsh and Hoyt’s Clinical Neuroophthalmology. Vol. 4. 4th ed. Baltimore: Williams & Wilkins; 1982.13. Kokame GT, Yamamoto I, Kishi S, Tamura A, Drouilhet JH. Intrapapillary hemorrhage with adjacent peripapillary subretinal hemorrhage. Ophthalmology. 2004;111:926–930.14. Sibony P Fourman S, Honkanen R, El Baba F. Asymptomatic , peripapillary subretinal hemorrhage: a study of 10 cases. J Neu- roophthalmol. 2008;28:114–119.15. Rubenstein RA, Albert DM, Scheie HG. Ocular complications of hemophilia. Arch Ophthalmol. 1966;76:231–232.16. Manco-Johnson MJ. Update on treatment regimens: Prophylaxis versus on-demand therapy. Semin Hematol. 2003;40:3–9.17. World Federation of Hemophilia. Guidelines for the Management of Hemophilia. Canada: World Federation of Hemophilia; 2005.18. Grünewald M, Beneke H, Güthner C, Germowitz A, Brommer A, Griesshammer M. Acquired haemophilia: experiences with a standardized approach. Haemophilia. 2001;7:164-169.19. Lak M, Sharifian RA, Karimi K, Mansouritorghabeh H. Acquired hemophilia A: Clinical features, surgery and treatment of 34 cases, and experience of using recombinant factor VIIa. Clin Appl Thromb Hemost. 2009 Feb 11. [Epub ahead of print]APJOH 2009; 1: (3). September 2009 8 www.slm-oncology.com

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