Catheterization and Cardiovascular Diagnosis 25:144-147 (1992)
Percutaneous Transluminal Coronary Angioplasty in a Patient With Paroxysmal Nocturnal Hemoglobinuria Ping-Ching Fong, MD, Yau-Ting Tai, MD, Chu-Pak Lau, MD, John Li, MD, Florence Hiu-Yee Yap, MD, Raymond Liang, MD, and Albert Kwok-Wai Lie, MD Paroxysmal nocturnal hemoglobinuria (PNH) is an acquired chronic hemolytic anemia associated with an unusual susceptibility to hemolytic crisis, infection, and venous thrombosis which would be aggravated by a number of factors including surgery. We report a case of PNH undergoing percutaneous transluminal coronary angioplasty and discuss the corresponding perioperative management Key words: catheterization, hemolytic anemia, venous thrombosis
INTRODUCTION Paroxysmal nocturnal hemoglobinuria (PNH) is a rare acquired chronic hemolytic anemia secondary to a clonal stem cell disorder affecting erythrocytes, granulocytes, and platelets [l-3). Patients with PNH are prone to intravascular hemolysis, marrow aplasia, infections, and venous thrombosis in unusual sites such as mesenteric and hepatic veins [ 3 ] .The risks of hemolysis and thrombosis are particularly increased as a result of surgery, pregnancy, and infection. The anesthetic and peripartum management in PNH have been reported elsewhere [571. We report the first case of PNH to undergone a successful percutaneous transluminal coronary angioplasty (PTCA) and discuss the perioperative precautions required in the procedure. CASE REPORT A 35-yr-old man was hospitalized because of increasing frequency of exertional and resting retrosternal pain for 3 days. He had been a known case of PNH for more than 10 years, documented by a positive acidified serum test (Ham test). Initial presentation was dark color urine and anemia. His hemoglobin (Hb) level had been stabilized between 8.3-1 1 g/dL and reticulocyte count 6.514.9% by regular blood transfusions and long-term corticosteriod therapy, with which he developed secondary diabetes mellitus and required glibenclamide 2.5 mg daily. He was also a chronic smoker for over 10 years. Apart from these. there was no past history of hypertension, exertional angina, or venous thrombosis. Family history was non-contributory . Physical examination was unremarkable except for mild pallor. Electrocardiogram performed during pain 0 1992 Wiley-Liss, Inc.
showed downsloping ST depression and T wave inversion in leads V, to V, without Q wave formation. Serial cardiac enzyme measurements showed no evidence of myocardial infarction. Thus, he was treated as having unstable angina with bed rest, oxygen, aspirin, intravenous nitrate, and full dose intravenous heparin to keep the activated partial thromboplastin time ( A m ) ratio between 1.5 and 2.0. Despite intensive therapy, there were still intermittent attacks of rest pain. Coronary angiography was therefore performed at day 7 . Pre-catheterization hematological data included Hb 9.6 g/dL(MCV 117.5 fL,MCHC 28.7 g/dL), WBC 8.3 x 109/L, platelet 183 X 109/L, reticulocyte 13%, and a positive Ham test. Blood biochemistry revealed an elevated total bilirubin of 48 pmol/L with conjugated bilirubin of only 7 kmol/L and lactic dehydrogenase of 2,835 IU/L. Urea, creatinine, transaminases, and creatine kinase were within normal ranges. Coronary angiography was performed with the standard femoral approach under local anesthesia using 10 ml 2% lignocaine. Premedication included intravenous hydrocortisone 100 mg. Left ventriculogram using Cardio-conray as the radiocontrast showed normal wall motion, whereas selective coronary angiograms using Urografin 76% revealed a critical but discrete lesion in the proximal left anterior descending artery (LAD) which was amenable to PTCA. However, in the following day after the coronary angiography, the patient’s Hb was From the Divisions of Cardiology and Hematology, University Department of Medicine, Queen Mary Hospital, Hong Kong.
Received June 3. 1991; revision accepted August 18, 1991 Address reprint requests to Ping-Ching Fong, MD, University Department of Medicine. Queen Mary Hospital. Hong Kong.
