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Pharmacological thrombolysis in Budd Chiari syndrome: a single centre experience and review of the literature
Journal of Hepatology 40 (2004) 172–180 www.elsevier.com/locate/jhep
Case report
Pharmacological thrombolysis in Budd Chiari syndrome: a single centre experience and review of the literature S. Sharma1, A. Texeira2, P. Texeira2, E. Elias2,*, J. Wilde3, S.P. Olliff1 1
Department of Radiology, Queen Elizabeth Hospital, University Hospital Birmingham NHS Trust, The Liver Unit, Birmingham B15 2TH, UK 2 The Liver Unit, Queen Elizabeth Hospital, University Hospital Birmingham NHS Trust, Birmingham B15 2TH, UK 3 Department Haematology, The Liver Unit, Queen Elizabeth Hospital, University Hospital Birmingham NHS Trust, Birmingham B15 2TH, UK
Background/Aims: To review our experience of thrombolytic therapy in patients with acute Budd Chiari syndrome (BCS). Methods: Records of 10 patients with BCS, treated by thrombolysis over a 12-year period were retrospectively analysed for demographics, clinical presentation/duration, primary disease, thrombolytic regimen, and follow-up. The same characteristics were also studied in previously reported patients. The agent used was recombinant tissue plasminogen activator (tPA) in all patients. Results: Thrombolysis was used 12 times in 10 patients. Infusion was made systemically in three patients, into the hepatic artery in one patient, locally into a hepatic vein and/or IVC in four patients and locally within TIPS/portal vein in two patients. Only one infusion made systemically was partially successful. Adjunctive balloon angioplasty and/or stent insertion was undertaken for all eight procedures (in six patients) where local infusion was into the hepatic vein or TIPS. Six of these were ultimately successful (in five patients) and two were unsuccessful. Thrombolysis was more likely to be successful in the presence of a short history of thrombosis, when the thrombolytic agent was locally infused and when it was combined with a successful radiological procedure. Mean follow-up was 4.5 years (range 1 –10 years). No serious bleeding complication occurred. Conclusions: We observed no benefit from thrombolysis when delivered systemically or arterially except in one case. Thrombolysis was useful in adjunctive management of BCS when the drug was infused locally into recently thrombosed veins that had appreciable flow following partial recanalisation. Thrombolysis was clearly of benefit in the repermeation of occluded/partially occluded hepatic veins/TIPS when early detection of new thrombus followed interventional procedures such as balloon angioplasty or stenting of hepatic veins. q 2003 Published by Elsevier B.V. on behalf of European Association for the Study of the Liver. Keywords: Thrombolysis; Budd Chiari syndrome; TIPS; Hepatic venous outflow obstruction
1. Introduction Budd Chiari syndrome (BCS) is a rare condition caused by hepatic venous outflow obstruction, most commonly due to thrombotic occlusion of the hepatic veins (HV) and/or the intra- or supra-hepatic inferior vena cava (IVC) [1]. We have developed an algorithm for management of BCS involving a primary preference for dilating/recanalising hepatic veins to restore venous outflow whenever possible[2,3]. Bypass by TIPS or surgical shunt is Received 5 March 2003; received in revised form 23 September 2003; accepted 29 September 2003 * Corresponding author. E-mail address: [email protected] (E. Elias).
reserved for those symptomatic patients in whom restoration of hepatic vein outflow is unsuccessful or impossible [4]. Numerous case reports describe treatment by thrombolysis for which there is a theoretical basis in the BCS [5 – 18]. However there are no published guidelines for thrombolysis in this condition and our own usage has been on a case by case basis. Warren et al. [5] first reported the successful use of streptokinase in a patient with BCS. Guerin et al. [6] suggested early thrombolysis to be an alternative to surgery in acute BCS. To be effective, it was suggested that the treatment should consist of early intensive thrombolysis for up to 1 week, followed without interruption by APTTcontrolled heparin infusion [19]. More recently Slakey et al.
0168-8278/$30.00 q 2003 Published by Elsevier B.V. on behalf of European Association for the Study of the Liver. doi:10.1016/j.jhep.2003.09.028
173
75 80
[18] reported successful thrombolytic treatment in five patients with underlying haematological disease. Nevertheless thrombolysis is of uncertain therapeutic utility in this condition and exposes the patient to the risk of bleeding and pulmonary embolism [20,21]. Contraindications to thrombolytic agents include—a history of cerebrovascular accident, recent invasive or surgical procedure, recent prolonged cardio-pulmonary resuscitation, marked hypertension and active peptic ulcer disease [22]. We report 12 years experience of thrombolytic treatment of BCS both during initial treatment and after a primary radiological intervention such as TIPS or hepatic vein stent insertion. We discuss several issues that may determine the success of thrombolytic treatment, the potential risks involved and complications encountered.
38 2.7 524 365
62 2.0
38 39
71
191 157 269 38 78 115
3.4
87 81 160 819 126 48
4.5 3.3
180 17.6 235 55
AST (U/l)
Alkaline phosphatase (U/l)
Urea (mmol/l)
Creatinine (mmol/l)
S. Sharma et al. / Journal of Hepatology 40 (2004) 172–180
31 43 Missing data are unknown. Ascites are graded as mild (1), moderate (2) or severe (3).
27 30 3 0 Essential thrombocythaemia Protein C deficiency (B) (9) 29/F (10) 27/F
B(8) C(12) B(9)
PNH Myeloproliferative disorder Polycythaemia rubra vera Essential thrombocythaemia Essential thrombocythaemia Myeloproliferative disorder Protein C deficiency Protein C deficiency (A) (1) 58/M (2) 45/F (3) 23/M (4) 28/F (5) 34/F (6) 16/F (7) 30/F (8) 40/F
C(11) A
48 29 24 10 135 14
38 30
3 3 3 1 2 3 B(8) B(9)
18 42
26 129 3 C(11)
Serum albumin (g/l) Serum bilirubin (mmol/l) Ascites grade Child pugh score Primary disease Patient, age/sex
Table 1 General characteristics and laboratory profile, at presentation, of patients of BCS (A), and BCS with TIPS thrombosis (B)
2. Materials and methods Ten patients (2M/8F; age range 16–58; mean age 33 years) with acute and subacute BCS, who received thrombolysis as primary or adjunctive management between September 1990 and January 2002 formed the study group. General characteristics and laboratory profile of these patients at presentation are shown in Table 1A and B. We retrospectively analysed demographics, clinical presentation, primary disease, duration of symptoms, details of thrombolytic treatment (agent, regimen and route), results, complications and follow-up (Tables 2 and 3). The same characteristics were studied in a review of previously reported patients (Table 4). The extent of thrombosis in the major veins was graded as mild (þ; involving HV or IVC), moderate (þ þ ; involving any two of HV, IVC or portal vein), and marked (þ þþ ; involving HV, IVC and portal/splenic/ superior mesenteric vein). The underlying occlusion or obstruction of the hepatic veins and/or IVC was also graded as short (less than 2 cm) or long (more than 2 cm). The amount of thrombus within IVC and/or hepatic veins was graded as minor (i.e. significant remaining patent vein lumen) or major (i.e. extensive or complete occlusion by thrombus). Written informed consent was obtained in all cases prior to thrombolytic treatment. Thrombolytic therapy was arbitrarily considered as early when it was instituted within 4 weeks of the start of symptoms, and late when it was started at 4 weeks or later. Treatment was by local or systemic thrombolysis, usually in association with other recanalisation procedure(s) viz. hepatic vein/IVC balloon dilatation or stenting. Adjunctive balloon angioplasty was undertaken for all procedures where local infusion into hepatic veins or IVC was used, irrespective of the initial length of stenosis or thrombotic occlusion. End points were resolution of the thrombosis or a bleeding