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Keywords:

  • inflammatory bowel disease;
  • thromboembolism;
  • thrombolytic therapy;
  • gastrointestinal hemorrhage;
  • colitis

Abstract

  1. Top of page
  2. Abstract
  3. MATERIALS AND METHODS
  4. RESULTS
  5. DISCUSSION
  6. CONCLUSION
  7. Acknowledgements
  8. REFERENCES

Background:

Thromboembolism (TE) is a common extraintestinal complication of inflammatory bowel disease (IBD). Catheter-directed thrombolysis (CDT) is being increasingly used to treat TE but often evokes fears of hemorrhagic complications (HCs) in patients with IBD. We reviewed clinical outcomes with anticoagulation (AC) and CDT in IBD patients with TE.

Methods:

Published cases of IBD patients with TE were identified by a PubMed search. Cases were divided into two groups based on treatment modality: AC alone or CDT. Pretreatment variables and treatment-related outcomes were compared between treatment groups.

Results:

Fifty-two cases of IBD-associated TE were identified. Thirty-five cases were treated with AC alone and 17 with CDT. There were no significant differences in pretreatment variables. Patients treated with CDT tended to be more likely to achieve complete or partial symptomatic (P = 0.02) and radiologic resolution (P = 0.06). Gastrointestinal (GI) and non-GI HCs tended to occur more frequently with CDT, although these differences were not statistically significant (P = 0.44 and 0.15, respectively).

Conclusions:

CDT and AC both appear to be well tolerated by IBD patients with TE. CDT may be used preferentially in patients with life-threatening TE, while AC may be preferable in patients with less clinically significant TE or patients at higher risk for bleeding. Further prospective studies are warranted to confirm these results and more definitively identify the best therapeutic approach for patients with IBD-associated TE. (Inflamm Bowel Dis 2011;)

Thromboembolism (TE) is a well recognized extraintestinal complication of inflammatory bowel disease (IBD).1 The pathogenesis of TE in IBD patients is complex and is likely precipitated by a combination of prothrombotic alterations in coagulation factors (e.g., elevated factor VIII) and endogenous antithrombotic proteins (e.g., decreased free protein S) as well as vascular endothelial changes secondary to the underlying inflammatory process. The annual incidence of IBD-associated TE has been estimated to be ≈0.1%–0.5% per year, with an overall mortality rate as high as 25% per episode.2, 3 Given rising hospital admission rates for IBD and the TE risks associated with hospitalization, it is likely that the incidence, morbidity, and mortality of IBD-associated TE will continue to increase in the future.4, 5

It remains unclear which therapy for IBD-associated TE offers the best balance between efficacy and safety. This uncertainty is in part due to variables such as the anatomical site of TE, the overall clinical stability of the patient, and provider or institutional experience with different therapies. Conservative treatment (e.g., bowel rest, corticosteroids, and/or antibiotics) may be ineffective and lead to devastating thromboembolic sequelae, while surgical treatment is not generally feasible in many instances and is fraught with considerable risk. More recently, antithrombotic therapies such as anticoagulation (AC) and catheter-directed thrombolysis (CDT) have been employed. However, antithrombotic therapy in patients with IBD often raises concern over the potential for gastrointestinal (GI) or systemic hemorrhagic complications (HCs).

Previously, we found outcomes with CDT for TE to be comparable in patients with and without IBD.6 The purpose of the current literature review is to examine the outcome of IBD patients with TE treated with CDT versus AC in order to help guide clinicians caring for this unique patient population.

MATERIALS AND METHODS

  1. Top of page
  2. Abstract
  3. MATERIALS AND METHODS
  4. RESULTS
  5. DISCUSSION
  6. CONCLUSION
  7. Acknowledgements
  8. REFERENCES

IBD-Associated Thromboembolism Case Search Criteria and Organization

We searched PubMed for letters, case reports, case series, and original studies of IBD-associated TE in the English, Spanish, Portuguese, French, and German language literature from January 1997 to January 2007 using the following search criteria: “Colitis, Ulcerative” [MeSH] AND “Thrombosis” [MeSH], “Crohn Disease” [MeSH] AND “Thrombosis” [MeSH], “Inflammatory Bowel Diseases” [MeSH] AND “Thrombosis” [MeSH], “Colitis, Ulcerative” [MeSH] AND “Thromboembolism”[MeSH], “Crohn Disease” [MeSH] AND “Thromboembolism” [MeSH], “Inflammatory Bowel Diseases” [MeSH] AND “Thromboembolism”[MeSH], “Colitis, Ulcerative”[Mesh] AND “Thrombolytic Therapy” [MeSH], “Crohn Disease” [Mesh] AND “Thrombolytic Therapy” [MeSH], “Inflammatory Bowel Diseases” [MeSH] AND “Thrombolytic Therapy” [MeSH], “Ulcerative Colitis Thrombolysis,” “Crohn's Disease Thrombolysis,” and “Inflammatory Bowel Disease Thrombolysis.” We supplemented this electronic search with a hand-search of references from all of the publications identified by these search criteria. Due to the large number of cases treated with AC and the small number of cases treated with CDT, we expanded the search for CDT cases to include all published cases.