PTCA in a Patient With PNH
found to have dropped to 6.8 g/dL and 2 pints of salinewashed red cells were required to bring the Hb level back to 10.8 g/dL. The PTCA was performed 2 days later. Prior to the day of angioplasty, 4 units of saline-washed red cells were reserved. The patient was fasted after midnight while maintaining on intravenous nitrate and heparin infusions. In the morning, the prednisolone and glibenclamide were omitted. Oral diazepam 5 mg and intravenous hydrocortisone 100 mg were given as premedication. The same site of entry and local anesthesia were used as in the coronary angiography, but only the Urografin 76% was selected as the radiocontrast. The PTCA was done according to the standard balloon-over-the-wire method. Heparin 10,000 units was given intravenously prior to balloon dilatations. During the procedure, 500 ml of normal saline was also given to maintain the hydration. The dilatation procedure itself was straightforward, using a 3.0 mm diameter ACX balloon catheter (Advanced Cardiovascular Systems, Santa Clara, CA) with a 0.014-in. high torque floppy guidewire (Advanced Cardiovascular Systems). A total of three dilatations to the proximal LAD at 51 120, 7/ 120, and 9/ 120 atmospheric pressures/ sec were attempted, achieving a satisfactory result of 20% residual diameter stenosis only. No untoward events occurred during the procedure apart from some mild chest pain during each balloon inflation. The post-PTCA course was uneventful. Intravenous nitrate infusion was given for another 24 hr while the heparin infusion was continued for a total of 7 days, again with the dosage adjusted to keep the APTT ratio between 1.5 and 2.0. After the femoral arterial and venous sheaths were removed on post-PTCA day 2, the patient was mobilized and encouraged to be ambulatory. There was no recurrence of angina or ischemic changes in the ECG during this period. Hematologically, the Hb level was stable at around 10 g/dL and there was no evidence of increased hemolysis or venous thrombosis. The patient was thus discharged after the course of heparin infusion was completed. DISCUSSION PNH is a rare acquired disease that results from a clonal hematopoietic stem cell disorder affecting all hematologic cell lines. It affects both sexes, usually between the ages of 20 and 40 years, and probably individuals of all ethnic groups [8]. The disease is characterized by an increased membrane susceptibility of the affected erythrocytes to the lvtic action of complements via the classical and the alternate pathways [9], an abnormal neutrophil and lymphocyte function, as well as an unusual sensitivity of platelet aggregation [lo]. The underlying molecular basis of the defect lies in the defi-
145
ciency of membrane glycoproteins such as decay-accelerating factor, homologous restriction factor, acetylcholinesterase, and lymphocyte function-associated antigen 3 in the surface of the abnormal cells, which may, in fact, reflect a defect in the biosynthesis of glycosyl-phosphatidylinositol-a glycolipid anchor in the cell membrane [ 1 11. These pathophysiologic abnormalities are found to be directly or indirectly responsible for the many clinical manifestations of the disease. They include chronic intravascular hemolysis with or without hemoglobinuria, increased susceptibility to infections, pancytopenia, aplastic anemia, and higher tendency in venous thrombosis. In fact, the latter is a common complication in PNH. It occurs frequently at unusual sites such as mesenteric and hepatic veins resulting in the Budd-Chiari syndrome, which has a high mortality rate [12]and accounts for the major cause of death in PNH patients [6]. Despite the fact that PNH is not commonly encountered, interventionalists should be aware of this disease for its potential notorious complications. Surgical procedures, improper blood transfusion, and drugs that activate complements are well-known hazards to PNH patients for their tendencies to precipitate hemolytic crisis and venous thrombosis. In addition, because of defective leukocyte functions and/or leukopenia, these patients are prone to bacterial infections which are also known to exacerbate the hemolysis. While successful perioperative management of surgical PNH patients has been described in the literature [5,6], there has, to our knowledge, not been any previous report on the management of PNH patients undergoing R C A and ours is probably the first one. It will serve as a useful reference for similar cases in the future. Based on the pathophysiologic considerations of the disease, certain principles for the perioperative management of surgical PNH patients which aim at mitigating complement activation and decreasing red cell susceptibility to complement-mediated lysis have previously been outlined [ 5 ] . They include 1) avoiding dehydration, hypoxemia, and acidosis, 2) using transfused red cells for prophylaxis and treatment of lytic crisis, 3) using corticosteriods to prevent and treat hemolysis, 4) avoiding infection, and 5) avoiding drugs known to activate complements such as acetazolamide, some radiocontrast media, magnesium compounds, and drugs formulated in Cremophor (e.g., vitamin K) [ 5 ] . Undoubtedly, these principles are also applicable to the management of PNH patients undergoing PTCA and will be discussed as follows. Prevention of dehydration before, during, and after PTCA is needed. In this case, hydration by continuous intravenous nitrate and heparin infusions during the fasting period, an addition of 500 ml normal saline intravenously during the PTCA, and early resumption of oral
146
Fong et al.
feeding afterward seem adequate. However, should acute hemolysis occur, a more vigorous hydration regime would be required to enhance urine output in order to protect the kidneys from the effects of hemoglobinuria
PI.