complication. Treatment was abandoned if there was no sign of improvement on the check venogram performed 1 or 2 days after starting therapy. APTT-controlled heparin infusion was continued during thrombolysis and extended until oral anticoagulation with Warfarin, and definitive haematological treatment was instituted. The procedure was considered successful when there was sustained dilatation of the vein caliber, improved blood flow, reduction in pressure gradients and improvement was maintained on subsequent review, accompanied by alleviation of symptoms and near normalization of liver function tests. It was considered partially successful when flow in the HV and/or IVC could be partially restored; or flow in the IVC could be restored but not in the HV; accompanied by only suboptimal recovery in laboratory parameters and symptoms. The procedure failed when the flow in affected veins could not be restored. Mesocaval shunting or TIPS were used as rescue procedures. Two patients (nos. 9 and 10) already had TIPS inserted for BCS at the time of thrombolysis. The initial clinical diagnosis was confirmed using ultrasound with Doppler. Ultrasound revealed the extent of venous thrombosis/obstruction, ascites and evidence of portal hypertension. Hepatic venography and inferior vena cavography were performed via the transjugular route initially. Ultrasound guided percutaneous transhepatic puncture of hepatic
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Table 2 Characteristics of eight patients with Budd Chiari syndrome treated by tPA thrombolysis Length of history
# tPA regimen and time elapsed in starting therapy
Site of infusion
Extent of thrombosis and occlusion
Result
Complication related to thrombolysis
Rescue procedure
Follow-up time
(1)
Not known
Not known
Systemic
HV (mild); þ; major
Unsuccessful
None
TIPS day after
Died after 1 year
(2)
Few months
(Delayed) Bolus of 10 mg 40 mg/h 50 mg/2 h
Systemic
HV, IVC, PV, SMV (marked); þþ þ; major
Unsuccessful
None
–
Died day after
(3)
3 weeks
(Early) 0.5 mg/h for 24 h
Local (hepatic vein)
HV (mild); þ; minor/short
Successful
None
–
9 years
(4)
3 weeks
(Early) Bolus of 5 mg 1 mg/h for 48 h
Hepatic artery
HV, IVC (moderate); þþ ; major
Unsuccessful
None
TIPS 7 days after
4 years
(5)
Several weeks
(Delayed) Bolus of 10 mg 2 mg/h for 72 h
Systemic
HV, IVC (moderate); þþ ; major
Partially successful
Bruise over sternal aspiration site
Meso-caval shunt 10 days after
10 years
(6)
Few weeks
(Early) Bolus of 5 mg 1 mg/h for 48 h
Local (hepatic vein and IVC)
HV (mild); þ; short/minor
Successful
None
–
6 years
(7)
3 Weeks
(Early) 1 mg/h for 96 h
Local (hepatic vein)
HV (mild); þ; major
Unsuccessful
None
Mesocaval shunt 2 day after
7 year
(8)
4 weeks
First time: (delayed) Bolus of 5 mg 1 mg/h for 48 h Second time: (early) 0.5 mg/h for 96 h
First time: local (hepatic vein and IVC)
HV, IVC (moderate); þþ ; major/short
Initially failed
None
–
8 years
Second time: local; (hepatic vein and IVC)
HV, IVC (moderate); þþ ; major/short
Then successful
None
3 weeks
S. Sharma et al. / Journal of Hepatology 40 (2004) 172–180
Patient
1 year Bleed from neck sheath Successful Local (TIPS)
None Later completely successful Local (SMV)
175
vein segments was used when the hepatic veins could not be entered from the IVC but were visibly present on ultrasound [23]. The femoral approach to the IVC was also used in selected cases. Percutaneous liver biopsy was not generally done as patients had ascites and were candidates for thrombolysis and anticoagulation. After fluoroscopic placement of 5f multiple side hole infusion catheter in the target vein, the infusion was started in the angio suite and later continued in liver ITU. Patients were monitored for vital signs and bleeding complications. For systemic infusion a peripheral IV line in the arm was used. Hepatic artery infusion was performed by a 5f catheter placed in the common hepatic artery. Resolution of the thrombus was assessed by injecting contrast through the catheter used for local thrombolysis. Once a satisfactory venogram was obtained and balloon angioplasty/stenting completed, the catheter was removed. Early in our series thrombolysis was used as a sole therapy, but more recently it has been used in combination with other recanalisation procedures. Thrombolysis was indicated when venography suggested significant intraluminal thrombus complicating or preventing adequate restoration of venous flow. If the vein rethrombosed or failed to display a wide and smooth lumen, thrombolysis was continued or repeated. Balloon angioplasty and/or stent insertion were also performed and repeated as required. Patients were discharged from hospital 1–3 weeks after treatment and followed up at 3 month intervals or sooner if indicated. At the follow-up visits, physical examination and liver function tests and ultrasound were done. Contrast venography and pressure measurements were repeated if there was any clinical or ultrasound suggestion of rethrombosis or narrowing, reversed or poor venous flow. Patients with TIPS were followed up by ultrasound with routine venography at 12 months or earlier if there were clinical or ultrasound signs of stenosis or occlusion. The underlying thrombotic disorder was sought in all patients and appropriately trated.
Nil
1 year Nil Initial success temporary Local (TIPS)
None
Result Site of infusion
Complication related to thrombolysis
Rescue procedure
Follow-up time
S. Sharma et al. / Journal of Hepatology 40 (2004) 172–180
3. Results
3.1. Thrombolysis **Thrombosis discovered during routine follow-up in asymptomatic patient.
Bolus 5 mg (not known) 1 mg/h for 48 h ** Protein C deficiency
8 weeks
(10) 27/F
First time: (late) Bolus 5 mg 1 mg/h for 6 days Second time: (late) Bolus 5 mg 0.5 mg/h for 48 h 7 weeks Essential thrombocythaemia (9) 29/F
tPA regimen and time elapsed since starting therapy Length of history Primary disease Patient, age/sex
Table 3 Characteristics of two BCS patients with thrombosed TIPS, treated by thrombolysis
Eight surviving patients have been followed up for 1– 9 years (mean 4.5 years).
3.1.1. Non-TIPS patients Eight patients (nos. 1 – 8, Tables 1A and 2) had thrombolysis either before or after their initial interventional radiology investigation and treatment. Three patients had successful radiological dilatation/recanalisation procedures of HV and/or IVC (nos. 3, 6 and 8). One procedure (no. 5) was partially successful in reducing IVC thrombus such that surgical mesocaval shunt could be performed. One patient (no. 2) died the day after thrombolysis commenced. TIPS (patients 1 and 4) and mesocaval shunt (patient no. 7) were definitive treatments after angioplasty and thrombolysis proved unsuccessful in the other three patients. 3.1.2. Following TIPS for Budd Chiari syndrome Patients 9 and 10 had TIPS performed for treatment of Budd Chiari and later developed thrombosis of TIPS and portal vein. They were successfully thrombolysed and recanalised (Tables 1B and 3). A large thrombus occluding the TIPS was discovered during routine follow-up ultrasound in one patient (no. 10) while clinically asymptomatic.
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Table 4 Characteristics of reported cases of thrombolytic therapy in BCS Number of cases, age/sex
Primary aetiology
Length of history
Agent, regimen and time elapsed in starting therapy
Site of infusion
Extent of thrombosis
Result
Complication related to procedure
Follow-up duration
Assisted recanalisation procedure
Greenwood et al. [7]
1, 41/M
?
?
Urokinase: (not known) Bolus 4400 U/kg 4400 U/kg/h for 55 h
Local (IVC)
Mild; þ
Successful
Intraperitoneal haemorrhage
Well at 1 year, died 18 months after
Nil
Cassel et al. [6]
1, 46/F
Polycythaemia vera
3 months
Streptokinase: (delayed) Bolus 600,000 U 100,000 U/h for 96 h
Systemic
Mild; þ
Successful
Mild pyrexia
12 months
Nil
Guerin et al. [10]
1, 34/M
Recent pregnancy and oral contraceptives
?
Streptokinase: (not known) Bolus of 250,000 U 150,000 U/h/48 h; Lys-plasminogen 100 mg/2 h 160,000/h/48 h
Systemic
Mild; þ
Successful
None
?
Nil
Warren et al. [5]
1, 22/F
Oral contraceptives
?
