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Heparin-induced thrombocytopenia: A possible complication of heparin-coated pulmonary artery catheters
Heparin-Induced Thrombocytopenia: A Possible Complication Heparin-Coated Pulmonary Artery Catheters
of
Paul Q. Moberg, MD, Vincent M. Geary, MB, FFARCSI, and Farhan M. Sheikh, MB
H
EPARIN-INDUCED platelet aggregation (HIPA) is a known but rare complication of heparin therapy. This immune-mediated phenomenon has been associated with thrombocytopenia, arterial and venous thromboses, and systemic embolization.‘V2 A patient with this syndrome is described in whom successful heparin anticoagulation during extracorporeal circulation was accomplished in conjunction with the platelet inhibitor Iloprost (Berlex Laboratories, Inc, Cedar Knolls, NJ). The postoperative course was complicated by two marked episodes of thrombocytopenia. The etiology of the first episode occurring 24 hours postoperatively was considered multifactorial. However, a second episode of thrombocytopenia occurred on the third postoperative day that may have been associated with reinsertion of a heparin-coated pulmonary artery catheter. CASE REPORT A 64-year-old white man came to the emergency department with an anterior wall myocardial infarction complicated by cardiac arrest, from which he was successfully resuscitated. Subsequently, he was noted to be in third-degree heart block, necessitating placement of a right subclavian transvenous pacing wire. The pacing wire became frayed, requiring replacement via the right internal jugular vein the following day. On the fourth hospital day, the patient developed a staphylococcal bacteremia and was treated with intravenous oxacillin. On the seventh hospital day, he was noted to have right upper extremity swelling. Venography revealed thrombosis of the right axillary vein; intravenous heparin therapy was initiated. Because of persistent pyrexia, the patient’s antibiotic therapy was changed to vancomycin. Other than low-grade fever, his course was stable over the next 5 days. On the 12th hospital day, the patient began having amnesic spells; neurologic workup did not reveal a cause. A platelet count of 58,000/mm3 was noted. Hematologic studies were positive for antiplatelet antibodies, and a working diagnosis of HIPA was made. Intravenous heparin
From the Department of Anesthesiology, Albany Medical Center, Albany, NY. Address reprint requests to Vincent Geary, MB, FFARCSI, Pediatric/Surgical ICU, Cleveland Clinic Foundation, 9500 Euclid Avenue, Cleveland, OH 44106. Q 1990 by W.B. Saunders Company. 0888~6296/90/0402-0011$3.00/0
226
therapy was discontinued and replaced with coumadin orally and subcutaneous low-molecular-weight heparin. The lowmolecular-weight heparin was discontinued after 48 hours, once adequate anticoagulation was achieved with coumadin. Over the next several days, the platelet counts recovered (Fig 1). Subsequently, the patient developed unstable angina refractory to medical therapy. Cardiac catheterization on the 19th hospital day revealed severe triple-vessel coronary artery disease with impaired left ventricular function. Surgical management was recommended, but was delayed until Iloprost became available. On the 32nd hospital day, the patient underwent coronary artery revascularization using high-dose narcotic anesthesia. Hemcdynamic monitoring included radial arterial and heparin-coated pulmonary arterial catheters. An Iloprost infusion was initiated in accordance with the Berlex Laboratory protocol 10 minutes after the induction of general anesthesia. Approval of the Institutional Review Board of the Albany Medical Center Hospital and verbal and written informed consent of the patient were obtained before the operation. The infusion was begun at 3 ng/kg/min and increased at 15-minute intervals to 6 ng/kg/ min. and then to 12 ng/kg/min, at which time his platelets no longer aggregated in the presence of heparin. Anticoagulation with heparin, 350 U/kg, achieved an activated clotting time of 880 seconds; the patient was then placed on cardiopulmonary bypass (CPB). During the Iloprost infusion it was necessary to use a norepinephrine infusion to maintain adequate blood pressure and systemic vascular resistance. Following separation from CPB, heparin was reversed with protamine sulfate, and the Iloprost infusion was discontinued 15 minutes later. The patient was subsequently transferred to the recovery unit hemodynamically stable. The postoperative platelet count immediately after surgery was 180,000/mm’, which decreased to 84,000/mm3 at 8 hours and to 39,OOO/mm’at 24 hours postoperatively (Fig 1). Eight units of platelets were administered, and the platelet count returned to 71,000/mm3. The patient remained hemodynamically stable, and invasive monitoring catheters were removed on the first postoperative day. The patient was transferred from the recovery unit on the second postoperative day. The patient had a cardiac arrest on the third postoperative day and was successfully resuscitated. It was necessary to reinsert a pulmonary artery catheter (heparin-bonded) to optimize hemodynamic management. A platelet count taken at this time was noted to be 131,000/mm3, which decreased to 79,00O/mm’ the next day. The pulmonary artery catheter was removed at this time, and the platelet count increased to 163,00O/mm’ 2 days later. Shortly thereafter, the patient developed a fatal dysrhythmia. Postmortem findings included recent bilateral thromboses of the jugular and subclavian veins and scattered pulmonary emboli.