Blood transfusion is valuable in PNH patients because not only can it treat the hemolytic crisis, it can also be used as a prophylaxis to prevent its occurrence. Though not completely understood, the protective nature of preoperative transfusion appears to be related to the suppression of the production of PNH-sensitive cells by the bone marrow and to the dilution of abnormal cells in the blood by normal erythrocytes [13]. It is, however, CNcia1 to use saline-washed red cells for transfusion because of the possibility of complement activation by nonred cell antigens contained in the plasma of non-washed preparations which cause direct hemolysis without the presence of antibodies [14]. Thus liaison with the blood bank prior to PTCA is of utmost importance in reserving an adequate amount of washed red cells so that in case the patient needs emergency bypass grafting, suitable preparations of blood will be available without unnecessary delay. In our case, two units of saline-washed red cells had to be transfused after the diagnostic study to halt the hemolytic episode and to replenish the dropping hemoglobin. Also, four more units of washed blood were cross-matched in reserve for the PTCA. Hemolysis occurred after the coronary angiography and not after the PTCA in this patient. Whether it is due to the difference between Cardio-conray and Urografin, or to the protecting effect of pre-PTCA transfusion is unclear. Nevertheless, it is noteworthy that radiocontrast agents can activate complements via idiosyncratic anaphylactic reactions which are rarely dose dependent or agent specific [ 151. Most PNH patients are, as in our case, on long-term steriod therapy. Apart from avoiding acute adrenal insufficiency, premedication with steriod in these patients may have an additional benefit of preventing hemolysis induced by invasive procedures [5]. Hence, adequate steriod, such as 100 mg hydrocortisone intravenously in this instance, should always be used prior to interventional procedures. The issue on anesthetic management in coronary interventions is largely simplified by the fact that general anesthesia is not required. However, it would be useful to note that intravenous induction agents are liable to activate complements through anaphylactoid reactions, albeit subclinical or minor [16]. Reports on successful anesthetic management using thiopental, lorazepam, ketamine, midazolam, fentanyl, isoflurane, and enflurane in PNH patients have been described [5,6]. Benzodiazepines are one of the few least likely to induce complement activation and have been used safely as premedi-
cation [6]. Therefore, using diazepam in premedication, as in our case, is acceptable. Local anesthesia using lignocaine appears to be safe in our patient as well. In spite of the susceptibility to infection in PNH, the low risk of systemic infection in coronary interventions [ 171 renders the use of prophylactic broad-spectrum antibiotics, which have been advocated for surgical procedures in these patients [5,6], unnecessary. As pointed out previously, PNH is associated with a striking predisposition for venous thrombosis. This is because the PNH platelets also lack DAF which renders them more susceptible to complements leading to the release reaction [lo]. Most of the complements have been demonstrated to behave as acute-phase reactants which increase significantly 12 hr after surgery and peak on about postoperative day 4 [ 18,191. This may account for the heightened risk of postoperative venous thrombosis in PNH patients and outline the vulnerable period in which thrombosis may occur. Although it is unclear whether or not PTCA will cause an acute-phase response, prophylactic anticoagulation during the first post-PTCA week may be a reasonable measure to prevent the consequences if this is the case. While the use of heparin in PNH is controversial and has been associated with increased hemolysis in some patients, it should be realized that complement activation is inhibited by a higher dose of heparin [20]. In this patient, a full intravenous dose of heparin to keep the APTT ratio between 1.5 and 2.0 was given and continued for 1 week postPTCA without any evidence of acute hemolysis or venous thrombosis. Although high molecular weight dextran has also been shown to be useful in this situation, it is not recommended owing to its inherent risk of anaphylactic reactions and hemorrhagic complications [2l]. Warfarin would be the drug of choice only if long-term anticoagulation therapy were indicated [ 51. It is interesting to note that this 35-year-old man has coronary artery disease. While he certainly has risk factors such as chronic smoking, long-term steriod therapy, secondary diabetes, and male gender, it is unclear whether the platelet disorder in PNH may contribute to the early coronary involvement. Venous thrombosis has been well documented in PNH but arterial thrombosis has not [4].Even in the most recent reviews, there has been no mention that early coronary disease may be a problem with this patient population [22,23]. Therefore, the significance of the inherent platelet dysfunction in early coronary atherosclerosis does not seem very high. In summary, PNH patients undergoing interventional procedures are at high risk for a number of complications (hemolysis, venous thrombosis, and infection). However, it should be pointed out that while the perioperative management of surgical PNH patients is often complex and should serve as the reference for that of PNH patients
PTCA in a Patient With PNH
undergoing PTCA, the latter is likely to be much more straightforward. Still, a successful outcome relies much on the adequacy of the pre-PTCA patient preparation, careful selection of premedications and anesthetic agents, prompt treatment of hemolytic crisis, and prevention of venous thrombosis in the post-PTCA period. Thorough understanding of the pathophysiology of the disease, good liaison with the blood bank, consultation with the hematologists, and close monitoring of the patient’s clinical and hematological status cannot be overemphasized as well. Particularly with procedures where radiocontrasts are used, appropriate agents should be carefully selected. PNH is a chronic disorder and some patients have survived for 20 years or more after diagnosis [8]. Moreover, with the acidified serum or sucrose lysis test performed more commonly nowadays, previously undiagnosed patients with mild chronic disease are being identified. Coronary artery disease will be encountered more in this patient population, and it is important that coronary interventionists should know how to manage these patients properly.