Streptokinase: (not known) 250,000 U/h 100,000 U/h/72 h
Systemic
Moderate; þþ
Successful
Recurrent pulmonary emboli
4 months
Nil
Sholar [8]
2, 33/F
PNH
Case 1: 5 days
Case 1 (first time) Streptokinase: (early) 7500 U/h, then 5000 U/h (total 72 h) (Second time, 2 months after) Urokinase: (delayed) 250,000 U/40 min 250,000 U/2 h Case 2 Streptokinase: (early) 250,000 U/30 min 100,000 U/h/48 h
Case 1 First time: local (hepatic vein)
Marked; þþþ
Successful
None
Case 1: 2 years
Nil
Second time: systemic
Moderate; þþ
Successful
Case 2: systemic
Moderate; þþ
Successful
None
Case 2: 5 years
Nil
Case 1: tPA 30 mg/24 h (early) Case 2: tPA First time 15 mg/3 h (delayed) Second time (after 9 days) 24 mg/48 h (delayed) Third time (after 2 days) 25 mg/3 h (delayed) Then, 50 mg/24 h
Case 1: systemic
Moderate; þþ
Successful
None
Nil
Case 2: Systemic
Mild; þ
Unsuccessful
None
Case 1: 6 years Case 2: 2 years
Hepatic artery
Mild; þ
Unsuccessful
Systemic
Mild; þ
Successful
Local (IVC)
Mild; þ
Successful
12 months
Nil
33/M
McMullin et al. [15]
Raju et al. [16]
Case 2: 7–10 days
2, 33/F
PNH
22/F
PNH
1, 59/M
?
Case 1: 3 weeks Case 2: several weeks
Few hours
Urokinase: (early) 300,000 U bolus 300,000 U/h for 72 h
None
Nil
S. Sharma et al. / Journal of Hepatology 40 (2004) 172–180
Author
Nil
IVC and HV Angioplasty
Died 10 days after
Died 9 months after
3.1.4. Outcome versus route of infusion None of the three systemic infusions were completely successful. An infusion into the hepatic artery failed to restore flow in the hepatic veins in one patient. Systemic infusion in one patient (no. 5) in whom the patency of hepatic veins could not be restored, cleared the IVC of thrombus and enabled mesocaval shunt surgery with an excellent long-term outcome. Of five local infusions in four patients, three patients were ultimately successful treated by thrombolysis and dilatation/stenting. Local infusion into thrombosed TIPS/portal vein was successful in two patients. 3.1.5. Outcome versus length of history (age of thrombus) No success could be achieved in a patient (no. 1) in whom the length of history was unknown but presumed long. No success was achieved in a patient (no. 2) with a history of several months. All other patients had symptoms ranging from a few to several weeks duration. Four (nos. 3, 6, 8 and 9) of these were treated successfully, one (no. 5) had partial success and two (nos. 4 and 7) were unsuccessful. One patient (no. 8) with a few weeks history did not respond until the hepatic veins were recanalised by transhepatic balloon dilatation.
?, not known; *, IVC markedly narrow and calcified.
Partially successful Moderate; þþ Local (IVC) 1, 29/F Ilan et al. [11]
Post-partum
Few days
Streptokinase: (early) for 72 h (dose?)
Partially successful Mild; þ Systemic tPA: (early) 100 mg over 3 h 2 weeks PNH 1, 47/F Kwan et al. [14]
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3.1.3. Outcome versus assisted recanalisation procedure An appropriate adjunctive procedure (balloon dilatation or stenting of HV/IVC) was used to ensure improved blood flow before (nos. 6 and 7) or after (nos. 3 and 8) thrombolysis in all four patients in whom local infusion was made. Three patients had a successful outcome. In one patient (no. 7) the patency of the HV could not be maintained during thrombolysis even after HV dilatation.
None
Nil 9 months Successful Systemic 1, 26/F McKee et al. [9]
Post-partum
3 weeks
Streptokinase: (early) Three injections: 10 mg, 10 mg, 5 mg (total 25 mg)
Mild; þ
None
IVC angioplasty and stenting 14 months None Successful Moderate; þþ 1, 42/F Ishiguchi et al. [9]
PNH
Chronic* (several months)
Local (IVC)
Successful Mild; þ Systemic
Urokinase: (delayed) 10,000 U/min for 35 min Then 240,000 U/day for 7 days
Successful temporary Moderate; þþ 1, 29/F De Stefano [12]
PNH With pregnancy
?
tPA first time: (not known) 50 mg/5 h Same repeated after 48 h Second time: (not known) 50 mg/5 h Same repeated after 48 h
Systemic
Mild wheeze
Nil Severe haematuria
? (Caesarean delivery at 33 weeks) Well at 2 weeks
S. Sharma et al. / Journal of Hepatology 40 (2004) 172–180
3.1.6. Outcome versus length of venous stenosis Two patients (nos. 3 and 8) had short focal stenoses due to ‘webs’ in the hepatic vein and IVC, respectively. The short length of occlusion was only appreciated after the diffusely thrombosed lumen was satisfactorily cleared. Hepatic vein balloon angioplasty and thrombolysis was very effective in one patient (no. 3). Extensive IVC thrombosis below a web (patient no. 8) was treated by serial thrombolysis and balloon dilatation. The central hepatic vein in this patient remained occluded even after IVC clearance and was recanalised 8 days later by a combined transhepatic/transjugular dilatation procedure. Patient 6 also had a short length occlusion of the hepatic vein confluence, which was traversed, dilated and stented prior to an acute thrombosis, which then responded to thrombolysis. These three patients have had excellent longterm clinical benefit. In contrast, patient 7 had very extensive thrombosis of hepatic veins and failed to respond to thrombolysis and angioplasty. 3.1.7. Outcome versus extent of thrombosis Eight procedures were employed for thrombosis that was graded as mild or moderate in extent, i.e. either only
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hepatic veins involved or hepatic veins and IVC were thrombosed. Those with a smaller amount of thrombus in the hepatic veins (patients 3 and 6) did well. Patient 8 initially had very extensive IVC thrombus and short length occlusion of hepatic veins, which were ultimately successfully treated by thrombolysis and dilatation. One patient (no. 2) who had extensive thrombotic occlusion of all hepatic veins, spleno-portal-mesenteric axis and had extensive gastro-esophageal varices succumbed despite aggressive thrombolytic therapy. 3.1.8. Outcome versus treatment of underlying hematological condition All patients were treated for the underlying cause of thrombosis. In one patient (no. 9), local infusion made into the TIPS and portal vein resulted in a slow recanalisation that persisted only for the next 8 weeks. Essential thrombocythaemia was only diagnosed at this stage. Repeat local thrombolysis with balloon dilatation along with the specific anti-platelet treatment, resulted in a more prolonged patency. 3.1.9. Complications Only two patients developed minor bleeding complications (Tables 2 and 3). None required transfusion. In one patient (no. 10) the treatment was stopped after ooze around the neck sheath, but thrombolysis was complete by this time.
4. Discussion We describe the successful use of thrombolysis in five patients when deployed in association with repermeation of thrombus within recanalised hepatic veins, inferior vena cava or TIPS. Success may be attributable to more than one factor. Firstly, the thrombus was recent in origin and of known age particularly when it followed diagnostic or therapeutic interventional radiology. Secondly, thrombolysis was instituted immediately after mechanically reestablishing venous patency. Maintenance of flow through the thrombosed vein appears critical to the success of the technique. When hepatic venous outflow obstruction is complete, blood is likely to bypass the severely congested liver via retrograde flow in the portal vein and/or collaterals and there will be poor contact of systemically administered thrombolytic drug to the thrombosed hepatic veins. Local thrombolysis also requires some local blood flow to maintain and improve the patent channel. Thirdly, local infusion into the vein immediately proximal to or within the thrombus achieves high concentrations of the thrombolytic agent around the thrombus. Reduction of portal pressure by recanalisation procedure immediately before thrombolysis also reduces the risk of a complicating variceal haemorrhage.