Jmrnal of Cardiofhoracic Anesthesia,
Vol4,
No 2
(April),1990: pp 226-226
HEPARIN-INDUCED
THROMBOCMOPENIA
227
400
Fig 1. Patient platelet count at the following times: (A) before heparin anticoagulation; (B) diagnosis of HIPA, heparin discontinued preoparatively: (C) coronary artery bypass surgery; iDI pulmonary artery catheter removed; (El reinsertion of heparin-coated pulmonary artery catheter: IFI pulmonary artery catheter removed.
tG
f
2 tt: E
250
3
200
Q 150 100 50 0
DISCUSSION
HIPA is a rare but pernicious process associated with heparin therapy. It is associated with progressive thrombocytopenia and the development of intravascular thrombosis and embolization, leading to significant morbidity and mortality.3 The mechanism leading to thrombocytopenia is an autoimmune phenomenon in which antibodies to platelets are formed, causing activation and clumping with subsequent thrombotic and embolic sequelae.iY3 The resultant thrombocytopenia arises from platelet consumption. The exact amount of heparin required to initiate primary autoimmune reactions or a subsequent recrudesence is unknown, but has been shown to be as little as 3 U/h.4 Management of patients with HIPA who require anticoagulation for surgical procedures presents a significant clinical problem. The experimental platelet inhibitor Iloprost and its use in patients with HIPA requiring heparin anticoagulation during CPB has been describede4 Iloprost inhibits platelet aggregation by stimulating adenylate cyclase, resulting in subsequent increases in intracellular cyclic adenosine monophosphate. The onset of action with Iloprost is immediate, and it has a 15- to 30-minute half-life of elimination; platelet reactivity returns within 3 hours after cessation of therapy. Hypotension secondary to decreased systemic vascular resistance associated with Iloprost infusion has been success-
IO
15
al
25
30
35
DAYS
fully managed with the use of phenylephrine or norepinephrine.2 In the case presented, anticoagulation with heparin was successfully achieved; there were no decreases in platelet count during the intraoperative and immediate postoperative periods when Iloprost was used as a platelet inhibitor. Marked decreases in platelet number occurred on two separate occasions. On the first, the platelet count decreased to 39,000/mm3 24 hours postoperatively. Speculation as to the etiology of the thrombocytopenia included three possible explanations: First, the patient had a documented right subclavian vein thrombosis, which could act as a source of platelet activation and consumption. Second, although careful attention was paid to obviate exogenous sources of heparin, retrospective analysis showed a possible source of heparin in the form of a heparin-coated pulmonary artery catheter. After in-situ placement, heparin from heparin-coated catheters is exchanged with plasma proteins. Sixty-five percent of the heparin has been shown to be released in the first 3 hours after exposure to plasma, whereas 14% to 24% of heparin activity is retained for several weeks.4 Third, so-called “heparin rebound” may explain the observed thrombocytopenia. Heparin rebound, as described by Kolff et al in 1956,6 is “a phenomenon in which heparin is neutralized by protamine sulfate and the clotting time becomes normal in a matter of
MOBERG. GEARY, AND SHEIKH
228
minutes. However, protamine seems to be eliminated from the blood before heparin is, thus leaving the heparin uncovered as demonstrated by protamine titration.“697 Heparin administered intravenously during the surgical procedure may accumulate in extravascular storage sites, ie, lymphatics, and be redistributed slowly into the circulation over time.7 It is entirely possible that low levels of heparin may have been present from one or a combination of the causes mentioned. These levels may not produce clinically significant bleeding but may be sufficient to trigger HIPA in a susceptible patient. If this spectulation is true, it is interesting to consider whether or not an Iloprost infusion should be continued into the postoperative period. The patient’s clinical condition deteriorated significantly on the third postoperative day to such an extent that a heparin-coated pulmonary artery catheter was inserted to optimize the
patient’s hemodynamic management. A decrease in his platelet count from 131,000/mm3 to 74,000/mm3 was noted. Meticulous analysis of the records did not reveal any exogenous source of heparin other than the heparin-coated pulmonary artery catheter. An alternative explanation for the decreased platelet count may have been the presence of intravascular thrombi. However, when the pulmonary artery catheter was removed, the platelet count returned to 163,000/ mm3, the pre-pulmonary catheter placement level. In summary, a patient with HIPA had been documented to have thrombocytopenia on two occasions following myocardial revascularization, which may have been associated with placement of a heparin-coated pulmonary artery catheter. In a susceptible patient population, the possible benefits of pulmonary artery catheterization, especially with a heparin-coated catheter, should be carefully considered.