Using a standardized data collection form, demographic and clinical data were collected including TE-treatment regimen, radiologic and symptomatic outcomes, treatment-related HCs, new or progressive TE, and death. Cases were excluded if they: 1) did not have information on the treatment regimen, 2) were not treated with CDT or AC, 3) did not have information on the radiologic and/or symptomatic outcome, 4) had concomitant surgical treatment or systemic thrombolysis, or 5) were due to septic thrombophlebitis. Cases were not excluded if: 1) there was no mention of HCs, new TE, or death, as it was assumed that these discrete, treatment-related outcomes would be reported if they had occurred, and 2) an unspecified dose of anticoagulant (most commonly unfractionated heparin [UFH]) was used, as it was assumed that therapeutic, not prophylactic dose, AC would be employed in the treatment of TE.

Two treatment groups were defined a priori: 1) CDT (with or without AC), and 2) AC only cases. If initial treatment consisted of AC only but rescue CDT was later used, then the modality-specific case outcomes would be included in both the AC only and CDT group, each with its respective outcomes. For example, if AC was used initially and CDT was subsequently required, AC would be deemed a failure and CDT would be assigned the ultimate outcome.

If all the retrieved literature cases pertaining to a particular anatomic area were treated with only one treatment modality (e.g., thoracocervical venous, splanchnic arterial, and coronary arterial TE), all the cases for that anatomic area were excluded since comparative outcomes for each of the treatment modalities would not be available. Cases conforming to the inclusion and exclusion criteria were classified according to treatment modality and stratified by the anatomic site of TE.

Outcomes and Definitions

Demographic and clinical variables consisting of age, sex, IBD type, IBD activity, presence of pre-TE treatment hematochezia, presence of prothrombotic risk factors, and the site of TE were recorded. Treatment-related variables and outcomes were also recorded, as explained below.

“Radiologic outcome” was divided into three categories: complete (grade III lysis), partial (grade II lysis), and no (grade I lysis) resolution. While complete resolution and no resolution were quantified objectively by the respective authors, we chose to define “partial” (grade II) resolution as >50% (but not complete) radiologic resolution, and in cases where a percent value was not provided, “significant,” “substantial,” “good,” or “fair” radiologic resolution were considered surrogates for “partial.”

“Symptomatic outcome” was similarly divided into three categories: complete resolution, partial resolution, and no resolution. Partial resolution was subjectively defined as cases with “significant,” “substantial,” “good,” or “fair” symptomatic resolution.

If data on either the radiologic or symptomatic outcome were not provided, this outcome was designated as not available (“NA”) in the evidence tables. If neither of these two outcomes was reported, the case was excluded from this study, as described previously.

“Treatment-related bleeding” (HCs) was separated into GI versus non-GI sites. These events were recorded as discrete (yes or no), as were “new or progressive TE” and “death.” Treatment-related non-GI bleeding was defined, based on the International Society of Haemostasis and Thrombosis criteria for major bleeding, as blood loss that resulted in a decline in the hemoglobin of 2 g/dL or more or required transfusion of two or more units of blood, or intracranial, retroperitoneal, or intraocular bleeding.7 Treatment-related GI bleeding was defined as new or subjectively worsened hematochezia. A new TE event was defined as an objectively documented TE that occurred in a noncontiguous vascular location, and progressive TE was defined as an objectively documented extension of the existing TE. If the source case did not mention bleeding, TE complications (such as new or distal TE), or death, it was assumed that these outcomes did not occur.

Data Analysis

Chi-square test or Fisher's exact test, as appropriate based on group and cell size, was used to identify baseline differences in discrete variables between treatment groups. Analysis of variance was used to assess for differences in age.

Treatment-related outcomes were compared between the two treatment groups with respect to 1) the specific anatomic areas of involvement (for detailed information) and 2) the aggregate of anatomic areas (for better overall clinical impression). P < 0.05 was considered statistically significant.