Thrombolysis can be repeated after previously successful or unsuccessful treatment. TIPS or shunt surgery can be done after thrombolysis fails. Indeed three of our patients who had failed thrombolysis were successfully salvaged by TIPS and shunt surgery. In one of the patients, whom the HVs remained occluded after thrombolysis, a surgical mesocaval shunt could be created because of repermeation of the previously occluded vena cava. Vena caval occlusions have been treated with combinations of local thrombolysis, balloon angioplasty and metallic stent(s) [13]. Local thrombolysis via the transjugular and transhepatic approach has been used successfully in early post-liver transplant portal vein thrombosis [24,25]. Blum et al. [26] recently reported the successful placement of TIPS followed immediately by local low dose thrombolysis in seven cirrhotic patients with portal vein thrombosis, without complication. Before the administration of the thrombolytic therapy, balloon angioplasty was performed in the thrombosed main portal vein to restore some patency. Portal vein blood flow could not be established with mechanical means alone. Mechanical thrombectomy using an Amplatz Thrombectomy Device (ATD) is recently reported as a useful complementary technique in patients with thrombosis of large native vessels, grafts or TIPS shunts where thrombolysis alone has either failed or is contraindicated [27,28]. While hepatic decompression is immediate after TIPS or surgical shunt, thrombolysis produces a slow improvement. TIPS is now established as an effective treatment for variceal bleeding and ascites and also for selected cases of BCS [29]. TIPS is generally accepted to have a significant risk of stenosis or occlusion but Budd Chiari patients may have a potentially greater risk especially if there is an aggressive underlying thrombotic tendency. Our two patients show that thrombolysis can have a beneficial role in combination with balloon dilatation and/or restenting in completely occluded thrombosed TIPS in Budd Chiari patients. Both local and systemic administration of thrombolytic drugs have been used in the treatment of BCS. There are no studies directly comparing the efficacy of local versus systemic infusion. Catheter directed infusion is of proven efficacy in arterial and venous thrombosis [30]. We used the hepatic artery to deliver tPA for 2 days in one of our patients with blocked HVs with no success. tPA infusion into the hepatic artery was used by Mc Mullin et al. [15] to no advantage in their patient after initially failed systemic infusion. Success with systemic infusion of thrombolytic agents has been described [5,6,8 – 10,12,15], but we had partial success only in one of our patients. Surgical thrombectomy is usually not technically possible in BCS patients to restore flow [31]. No data is available to direct the choice of thrombolytic agent in the setting of BCS. tPA is a natural human enzyme with no antigenicity. It has a very short half-life of 5 min and may be discontinued if bleeding occurs. tPA was
S. Sharma et al. / Journal of Hepatology 40 (2004) 172–180
reported to be most effective and produced earlier reperfusion following pulmonary embolism [32]. In the treatment of acute myocardial infarction, the accelerated regimen using tPA offers a small advantage over streptokinase (SK) in lysing clots from the coronary arteries but with a marginally higher incidence of stroke [33]. Urokinase or tPA should be preferred in a patient who has high levels of circulating antistreptococcal antibodies due to previous SK administration. tPA is more expensive than SK per therapeutic dose. Thrombolysis in advanced age is associated with increased risk of bleeding complications [34]. BCS patients tend to be younger and therefore more likely to withstand thrombolytic therapy without complication as compared to those treated for myocardial infarction or stroke. The thrombus ‘load’ may have a bearing on the eventual outcome of thrombolysis [13]. It is known that the patients with massive thrombus have a poorer prognosis [35]. In our experience the finding of a short underlying occlusion or stenosis increased the chance of eventual clinical success for thrombolysis/recanalisation even when it was associated with a large amount of thrombus occluding or partially occluding the veins. This is a retrospective, observational study in a small number of patients. The patients treated are heterogeneous in terms of their clinical presentation, extent of thrombosis, chronicity, underlying etiologies, risk factors, and thrombolytic dosage regimens used. In most published reports the thrombolytic treatment was primary, whereas in our cases it was often adjunctive. We propose that thrombolysis has an important role in the management of acute and subacute forms of BCS in selected patients in combination with other interventional radiological techniques. Local infusion into partially recanalised veins with some appreciable flow is best. It is potentially repeatable and does not preclude other more invasive treatments. As an adjunct, thrombolysis is best employed in a patient who presents early, has a thrombus that is limited in extent and not completely occlusive. Close clinical, imaging and laboratory followup along with appropriate treatment of underlying haematological disorders can ensure improved long-term venous patency and hence patient survival. Thrombolysis alone especially when systemically administered appears of limited value, contrary to the earlier literature. Pooling and analysis of data from other centres is needed before more extensive conclusions and recommendations can be made.
References [1] Janssen HLA, Garcia-Pagan J-C, Elias E, Mentha G, Hadengue A, Valla D-C. Budd Chiari syndrome: a review by an expert panel. J Hepatol 2003;364–371.
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[2] Griffith JF, Mahmoud AE, Cooper S, Elias E, West RJ, Olliff S. Radiological intervention in Budd Chiari syndrome: techniques and outcome in 18 patients. Clin Radiol 1996;51:775–784. [3] Fisher NC, McCafferty I, Dolapci M, Wali M, Buckels JAC, Olliff SP, et al. Managing Budd Chiari syndrome: a retrospective review of percutaneous hepatic vein angioplasty and surgical shunting. Gut 1999;44:568 –574. [4] Olliff S. Radiological treatment of Budd Chiari syndrome. Imaging 1998;10:81 –88. [5] Warren RL, Schlant RC, Wenger NK, Galambos JT. Treatment of Budd Chiari syndrome with streptokinase (abstr). Gastroenterology 1972;62:200. [6] Cassel GA, Morley JE. Hepatic vein thrombosis treated with streptokinase. S A Med J 1974;16:2319–2320. [7] Greenwood LH, Yrizarry JM, Hallett Jr JW, Scoville Jr GS. Urokinase treatment of Budd Chiari syndrome. Am J Radiol 1983;141: 1057– 1059. [8] Sholar PW, Bell WR. Thrombolytic therapy for inferior vana cava thrombosis in paroxysmal nocturnal haemoglobinuria. Ann Internl Med 1985;103:539–541. [9] McKee CM, Mayne EE, Crothers JG, Callender ME. Budd Chiari syndrome treated with acylated streptokinase–plasminogen complex. J Roy Soc Med 1985;78:768–769. [10] Guerin JM, Meyer P. Need for early thrombolysis in Budd Chiari syndrome. Gastroenterology 1988;94:1109. [11] Ilan Y, Oren R, Shouval D. Postpartum Budd Chiari syndrome with prolonged hypercoagulability state. Am J Obstet Gynecol 1990;162: 1164– 1165. [12] De Stefano V, Leone G, Teofili L, Ricerca BM, Pearelli L, Menichella G, Caruso A, et al. Hepatic and portal vein thrombosis in a pregnant women with paroxysmal nocturnal haemoglobinuria (PNH) and severe thrombocytopenia: Efficacy of tissue plasminogen activator in the treatment of Budd Chiari syndrome and successful outcome of pregnancy (abstract). Thrombo Haemost 1991;65:1188. [13] Ishiguchi T, Fukatso H, Itoh S, Shimamoto K, Sakuma S. Budd Chiari syndrome with long segmental inferior vana cava obstruction: treatment with Thrombolysis, angioplasty and intravascular stents. J Vasc Interven Radiol 1992;3:421–425. [14] Kwan T, Hansard P. Recombinant tissue-plasminogen activator for acute Budd Chiari syndrome secondary to paroxysmal nocturnal haemoglobinuria. NY State J Med 1992;92:109– 110. [15] McMullin MF, Hillmen P, Jackson J, Ganly P, Luzzatto L. Tisue plasminogen activator for hepatic vein thrombosis in paroxysmal nocturnal haemoglobinuria. J Internal Med 1994;235:85–89. [16] Raju GS, Felver M, Olin JW, Satti SD. Thrombolysis for acute Budd Chiari syndrome: Case report and literature review. Am J Gastroenterol 1996;91:1262–1263. [17] Leebeek PWG, Lameris JS, van Buren HR, Gomez E, Madretsma S, Sonneveld P. Budd Chiari syndrome, portal vein and mesenteric vein thrombosis in a patient homozygous for factor V Leiden mutation treated by TIPS and thrombolysis. Br J Haematol 1998; 102:929–931. [18] Slakey DP, Klein AS, Venbrux AC, Cameron JL. Budd Chiari syndrome: current management options. Ann Surg 2001;233: 522–527. [19] Loliger EA. Fibrinolytic and anticoagulation therapy in Budd Chiari syndrome. Review and recommendations (in German). Wien Klin Wochenschr 1988;100:43–46. [20] Sherlock S, DooleyJ J. The hepatic artery and hepatic veins: The liver in circulatory failure. In: Sherlock S, Dooley J, editors. Diseases of the liver and biliary system, 11th ed. Oxford: Blackwell Science; 2001. p. 192–197. [21] Elliot MS, Immelman EJ, Jeffery P, et al. A comparative randomised trial of heparin versus streptokinase in treatment of acute proximal venous thrombosis: an interim report of prospective trial. Br J Surg 1979;66:838 –843.
