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Systemic Thrombolytic Therapy After Recent Abdominal Aortic Aneurysm Repair: An Absolute Contraindication?

      Systemic thrombolysis in the early postoperative period can cause fatal hemorrhage. Systemic thrombolysis is often considered contraindicated after major vascular procedures; thus, experience with this scenario is limited. A 67-year-old man experienced massive pulmonary embolization after his abdominal aortic aneurysm was repaired with a bifurcated, woven Dacron graft. Because systemic thrombolysis was the only option for our patient's survival, he underwent this procedure with recombinant tissue-type plasminogen activator just 2 weeks after the Dacron graft repair of his abdominal aortic aneurysm. After clinical stabilization, abdominal and pelvic computed tomography showed no periprosthetic graft hemorrhage. The successful systemic thrombolysis suggests that this therapy may prove useful in extreme situations.
      APTT (activated partial thromboplastin time), CT (computed tomography), r-tPA (recombinant tissue-type plasminogen activator)
      Thrombolytic agents are used in an increasing number of clinical scenarios. They are used clinically to treat acute ischemic stroke, myocardial infarction, acute arterial occlusion, and venous thromboembolism. However, a wide variation in the use of thrombolytic agents was documented in a recent survey of perceived contraindications in several medical conditions.
      • Wald DS
      Perceived contraindications to thrombolytic treatment in acute myocardial infarction: a survey at a teaching hospital.
      Such perceived contraindications are often based on qualitative concerns, not quantitative analysis, of the clinician, and should be defined as relative contraindications. The risk of hemorrhage resulting from thrombolysis after surgery has limited the use of systemic thrombolytic therapy after major vascular procedures.
      Hemorrhage or contrast extravasation can occur after local or systemic thrombolysis with knitted
      • Pope M
      • Kalman PG
      Aortic transgraft hemorrhage after systemic thrombolytic therapy.
      • Ward AS
      • Cripps N
      Remote transgraft hemorrhage complicating thrombolysis with tissue plasminogen activator [letter].
      • Perler BA
      • Kinnison M
      • Halden WJ
      Transgraft hemorrhage: a serious complication of low-dose thrombolytic therapy.
      • Rabe FE
      • Becker GJ
      • Richmond BD
      • et al.
      Contrast extravasation through Dacron grafts: a sequela of low-dose streptokinase therapy.
      • Sequeira MJ
      • Shiralkar S
      • Edwards AT
      • Lewis MH
      Systemic thrombolysis causing anastomotic dehiscence of an aortobifemoral graft.
      • Irvine C
      • Whyman M
      Systemic thrombolysis causing anastomotic dehiscence of an aortobifemoral graft [letter].
      and woven
      • London NJ
      • Williams B
      • Stein A
      Systemic thrombolysis causing haemorrhage around a prosthetic abdominal aortic graft.
      Dacron grafts and polytetrafluorethylene
      • Becker GJ
      • Holden RW
      • Rabe FE
      Contrast extravasation from a Gore-Tex graft: a complication of thrombolytic therapy.
      grafts. We describe a patient who underwent successful thrombolytic therapy after sustaining massive pulmonary embolization after the repair of an abdominal aortic aneurysm and concomitant aortocaval fistula. Previous conventional therapy with anticoagulation and the placement of a Greenfield filter failed to influence the clinical course of the patient.

      REPORT OF A CASE

      A 67-year-old man presented with sudden onset of sharp chest and abdominal pain. The pain woke the patient from sleep and was associated with severe shortness of breath. Examination of the patient revealed tachycardia, hypotension, a pulsatile abdominal mass, and a machinery thrill over the abdomen. Abdominal and pelvic computed tomography (CT) revealed a 7-cm-diameter infrarenal aortic aneurysm and an 8-cm-diameter right common iliac aneurysm. The left common femoral vein was also enlarged. A small amount of fluid in the culdesac was also noted.
      The patient underwent emergent replacement of the aneurysms with a bifurcated, woven, double-velour Dacron graft with distal anastomoses to the left common iliac artery and to the right common femoral artery, excluding the right common iliac aneurysm. An aortocaval fistula was noted on exploration and was repaired with a filamentous velour Dacron patch. The abdomen was too tense to be closed initially and the incision was approximated with a 2-mm polytetrafluorethylene patch.