RESULTS

  1. Top of page
  2. Abstract
  3. MATERIALS AND METHODS
  4. RESULTS
  5. DISCUSSION
  6. CONCLUSION
  7. Acknowledgements
  8. REFERENCES

Demographic Variables

A total of 52 cases of IBD-associated TE were identified, including 17 cases treated with CDT (two of which had initially failed AC alone8, 9)10–21 and 35 with AC alone (intravenous UFH in 22 cases, low molecular weight heparin [LMWH] in nine cases, warfarin in two cases, and unspecified AC in two cases).9, 22–49 The median age was 29 (range 12–74) years and 32 patients (64%) were female. Of the cases with sufficient information, 78% had ulcerative colitis, 81% had active IBD, 42% had pretreatment hematochezia, 33% had an acquired prothrombotic risk factor (aside from active IBD), and up to 35% had an identified (inheritable) thrombophilia. All patients were hospitalized for their IBD and/or TE disease.

The demographic and clinical characteristics of the two treatment groups are presented in chronological order in Table 1a,b and summarized in Table 2. There were no statistically significant differences in demographic or clinical characteristics.

Table 1a. Demographics and Clinical Characteristics of Patients Treated with Catheter-Directed Thrombolysis
Ref.Age (years)SexIBD typeActive IBDHematocheziaThrombophiliaaAcquired Thrombotic RiskaSite of TE
  • APA = Antiphospholipid syndrome, CD = Crohn's disease, F = Factor, Fgn = fibrinogen, Hematochezia = pre-treatment hematochezia, IBD = Inflammatory bowel disease, IVC = Inferior vena cava, L = left, Mdn = median, NA = not available or not specified, OCP = Oral contraceptives, Pr = Protein, R = right, Ref = reference, SM = Superior mesenteric, SSS = Superior sagittal sinus, UC = Ulcerative colitis.

  • a

    Does not include active IBD.

  • b

    Likely relative deficiency during thrombosis, as levels later normalized.

  • c

    Measured during and likely related to acute thrombosis; not confirmed by repeat testing.

  • d

    No repeat values obtained; does not meet diagnostic criteria for Antiphospholipid syndrome.

 833FUCYesNoHigh F VIIIc and FgncNoIVC, R. Renal vein
1043FUCNoNoNANASSS, Cortical vein
1128FCDYesNoNoNoL. Renal vein
1240FUCYesYesLow ATIII and High F VIIIcNoMain and R. portal and SM vein
 914FUCYesNANoNoSSS, R. Vein of Labbé
1323FUCNANANANASSS, Deep cerebral vein
1334FUCNANANANASSS, Deep cerebral vein
1329MUCNANANANASSS, Cortical vein
1450FCDYesNAAPAdOCPR. Popliteal artery
1535FUCNANANoNoSSS
1514FNANANANoNoSSS, Deep cerebral vein
1618FUCYesNoLow ATIIIbNoR. Iliac and femoral veins
1744MCDNoNoNoNoPortal, splenic, and SM veins
1842MUCYesYesNANAPortal vein
1943FUCNANANoOCPSSS, Transverse sinus
2027FUCYesNoAPAd, low Pr COCPBilateral Iliofemoral arteries
2125MCDNoNoNoNoR. Popliteal artery
n = 17Mdn = 33%F = 76%UC = 75%Yes = 73%Yes = 25%Yes = 42%Yes = 25 
Table 1b. Demographics and Clinical Characteristics of Patients Treated with Anticoagulation
RefAge (years)SexIBD typeActive IBDHematocheziaThrombophiliaaAcquired Thrombotic RiskaSite of TE
  • APA = Antiphospholipid syndrome, APC = Activated Protein C, ATIII = Anti-thrombin III, CD = Crohn's disease, DVT = Deep vein thrombosis, F = Factor, Fem-Pop = FemoropopliteaI, Fgn = fibrinogen, Hcy = homocysteine, Hematochezia = pre-treatment hematochezia, heterozyg = heterozygous, IBD = Inflammatory bowel disease, IVC = Inferior vena cava, L. = left, NA = not available or not specified, Mdn = median, OCP = Oral contraceptives, PAI = Plasminogen activator inhibitor, Pr = Protein, Prothr gene = Prothrombin G20210A mutation, R. = right, Ref = reference, SM = Superior mesenteric, SSS = Superior sagittal sinus, TV = Transverse, UC = Ulcerative colitis.