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[22] Antman EM, Braunwald E. Acute myocardial infarction. In: Antman EM, Braunwald E, editors. Harrison’s principles of medicine, 15th ed. Singapore: McGraw-Hill; 2001. p. 1386–1398. [23] Cooper S, Olliff S, Elias E. Recanalisation of hepatic veins by a combined transhepatic, transjugular approach in three cases of Budd Chiari syndrome. J Interven Radiol 1996;11:9–13. [24] Ciccarelli O, Goffette P, Lattere PF, Danse E, Wittenbolle X, Lerut J. Transjugular intrahepatic portosystemic shunt approach and local thrombolysis for treatment of early post transplant portal vein thrombosis. Transplantation 2001;72:159–161. [25] Bhattacharya T, Olliff SP, Bhattcharya S, Mirza DF, Mc Master P. Percutaneous portal vein thrombolysis and endovascular stent for management of post transplant portal vein conduit thrombosis. Transplantation 2000;27:2195–2198. [26] Blum U, Haag K, Rossle M, Ochs A, Gableman A, Boos S, Langer M. Noncavernomatous portal vein thrombosis in hepatic cirrhosis: treatment with transhepatic intrahepatic portosystemic shunt and local thrombolysis. Radiology 1995;195:153– 157. [27] Muller HS, Hopfner M, Hilbert C, Krammer HH, Heller M. Mechanical thrombectomy of acute thrombosis in transjugular intrahepatic portosystemic shunt. Invest Radiol 2000;35:385–391. [28] Uflacker R. Mechanical thrombectomy in acute and subacute thrombosis with use of Amplatz device: arterial and venous applications. J Vasc Interv Radiol 1997;8:923–932.
[29] Blum U, Rossle M, Haag K, Ochs A, Blum HE, Hauenstein KH, et al. Budd-Chiari syndrome: technical, hemodynamic, and clinical results of treatment with transjugular intrahepatic portosystemic shunt. Radiology 1995;197:805 –811. [30] van Breda A, Katzen BT, Deutsch AS. Urokinase versus streptokinase in local thrombolysis. Radiology 1987;165:109– 111. [31] Vogt PR, Anderson LC, Jenni R, et al. Dorsocranial liver resection and direct hepato-atrial liver anastomosis for hepatic venous outflow obstruction: long term outcome and functional results. Am J Gastroenterol 1996;91:539–544. [32] Bozzoli C, Renzi C, Puddu GM, Muscari A, Puddu P. Treatment of pulmonary emobolism: Current status and future prospects (in Italian). Clin Ter 1993;142:497–505. [33] Ganz P, Barunwald E, editors. Acute myocardial ischaemia, 5th ed. Heart disease: a text book of cardiovascular medicine, vol. 2. Singapore: WB Saunders; 1997. p. 1184–1288. [34] Braithwaite BD, Davies B, Birch PA, Heather BP, Earnshaw JJ. Managemant of acute leg ischaemia in the elderly. Br J Surgery 1988; 85:217–220. [35] Mahmoud AEA, Helmy AS, Billingham L, Elias E. Poor prognosis and limited therapeutic options in patients with Budd Chiari syndrome and portal vein system thrombosis. Eur J Gastroenterol Hepatol 1997; 9:485–489.
Case report
Pharmacological thrombolysis in Budd Chiari syndrome: a single centre experience and review of the literature S. Sharma1, A. Texeira2, P. Texeira2, E. Elias2,*, J. Wilde3, S.P. Olliff1 1
Department of Radiology, Queen Elizabeth Hospital, University Hospital Birmingham NHS Trust, The Liver Unit, Birmingham B15 2TH, UK 2 The Liver Unit, Queen Elizabeth Hospital, University Hospital Birmingham NHS Trust, Birmingham B15 2TH, UK 3 Department Haematology, The Liver Unit, Queen Elizabeth Hospital, University Hospital Birmingham NHS Trust, Birmingham B15 2TH, UK
Background/Aims: To review our experience of thrombolytic therapy in patients with acute Budd Chiari syndrome (BCS). Methods: Records of 10 patients with BCS, treated by thrombolysis over a 12-year period were retrospectively analysed for demographics, clinical presentation/duration, primary disease, thrombolytic regimen, and follow-up. The same characteristics were also studied in previously reported patients. The agent used was recombinant tissue plasminogen activator (tPA) in all patients. Results: Thrombolysis was used 12 times in 10 patients. Infusion was made systemically in three patients, into the hepatic artery in one patient, locally into a hepatic vein and/or IVC in four patients and locally within TIPS/portal vein in two patients. Only one infusion made systemically was partially successful. Adjunctive balloon angioplasty and/or stent insertion was undertaken for all eight procedures (in six patients) where local infusion was into the hepatic vein or TIPS. Six of these were ultimately successful (in five patients) and two were unsuccessful. Thrombolysis was more likely to be successful in the presence of a short history of thrombosis, when the thrombolytic agent was locally infused and when it was combined with a successful radiological procedure. Mean follow-up was 4.5 years (range 1 –10 years). No serious bleeding complication occurred. Conclusions: We observed no benefit from thrombolysis when delivered systemically or arterially except in one case. Thrombolysis was useful in adjunctive management of BCS when the drug was infused locally into recently thrombosed veins that had appreciable flow following partial recanalisation. Thrombolysis was clearly of benefit in the repermeation of occluded/partially occluded hepatic veins/TIPS when early detection of new thrombus followed interventional procedures such as balloon angioplasty or stenting of hepatic veins. q 2003 Published by Elsevier B.V. on behalf of European Association for the Study of the Liver. Keywords: Thrombolysis; Budd Chiari syndrome; TIPS; Hepatic venous outflow obstruction
1. Introduction Budd Chiari syndrome (BCS) is a rare condition caused by hepatic venous outflow obstruction, most commonly due to thrombotic occlusion of the hepatic veins (HV) and/or the intra- or supra-hepatic inferior vena cava (IVC) [1]. We have developed an algorithm for management of BCS involving a primary preference for dilating/recanalising hepatic veins to restore venous outflow whenever possible[2,3]. Bypass by TIPS or surgical shunt is Received 5 March 2003; received in revised form 23 September 2003; accepted 29 September 2003 * Corresponding author. E-mail address: [email protected] (E. Elias).
reserved for those symptomatic patients in whom restoration of hepatic vein outflow is unsuccessful or impossible [4]. Numerous case reports describe treatment by thrombolysis for which there is a theoretical basis in the BCS [5 – 18]. However there are no published guidelines for thrombolysis in this condition and our own usage has been on a case by case basis. Warren et al. [5] first reported the successful use of streptokinase in a patient with BCS. Guerin et al. [6] suggested early thrombolysis to be an alternative to surgery in acute BCS. To be effective, it was suggested that the treatment should consist of early intensive thrombolysis for up to 1 week, followed without interruption by APTTcontrolled heparin infusion [19]. More recently Slakey et al.
