Factor V Leiden mutation

* There is a well-known risk of thrombosis in patients with inflammatory bowel disease. Documented cases of intracranial sinus thrombosis in this setting are rare. We present the case of a 30-year-old man with Crohn disease who spontaneously developed a superior sagittal sinus thrombosis and bifrontal infarcts that resulted in death. The patient was heterozygous for factor V Leiden mutation. The literature was searched to assess the frequency of cerebral venous infarcts in inflammatory bowel disease and the role that factor V Leiden plays in thrombosis in such patients.

It is well recognized that patients with inflammatory bowel disease (IBD) have an increased risk of thrombosis compared to the rest of the population. In a larger series of 7199 patients with IBD, 1.3% (n = 92) suffered a thrombotic complication, excluding those complications that were related to atherosclerosis, diabetes, or obesity.1 Of the 92 patients affected, 9 had cerebral vessel involvement, none of which involved the sagittal sinus.1 Deep venous thrombosis and pulmonary emboli are the most common thrombotic complications in IBD.1-3 Markowitz et al2 reviewed a series of 36 cases of cerebral and retinal thromboembolic events in IBD patients in the literature and noted involvement of the venous circulation in 14 patients. Of these 14 patients, 6 died as a result of venous thrombosis. Ten suffered from ulcerative colitis, and 4 suffered from Crohn disease. The age range of these patients was 14 to 56 years (mean, 31 years). The presence or absence of any hypercoagulable states among the reported cases was not mentioned.2 Patients with IBD tend to suffer thrombosis earlier in life than thrombotic patients without IBD,3,4 with 75% of the events occurring in patients younger than 45 years.4 The mortality of thromboembolic events in the setting of IBD is significant-in the range of 8% to 25%.1,3

We report a fatal outcome in a young man with Crohn disease who developed severe venous thrombosis.

REPORT OF A CASE

A 30-year-old white man presented to the emergency department complaining of a 1-day history of headache and bilateral lower extremity weakness. His medical history was significant for Crohn disease, which, until recently, had been asymptomatic for some time. He was on no medications. While on a recent trip, he began to have bloody diarrhea and abdominal cramping. The day after his return home, his headache began. During his emergency department visit, he experienced mental status changes and rapidly became obtunded. A computed tomographic scan of the head demonstrated a superior sagittal sinus thrombosis and bilateral hemorrhagic infarcts of the parietal lobes (Figures 1 and 2). He underwent a procedure to recanalize the sagittal sinus using an AngioJet (Possis Medical, Minneapolis, Minn). However, an intraoperative magnetic resonance angiogram showed extensive external cerebral venous system thrombosis. The patient died shortly thereafter, less than 24 hours after presentation.

PATHOLOGIC FINDINGS

At autopsy, the superior sagittal sinus as well as the bilateral sigmoid and transverse sinuses were filled with acute thrombi that were adherent to the sinus walls (Figure 1, b). Bilateral frontoparietal hemorrhagic infarcts were present (Figure 2, b). The brain was diffusely edematous (weight, 1.56 kg), and bilateral cerebellar tonsillar herniation was evident. Thrombi were found in the microvascularure of the liver along with passive venous congestion. The colon was diffusely thickened, granular, and hemorrhagic. Microscopic sections demonstrated a dense lymphocytic infiltrate in the mucosa as well as thrombi in several of the submucosal vessels. The mucosa had undergone autolysis, making the architecture difficult to evaluate. The small bowel and remainder of the gastrointestinal tract were uninvolved.

Laboratory evaluations on premortem blood samples revealed the following: hemoglobin level, 12.8 g/dL (normal, 13.5-17.5 g/dL); platelet count, 61 x 10^sup 3^/[mu]L (normal, 150-400 x 10^sup 3^/[mu]L); activated partial thromboplastin time, 29.1 seconds (normal, 21.5-32.5 seconds); prothrombin time, 19.3 seconds (normal, 8.0-13.3 seconds); international normalized ratio, 1.69 (normal, 0.81-1.21); D-dimer, >20 000 ng/mL (normal, 250 ng/mL); fibrinogen, 0.177 g/dL (normal, 0.2-0.4 g/dL) (5.21 [mu]mol/L [normal, 5.88-11.76 [mu]mol/L]); antithrombin III, 79 mg/dL (normal, 23-32 mg/dL); protein S, 31% of normal (59%-140% of normal); protein C, 38% of normal (70%-120% of normal); and plasminogen, 50% of normal (68%-122% of normal). These findings were interpreted as being consistent with disseminated intravascular coagulation. Polymerase chain reaction gene studies were negative for methylenetetrahydrafolate reductase polymorphism and for the prothrombin G20210A mutation. The patient was heterozygous for factor V Leiden mutation, with the replacement of arginine by glutamine at position 506.

Colonic biopsies performed 5 years previously demonstrated focal architectural distortion of the crypts, thickened muscularis propria, and basal plasmacytosis. No granulomas were identified, and there was no evidence of dysplasia. The focal distribution of these findings, evidenced by skip lesions and sparing of the rectum, was interpreted as being consistent with Crohn disease.