  • a

    Does not include active IBD.

  • b

    Likely relative deficiency during thrombosis, as levels later normalized.

  • c

    Measured during acute thrombosis, not confirmed by repeat testing.

  • d

    No repeat values obtained; does not meet diagnostic criteria for Antiphospholipid syndrome.

  • Same patient had TE in two distinct anatomic areas; therefore, 34 patients, 35 cases/anatomic areas.

 833FUCYesNoHigh F VIIIc and FgncNoIVC, Renal veins
2218MUCYesYesNoNoL. Lateral sinus
2335FUCYesYesNoNoSS, TV, and Sigmoid sinuses
2426FUCYesNoNoCigarettesSS & L. TV & Sigmoid sinus
2532FUCYesYesNoNoHepatic, Portal, and SM veins
2612FUCNANANoRecent surgeryPortal vein
2723FCDYesNANoNoPortal, SM, and Splenic veins
2853MUCYesYesF V Leiden heterozyg.NoSS and R. TV sinus
2918FCDNoNoNoNoPortal vein
3048FUCYesNAHigh F VIIIc and FgncNoL TV and Sigmoid Sinus
31b22FUCYesNoHigh FgncNoL. Fem-pop veins and arteries
3214FUCYesYesHigh FgncNoColonic arterioles, hepatic vein
3329MUCYesNoNoCigarettesPortal and SM vein
3420MCDYesYesNoNoSS and L. TV sinus
3538FUCYesYesLow Pr C, S, and ATIIIbNoHepatic vein
3661MUCNoNoNoPrevious DVTSM vein
3763MUCNoNoNoPrevious DVTSM vein
3731FUCYesNANoRecent surgerySM vein
3838FCDYesNAProthrombin G20210ARecent surgerySM vein
3850MUCYesNANoRecent surgerySM vein
3839FCDYesNoNoCigarettesR. Brachiocephalic vein
3920FUCYesNAAPAdNoSS and bilateral TV sinuses
 914FUCYesNANoNoSSS, R. Vein of Labbé
 913FUCYesNAHigh Hcy, Prothr geneNoSS, L. TV, and Sigmoid sinuses
 929MUCYesNoNoNoSS, L. Lateral, Sigmoid sinuses
4017FUCYesYesNoOCPSSS, superficial cortical veins
4129MCDYesNANoNoPortal vein
4230MUCYesYesNoNoSSS
4352MUCYesNAAPAdNoHepatic vein
4419MUCNoNoNoNoLeft transverse sinus, Superior longitudinal sinus
4574MCDYesNANoNoL. lower extremity artery
4626FUCNoNoNoPrevious DVTL. Sylvian vein
4715MUCYesYesNoNoHepatic vein
4830FUCYesYesHigh Hcy and FgncOCPSSS
n = 35Mdn = 29%F = 60%UC = 80%Yes = 85%Yes = 48%Yes = 32%%Yes = 35%NA
Table 2. Summary of Demographic and Clinical Characteristics of the Two Treatment Groups
GroupnMedian Age (years)%Female%UC%Active IBD%Hematochezia%Thrombophiliaa%Acquired Thrombotic Risk
  • AC = Anticoagulation group, CDT = Catheter-directed thrombolysis group, Hematochezia = pre-treatment hematochezia, IBD = Inflammatory bowel disease, UC = ulcerative colitis.

  • a

    Does not include active IBD.

  • b

    Same patient had TE in two distinct anatomic areas; therefore, 34 patients, 35 cases/anatomic areas.

CDT1733767573504225
AC35b29608085483235
Total5029647881443533

Treatment Outcomes

Overview of Treatment-Related Variables and Outcomes

Table 3a,b contains information on treatment-related variables for all cases in the two treatment groups arranged in chronological order. The following two subsections examine the treatment outcomes in greater depth.

Table 3a. Treatment and Outcomes in Patients Treated with Catheter-Directed Thrombolysis
RefTreatmentRadiologic ResolutionSymptomatic ResolutionTreatment-Related Bleed
  • LMWH = low molecular weight heparin, NA = not available or not specified, Ref = reference, TNK = tenecteplase, tPA = tissue plasminogen activator, UFH = unfractionated heparin, UK = Urokinase.

  • a

    Complete or partial resolution.