REFERENCES I . Rosse WF, Parker CJ: Paroxysmal nocturnal hemoglobinuria. Clin Haematol 14:105-125, 1985. 2. Dessypris EN, Clark DA, Mckee L Jr, Krantz SB: Increased sensitivity to complement of erythroid and myeloid progenitors in paroxysmal nocturnal hemoglobinuria. N Engl J Med 309:690693, 1983. 3. Terasawa T, Shichishima T, Matsuda M, Uchida T, Kariyone S: Characterization of the erythropoietic progenitor cells (BFU-E) in paroxysmal nocturnal hemoglobinuria. Br J Haematol 75428432, 1990. 4. Valla D, Dhumeaux D, Babany G, Hillon P, Rueff B, Rochant H, Benhamon JP: Hepatic vein thrombosis in paroxysmal nocturnal hemoglobinuria. A spectrum from asymptomatic occlusion of hepatic venules to fatal Budd-Chiari syndrome. Gastroenterology 931569-575, 1987. 5 . Ogin GA: Cholecystectomy in a patient with paroxysmal nocturnal hemoglobinuria. Anesthetic implications and management in the perioperative period. Anesthesiology 72:761-764, 1990. 6. Taylor MB, Whitwam JG, Worsley A: Paroxysmal nocturnal hemoglobinuria. Perioperative management of a patient with BuddChiari syndrome. Anaesthesia 42:639-642, 1987. 7. Solal-Celigny P, Tertian G, Fernandez H, Pons J-C, Lambert T, Najean Y,Clauvel J-P, Papiernik E, Tehernia G: Pregnancy and
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paroxysmal nocturnal hemoglobinuria. Arch Intern Med 148: 593-595. 1988. 8. Dacie JV: Paroxysmal nocturnal haemoglobinuria. In Weatherall DJ, Ledingham JGG, Warrell DA (eds): “Oxford Textbook of Medicine,” 2nd Edition. Oxford: Oxford University Press, 1987, pp 19.54-19.58. 9. Gotze 0, Muller-Eberhard HJ: Hemolysis initiated by the C3 activator system. N Engl J Med 286180-184, 1972. 10. Dixon RH, Rosse WF: Mechanism of complement-mediated activation of human blood platelets in vitro: Comparison of paroxysmal nocturnal hemoglobinuria platelets. J Clin Invest 59:360368, 1977. 1 1 . Yamashina M, Ueda E, Kinoshita T, Takami T, Ojima A, Ono H, Tanaka H. Kondo N , Orii T, Okada N, Okada H, Inoue K, Kitani T: Inherited complete deficiency of 20-kilodalton homologous restriction factor (CD59) as a cause of paroxysmal nocturnal hemoglobinuria. N Engl J Med 323:1184-1189, 1990. 12. Maddey WC: Hepatic vein thrombosis (Budd-Chiari syndrome). Hepatology 4: 1445 - 1 4 6 , 1984. 13. Gockerman JP, Brouillard R P RBC transfusions in paroxysmal nocturnal hemoglobinuria. Arch Intern Med 137536-538, 1977. 14. Yachnin S: The hemolysis of red cells from patients with paroxysmal nocturnal hemoglobinuria. J Clin Invest 44:1534-1546, 1965. 15. Grainger RG: lntravascular contrast media. In Grainger RG,Allison DJ (eds): “Diagnostic Radiology: An Anglo-American Textbook of Imaging,” I st Edition. Edinburgh: Churchill Livingstone, 1986, pp 99-1 10. 16. Watkins J: Immunological problems in anaesthesia. Br J Hosp Med 23583-590, 1980. 17. Grossman W: Complications of cardiac catheterization: Incidence, causes and prevention. In Grossman W (ed): “Cardiac Catheterization and Angiography,” 3rd Edition. Philadelpha: Lea & Febiger, 1986, pp 30-42. 18. Lewis RE, Cruse JM, Richey JV: Effects of anesthesia and operation on the classical pathway of complement activation. Clin lmmunol Immunopathol 23:666-67 I , 1982. 19. Schutte M, Dicamelli R, Murphy P, Sadove M, Gerwurz H: Effects of anaesthesia, surgery and inflammation upon host defense mechanisms. 1. Effects upon the complement system. Int Arch Allergy Appl lmmunol48:706-720, 1975. 20. Logue GL: Effect of heparin on complement activation and lysis of paroxysmal nocturnal hemoglobinuria red cells. Blood 50: 239-247, 1977. 21. Gardner FH, Laforet MT: The use of clinical dextran in patients with paroxysmal nocturnal hemoglobinuria. J Lab Clin Med 55: 946-958, 1960. 22. Rosse W F Paroxysmal nocturnal hemoglobinuria: The biochemical defects and the clinical syndrome. Blood Rev 3:192-200, 1989. 23. Rosse WF: Phosphatidylinositol-linked proteins and paroxysmal nocturnal hemoglobinuria. Blood 75: 1595-1601, 1990.