      The patient had an initially stable postoperative convalescence. Delayed closure of the abdomen was performed on postoperative day 6. The patient, however, developed left lower extremity edema on postoperative day 9. A Doppler ultrasound confirmed deep venous thrombosis, and systemic heparinization was initiated. On postoperative day 12, the patient developed an acute hemodynamic compromise associated with persistent hypoxia. Pulmonary angiography showed multiple large peripheral emboli bilaterally. The main pulmonary arterial pressure level was 62/41 mm Hg (mean, 50 mm Hg). A thrombus was noted in the inferior vena cava, which extended to 5 cm below the renal veins. A Greenfield filter was placed into the inferior vena cava.
      Management with systemic heparin anticoagulation was maintained (activated partial thromboplastin time [APTT] range, 50.8-93.5 seconds; prothrombin time, 13.6 seconds). Despite paralysis and full ventilatory support (assistcontrol mode; rate, 18 breaths per minute; tidal volume, 800 mL; positive end-expiratory pressure, 7.5 cm water; fraction of inspired oxygen, 100%), the patient could not be adequately ventilated or oxygenated (arterial pH, 7.43; Pco2, 47 mm Hg; Po2, 54 mm Hg; oxygen saturation, 86%). Pulmonary thromboembolectomy was not believed to be an option because of the technical challenge presented by multiple peripheral emboli. No interim improvement was noted during the subsequent 2 days. Proceeding with systemic thrombolysis was the only available option for the patient's survival. Consequently, recombinant tissue-type plasminogen activator (r-tPA) was infused through a central venous catheter, 100 mg over 2 hours, a large dosage compared with the literature.
      • Anderson DR
      • Levine MN
      Thrombolytic therapy for the treatment of acute pulmonary embolism.
      Fibrinogen levels measured after infusion ranged from 404 to 773 mg/dL (reference range, 175-350 mg/dL) after r-tPA administration. The APTT did not vary substantially after r-tPA infusion (APTT range, 66.4-98.1 seconds), nor did the prothrombin time (12.3-13.5 seconds). Rapid improvements in both ventilation and oxygenation were observed. The patient's recovery continued, and extubation was performed 5 days after lytic therapy.
      After the initiation of lytic therapy, the patient required transfusions of 4 U of red blood cells during the ensuing 24 hours. An abdominal wall hematoma arose, likely representing the entire volume of transfused blood, and was evacuated at the bedside. There was no other evidence of bleeding. An abdominal CT obtained the week after lytic therapy showed no evidence of hemorrhage in the retro- peritoneum (Figure 1).
      Figure thumbnail gr1
      Figure 1Computed tomogram of the abdomen and pelvis after oral and intravenous contrast, obtained 10 days after systemic lytic therapy. Left, The suprarenal aorta is clearly delineated. An abdominal wall hematoma was subsequently evacuated at the bedside; the midline abdominal wall defect is noted. Right, Postoperative fluid surrounds the bifurcation of the graft. No other fluid collections were identified within the abdominal cavity.
      The patient also sustained multiple cerebrovascular emboli due to a previously unknown patent foramen ovale. Seizures were noted on postoperative day 12 at the time of pulmonary embolization and responded to benzodiazepine therapy. High-resolution head CT subsequently showed infarcts in the right posterior cerebral artery distribution. No intracranial hemorrhage was identified. The left hemiparalysis resolved in time, but a left hemianopsia persisted. Three weeks after the appearance of the massive pulmonary embolism, the patient was transferred to the inpatient rehabilitation unit and was dismissed home after a 110-day hospitalization.
      The patient is fully independent 7 years after the event. Two years after his initial presentation, he underwent a Stoppa repair of a ventral hernia; 3 years after his initial presentation, he underwent a right inguinal herniorrhaphy. Surveillance CT performed annually showed no delayed complications of his aortic reconstruction; in particular, no anastomotic aneurysm was documented. He is maintained on long-term oral anticoagulant medication.

      DISCUSSION

      Massive pulmonary embolism is a recognized, albeit infrequent, complication of surgical intervention. High-risk groups include patients who have sustained major trauma and those undergoing orthopedic, neurosurgical, and intraabdominal general surgical procedures. Information is lacking on the incidence after emergent noncardiac vascular surgery. However, the incidence of deep venous thrombosis after elective aortic reconstruction varies from 4.3% to 20.5%,
      • Angelides NS
      • Nicolaides AN
      • Fernandes J
      • Gordon-Smith I
      • Bowers R
      • Lewis JD
      Deep venous thrombosis in patients having aortoiliac reconstruction.
      • Satiani B
      • Kuhns M
      • Evans WE
      Deep venous thrombosis following operations upon the abdominal aorta.