0168-8278/$30.00 q 2003 Published by Elsevier B.V. on behalf of European Association for the Study of the Liver. doi:10.1016/j.jhep.2003.09.028
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75 80
[18] reported successful thrombolytic treatment in five patients with underlying haematological disease. Nevertheless thrombolysis is of uncertain therapeutic utility in this condition and exposes the patient to the risk of bleeding and pulmonary embolism [20,21]. Contraindications to thrombolytic agents include—a history of cerebrovascular accident, recent invasive or surgical procedure, recent prolonged cardio-pulmonary resuscitation, marked hypertension and active peptic ulcer disease [22]. We report 12 years experience of thrombolytic treatment of BCS both during initial treatment and after a primary radiological intervention such as TIPS or hepatic vein stent insertion. We discuss several issues that may determine the success of thrombolytic treatment, the potential risks involved and complications encountered.
38 2.7 524 365
62 2.0
38 39
71
191 157 269 38 78 115
3.4
87 81 160 819 126 48
4.5 3.3
180 17.6 235 55
AST (U/l)
Alkaline phosphatase (U/l)
Urea (mmol/l)
Creatinine (mmol/l)
S. Sharma et al. / Journal of Hepatology 40 (2004) 172–180
31 43 Missing data are unknown. Ascites are graded as mild (1), moderate (2) or severe (3).
27 30 3 0 Essential thrombocythaemia Protein C deficiency (B) (9) 29/F (10) 27/F
B(8) C(12) B(9)
PNH Myeloproliferative disorder Polycythaemia rubra vera Essential thrombocythaemia Essential thrombocythaemia Myeloproliferative disorder Protein C deficiency Protein C deficiency (A) (1) 58/M (2) 45/F (3) 23/M (4) 28/F (5) 34/F (6) 16/F (7) 30/F (8) 40/F
C(11) A
48 29 24 10 135 14
38 30
3 3 3 1 2 3 B(8) B(9)
18 42
26 129 3 C(11)
Serum albumin (g/l) Serum bilirubin (mmol/l) Ascites grade Child pugh score Primary disease Patient, age/sex
Table 1 General characteristics and laboratory profile, at presentation, of patients of BCS (A), and BCS with TIPS thrombosis (B)
2. Materials and methods Ten patients (2M/8F; age range 16–58; mean age 33 years) with acute and subacute BCS, who received thrombolysis as primary or adjunctive management between September 1990 and January 2002 formed the study group. General characteristics and laboratory profile of these patients at presentation are shown in Table 1A and B. We retrospectively analysed demographics, clinical presentation, primary disease, duration of symptoms, details of thrombolytic treatment (agent, regimen and route), results, complications and follow-up (Tables 2 and 3). The same characteristics were studied in a review of previously reported patients (Table 4). The extent of thrombosis in the major veins was graded as mild (þ; involving HV or IVC), moderate (þ þ ; involving any two of HV, IVC or portal vein), and marked (þ þþ ; involving HV, IVC and portal/splenic/ superior mesenteric vein). The underlying occlusion or obstruction of the hepatic veins and/or IVC was also graded as short (less than 2 cm) or long (more than 2 cm). The amount of thrombus within IVC and/or hepatic veins was graded as minor (i.e. significant remaining patent vein lumen) or major (i.e. extensive or complete occlusion by thrombus). Written informed consent was obtained in all cases prior to thrombolytic treatment. Thrombolytic therapy was arbitrarily considered as early when it was instituted within 4 weeks of the start of symptoms, and late when it was started at 4 weeks or later. Treatment was by local or systemic thrombolysis, usually in association with other recanalisation procedure(s) viz. hepatic vein/IVC balloon dilatation or stenting. Adjunctive balloon angioplasty was undertaken for all procedures where local infusion into hepatic veins or IVC was used, irrespective of the initial length of stenosis or thrombotic occlusion. End points were resolution of the thrombosis or a bleeding complication. Treatment was abandoned if there was no sign of improvement on the check venogram performed 1 or 2 days after starting therapy. APTT-controlled heparin infusion was continued during thrombolysis and extended until oral anticoagulation with Warfarin, and definitive haematological treatment was instituted. The procedure was considered successful when there was sustained dilatation of the vein caliber, improved blood flow, reduction in pressure gradients and improvement was maintained on subsequent review, accompanied by alleviation of symptoms and near normalization of liver function tests. It was considered partially successful when flow in the HV and/or IVC could be partially restored; or flow in the IVC could be restored but not in the HV; accompanied by only suboptimal recovery in laboratory parameters and symptoms. The procedure failed when the flow in affected veins could not be restored. Mesocaval shunting or TIPS were used as rescue procedures. Two patients (nos. 9 and 10) already had TIPS inserted for BCS at the time of thrombolysis. The initial clinical diagnosis was confirmed using ultrasound with Doppler. Ultrasound revealed the extent of venous thrombosis/obstruction, ascites and evidence of portal hypertension. Hepatic venography and inferior vena cavography were performed via the transjugular route initially. Ultrasound guided percutaneous transhepatic puncture of hepatic
174
Table 2 Characteristics of eight patients with Budd Chiari syndrome treated by tPA thrombolysis Length of history
# tPA regimen and time elapsed in starting therapy
Site of infusion
Extent of thrombosis and occlusion
Result
Complication related to thrombolysis
Rescue procedure
Follow-up time
(1)
Not known
Not known
Systemic
HV (mild); þ; major
Unsuccessful
None
TIPS day after
Died after 1 year
(2)
Few months
(Delayed) Bolus of 10 mg 40 mg/h 50 mg/2 h
Systemic
HV, IVC, PV, SMV (marked); þþ þ; major
Unsuccessful
None
–
Died day after
(3)
3 weeks
(Early) 0.5 mg/h for 24 h
Local (hepatic vein)
HV (mild); þ; minor/short
Successful
None
–
9 years
(4)
3 weeks
(Early) Bolus of 5 mg 1 mg/h for 48 h
Hepatic artery
HV, IVC (moderate); þþ ; major
Unsuccessful
None
TIPS 7 days after
4 years
(5)
Several weeks
(Delayed) Bolus of 10 mg 2 mg/h for 72 h
Systemic
HV, IVC (moderate); þþ ; major
Partially successful
Bruise over sternal aspiration site
Meso-caval shunt 10 days after
10 years
(6)
Few weeks
(Early) Bolus of 5 mg 1 mg/h for 48 h
Local (hepatic vein and IVC)
HV (mild); þ; short/minor
Successful
None
–
6 years
(7)
3 Weeks
(Early) 1 mg/h for 96 h
Local (hepatic vein)
HV (mild); þ; major
Unsuccessful
None
Mesocaval shunt 2 day after
7 year
(8)
4 weeks
First time: (delayed) Bolus of 5 mg 1 mg/h for 48 h Second time: (early) 0.5 mg/h for 96 h
First time: local (hepatic vein and IVC)
HV, IVC (moderate); þþ ; major/short
Initially failed
None
–
8 years
Second time: local; (hepatic vein and IVC)
HV, IVC (moderate); þþ ; major/short
Then successful
None
3 weeks
S. Sharma et al. / Journal of Hepatology 40 (2004) 172–180
Patient
1 year Bleed from neck sheath Successful Local (TIPS)
None Later completely successful Local (SMV)
175
vein segments was used when the hepatic veins could not be entered from the IVC but were visibly present on ultrasound [23]. The femoral approach to the IVC was also used in selected cases. Percutaneous liver biopsy was not generally done as patients had ascites and were candidates for thrombolysis and anticoagulation. After fluoroscopic placement of 5f multiple side hole infusion catheter in the target vein, the infusion was started in the angio suite and later continued in liver ITU. Patients were monitored for vital signs and bleeding complications. For systemic infusion a peripheral IV line in the arm was used. Hepatic artery infusion was performed by a 5f catheter placed in the common hepatic artery. Resolution of the thrombus was assessed by injecting contrast through the catheter used for local thrombolysis. Once a satisfactory venogram was obtained and balloon angioplasty/stenting completed, the catheter was removed. Early in our series thrombolysis was used as a sole therapy, but more recently it has been used in combination with other recanalisation procedures. Thrombolysis was indicated when venography suggested significant intraluminal thrombus complicating or preventing adequate restoration of venous flow. If the vein rethrombosed or failed to display a wide and smooth lumen, thrombolysis was continued or repeated. Balloon angioplasty and/or stent insertion were also performed and repeated as required. Patients were discharged from hospital 1–3 weeks after treatment and followed up at 3 month intervals or sooner if indicated. At the follow-up visits, physical examination and liver function tests and ultrasound were done. Contrast venography and pressure measurements were repeated if there was any clinical or ultrasound suggestion of rethrombosis or narrowing, reversed or poor venous flow. Patients with TIPS were followed up by ultrasound with routine venography at 12 months or earlier if there were clinical or ultrasound signs of stenosis or occlusion. The underlying thrombotic disorder was sought in all patients and appropriately trated.