Percutaneous Transluminal Coronary Angioplasty in a Patient With Paroxysmal Nocturnal Hemoglobinuria Ping-Ching Fong, MD, Yau-Ting Tai, MD, Chu-Pak Lau, MD, John Li, MD, Florence Hiu-Yee Yap, MD, Raymond Liang, MD, and Albert Kwok-Wai Lie, MD Paroxysmal nocturnal hemoglobinuria (PNH) is an acquired chronic hemolytic anemia associated with an unusual susceptibility to hemolytic crisis, infection, and venous thrombosis which would be aggravated by a number of factors including surgery. We report a case of PNH undergoing percutaneous transluminal coronary angioplasty and discuss the corresponding perioperative management Key words: catheterization, hemolytic anemia, venous thrombosis
INTRODUCTION Paroxysmal nocturnal hemoglobinuria (PNH) is a rare acquired chronic hemolytic anemia secondary to a clonal stem cell disorder affecting erythrocytes, granulocytes, and platelets [l-3). Patients with PNH are prone to intravascular hemolysis, marrow aplasia, infections, and venous thrombosis in unusual sites such as mesenteric and hepatic veins [ 3 ] .The risks of hemolysis and thrombosis are particularly increased as a result of surgery, pregnancy, and infection. The anesthetic and peripartum management in PNH have been reported elsewhere [571. We report the first case of PNH to undergone a successful percutaneous transluminal coronary angioplasty (PTCA) and discuss the perioperative precautions required in the procedure. CASE REPORT A 35-yr-old man was hospitalized because of increasing frequency of exertional and resting retrosternal pain for 3 days. He had been a known case of PNH for more than 10 years, documented by a positive acidified serum test (Ham test). Initial presentation was dark color urine and anemia. His hemoglobin (Hb) level had been stabilized between 8.3-1 1 g/dL and reticulocyte count 6.514.9% by regular blood transfusions and long-term corticosteriod therapy, with which he developed secondary diabetes mellitus and required glibenclamide 2.5 mg daily. He was also a chronic smoker for over 10 years. Apart from these. there was no past history of hypertension, exertional angina, or venous thrombosis. Family history was non-contributory . Physical examination was unremarkable except for mild pallor. Electrocardiogram performed during pain 0 1992 Wiley-Liss, Inc.
showed downsloping ST depression and T wave inversion in leads V, to V, without Q wave formation. Serial cardiac enzyme measurements showed no evidence of myocardial infarction. Thus, he was treated as having unstable angina with bed rest, oxygen, aspirin, intravenous nitrate, and full dose intravenous heparin to keep the activated partial thromboplastin time ( A m ) ratio between 1.5 and 2.0. Despite intensive therapy, there were still intermittent attacks of rest pain. Coronary angiography was therefore performed at day 7 . Pre-catheterization hematological data included Hb 9.6 g/dL(MCV 117.5 fL,MCHC 28.7 g/dL), WBC 8.3 x 109/L, platelet 183 X 109/L, reticulocyte 13%, and a positive Ham test. Blood biochemistry revealed an elevated total bilirubin of 48 pmol/L with conjugated bilirubin of only 7 kmol/L and lactic dehydrogenase of 2,835 IU/L. Urea, creatinine, transaminases, and creatine kinase were within normal ranges. Coronary angiography was performed with the standard femoral approach under local anesthesia using 10 ml 2% lignocaine. Premedication included intravenous hydrocortisone 100 mg. Left ventriculogram using Cardio-conray as the radiocontrast showed normal wall motion, whereas selective coronary angiograms using Urografin 76% revealed a critical but discrete lesion in the proximal left anterior descending artery (LAD) which was amenable to PTCA. However, in the following day after the coronary angiography, the patient’s Hb was From the Divisions of Cardiology and Hematology, University Department of Medicine, Queen Mary Hospital, Hong Kong.
Received June 3. 1991; revision accepted August 18, 1991 Address reprint requests to Ping-Ching Fong, MD, University Department of Medicine. Queen Mary Hospital. Hong Kong.