 8TNK and UFHPartialCompleteNo
10tPA and UFHCompletePartialNo
11tPA and UFHCompleteCompleteNo
12tPAPartialCompleteWorsened hematochezia, intracerebral hemorrhage
 9UK and UFHNAPartialNo
13UKNAPartialNo
13UKNACompleteNo
13UKNAPartialNo
14UKPartialCompleteNo
15UK and UFHPartialCompleteNo
15UK and UFHCompleteCompleteNo
16tPA and UFHPartialPartialNo
17tPAPartialCompleteNo
18tPACompleteCompleteNo
19UK and UFHPartialPartialNo
20UK and UFHPartialPartialDeveloped hematochezia
21UKCompleteCompleteNo
n = 17 13/13 (100%)a17/17 (100%)a2/17 (12%)
Table 3b. Treatment and Outcomes in Patients Treated with Anticoagulation Alone
AuthorTreatmentRadiologic ResolutionClinical ResolutionTreatment-Related Bleed
  • AC = unspecified anticoagulation, LMWH = low molecular weight heparin, NA = not available or not specified, Ref = reference, UFH = unfractionated heparin.

  • a

    Complete or partial resolution.

  • b

    Same patient had TE in two distinct anatomic areas; therefore, 34 patients, 35 cases/anatomic areas.

  • c

    Patient died.

 8UFHPartialNoneNo
22UFHCompleteCompleteNo
23UFHPartialNANo
24UFHNoneNonecNo
25UFHNoneNoneNo
26UFHCompleteNANo
27UFHCompleteCompleteNo
28LMWHNoneNonecNo
29UFHNANoneNo
30UFHNAPartialNo
31bLMWHNACompleteNo
32LMWHCompleteCompleteWorsened hematochezia
33UFHCompleteCompleteNo
34WarfarinNAPartialNo
35UFHCompleteCompleteNo
36UFHCompleteCompleteWorsened hematochezia
37ACNACompleteNo
37ACNACompleteNo
38UFHCompleteCompleteNo
38UFHCompleteCompleteNo
38UFHCompleteCompleteNo
39LMWHNonePartialNo
 9LMWHCompleteCompleteNo
 9UFHNANoneNo
 9LMWHCompleteCompleteNo
40LMWHPartialCompleteNo
41LMWHPartialCompleteNo
42UFHNoneNoneNo
43LMWHNACompleteNo
44UFHNAPartialNo
45UFHNACompleteNo
46UFHCompleteCompleteNo
47WarfarinNAPartialNo
48UFHNACompleteNo
49UFHNANoneWorsened hematochezia
n = 35 17/22 (77.3%)a25/33 (75.8%)a3/35 (9%)
Outcomes by Anatomic Area

Cases were stratified into the following anatomic areas: Cerebral venous, Splanchnic venous, Renal venous/Reno-Caval, Extremity deep venous, and Extremity arterial. The outcomes for each anatomic area, although not subjected to statistical analysis due to small group sizes, are summarized in Table 4a–e, respectively. The denominator in some cells (columns) was smaller than the total group size for some groups (rows); this was due to lack of information for a given outcome in that group.