Nil
1 year Nil Initial success temporary Local (TIPS)
None
Result Site of infusion
Complication related to thrombolysis
Rescue procedure
Follow-up time
S. Sharma et al. / Journal of Hepatology 40 (2004) 172–180
3. Results
3.1. Thrombolysis **Thrombosis discovered during routine follow-up in asymptomatic patient.
Bolus 5 mg (not known) 1 mg/h for 48 h ** Protein C deficiency
8 weeks
(10) 27/F
First time: (late) Bolus 5 mg 1 mg/h for 6 days Second time: (late) Bolus 5 mg 0.5 mg/h for 48 h 7 weeks Essential thrombocythaemia (9) 29/F
tPA regimen and time elapsed since starting therapy Length of history Primary disease Patient, age/sex
Table 3 Characteristics of two BCS patients with thrombosed TIPS, treated by thrombolysis
Eight surviving patients have been followed up for 1– 9 years (mean 4.5 years).
3.1.1. Non-TIPS patients Eight patients (nos. 1 – 8, Tables 1A and 2) had thrombolysis either before or after their initial interventional radiology investigation and treatment. Three patients had successful radiological dilatation/recanalisation procedures of HV and/or IVC (nos. 3, 6 and 8). One procedure (no. 5) was partially successful in reducing IVC thrombus such that surgical mesocaval shunt could be performed. One patient (no. 2) died the day after thrombolysis commenced. TIPS (patients 1 and 4) and mesocaval shunt (patient no. 7) were definitive treatments after angioplasty and thrombolysis proved unsuccessful in the other three patients. 3.1.2. Following TIPS for Budd Chiari syndrome Patients 9 and 10 had TIPS performed for treatment of Budd Chiari and later developed thrombosis of TIPS and portal vein. They were successfully thrombolysed and recanalised (Tables 1B and 3). A large thrombus occluding the TIPS was discovered during routine follow-up ultrasound in one patient (no. 10) while clinically asymptomatic.
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Table 4 Characteristics of reported cases of thrombolytic therapy in BCS Number of cases, age/sex
Primary aetiology
Length of history
Agent, regimen and time elapsed in starting therapy
Site of infusion
Extent of thrombosis
Result
Complication related to procedure
Follow-up duration
Assisted recanalisation procedure
Greenwood et al. [7]
1, 41/M
?
?
Urokinase: (not known) Bolus 4400 U/kg 4400 U/kg/h for 55 h
Local (IVC)
Mild; þ
Successful
Intraperitoneal haemorrhage
Well at 1 year, died 18 months after
Nil
Cassel et al. [6]
1, 46/F
Polycythaemia vera
3 months
Streptokinase: (delayed) Bolus 600,000 U 100,000 U/h for 96 h
Systemic
Mild; þ
Successful
Mild pyrexia
12 months
Nil
Guerin et al. [10]
1, 34/M
Recent pregnancy and oral contraceptives
?
Streptokinase: (not known) Bolus of 250,000 U 150,000 U/h/48 h; Lys-plasminogen 100 mg/2 h 160,000/h/48 h
Systemic
Mild; þ
Successful
None
?
Nil
Warren et al. [5]
1, 22/F
Oral contraceptives
?
Streptokinase: (not known) 250,000 U/h 100,000 U/h/72 h
Systemic
Moderate; þþ
Successful
Recurrent pulmonary emboli
4 months
Nil
Sholar [8]
2, 33/F
PNH
Case 1: 5 days
Case 1 (first time) Streptokinase: (early) 7500 U/h, then 5000 U/h (total 72 h) (Second time, 2 months after) Urokinase: (delayed) 250,000 U/40 min 250,000 U/2 h Case 2 Streptokinase: (early) 250,000 U/30 min 100,000 U/h/48 h
Case 1 First time: local (hepatic vein)
Marked; þþþ
Successful
None
Case 1: 2 years
Nil
Second time: systemic
Moderate; þþ
Successful
Case 2: systemic
Moderate; þþ
Successful
None
Case 2: 5 years
Nil
Case 1: tPA 30 mg/24 h (early) Case 2: tPA First time 15 mg/3 h (delayed) Second time (after 9 days) 24 mg/48 h (delayed) Third time (after 2 days) 25 mg/3 h (delayed) Then, 50 mg/24 h
Case 1: systemic
Moderate; þþ
Successful
None
Nil
Case 2: Systemic
Mild; þ
Unsuccessful
None
Case 1: 6 years Case 2: 2 years
Hepatic artery
Mild; þ
Unsuccessful
Systemic
Mild; þ
Successful
Local (IVC)
Mild; þ
Successful
12 months
Nil
33/M
McMullin et al. [15]
Raju et al. [16]
Case 2: 7–10 days
2, 33/F
PNH
22/F
PNH
1, 59/M
?
Case 1: 3 weeks Case 2: several weeks
Few hours
Urokinase: (early) 300,000 U bolus 300,000 U/h for 72 h
None
Nil
S. Sharma et al. / Journal of Hepatology 40 (2004) 172–180
Author
Nil
IVC and HV Angioplasty
Died 10 days after
Died 9 months after
3.1.4. Outcome versus route of infusion None of the three systemic infusions were completely successful. An infusion into the hepatic artery failed to restore flow in the hepatic veins in one patient. Systemic infusion in one patient (no. 5) in whom the patency of hepatic veins could not be restored, cleared the IVC of thrombus and enabled mesocaval shunt surgery with an excellent long-term outcome. Of five local infusions in four patients, three patients were ultimately successful treated by thrombolysis and dilatation/stenting. Local infusion into thrombosed TIPS/portal vein was successful in two patients. 3.1.5. Outcome versus length of history (age of thrombus) No success could be achieved in a patient (no. 1) in whom the length of history was unknown but presumed long. No success was achieved in a patient (no. 2) with a history of several months. All other patients had symptoms ranging from a few to several weeks duration. Four (nos. 3, 6, 8 and 9) of these were treated successfully, one (no. 5) had partial success and two (nos. 4 and 7) were unsuccessful. One patient (no. 8) with a few weeks history did not respond until the hepatic veins were recanalised by transhepatic balloon dilatation.
?, not known; *, IVC markedly narrow and calcified.
Partially successful Moderate; þþ Local (IVC) 1, 29/F Ilan et al. [11]
Post-partum
Few days
Streptokinase: (early) for 72 h (dose?)
Partially successful Mild; þ Systemic tPA: (early) 100 mg over 3 h 2 weeks PNH 1, 47/F Kwan et al. [14]
177
3.1.3. Outcome versus assisted recanalisation procedure An appropriate adjunctive procedure (balloon dilatation or stenting of HV/IVC) was used to ensure improved blood flow before (nos. 6 and 7) or after (nos. 3 and 8) thrombolysis in all four patients in whom local infusion was made. Three patients had a successful outcome. In one patient (no. 7) the patency of the HV could not be maintained during thrombolysis even after HV dilatation.