COMMENT

Hypercoagulability has been suggested by some researchers as an etiologic agent in the development of IBD.5,6 Multifocal gastrointestinal infarction has been proposed as a mechanism underlying Crohn disease. Wakefield et al5 demonstrated the phenomenon of focal occlusive fibrinoid lesions, occurring early in the course of the disease, which lead to inflammation and ulceration.5 Uninvolved areas of the bowel were free of such infarcts.5 Extraintestinal thrombosis parallels disease activity, occurring more frequently when the disease is active than when it is quiescent.3 Levels of D-dimer, fibrinogen, and fibrin split products are higher in patients with active disease than in IBD patients without active disease.7 In a study of 110 patients with IBD, the level of factor VII:C was significantly higher than in a control population.8 Of the thrombotic risk factors studied, which included factor VII:C, lipoprotein A, increased fibrinogen levels, and smoking, 93% of the patients with Crohn disease had at least one risk factor, as did 86% of those with ulcerative colitis. Only 61% of the controls had one of these risk factors.8 Further evidence for the role of thrombosis in IBD is the response of patients with refractory cases of ulcerative colitis to anticoagulant therapy with heparin, suggesting that mitigation of the thrombotic process will ameliorate disease symptoms.6

Protein C is part of an anticoagulant pathway that inactivates factors Va and VIIa. Factor V Leiden is a point mutation that makes coagulation cofactor Va resistant to proteolytic cleavage and, in turn, resistant to inactivation by protein C. This mutation is found in 3% to 7% of healthy control populations4 and in 15.5% to 20% of patients with thrombosis.7,9 The patient of our study was heterozygous for this mutation, which connotes an eightfold increase in risk for thrombosis.9

Studies show conflicting evidence regarding the role of factor V Leiden mutation and the risk of thrombosis in patients with IBD.4,7,9,10 Factor V Leiden mutation does not appear to be associated with IBD. However, the incidence of this mutation in thrombotic patients with IBD is similar to that in patients without IBD-14.3% and 15.5%, respectively.7 This supports an association of factor V Leiden with an increased risk of thrombosis in IBD when compared to IBD patients without the mutation.5 This same study did not find a significant link between thrombosis in IBD and C677T methylenetetrahydrafolate reductase, prothrombin G20210A, or factor V 407OG. A similar study, performed with 102 patients having IBD, found that activated protein C resistance was associated with an increased incidence of thrombosis in IBD but was not necessarily associated with IBD.4 Factor V mutation, which is one cause of activated protein C resistance, was not assessed in this study.

Thrombosis in IBD is a concern because of the high mortality associated with this complication and its occurrence in a relatively young population. Known genetic causes of hypercoagulability have been studied repeatedly in IBD patients, often with mixed results. It seems likely that the cause of thrombosis in IBD patients is multifactorial and that factor V Leiden is a risk factor in a subset of patients.

References

1. Talbot RW, Heppell J, Dozois RR, Beart RW. Vascular complications of inflammatory bowel disease. Mayo Clin Proc. 1986;61:140-145.

2. Markowitz RL, Ment LR, Gryboski JD. Cerebral thromboembolic disease in pediatric and adult inflammatory bowel disease: case report and review of the literature. J Pediatr Gastroenterol Nutr. 1989;8:413-420.

3. Jackson LM, O'Gorman PJ, O'Connell J, Cronin CL, Cotter KP, Shanahan F. Thrombosis in inflammatory bowel disease: clinical setting, procoagulant profile, and factor V Leiden. Q J Med. 1997;90:183-188.

4. Novacek G, Miehsler W, Kapiotis S, Katzenschlager R, Speiser W, Vogelsang M. Thromboembolism and resistance to activated protein C in patients with inflammatory bowel disease. Am J Gastroenterol. 1999:94:685-690.

5. Wakefield AJ, Sawyerr AM, Dhillon AP, et al. Pathogenesis of Crohn's disease: multifocal gastrointestinal infarction. Lancet. 1989;2:1057-1062.

6. Gaffney PR, Doyle CT, Gaffney A, Hogan J, Hayes DP, Annis P. Paradoxical response to heparin in 10 patients with ulcerative colitis. Am J Gastroenterol. 1995;90:220-223.

7. Guedon C, Le Cam-Duchez V, Lalaude O, Menard JF, Lerebours F, Borg JY. Prothrombotic inherited abnormalities other than factor V Leiden mutation do not play a role in venous thrombosis in inflammatory bowel disease. Am J Gasfroenterol. 2001;96:1448-1454.

8. Hudson M, Chitolie A, Mutton RA, Smith MSM, Pounder RE, Wakefield AJ. Thrombotic vascular risk factors in inflammatory bowel disease. Gut. 1996;38:733-737.

9. Koutroubakis IE. Unraveling the mechanisms of thrombosis in inflammatory bowel disease. Am J Gastroenterol. 2001;96:1325-1327.

10. Turri D, Rosselli M, Simioni P, et al. Factor V Leiden and prothrombin gene mutation in inflammatory bowel disease in a Mediterranean area. Dig Liver Dis. 2001:33:559-562.

Jennifer Maag, MD; Richard A. Prayson, MD

Accepted for publication March 20, 2003.

From the Department of Anatomic Pathology, Cleveland Clinic Foundation, Cleveland, Ohio.

Corresponding author: Richard A. Prayson, MD, Cleveland Clinic Foundation, Department Anatomic Pathology (L25), 9500 Euclid Ave, Cleveland, OH 44195 (e-mail: praysor@ccf.org).

Copyright College of American Pathologists Aug 2003
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