Table 4a. Treatment Outcomes with Cerebral Venous Thromboembolism
GroupnRadiologic ResolutionSymptomatic ResolutionTreatment Related GI BleedingTreatment Related Non-GI BleedingNew or Distal TEDeath
CDT8Complete: 2/4 (50%)Complete: 3/8 (38%)0/8 (0%)0/8 (0%)0/8 (0%)0/8 (0%)
  Partial: 2/4 (50%)Partial: 5/8 (62%)    
AC15Complete: 3/8 (38%)Complete: 7/14 (50%)1/15 (7%)0/15 (0%)0/15 (0%)2/15 (13%)
  Partial: 2/8 (25%)Partial: 3/14 (21%)    
Table 4b. Treatment Outcomes with Splanchnic Venous Thromboembolism
GroupnRadiologic ResolutionSymptomatic ResolutionTreatment Related GI BleedingTreatment Related Non-GI BleedingNew or Distal TEDeath
CDT3Complete: 2/3 (67%)Complete: 3/3 (100%)1/3 (33%)1/3 (33%)0/3 (0%)0/3 (0%)
  Partial: 1/3 (33%)     
AC15Complete: 8/9 (89%)Complete: 10/14 (71%)1/15 (7%)0/15 (0%)0/15 (0%)0/15 (0%)
  Partial: 0/9 (0%)Partial: 1/14 (7%)    
Table 4c. Treatment Outcomes with Renal Venous/Reno-Caval Thromboembolism
GroupnRadiologic ResolutionSymptomatic ResolutionTreatment Related GI BleedingTreatment Related Non-GI BleedingNew or Distal TEDeath
CDT2Complete: 1/2 (50%)Complete: 2/2 (100%)0/2 (0%)0/2 (0%)0/2 (0%)0/2 (0%)
  Partial: 1/2 (50%)     
AC1Partial: 1/1 (100%)Complete: 0/1 (0%)0/1 (0%)0/1 (0%)0/1 (0%)0/1 (0%)
   Partial: 0/1 (0%)    
Table 4d. Treatment Outcomes with Extremity Deep Venous Thromboembolism
GroupnRadiologic ResolutionSymptomatic ResolutionTreatment Related GI BleedingTreatment Related Non-GI BleedingNew or Distal TEDeath
CDT1Complete: 1/1 (100%)Complete: 1/1 (100%)0/1 (0%)0/1 (0%)0/1 (0%)0/1 (0%)
AC2Complete: 0/1 (0%)Complete: 1/2 (50%)0/2 (0%)0/2 (0%)0/2 (0%)0/2 (0%)
  Partial: 0/1 (0%)Partial: 1/2 (50%)    
Table 4e. Treatment Outcomes with Extremity Arterial Thromboembolism
GroupnRadiologic ResolutionSymptomatic ResolutionTreatment Related GI BleedingTreatment Related Non-GI BleedingNew or Distal TEDeath
CDT3Complete: 1/3 (33%)Complete: 2/3 (66%)1/3 (33%)0/3 (0%)0/3 (0%)0/3 (0%)
  Partial: 2/3 (67%)Partial: 1/3 (33%)    
AC2NAComplete: 1/2 (50%)0/2 (0%)0/2 (0%)0/2 (0%)0/2 (0%)
   Partial: 0/2 (0%)    
Select Outcomes in All Anatomic Areas Combined

Due to the small numbers of patients in each anatomic area, cases were aggregated to permit comparison of outcomes by treatment modality. Figure 1a contains the incidence of complete, partial, and no radiologic resolution for all anatomic areas combined in the two treatment groups. There was no difference in the incidence of complete or partial (P = 0.06), partial (P = 0.07), and no radiologic resolution (P = 0.06).

thumbnail image

Figure 1. (a) Incidence and degree of radiologic resolution in CDT vs. AC group. (b) Incidence and degree of symptomatic resolution in CDT vs. AC group. (c) Incidence of GI and non-GI bleeding in CDT vs. AC group.

Download figure to PowerPoint

Figure 1b contains the incidence of complete, partial, and no symptomatic resolution for all anatomic areas combined in the two treatment groups. There were significant differences in the incidence of complete or partial (P = 0.02) and no symptomatic resolution (P = 0.02). Although not shown, two patients in the AC group died despite therapy,24, 28 although this result was not statistically significant compared to the CDT group (P = 0.31).

Figure 1c contains the incidence of treatment-related GI and non-GI bleeding in the two treatment groups. HCs tended to be less frequent in the AC group, although the difference in the incidence of both GI and non-GI bleeding was not significantly different between the treatment groups (P = 0.40 and 0.15, respectively).

These results are summarized in Table 5.

Table 5. Comparison of Outcomes in CDT Group vs. AC Group
 CDTACP-value
Radiological resolution   
 Complete or partial (%)13/13 (100%)11/19 (74%)0.06
 Complete (%)7/13 (54%)11/19 (58%)0.7
 Partial (%)6/13 (46%)3/19 (16%)0.07
 None (%)0/13 (0%)5/19 (26%)0.06
Symptomatic resolution   
 Complete or partial (%)17/17 (100%)24/33 (73%)0.02
 Complete (%)11/17 (65%)19/33 (58%)0.4
 Partial (%)6/17 (35%)5/33 (15%)0.1
 None (%)0/17 (0%)9/33 (27%)0.02
Hemorrhagic complications   
 GI bleeding (%)2/17 (12%)1/17 (6%)0.44
 Non-GI bleeding (%)2/35 (6%)0/35 (0%)0.15

DISCUSSION

  1. Top of page
  2. Abstract
  3. MATERIALS AND METHODS
  4. RESULTS
  5. DISCUSSION
  6. CONCLUSION
  7. Acknowledgements
  8. REFERENCES

Epidemiology and Pathogenesis of IBD-associated Thromboembolism

TE has long been known to be one of several extraintestinal manifestations of IBD. It may occur in any vascular bed, arterial or venous, with a spectrum of outcomes ranging from subclinical to rapidly fatal consequences.3, 50

The pathogenesis of IBD-associated TE has yet to be fully elucidated. In common with all patients, recent surgery, prolonged immobilization, malignancy, central venous catheters, and estrogen use can increase thromboembolic risk in IBD patients. In the specific case of IBD patients, prothrombotic alterations affecting coagulation factors V and VIII, antithrombin III, protein S, plasminogen activator inhibitor, fibrinogen, endothelial cell adhesion molecules, and/or platelet quantity and function may also contribute to thrombotic risk.8, 51–54 Although these and other prothrombotic abnormalities have been previously described, the relative contribution of each one to IBD-associated TE is not well known.