None
Nil 9 months Successful Systemic 1, 26/F McKee et al. [9]
Post-partum
3 weeks
Streptokinase: (early) Three injections: 10 mg, 10 mg, 5 mg (total 25 mg)
Mild; þ
None
IVC angioplasty and stenting 14 months None Successful Moderate; þþ 1, 42/F Ishiguchi et al. [9]
PNH
Chronic* (several months)
Local (IVC)
Successful Mild; þ Systemic
Urokinase: (delayed) 10,000 U/min for 35 min Then 240,000 U/day for 7 days
Successful temporary Moderate; þþ 1, 29/F De Stefano [12]
PNH With pregnancy
?
tPA first time: (not known) 50 mg/5 h Same repeated after 48 h Second time: (not known) 50 mg/5 h Same repeated after 48 h
Systemic
Mild wheeze
Nil Severe haematuria
? (Caesarean delivery at 33 weeks) Well at 2 weeks
S. Sharma et al. / Journal of Hepatology 40 (2004) 172–180
3.1.6. Outcome versus length of venous stenosis Two patients (nos. 3 and 8) had short focal stenoses due to ‘webs’ in the hepatic vein and IVC, respectively. The short length of occlusion was only appreciated after the diffusely thrombosed lumen was satisfactorily cleared. Hepatic vein balloon angioplasty and thrombolysis was very effective in one patient (no. 3). Extensive IVC thrombosis below a web (patient no. 8) was treated by serial thrombolysis and balloon dilatation. The central hepatic vein in this patient remained occluded even after IVC clearance and was recanalised 8 days later by a combined transhepatic/transjugular dilatation procedure. Patient 6 also had a short length occlusion of the hepatic vein confluence, which was traversed, dilated and stented prior to an acute thrombosis, which then responded to thrombolysis. These three patients have had excellent longterm clinical benefit. In contrast, patient 7 had very extensive thrombosis of hepatic veins and failed to respond to thrombolysis and angioplasty. 3.1.7. Outcome versus extent of thrombosis Eight procedures were employed for thrombosis that was graded as mild or moderate in extent, i.e. either only
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hepatic veins involved or hepatic veins and IVC were thrombosed. Those with a smaller amount of thrombus in the hepatic veins (patients 3 and 6) did well. Patient 8 initially had very extensive IVC thrombus and short length occlusion of hepatic veins, which were ultimately successfully treated by thrombolysis and dilatation. One patient (no. 2) who had extensive thrombotic occlusion of all hepatic veins, spleno-portal-mesenteric axis and had extensive gastro-esophageal varices succumbed despite aggressive thrombolytic therapy. 3.1.8. Outcome versus treatment of underlying hematological condition All patients were treated for the underlying cause of thrombosis. In one patient (no. 9), local infusion made into the TIPS and portal vein resulted in a slow recanalisation that persisted only for the next 8 weeks. Essential thrombocythaemia was only diagnosed at this stage. Repeat local thrombolysis with balloon dilatation along with the specific anti-platelet treatment, resulted in a more prolonged patency. 3.1.9. Complications Only two patients developed minor bleeding complications (Tables 2 and 3). None required transfusion. In one patient (no. 10) the treatment was stopped after ooze around the neck sheath, but thrombolysis was complete by this time.
4. Discussion We describe the successful use of thrombolysis in five patients when deployed in association with repermeation of thrombus within recanalised hepatic veins, inferior vena cava or TIPS. Success may be attributable to more than one factor. Firstly, the thrombus was recent in origin and of known age particularly when it followed diagnostic or therapeutic interventional radiology. Secondly, thrombolysis was instituted immediately after mechanically reestablishing venous patency. Maintenance of flow through the thrombosed vein appears critical to the success of the technique. When hepatic venous outflow obstruction is complete, blood is likely to bypass the severely congested liver via retrograde flow in the portal vein and/or collaterals and there will be poor contact of systemically administered thrombolytic drug to the thrombosed hepatic veins. Local thrombolysis also requires some local blood flow to maintain and improve the patent channel. Thirdly, local infusion into the vein immediately proximal to or within the thrombus achieves high concentrations of the thrombolytic agent around the thrombus. Reduction of portal pressure by recanalisation procedure immediately before thrombolysis also reduces the risk of a complicating variceal haemorrhage.
Thrombolysis can be repeated after previously successful or unsuccessful treatment. TIPS or shunt surgery can be done after thrombolysis fails. Indeed three of our patients who had failed thrombolysis were successfully salvaged by TIPS and shunt surgery. In one of the patients, whom the HVs remained occluded after thrombolysis, a surgical mesocaval shunt could be created because of repermeation of the previously occluded vena cava. Vena caval occlusions have been treated with combinations of local thrombolysis, balloon angioplasty and metallic stent(s) [13]. Local thrombolysis via the transjugular and transhepatic approach has been used successfully in early post-liver transplant portal vein thrombosis [24,25]. Blum et al. [26] recently reported the successful placement of TIPS followed immediately by local low dose thrombolysis in seven cirrhotic patients with portal vein thrombosis, without complication. Before the administration of the thrombolytic therapy, balloon angioplasty was performed in the thrombosed main portal vein to restore some patency. Portal vein blood flow could not be established with mechanical means alone. Mechanical thrombectomy using an Amplatz Thrombectomy Device (ATD) is recently reported as a useful complementary technique in patients with thrombosis of large native vessels, grafts or TIPS shunts where thrombolysis alone has either failed or is contraindicated [27,28]. While hepatic decompression is immediate after TIPS or surgical shunt, thrombolysis produces a slow improvement. TIPS is now established as an effective treatment for variceal bleeding and ascites and also for selected cases of BCS [29]. TIPS is generally accepted to have a significant risk of stenosis or occlusion but Budd Chiari patients may have a potentially greater risk especially if there is an aggressive underlying thrombotic tendency. Our two patients show that thrombolysis can have a beneficial role in combination with balloon dilatation and/or restenting in completely occluded thrombosed TIPS in Budd Chiari patients. Both local and systemic administration of thrombolytic drugs have been used in the treatment of BCS. There are no studies directly comparing the efficacy of local versus systemic infusion. Catheter directed infusion is of proven efficacy in arterial and venous thrombosis [30]. We used the hepatic artery to deliver tPA for 2 days in one of our patients with blocked HVs with no success. tPA infusion into the hepatic artery was used by Mc Mullin et al. [15] to no advantage in their patient after initially failed systemic infusion. Success with systemic infusion of thrombolytic agents has been described [5,6,8 – 10,12,15], but we had partial success only in one of our patients. Surgical thrombectomy is usually not technically possible in BCS patients to restore flow [31]. No data is available to direct the choice of thrombolytic agent in the setting of BCS. tPA is a natural human enzyme with no antigenicity. It has a very short half-life of 5 min and may be discontinued if bleeding occurs. tPA was
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reported to be most effective and produced earlier reperfusion following pulmonary embolism [32]. In the treatment of acute myocardial infarction, the accelerated regimen using tPA offers a small advantage over streptokinase (SK) in lysing clots from the coronary arteries but with a marginally higher incidence of stroke [33]. Urokinase or tPA should be preferred in a patient who has high levels of circulating antistreptococcal antibodies due to previous SK administration. tPA is more expensive than SK per therapeutic dose. Thrombolysis in advanced age is associated with increased risk of bleeding complications [34]. BCS patients tend to be younger and therefore more likely to withstand thrombolytic therapy without complication as compared to those treated for myocardial infarction or stroke. The thrombus ‘load’ may have a bearing on the eventual outcome of thrombolysis [13]. It is known that the patients with massive thrombus have a poorer prognosis [35]. In our experience the finding of a short underlying occlusion or stenosis increased the chance of eventual clinical success for thrombolysis/recanalisation even when it was associated with a large amount of thrombus occluding or partially occluding the veins. This is a retrospective, observational study in a small number of patients. The patients treated are heterogeneous in terms of their clinical presentation, extent of thrombosis, chronicity, underlying etiologies, risk factors, and thrombolytic dosage regimens used. In most published reports the thrombolytic treatment was primary, whereas in our cases it was often adjunctive. We propose that thrombolysis has an important role in the management of acute and subacute forms of BCS in selected patients in combination with other interventional radiological techniques. Local infusion into partially recanalised veins with some appreciable flow is best. It is potentially repeatable and does not preclude other more invasive treatments. As an adjunct, thrombolysis is best employed in a patient who presents early, has a thrombus that is limited in extent and not completely occlusive. Close clinical, imaging and laboratory followup along with appropriate treatment of underlying haematological disorders can ensure improved long-term venous patency and hence patient survival. Thrombolysis alone especially when systemically administered appears of limited value, contrary to the earlier literature. Pooling and analysis of data from other centres is needed before more extensive conclusions and recommendations can be made.
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