BRIEFCLINICALOBSERVATIONS DEEPVENOUSTHROMBOSISIN HEMOPHILIAA Inherited deficiency of factor VIII (FVIII) coagulant activity causes the important hemorrhagic disorder, hemophilia A (classic hemophilia) [l]. Plasma levels of FVIII can be temporarily corrected and the bleeding tendency reversed in most patients following infusion of FVIII in appropriate blood products [l]. One would expect that correction of the hemostatic defect would place such a patient at the same risk of thromboembolism as an unaffected individual. However, thromboembolic events in patients with hemophilia A are distinctly uncommon [2,3]. We describe a man with hemophilia A who developed symptomatic postoperative deep venous thrombosis while receiving FVIII concentrate. Case Report. A 67-year-old man with hemophilia A was hospitalized for proximal tibial osteotomy of the left leg under coverage of intermediate purity FVIII concentrate to maintain the FVIII level between 0.5 and 1.0 U/mL (50% to 100% activity). Shortly after surgery, he required univalving of his cast because of pain and swelling of the left leg. The following day, he developed left calf pain and weakness of the dorsiflexors of the left foot. During this postoperative period, the FVIII level was approximately 0.5 U/mL prior to each infusion of FVIII concentrate. Contrast venography showed a filling defect in the long saphenous vein; filling of the deep venous system was limited to retrograde filling of the proximal femoral vein (Figure 1A). In addition to the same dosage of FVIII concentrate, the patient received continuous intravenous heparin to maintain the activated partial thromboplastin time at 1.5 to 2.5 times control values. Eleven days postoperatively, he had an exacerbation of his calf pain, swelling, and bruising with loss of peripheral pulses
in the foot and a 20 g/L decrease in the hemoglobin level. Heparin was discontinued and he was transferred to the Foothills Hospital. The FVIII level had not been monitored during heparin therapy, but was 0.6 U/mL when heparin was discontinued. Anterior and posterior fasciotomies were performed to release a compartment syndrome, and a large clot was removed from the posterior compartment. The muscle in this region looked dusky. Radionuclide venography performed 7 days later showed extensive collateral circulation with continued failure to fill the deep venous system of the left leg (Figure 1B). The left leg became nonviable and an above-knee amputation was performed 65 days after his arthrotomy. Additional studies at the Foothills Hospital showed normal plasma levels of antithrombin III, protein C, protein S, and plasminogen as well as absence of a lupus-type inhibitor. FVIII inhibitor was not present. Comments. We believe this to be the first reported case of symptomatic deep venous thrombosis in a patient with hemophilia A receiving FVIII concentrate. In a review of postoperative thrombosis in hemophilia, Kasper [2] found no thrombotic complications in 72 major operations on patients with hemophilia A receiving FVIII concentrate. However, 6 thrombotic episodes in 13 operations occurred in patients with hemophilia B receiving prothrombin complex concentrate [2]. Goodnough et al [3] identified no thrombotic events in their review of 178 patients with hemophilia A followed over a 30-year period, although they excluded patients with thrombosis after treatment with clotting factor preparations. They subsequently treated a man with superficial thrombophlebitis at the site of an indwelling catheter. They also reviewed a second
Figure 1. A. Contrast venogram on the first postoperative day. Note the filling defect in the long saphenous vein (arrow), and the absence of filling of the deep veins. B. Radionuclide venogram on the seventh day following fasciotomy. Note the absence of filling of the deep veins of the left leg, and the extensive collateral circulation in the superficial veins, compared with the right leg.