While some of these prothrombotic abnormalities may be inherited, possibly with a greater frequency in IBD patients than in the general population, there is little question that some are acquired as a result of the underlying inflammatory state associated with IBD. This conclusion is supported by the observations that: 1) IBD-associated TE mainly occurs in patients with active IBD, 2) prothrombotic hematological abnormalities are more common in patients with active IBD, likely in part due to acute phase changes, and 3) the majority of patients with IBD-associated TE have extensive diseased intestinal surface area.3, 6, 50, 51, 55 The mechanism through which inflammation may mediate systemic hypercoagulability is most likely via various cytokines that affect the coagulation cascade as well as platelet quantity and physiology at various regulatory points.51, 52 In our review, based on the available information, 35 of 43 patients (81%) had active IBD, 27 of 46 (59%) had at least one inheritable and/or acquired prothrombotic risk factor, and 8 of 11 UC patients (73%) and 3 of 6 CD patients (50%) had pancolitis and colonic involvement, respectively, which is consistent with prior findings.

Given the diversity of prothrombotic abnormalities that can exist in IBD patients as well as their likely multifactorial etiology, no single one to date has been shown to be a consistent or specific marker for IBD-associated thrombotic risk.39 Large epidemiological studies are needed to better delineate the types and incidence of prothrombotic abnormalities in patients with IBD, both during times with and without TE, and to provide more substrate for bench research on this topic.

Outcomes with AC vs. CDT

Our review suggests that CDT and AC are both useful treatments in the management of IBD patients with TE. However, it appears that CDT may result in more favorable outcomes than AC alone. CDT resulted in significantly improved symptomatic resolution and trended toward significantly greater radiologic resolution of TE compared to AC alone. One could speculate that this difference in efficacy would have been even greater with a larger sample size and with controlling for TE disease severity, as it is likely that CDT may have been reserved for patients with greater TE burden.8, 24, 56 Regarding safety, both GI and non-GI HCs tended to be more common in the CDT group, although neither difference reached statistical significant. The lack of a significant difference may again be the result of small sample size, or it may reflect the relative safety of CDT, even in patients with IBD. The seemingly preserved safety profile of CDT could be related to: 1) the low systemic concentrations of thrombolytic agents in CDT as a result of using lower dosages and local as compared to systemic administration6; 2) the fact that GI bleeding in IBD usually originates from small vessels (capillaries), as opposed to bleeding associated with a gastric or duodenal ulcer or colonic diverticulum, which may pose greater risk for HCs with the use of any antithrombotic agent, be it anticoagulants or thrombolytics6; 3) a protective buffer effect rendered by the systemic hypercoagulable state present in a large proportion of patients with IBD-associated TE6; and 4) the increasing use of more fibrinoselective thrombolytic agents, such as tissue plasminogen activator and tenecteplase as opposed to streptokinase (although this has not been clearly shown in vivo).8, 57

Synopsis of the Management of IBD-associated TE and Minimization of Risk

Despite ongoing research, the armamentarium against IBD-associated TE still leaves much to be desired. Because the thrombotic risk in IBD patients is likely due to a variety of factors, there is no universal screening test. Therefore, prevention of TE in the outpatient setting is limited to control of the underlying IBD, and in the inpatient setting, to the use of effective TE prophylaxis.5, 39, 53, 58

Treatment of TE is a challenging issue given the heterogeneity of patient presentations. Therefore, therapy should be determined on a patient-by-patient basis according to the location, extent, severity, and duration of the TE, patient comorbidities, the risk and relative impact of HCs, and the expertise and resources of the treatment team.