REFERENCES 1. Addonizio VP, Kappa JR, Horn MK, et al: Efficacy of Iloprost (2336374) versus aspirin in preventing heparin-induced platelet activation during cardiac operations. J Thorac Cardiovasc Surg 94:405-413,1987 2. Addonizio VP, Kappa JR, Fisher CA, et al: Heparin-induced platelet activation in sixteen surgical patients: Diagnosis and management. J Vast Surg 3:101-l lo,1987 3. Starr NJ, Kraenzler EJ: Heparin-associated thrombocytopenia: Management of patients for open heart surgery. Case reports describing the use of Iloprost. Anes 69:964-967, 1988 4. Silver D, Laster J: Heparin-coated catheters and
heparin-induced thrombocytopenia. J Vast Surg 7:667-672, 1988 5. Kutti J, Wadenvik H: Effect of Iloprost (ZK36374), a novel prostacyclin analogue, on ADP-induced aggregation. Acta Haemat 73:224-227, 1985 6. Kolff WJ, Effler DB, Groves LK, et al: Disposable membrane oxygenator (heart-lung machine) and its use in experimental surgery. Cleve Clin Q 23:69-75, 1956 7. Ellison N, Jobes DR, Schwartz AJ: Heparin therapy during cardiac surgery, in Ellison N, Jobes DR (eds): Effective Hemostasis in Cardiac Surgery. Philadelphia, PA, Saunders, 1988, pp 1-14
of
Paul Q. Moberg, MD, Vincent M. Geary, MB, FFARCSI, and Farhan M. Sheikh, MB
H
EPARIN-INDUCED platelet aggregation (HIPA) is a known but rare complication of heparin therapy. This immune-mediated phenomenon has been associated with thrombocytopenia, arterial and venous thromboses, and systemic embolization.‘V2 A patient with this syndrome is described in whom successful heparin anticoagulation during extracorporeal circulation was accomplished in conjunction with the platelet inhibitor Iloprost (Berlex Laboratories, Inc, Cedar Knolls, NJ). The postoperative course was complicated by two marked episodes of thrombocytopenia. The etiology of the first episode occurring 24 hours postoperatively was considered multifactorial. However, a second episode of thrombocytopenia occurred on the third postoperative day that may have been associated with reinsertion of a heparin-coated pulmonary artery catheter. CASE REPORT A 64-year-old white man came to the emergency department with an anterior wall myocardial infarction complicated by cardiac arrest, from which he was successfully resuscitated. Subsequently, he was noted to be in third-degree heart block, necessitating placement of a right subclavian transvenous pacing wire. The pacing wire became frayed, requiring replacement via the right internal jugular vein the following day. On the fourth hospital day, the patient developed a staphylococcal bacteremia and was treated with intravenous oxacillin. On the seventh hospital day, he was noted to have right upper extremity swelling. Venography revealed thrombosis of the right axillary vein; intravenous heparin therapy was initiated. Because of persistent pyrexia, the patient’s antibiotic therapy was changed to vancomycin. Other than low-grade fever, his course was stable over the next 5 days. On the 12th hospital day, the patient began having amnesic spells; neurologic workup did not reveal a cause. A platelet count of 58,000/mm3 was noted. Hematologic studies were positive for antiplatelet antibodies, and a working diagnosis of HIPA was made. Intravenous heparin
From the Department of Anesthesiology, Albany Medical Center, Albany, NY. Address reprint requests to Vincent Geary, MB, FFARCSI, Pediatric/Surgical ICU, Cleveland Clinic Foundation, 9500 Euclid Avenue, Cleveland, OH 44106. Q 1990 by W.B. Saunders Company. 0888~6296/90/0402-0011$3.00/0