December 1992 The American Journal of Medicine
Volume 93
699
BRIEF CLINICAL OBSERVATIONS
patient with superficial thrombophlebitis during multiple venipunctures for analgesics and replacement therapy with frozen and lyophilized plasma [3]. Thrombosis of an arteriovenous fistula 4 days after graft puncture has been described in a hemophilia A patient who used the graft for parenteral analgesics and FVIII concentrate [4]. Arterial occlusion occurs rarely in patients with hemophilia A. Unstable angina and fatal myocardial infarction due to documented right coronary thrombosis during FVIII concentrate replacement therapy have been described in two cases [5,6]. In their review, Goodnough et al [3] reported seven cases of myocardial infarction, with one complicated by a stroke, unrelated to FVIII replacement therapy. Cerebral thrombosis was also reported in one patient following evacuation of a subdural hematoma under FVIII concentrate coverage [7]; in another patient, widespread cerebrovascular occlusion by eosinophilic particulate matter has also been reported after FVIII concentrate infusion [8]. Thrombosis is a well-described complication of prothrombin complex therapy, and is likely due to the presence of activated clotting factors [2,3]. FVIII concentrates do not contain activated clotting factors, but preparations other than the high purity concentrates may contain particulate matter [9]. This debris has been shown to reduce the singlebreath diffusion capacity of carbon monoxide [9] and may have contributed to cerebral thrombosis in one patient [8]. This material may also play a pathogenetic role in the development of pulmonary hypertension observed in some of these patients
Foothills Hospital Calgary, Alberta, Canada 1. Levine Hoffman principles 2. Kasper
PH, Brettler DB. Clinical aspects and therapy for hemophilia A. In: R. Benz EJ Jr, Shattil SJ, Furie S. Cohen HJ. editors. Hematology: basic and practice. New York Churchill Livingstone, 1991: 1290-1304. CK. Postoperative thromboses in hemophilia B. N Engl J Med 1973;
289: 160. 3. Goodnough LT, Saito H, Ratnoff OD. Thrombosis or myocardial infarction in congenital clotting factor abnormalities and chronic thrombocytopenias: a report of 21 patients and a review of 50 previously reported cases. Medicine (Baltimore) 1983: 62: 248-55. 4. Barasz M. Spontaneous thrombosis of an arteriovenous fistula in a hemophiliac Am Fam Physician 1978; 18: 23-6. 5. Kopitsky RD. Geltman EM Unstable angina associated with factor VIII concentrate therapy for hemophilia A. Ann Intern Med 1986; 105: 2156. 6. Small M. Jack AS, Lowe GDO, Mutch AF, Forbes CD, Prentice CR. Coronary artery disease in severe haemophilia. Br Heart J 1983; 49: 604-7. 7. lchinose A, Maruyama I, Yoshida Y, lgata A. Cerebral thrombosis in a haemophiliac. Thromb Haemost 1981; 45: 190. 8. Ghatak NR, Husain MH. Unusual intravascular material in the brain. Am J Clin Pathol 1976; 65: 508-12. 9.8oese EC, Tantum KR, Eyster ME. Pulmonary function abnormalities after infusion of antihemophiliac factor (AHF) concentrates. Am J Med 1979; 67: 474-6. 10. Goldsmith GH Jr, Baily RG, Brettler DB. et al. Primary pulmonary hypertension in patients with classic hemophilia. Ann Intern Med 1988, 108: 797-9. Submitted
June 5. 1992, and accepted
June 22, 1992
RESOLUTIONOF HIV RETINITISWITH ZIDOVUDINETHERAPY
Multiple opportunistic infections of the retina have been described in patients with human immunodeficiency virus (HIV) infection [l]. HIV itself can infect the retina, but a clear relationship with clinical disease has not yet been established [2-4]. We report the case of an asymptomatic HIV-infected WA. Our hemophilia A patient developed symptomatpatient who presented with retinitis that resolved ic deep venous thrombosis while he was receiving with zidovudine therapy. FVIII concentrate alone for an orthopedic surgical Case Report. A 34-year-old homosexual man procedure. Common coagulation disorders associ- presented to the Infectious Disease outpatient clinated with thromboembolic risk were not present ic with blurred vision in the right eye. On funduscoand he was otherwise healthy. Orthopedic proce- pit examination, frank retinitis was seen in the lowdures are commonly associated with thromboemer portion of the right retina, with multifocal fluffy bolic complications in normal individuals, and it is white patches and sheathing along the inferotempossible that hemophilia patients undergoing these poral vessels (Figure 1, arrow). Fluorescein angiogprocedures with FVIII replacement do develop