PTCA in a Patient With PNH
found to have dropped to 6.8 g/dL and 2 pints of salinewashed red cells were required to bring the Hb level back to 10.8 g/dL. The PTCA was performed 2 days later. Prior to the day of angioplasty, 4 units of saline-washed red cells were reserved. The patient was fasted after midnight while maintaining on intravenous nitrate and heparin infusions. In the morning, the prednisolone and glibenclamide were omitted. Oral diazepam 5 mg and intravenous hydrocortisone 100 mg were given as premedication. The same site of entry and local anesthesia were used as in the coronary angiography, but only the Urografin 76% was selected as the radiocontrast. The PTCA was done according to the standard balloon-over-the-wire method. Heparin 10,000 units was given intravenously prior to balloon dilatations. During the procedure, 500 ml of normal saline was also given to maintain the hydration. The dilatation procedure itself was straightforward, using a 3.0 mm diameter ACX balloon catheter (Advanced Cardiovascular Systems, Santa Clara, CA) with a 0.014-in. high torque floppy guidewire (Advanced Cardiovascular Systems). A total of three dilatations to the proximal LAD at 51 120, 7/ 120, and 9/ 120 atmospheric pressures/ sec were attempted, achieving a satisfactory result of 20% residual diameter stenosis only. No untoward events occurred during the procedure apart from some mild chest pain during each balloon inflation. The post-PTCA course was uneventful. Intravenous nitrate infusion was given for another 24 hr while the heparin infusion was continued for a total of 7 days, again with the dosage adjusted to keep the APTT ratio between 1.5 and 2.0. After the femoral arterial and venous sheaths were removed on post-PTCA day 2, the patient was mobilized and encouraged to be ambulatory. There was no recurrence of angina or ischemic changes in the ECG during this period. Hematologically, the Hb level was stable at around 10 g/dL and there was no evidence of increased hemolysis or venous thrombosis. The patient was thus discharged after the course of heparin infusion was completed. DISCUSSION PNH is a rare acquired disease that results from a clonal hematopoietic stem cell disorder affecting all hematologic cell lines. It affects both sexes, usually between the ages of 20 and 40 years, and probably individuals of all ethnic groups [8]. The disease is characterized by an increased membrane susceptibility of the affected erythrocytes to the lvtic action of complements via the classical and the alternate pathways [9], an abnormal neutrophil and lymphocyte function, as well as an unusual sensitivity of platelet aggregation [lo]. The underlying molecular basis of the defect lies in the defi-
145
ciency of membrane glycoproteins such as decay-accelerating factor, homologous restriction factor, acetylcholinesterase, and lymphocyte function-associated antigen 3 in the surface of the abnormal cells, which may, in fact, reflect a defect in the biosynthesis of glycosyl-phosphatidylinositol-a glycolipid anchor in the cell membrane [ 1 11. These pathophysiologic abnormalities are found to be directly or indirectly responsible for the many clinical manifestations of the disease. They include chronic intravascular hemolysis with or without hemoglobinuria, increased susceptibility to infections, pancytopenia, aplastic anemia, and higher tendency in venous thrombosis. In fact, the latter is a common complication in PNH. It occurs frequently at unusual sites such as mesenteric and hepatic veins resulting in the Budd-Chiari syndrome, which has a high mortality rate [12]and accounts for the major cause of death in PNH patients [6]. Despite the fact that PNH is not commonly encountered, interventionalists should be aware of this disease for its potential notorious complications. Surgical procedures, improper blood transfusion, and drugs that activate complements are well-known hazards to PNH patients for their tendencies to precipitate hemolytic crisis and venous thrombosis. In addition, because of defective leukocyte functions and/or leukopenia, these patients are prone to bacterial infections which are also known to exacerbate the hemolysis. While successful perioperative management of surgical PNH patients has been described in the literature [5,6], there has, to our knowledge, not been any previous report on the management of PNH patients undergoing R C A and ours is probably the first one. It will serve as a useful reference for similar cases in the future. Based on the pathophysiologic considerations of the disease, certain principles for the perioperative management of surgical PNH patients which aim at mitigating complement activation and decreasing red cell susceptibility to complement-mediated lysis have previously been outlined [ 5 ] . They include 1) avoiding dehydration, hypoxemia, and acidosis, 2) using transfused red cells for prophylaxis and treatment of lytic crisis, 3) using corticosteriods to prevent and treat hemolysis, 4) avoiding infection, and 5) avoiding drugs known to activate complements such as acetazolamide, some radiocontrast media, magnesium compounds, and drugs formulated in Cremophor (e.g., vitamin K) [ 5 ] . Undoubtedly, these principles are also applicable to the management of PNH patients undergoing PTCA and will be discussed as follows. Prevention of dehydration before, during, and after PTCA is needed. In this case, hydration by continuous intravenous nitrate and heparin infusions during the fasting period, an addition of 500 ml normal saline intravenously during the PTCA, and early resumption of oral
146
Fong et al.
feeding afterward seem adequate. However, should acute hemolysis occur, a more vigorous hydration regime would be required to enhance urine output in order to protect the kidneys from the effects of hemoglobinuria
PI.