      • Reilly MK
      • McCabe CJ
      • Abbott WM
      • et al.
      Deep venous thrombophlebitis following aortoiliac reconstructive surgery.
      • Olin JW
      • Graor RA
      • O'Hara P
      • Young JR
      The incidence of deep venous thrombosis in patients undergoing abdominal aortic aneurysm resection.
      and approximately 1% will develop a nonfatal pulmonary embolism.
      • Reilly MK
      • McCabe CJ
      • Abbott WM
      • et al.
      Deep venous thrombophlebitis following aortoiliac reconstructive surgery.
      • Killewich LA
      • Aswad MA
      • Sandager GP
      • Lilly MP
      • Flinn WR
      A randomized, prospective trial of deep venous thrombosis prophylaxis in aortic surgery.
      These reported frequencies of embolism likely underestimate the true frequency. Autopsy analysis in one study confirmed pulmonary embolization in 74.9% of patients with documented venous thromboembolism.
      • Lindblad B
      • Sternby NH
      • Bergqvist D
      Incidence of venous thromboembolism verified by necropsy over 30 years.
      In 70% of patients with pulmonary embolization, the pulmonary embolus was believed to be fatal or contributory to death. Our patient had not only an emergent repair of a ruptured abdominal aortic aneurysm, but also an aortocaval fistula closed with a Dacron patch. Both of these predisposing factors are likely contributory and may have potentiated each other in lessening the prophylactic benefits of the sequential compression devices that were used in this patient.
      Systemic thrombolysis has been extensively investigated in the treatment of massive pulmonary embolism. Recombinant tissue-type plasminogen activator is an exogenous stimulator of the fibrinolytic system, catalyzing the conversion of the inactive plasminogen into active plasmin. Plasmin is a nonspecific proteolytic enzyme that catalyzes the degradation of fibrin, fibrinogen, prothrombin, factor V, and factor VIII. Because the circulation contains a large concentration of plasmin inhibitor to neutralize the plasmin's effect, the action of plasmin is relatively specific to fibrin clots. Despite the relative specificity for active fibrin clots, bleeding complications are the most common adverse reactions to systemic thrombolysis. Approximately one third of patients receiving thrombolytic therapy for pulmonary embolism experience clinical bleeding; one quarter have hematocrit decreases of more than 5%.
      Interestingly, fibrinogen levels were not lowered below the normal range in our patient after thrombolytic therapy. A recent serologic evaluation of patients presenting with a ruptured abdominal aortic aneurysm showed a prothrombotic and hypofibrinolytic status,
      • Haggart PC
      • Adam DJ
      • Ludman PF
      • Ludman CA
      • Bradbury AW
      Myocardial injury and systemic fibrinolysis in patients undergoing repair of ruptured abdominal aortic aneurysm: a preliminary report.
      perhaps caused by increased plasmin inhibitor levels. This altered state presumably limited fibrinolysis to the emboli and thus protected against massive hemorrhage in the early postoperative period. Nonetheless, administration of r-tPA in our patient was associated with dramatic hemodynamic and ventilatory changes.
      An interesting issue is whether thrombolytic therapy delivered locally to the pulmonary arteries would be safer after major vascular procedures. Indeed, catheter administration of r-tPA has been described previously in case series.
      • Murphy JM
      • Mulvihill N
      • Mulcahy D
      • Foley B
      • Smiddy P
      • Molloy MP
      Percutaneous catheter and guidewire fragmentation with local administration of recombinant tissue plasminogen activator as a treatment for massive pulmonary embolism.
      • Stock KW
      • Jacob AL
      • Schnabel KJ
      • Bongartz G
      • Steinbrich W
      Massive pulmonary embolism: treatment with thrombus fragmentation and local fibrinolysis with recombinant human-tissue plasminogen activator.
      However, locally administered r-tPA may have more complications than systemically administered r-tPA and offer no increased effectiveness.
      • Forster A
      • Wells P
      Tissue plasminogen activator for the treatment of deep venous thrombosis of the lower extremity: a systematic review.
      • Verstraete M
      • Miller GA
      • Bounameaux H
      • et al.
      Intravenous and intrapulmonary recombinant tissue-type plasminogen activator in the treatment of acute massive pulmonary embolism.
      Periprosthetic graft hemorrhage was described previously with thrombolysis with 1 woven and 8 knitted Dacron aortic grafts (Table 1). The integrity of the loose- weave knitted grafts depends largely on the mural thrombus; therefore, these grafts understandably account for most cases of hemorrhaging reported to date. In addition, at least one previously reported case involved a graft pseudoaneurysm.