raphy revealed patchy and perivascular hyperdeep venous thrombosis more frequently than hithfluorescence (Figure 2). This patient was a previerto believed, but perhaps these are asymptomatic, ously asymptomatic HIV-1-seropositive man. His and hence not detected. Management of thrombosis temperature and the results of physical examinain hemophilia patients following surgery can be dif- tion were normal. A latex agglutination test for ficult. Heparin therapy in our patient was associ- cryptococcal antigen in the serum, and serologic ated with bleeding and a compartment syndrome, tests for toxoplasmosis and syphilis were negative. despite the administration of FVIII concentrate de- Although cytomegalovirus (CMV) was not cultured signed to maintain FVIII levels above 0.5 U/mL, from the blood, a diagnosis of CMV retinitis was considered, and the patient was treated with intrawith a disastrous outcome. BRUCERITCHIE, MJ). venous ganciclovir (10 mg/kg/d) for 4 weeks. His RICHARD C. WOODMAN,MJ). MAN-CHIU POON,M.D. vision did not improve, however, and the results of a University of Calgary funduscopic examination performed at the end of 700
December 1992 The American Journal of Medicine
Volume 93
in the foot and a 20 g/L decrease in the hemoglobin level. Heparin was discontinued and he was transferred to the Foothills Hospital. The FVIII level had not been monitored during heparin therapy, but was 0.6 U/mL when heparin was discontinued. Anterior and posterior fasciotomies were performed to release a compartment syndrome, and a large clot was removed from the posterior compartment. The muscle in this region looked dusky. Radionuclide venography performed 7 days later showed extensive collateral circulation with continued failure to fill the deep venous system of the left leg (Figure 1B). The left leg became nonviable and an above-knee amputation was performed 65 days after his arthrotomy. Additional studies at the Foothills Hospital showed normal plasma levels of antithrombin III, protein C, protein S, and plasminogen as well as absence of a lupus-type inhibitor. FVIII inhibitor was not present. Comments. We believe this to be the first reported case of symptomatic deep venous thrombosis in a patient with hemophilia A receiving FVIII concentrate. In a review of postoperative thrombosis in hemophilia, Kasper [2] found no thrombotic complications in 72 major operations on patients with hemophilia A receiving FVIII concentrate. However, 6 thrombotic episodes in 13 operations occurred in patients with hemophilia B receiving prothrombin complex concentrate [2]. Goodnough et al [3] identified no thrombotic events in their review of 178 patients with hemophilia A followed over a 30-year period, although they excluded patients with thrombosis after treatment with clotting factor preparations. They subsequently treated a man with superficial thrombophlebitis at the site of an indwelling catheter. They also reviewed a second
Figure 1. A. Contrast venogram on the first postoperative day. Note the filling defect in the long saphenous vein (arrow), and the absence of filling of the deep veins. B. Radionuclide venogram on the seventh day following fasciotomy. Note the absence of filling of the deep veins of the left leg, and the extensive collateral circulation in the superficial veins, compared with the right leg.
December 1992 The American Journal of Medicine
Volume 93
699
BRIEF CLINICAL OBSERVATIONS
patient with superficial thrombophlebitis during multiple venipunctures for analgesics and replacement therapy with frozen and lyophilized plasma [3]. Thrombosis of an arteriovenous fistula 4 days after graft puncture has been described in a hemophilia A patient who used the graft for parenteral analgesics and FVIII concentrate [4]. Arterial occlusion occurs rarely in patients with hemophilia A. Unstable angina and fatal myocardial infarction due to documented right coronary thrombosis during FVIII concentrate replacement therapy have been described in two cases [5,6]. In their review, Goodnough et al [3] reported seven cases of myocardial infarction, with one complicated by a stroke, unrelated to FVIII replacement therapy. Cerebral thrombosis was also reported in one patient following evacuation of a subdural hematoma under FVIII concentrate coverage [7]; in another patient, widespread cerebrovascular occlusion by eosinophilic particulate matter has also been reported after FVIII concentrate infusion [8]. Thrombosis is a well-described complication of prothrombin complex therapy, and is likely due to the presence of activated clotting factors [2,3]. FVIII concentrates do not contain activated clotting factors, but preparations other than the high purity concentrates may contain particulate matter [9]. This debris has been shown to reduce the singlebreath diffusion capacity of carbon monoxide [9] and may have contributed to cerebral thrombosis in one patient [8]. This material may also play a pathogenetic role in the development of pulmonary hypertension observed in some of these patients