Blood transfusion is valuable in PNH patients because not only can it treat the hemolytic crisis, it can also be used as a prophylaxis to prevent its occurrence. Though not completely understood, the protective nature of preoperative transfusion appears to be related to the suppression of the production of PNH-sensitive cells by the bone marrow and to the dilution of abnormal cells in the blood by normal erythrocytes [13]. It is, however, CNcia1 to use saline-washed red cells for transfusion because of the possibility of complement activation by nonred cell antigens contained in the plasma of non-washed preparations which cause direct hemolysis without the presence of antibodies [14]. Thus liaison with the blood bank prior to PTCA is of utmost importance in reserving an adequate amount of washed red cells so that in case the patient needs emergency bypass grafting, suitable preparations of blood will be available without unnecessary delay. In our case, two units of saline-washed red cells had to be transfused after the diagnostic study to halt the hemolytic episode and to replenish the dropping hemoglobin. Also, four more units of washed blood were cross-matched in reserve for the PTCA. Hemolysis occurred after the coronary angiography and not after the PTCA in this patient. Whether it is due to the difference between Cardio-conray and Urografin, or to the protecting effect of pre-PTCA transfusion is unclear. Nevertheless, it is noteworthy that radiocontrast agents can activate complements via idiosyncratic anaphylactic reactions which are rarely dose dependent or agent specific [ 151. Most PNH patients are, as in our case, on long-term steriod therapy. Apart from avoiding acute adrenal insufficiency, premedication with steriod in these patients may have an additional benefit of preventing hemolysis induced by invasive procedures [5]. Hence, adequate steriod, such as 100 mg hydrocortisone intravenously in this instance, should always be used prior to interventional procedures. The issue on anesthetic management in coronary interventions is largely simplified by the fact that general anesthesia is not required. However, it would be useful to note that intravenous induction agents are liable to activate complements through anaphylactoid reactions, albeit subclinical or minor [16]. Reports on successful anesthetic management using thiopental, lorazepam, ketamine, midazolam, fentanyl, isoflurane, and enflurane in PNH patients have been described [5,6]. Benzodiazepines are one of the few least likely to induce complement activation and have been used safely as premedi-
cation [6]. Therefore, using diazepam in premedication, as in our case, is acceptable. Local anesthesia using lignocaine appears to be safe in our patient as well. In spite of the susceptibility to infection in PNH, the low risk of systemic infection in coronary interventions [ 171 renders the use of prophylactic broad-spectrum antibiotics, which have been advocated for surgical procedures in these patients [5,6], unnecessary. As pointed out previously, PNH is associated with a striking predisposition for venous thrombosis. This is because the PNH platelets also lack DAF which renders them more susceptible to complements leading to the release reaction [lo]. Most of the complements have been demonstrated to behave as acute-phase reactants which increase significantly 12 hr after surgery and peak on about postoperative day 4 [ 18,191. This may account for the heightened risk of postoperative venous thrombosis in PNH patients and outline the vulnerable period in which thrombosis may occur. Although it is unclear whether or not PTCA will cause an acute-phase response, prophylactic anticoagulation during the first post-PTCA week may be a reasonable measure to prevent the consequences if this is the case. While the use of heparin in PNH is controversial and has been associated with increased hemolysis in some patients, it should be realized that complement activation is inhibited by a higher dose of heparin [20]. In this patient, a full intravenous dose of heparin to keep the APTT ratio between 1.5 and 2.0 was given and continued for 1 week postPTCA without any evidence of acute hemolysis or venous thrombosis. Although high molecular weight dextran has also been shown to be useful in this situation, it is not recommended owing to its inherent risk of anaphylactic reactions and hemorrhagic complications [2l]. Warfarin would be the drug of choice only if long-term anticoagulation therapy were indicated [ 51. It is interesting to note that this 35-year-old man has coronary artery disease. While he certainly has risk factors such as chronic smoking, long-term steriod therapy, secondary diabetes, and male gender, it is unclear whether the platelet disorder in PNH may contribute to the early coronary involvement. Venous thrombosis has been well documented in PNH but arterial thrombosis has not [4].Even in the most recent reviews, there has been no mention that early coronary disease may be a problem with this patient population [22,23]. Therefore, the significance of the inherent platelet dysfunction in early coronary atherosclerosis does not seem very high. In summary, PNH patients undergoing interventional procedures are at high risk for a number of complications (hemolysis, venous thrombosis, and infection). However, it should be pointed out that while the perioperative management of surgical PNH patients is often complex and should serve as the reference for that of PNH patients
PTCA in a Patient With PNH
undergoing PTCA, the latter is likely to be much more straightforward. Still, a successful outcome relies much on the adequacy of the pre-PTCA patient preparation, careful selection of premedications and anesthetic agents, prompt treatment of hemolytic crisis, and prevention of venous thrombosis in the post-PTCA period. Thorough understanding of the pathophysiology of the disease, good liaison with the blood bank, consultation with the hematologists, and close monitoring of the patient’s clinical and hematological status cannot be overemphasized as well. Particularly with procedures where radiocontrasts are used, appropriate agents should be carefully selected. PNH is a chronic disorder and some patients have survived for 20 years or more after diagnosis [8]. Moreover, with the acidified serum or sucrose lysis test performed more commonly nowadays, previously undiagnosed patients with mild chronic disease are being identified. Coronary artery disease will be encountered more in this patient population, and it is important that coronary interventionists should know how to manage these patients properly.