226
therapy was discontinued and replaced with coumadin orally and subcutaneous low-molecular-weight heparin. The lowmolecular-weight heparin was discontinued after 48 hours, once adequate anticoagulation was achieved with coumadin. Over the next several days, the platelet counts recovered (Fig 1). Subsequently, the patient developed unstable angina refractory to medical therapy. Cardiac catheterization on the 19th hospital day revealed severe triple-vessel coronary artery disease with impaired left ventricular function. Surgical management was recommended, but was delayed until Iloprost became available. On the 32nd hospital day, the patient underwent coronary artery revascularization using high-dose narcotic anesthesia. Hemcdynamic monitoring included radial arterial and heparin-coated pulmonary arterial catheters. An Iloprost infusion was initiated in accordance with the Berlex Laboratory protocol 10 minutes after the induction of general anesthesia. Approval of the Institutional Review Board of the Albany Medical Center Hospital and verbal and written informed consent of the patient were obtained before the operation. The infusion was begun at 3 ng/kg/min and increased at 15-minute intervals to 6 ng/kg/ min. and then to 12 ng/kg/min, at which time his platelets no longer aggregated in the presence of heparin. Anticoagulation with heparin, 350 U/kg, achieved an activated clotting time of 880 seconds; the patient was then placed on cardiopulmonary bypass (CPB). During the Iloprost infusion it was necessary to use a norepinephrine infusion to maintain adequate blood pressure and systemic vascular resistance. Following separation from CPB, heparin was reversed with protamine sulfate, and the Iloprost infusion was discontinued 15 minutes later. The patient was subsequently transferred to the recovery unit hemodynamically stable. The postoperative platelet count immediately after surgery was 180,000/mm’, which decreased to 84,000/mm3 at 8 hours and to 39,OOO/mm’at 24 hours postoperatively (Fig 1). Eight units of platelets were administered, and the platelet count returned to 71,000/mm3. The patient remained hemodynamically stable, and invasive monitoring catheters were removed on the first postoperative day. The patient was transferred from the recovery unit on the second postoperative day. The patient had a cardiac arrest on the third postoperative day and was successfully resuscitated. It was necessary to reinsert a pulmonary artery catheter (heparin-bonded) to optimize hemodynamic management. A platelet count taken at this time was noted to be 131,000/mm3, which decreased to 79,00O/mm’ the next day. The pulmonary artery catheter was removed at this time, and the platelet count increased to 163,00O/mm’ 2 days later. Shortly thereafter, the patient developed a fatal dysrhythmia. Postmortem findings included recent bilateral thromboses of the jugular and subclavian veins and scattered pulmonary emboli.
Jmrnal of Cardiofhoracic Anesthesia,
Vol4,
No 2
(April),1990: pp 226-226
HEPARIN-INDUCED
THROMBOCMOPENIA
227
400
Fig 1. Patient platelet count at the following times: (A) before heparin anticoagulation; (B) diagnosis of HIPA, heparin discontinued preoparatively: (C) coronary artery bypass surgery; iDI pulmonary artery catheter removed; (El reinsertion of heparin-coated pulmonary artery catheter: IFI pulmonary artery catheter removed.