Foothills Hospital Calgary, Alberta, Canada 1. Levine Hoffman principles 2. Kasper
PH, Brettler DB. Clinical aspects and therapy for hemophilia A. In: R. Benz EJ Jr, Shattil SJ, Furie S. Cohen HJ. editors. Hematology: basic and practice. New York Churchill Livingstone, 1991: 1290-1304. CK. Postoperative thromboses in hemophilia B. N Engl J Med 1973;
289: 160. 3. Goodnough LT, Saito H, Ratnoff OD. Thrombosis or myocardial infarction in congenital clotting factor abnormalities and chronic thrombocytopenias: a report of 21 patients and a review of 50 previously reported cases. Medicine (Baltimore) 1983: 62: 248-55. 4. Barasz M. Spontaneous thrombosis of an arteriovenous fistula in a hemophiliac Am Fam Physician 1978; 18: 23-6. 5. Kopitsky RD. Geltman EM Unstable angina associated with factor VIII concentrate therapy for hemophilia A. Ann Intern Med 1986; 105: 2156. 6. Small M. Jack AS, Lowe GDO, Mutch AF, Forbes CD, Prentice CR. Coronary artery disease in severe haemophilia. Br Heart J 1983; 49: 604-7. 7. lchinose A, Maruyama I, Yoshida Y, lgata A. Cerebral thrombosis in a haemophiliac. Thromb Haemost 1981; 45: 190. 8. Ghatak NR, Husain MH. Unusual intravascular material in the brain. Am J Clin Pathol 1976; 65: 508-12. 9.8oese EC, Tantum KR, Eyster ME. Pulmonary function abnormalities after infusion of antihemophiliac factor (AHF) concentrates. Am J Med 1979; 67: 474-6. 10. Goldsmith GH Jr, Baily RG, Brettler DB. et al. Primary pulmonary hypertension in patients with classic hemophilia. Ann Intern Med 1988, 108: 797-9. Submitted
June 5. 1992, and accepted
June 22, 1992
RESOLUTIONOF HIV RETINITISWITH ZIDOVUDINETHERAPY
Multiple opportunistic infections of the retina have been described in patients with human immunodeficiency virus (HIV) infection [l]. HIV itself can infect the retina, but a clear relationship with clinical disease has not yet been established [2-4]. We report the case of an asymptomatic HIV-infected WA. Our hemophilia A patient developed symptomatpatient who presented with retinitis that resolved ic deep venous thrombosis while he was receiving with zidovudine therapy. FVIII concentrate alone for an orthopedic surgical Case Report. A 34-year-old homosexual man procedure. Common coagulation disorders associ- presented to the Infectious Disease outpatient clinated with thromboembolic risk were not present ic with blurred vision in the right eye. On funduscoand he was otherwise healthy. Orthopedic proce- pit examination, frank retinitis was seen in the lowdures are commonly associated with thromboemer portion of the right retina, with multifocal fluffy bolic complications in normal individuals, and it is white patches and sheathing along the inferotempossible that hemophilia patients undergoing these poral vessels (Figure 1, arrow). Fluorescein angiogprocedures with FVIII replacement do develop raphy revealed patchy and perivascular hyperdeep venous thrombosis more frequently than hithfluorescence (Figure 2). This patient was a previerto believed, but perhaps these are asymptomatic, ously asymptomatic HIV-1-seropositive man. His and hence not detected. Management of thrombosis temperature and the results of physical examinain hemophilia patients following surgery can be dif- tion were normal. A latex agglutination test for ficult. Heparin therapy in our patient was associ- cryptococcal antigen in the serum, and serologic ated with bleeding and a compartment syndrome, tests for toxoplasmosis and syphilis were negative. despite the administration of FVIII concentrate de- Although cytomegalovirus (CMV) was not cultured signed to maintain FVIII levels above 0.5 U/mL, from the blood, a diagnosis of CMV retinitis was considered, and the patient was treated with intrawith a disastrous outcome. BRUCERITCHIE, MJ). venous ganciclovir (10 mg/kg/d) for 4 weeks. His RICHARD C. WOODMAN,MJ). MAN-CHIU POON,M.D. vision did not improve, however, and the results of a University of Calgary funduscopic examination performed at the end of 700
December 1992 The American Journal of Medicine
Volume 93