REFERENCES I . Rosse WF, Parker CJ: Paroxysmal nocturnal hemoglobinuria. Clin Haematol 14:105-125, 1985. 2. Dessypris EN, Clark DA, Mckee L Jr, Krantz SB: Increased sensitivity to complement of erythroid and myeloid progenitors in paroxysmal nocturnal hemoglobinuria. N Engl J Med 309:690693, 1983. 3. Terasawa T, Shichishima T, Matsuda M, Uchida T, Kariyone S: Characterization of the erythropoietic progenitor cells (BFU-E) in paroxysmal nocturnal hemoglobinuria. Br J Haematol 75428432, 1990. 4. Valla D, Dhumeaux D, Babany G, Hillon P, Rueff B, Rochant H, Benhamon JP: Hepatic vein thrombosis in paroxysmal nocturnal hemoglobinuria. A spectrum from asymptomatic occlusion of hepatic venules to fatal Budd-Chiari syndrome. Gastroenterology 931569-575, 1987. 5 . Ogin GA: Cholecystectomy in a patient with paroxysmal nocturnal hemoglobinuria. Anesthetic implications and management in the perioperative period. Anesthesiology 72:761-764, 1990. 6. Taylor MB, Whitwam JG, Worsley A: Paroxysmal nocturnal hemoglobinuria. Perioperative management of a patient with BuddChiari syndrome. Anaesthesia 42:639-642, 1987. 7. Solal-Celigny P, Tertian G, Fernandez H, Pons J-C, Lambert T, Najean Y,Clauvel J-P, Papiernik E, Tehernia G: Pregnancy and
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paroxysmal nocturnal hemoglobinuria. Arch Intern Med 148: 593-595. 1988. 8. Dacie JV: Paroxysmal nocturnal haemoglobinuria. In Weatherall DJ, Ledingham JGG, Warrell DA (eds): “Oxford Textbook of Medicine,” 2nd Edition. Oxford: Oxford University Press, 1987, pp 19.54-19.58. 9. Gotze 0, Muller-Eberhard HJ: Hemolysis initiated by the C3 activator system. N Engl J Med 286180-184, 1972. 10. Dixon RH, Rosse WF: Mechanism of complement-mediated activation of human blood platelets in vitro: Comparison of paroxysmal nocturnal hemoglobinuria platelets. J Clin Invest 59:360368, 1977. 1 1 . Yamashina M, Ueda E, Kinoshita T, Takami T, Ojima A, Ono H, Tanaka H. Kondo N , Orii T, Okada N, Okada H, Inoue K, Kitani T: Inherited complete deficiency of 20-kilodalton homologous restriction factor (CD59) as a cause of paroxysmal nocturnal hemoglobinuria. N Engl J Med 323:1184-1189, 1990. 12. Maddey WC: Hepatic vein thrombosis (Budd-Chiari syndrome). Hepatology 4: 1445 - 1 4 6 , 1984. 13. Gockerman JP, Brouillard R P RBC transfusions in paroxysmal nocturnal hemoglobinuria. Arch Intern Med 137536-538, 1977. 14. Yachnin S: The hemolysis of red cells from patients with paroxysmal nocturnal hemoglobinuria. J Clin Invest 44:1534-1546, 1965. 15. Grainger RG: lntravascular contrast media. In Grainger RG,Allison DJ (eds): “Diagnostic Radiology: An Anglo-American Textbook of Imaging,” I st Edition. Edinburgh: Churchill Livingstone, 1986, pp 99-1 10. 16. Watkins J: Immunological problems in anaesthesia. Br J Hosp Med 23583-590, 1980. 17. Grossman W: Complications of cardiac catheterization: Incidence, causes and prevention. In Grossman W (ed): “Cardiac Catheterization and Angiography,” 3rd Edition. Philadelpha: Lea & Febiger, 1986, pp 30-42. 18. Lewis RE, Cruse JM, Richey JV: Effects of anesthesia and operation on the classical pathway of complement activation. Clin lmmunol Immunopathol 23:666-67 I , 1982. 19. Schutte M, Dicamelli R, Murphy P, Sadove M, Gerwurz H: Effects of anaesthesia, surgery and inflammation upon host defense mechanisms. 1. Effects upon the complement system. Int Arch Allergy Appl lmmunol48:706-720, 1975. 20. Logue GL: Effect of heparin on complement activation and lysis of paroxysmal nocturnal hemoglobinuria red cells. Blood 50: 239-247, 1977. 21. Gardner FH, Laforet MT: The use of clinical dextran in patients with paroxysmal nocturnal hemoglobinuria. J Lab Clin Med 55: 946-958, 1960. 22. Rosse W F Paroxysmal nocturnal hemoglobinuria: The biochemical defects and the clinical syndrome. Blood Rev 3:192-200, 1989. 23. Rosse WF: Phosphatidylinositol-linked proteins and paroxysmal nocturnal hemoglobinuria. Blood 75: 1595-1601, 1990.