      • London NJ
      • Williams B
      • Stein A
      Systemic thrombolysis causing haemorrhage around a prosthetic abdominal aortic graft.
      Interestingly, an interval of 3 months to 8 years transpired between graft implantation and thrombolysis. In contrast to these reported problems with knitted Dacron grafts or complications in the anastomoses, a woven Dacron graft was used in our patient, and he had no pseudoaneurysm. The single previous case involving a woven Dacron graft resulted in hemoperitoneum.
      • London NJ
      • Williams B
      • Stein A
      Systemic thrombolysis causing haemorrhage around a prosthetic abdominal aortic graft.
      Unfortunately, localization of the hemorrhage by angiography or CT was unavailable (N. J. London, oral communication); therefore, hemorrhaging may have occurred secondary to anastomotic incompetence or pseudoaneurysm. Clinical follow-up in that patient is unavailable. Animal studies suggest that woven Dacron grafts can be exposed to thrombolytic agents as early as 3 weeks after implantation.
      • Trudell LA
      • Whittemore AD
      • Sunwoo MH
      The performance of commercially available sealed Dacron vascular grafts in intraarterial thrombolytic therapy.
      Table 1Reported Cases of Aortic Transgraft Hemorrhage With Thrombolysis*
      ReferenceGraft typeGraft ageThrombolytic agentIndication for thrombolysisTransfusions
      Rabe et al,
      • Rabe FE
      • Becker GJ
      • Richmond BD
      • et al.
      Contrast extravasation through Dacron grafts: a sequela of low-dose streptokinase therapy.
      1982
      Knitted Dacron16 moStreptokinaseLimb ischemiaNone
      Knitted Dacron3 moStreptokinaseLimb ischemiaNone
      Knitted Dacron6 yStreptokinaseLimb ischemiaNone
      Perler et al,
      • Perler BA
      • Kinnison M
      • Halden WJ
      Transgraft hemorrhage: a serious complication of low-dose thrombolytic therapy.
      1986
      Knitted Dacron5 moUrokinaseLimb ischemiaNone
      Ward & Cripps,
      • Ward AS
      • Cripps N
      Remote transgraft hemorrhage complicating thrombolysis with tissue plasminogen activator [letter].
      1993
      Knitted DacronNAr-tPALimb ischemiaNA
      London et al,
      • London NJ
      • Williams B
      • Stein A
      Systemic thrombolysis causing haemorrhage around a prosthetic abdominal aortic graft.
      1993
      Woven Dacron3 moStreptokinaseMyocardial ischemia5 U RBC, 4 U FFP
      Pope & Kalman,
      • Pope M
      • Kalman PG
      Aortic transgraft hemorrhage after systemic thrombolytic therapy.
      1997
      Knitted Dacron3 yr-tPAMyocardial ischemia9 U RBC, 4 U FFP
      Sequeira et al,
      • Sequeira MJ
      • Shiralkar S
      • Edwards AT
      • Lewis MH
      Systemic thrombolysis causing anastomotic dehiscence of an aortobifemoral graft.
      1998
      Knitted Dacron8 yStreptokinaseMyocardial ischemiaFFP
      Irvine & Whyman,
      • Irvine C
      • Whyman M
      Systemic thrombolysis causing anastomotic dehiscence of an aortobifemoral graft [letter].
      1999
      Knitted Dacron10 moStreptokinase, r-tPAMyocardial ischemiaNA
      FFP = fresh frozen plasma; NA = not available; RBC = red blood cells; r-tPA = recombinant tissue-type plasminogen activator.
      In our patient, systemic thrombolytic therapy did necessitate the administration of blood transfusions to maintain acceptable hemoglobin levels. The associated abdominal wall hematoma represented a component of this transfusion requirement. However, abdominal and pelvic CT performed after clinical stabilization documented no evidence of periprosthetic graft hemorrhage. In particular, only minimal fluid surrounded the graft, consistent with postoperative changes. Possibly, a component of this perigraft fluid represented blood extravasation; however, no intravascular contrast was noted in this fluid.
      In conclusion, we report a successful case of systemic r-tPA infusion for fulminant pulmonary embolization 2 weeks after woven Dacron repair of an abdominal aortic aneurysm. Although not recommended as first-line therapy, systemic thrombolysis may prove useful in extreme situations unresponsive to more conventional treatments.

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