Our review of the published literature suggests that antithrombotic therapy, in the form of AC or CDT, appears to be effective and safe, and that the decision to implement it need not necessarily be altered due to the presence of IBD.6 If antithrombotic therapy is indeed pursued, in the absence of current treatment guidelines for IBD-associated TE, we would propose the following approach for clinicians caring for these patients:

  • 1)
    In life-threatening TE disease, CDT should be strongly considered because it more rapidly reduces the thrombotic burden and yields greater symptomatic resolution without being associated with an excessive risk of HCs.
  • 2)
    In less severe TE disease, and/or when the patient is deemed at higher risk for HCs, systemic AC can be started and the patient should be closely followed and reassessed for response and complications related to therapy. If there is no symptomatic or radiologic improvement, then CDT may be considered.

In addition, to further decrease the risk of GI and non-GI HCs, the following measures may be helpful:

  • 1)
    Induction of rapid remission in patients with pretreatment hematochezia: this may include pulse dose IV corticosteroids and/or initiation of other potent induction therapies such as biological agents or cyclosporine. These steps may also help to prevent propagation or worsening of TE. Of note, corticosteroid use may induce prothrombotic endothelial or hematological changes, but this has been described only with long term use.59–61
  • 2)
    Clot retrieval or maceration: thrombectomy, pulse-spray administration to lace the thrombus with thrombolytic agents and mechanically manipulate it, and ultrasound dissolution may be implemented to accelerate lysis and minimize the dosage and duration of thrombolytic agent required.15, 17, 62
  • 3)
    Close monitoring of the fibrinogen level: fibrinogen should be maintained above 100 mg/dL, with adjustment of the thrombolytic infusion rate, and if necessary, infusion of cryoprecipitate should levels drop below this threshold.63

If HCs occur despite these measures, transfusion of packed red blood cells may be a reasonable price to pay, depending on the clinical scenario, to avoid more severe, possibly fatal consequences due to the TE itself.

Two other considerations should be made in the peri-TE treatment period: 1) Depending on the size and location of TE, such as a large inferior vena cava thrombosis, it may be worthwhile considering the need for a temporary IVC filter placement (just as in a non-IBD patient) to prevent pulmonary embolism. 2) In addition to selecting an acute treatment, the need for continued AC should also be evaluated and is generally necessary to maintain patency since the underlying hypercoagulable state persists for (at least) months after the initial TE.

Study Limitations

Our study has several limitations. 1) The sample size was small as a result of the paucity of published literature regarding CDT and AC for the treatment of IBD-associated TE. 2) The data for the CDT and AC groups were retrospectively derived from case reports and case series; they are thus subject to the inherent weaknesses of retrospective study design and the nature of case reports to often report only favorable data. This potential bias should have affected both groups equally, although it is conceivable that publication bias may have been greater with CDT, thus favoring this group. 3) There was some variation among authors in the definition of outcomes; we tried to account for this lack of standardization by categorizing outcomes in a standard fashion as described in Materials and Methods to minimize confounding.

CONCLUSION

  1. Top of page
  2. Abstract
  3. MATERIALS AND METHODS
  4. RESULTS
  5. DISCUSSION
  6. CONCLUSION
  7. Acknowledgements
  8. REFERENCES

To date, IBD-associated TE is best prevented by optimized IBD control. It is a phenomenon that is clinically heterogeneous and often challenging to treat. Given its morbidity and mortality, and the potential that its incidence may be increasing, defining its optimal treatment is critical. Our study would indicate that while both CDT and AC appear to be reasonable treatment options for the IBD patient suffering TE, CDT may be more likely to result in better thrombus resolution without a significant increase in HCs. These conclusions are preliminary given the limited data available on which to base decision- making. Until further data are available, we would propose that the decision as to which of these therapies to employ be made on a case-by-case basis depending on the clinical scenario and the experience of the treatment team. CDT may be more effective than AC, but it also requires a greater amount of resources and is more invasive. Severely affected patients with TE may be better served by CDT while patients with less severe disease may warrant a trial of AC alone, particularly if the bleeding risk is high. To develop more precise recommendations and a definitive treatment algorithm for the management of IBD-associated TE, a multicenter trial wherein IBD patients with TE are randomized to receive either AC or CDT is needed; this should be the next step to determine the optimal treatment of TE in the IBD patient.

Acknowledgements

  1. Top of page
  2. Abstract
  3. MATERIALS AND METHODS
  4. RESULTS
  5. DISCUSSION
  6. CONCLUSION
  7. Acknowledgements
  8. REFERENCES

We thank Dr. Theodore M. Bayless for his invaluable scientific and clinical input.

REFERENCES

  1. Top of page
  2. Abstract
  3. MATERIALS AND METHODS
  4. RESULTS
  5. DISCUSSION
  6. CONCLUSION
  7. Acknowledgements
  8. REFERENCES
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