tG
f
2 tt: E
250
3
200
Q 150 100 50 0
DISCUSSION
HIPA is a rare but pernicious process associated with heparin therapy. It is associated with progressive thrombocytopenia and the development of intravascular thrombosis and embolization, leading to significant morbidity and mortality.3 The mechanism leading to thrombocytopenia is an autoimmune phenomenon in which antibodies to platelets are formed, causing activation and clumping with subsequent thrombotic and embolic sequelae.iY3 The resultant thrombocytopenia arises from platelet consumption. The exact amount of heparin required to initiate primary autoimmune reactions or a subsequent recrudesence is unknown, but has been shown to be as little as 3 U/h.4 Management of patients with HIPA who require anticoagulation for surgical procedures presents a significant clinical problem. The experimental platelet inhibitor Iloprost and its use in patients with HIPA requiring heparin anticoagulation during CPB has been describede4 Iloprost inhibits platelet aggregation by stimulating adenylate cyclase, resulting in subsequent increases in intracellular cyclic adenosine monophosphate. The onset of action with Iloprost is immediate, and it has a 15- to 30-minute half-life of elimination; platelet reactivity returns within 3 hours after cessation of therapy. Hypotension secondary to decreased systemic vascular resistance associated with Iloprost infusion has been success-
IO
15
al
25
30
35
DAYS
fully managed with the use of phenylephrine or norepinephrine.2 In the case presented, anticoagulation with heparin was successfully achieved; there were no decreases in platelet count during the intraoperative and immediate postoperative periods when Iloprost was used as a platelet inhibitor. Marked decreases in platelet number occurred on two separate occasions. On the first, the platelet count decreased to 39,000/mm3 24 hours postoperatively. Speculation as to the etiology of the thrombocytopenia included three possible explanations: First, the patient had a documented right subclavian vein thrombosis, which could act as a source of platelet activation and consumption. Second, although careful attention was paid to obviate exogenous sources of heparin, retrospective analysis showed a possible source of heparin in the form of a heparin-coated pulmonary artery catheter. After in-situ placement, heparin from heparin-coated catheters is exchanged with plasma proteins. Sixty-five percent of the heparin has been shown to be released in the first 3 hours after exposure to plasma, whereas 14% to 24% of heparin activity is retained for several weeks.4 Third, so-called “heparin rebound” may explain the observed thrombocytopenia. Heparin rebound, as described by Kolff et al in 1956,6 is “a phenomenon in which heparin is neutralized by protamine sulfate and the clotting time becomes normal in a matter of
MOBERG. GEARY, AND SHEIKH
228
minutes. However, protamine seems to be eliminated from the blood before heparin is, thus leaving the heparin uncovered as demonstrated by protamine titration.“697 Heparin administered intravenously during the surgical procedure may accumulate in extravascular storage sites, ie, lymphatics, and be redistributed slowly into the circulation over time.7 It is entirely possible that low levels of heparin may have been present from one or a combination of the causes mentioned. These levels may not produce clinically significant bleeding but may be sufficient to trigger HIPA in a susceptible patient. If this spectulation is true, it is interesting to consider whether or not an Iloprost infusion should be continued into the postoperative period. The patient’s clinical condition deteriorated significantly on the third postoperative day to such an extent that a heparin-coated pulmonary artery catheter was inserted to optimize the
patient’s hemodynamic management. A decrease in his platelet count from 131,000/mm3 to 74,000/mm3 was noted. Meticulous analysis of the records did not reveal any exogenous source of heparin other than the heparin-coated pulmonary artery catheter. An alternative explanation for the decreased platelet count may have been the presence of intravascular thrombi. However, when the pulmonary artery catheter was removed, the platelet count returned to 163,000/ mm3, the pre-pulmonary catheter placement level. In summary, a patient with HIPA had been documented to have thrombocytopenia on two occasions following myocardial revascularization, which may have been associated with placement of a heparin-coated pulmonary artery catheter. In a susceptible patient population, the possible benefits of pulmonary artery catheterization, especially with a heparin-coated catheter, should be carefully considered.
REFERENCES 1. Addonizio VP, Kappa JR, Horn MK, et al: Efficacy of Iloprost (2336374) versus aspirin in preventing heparin-induced platelet activation during cardiac operations. J Thorac Cardiovasc Surg 94:405-413,1987 2. Addonizio VP, Kappa JR, Fisher CA, et al: Heparin-induced platelet activation in sixteen surgical patients: Diagnosis and management. J Vast Surg 3:101-l lo,1987 3. Starr NJ, Kraenzler EJ: Heparin-associated thrombocytopenia: Management of patients for open heart surgery. Case reports describing the use of Iloprost. Anes 69:964-967, 1988 4. Silver D, Laster J: Heparin-coated catheters and
heparin-induced thrombocytopenia. J Vast Surg 7:667-672, 1988 5. Kutti J, Wadenvik H: Effect of Iloprost (ZK36374), a novel prostacyclin analogue, on ADP-induced aggregation. Acta Haemat 73:224-227, 1985 6. Kolff WJ, Effler DB, Groves LK, et al: Disposable membrane oxygenator (heart-lung machine) and its use in experimental surgery. Cleve Clin Q 23:69-75, 1956 7. Ellison N, Jobes DR, Schwartz AJ: Heparin therapy during cardiac surgery, in Ellison N, Jobes DR (eds): Effective Hemostasis in Cardiac Surgery. Philadelphia, PA, Saunders, 1988, pp 1-14