Article Text

PDF

Mesenteric infarction due to combined protein C deficiency and prothrombin 20210 defects
  1. C J Mainwaringa,
  2. M Makrisa,
  3. W E G Thomasb,
  4. K K Hamptona,
  5. F E Prestona
  1. aRoyal Hallamshire Hospital, Sheffield, UK Department of Haematology, bDepartment of Surgery
  1. Dr C J Mainwaring, Department of Haematology, Royal Hampshire County Hospital, Romsey Road, Winchester SO22 5DG, UK

Abstract

The prothrombin gene mutation, 20210A, a guanine to adenine substitution at nucleotide position 20210, has recently been described as an additional risk factor for venous thromboembolic disease. We describe the case of a patient with combined heterozygous prothrombin 20210A mutation and type 1 protein C deficiency who presented with massive mesenteric venous infarction of his small bowel and survived following the use of protein C concentrate and extensive small bowel resection.

  • mesenteric venous infarction
  • protein C deficiency
  • prothrombin 20210A

Statistics from Altmetric.com

A 49-year-old man presented with diffuse abdominal pain and no bowel action for 3 days. In 1975 surgery for a perforated duodenal ulcer had been complicated by a postoperative right leg deep venous thrombosis (DVT). Since then he had five further spontaneous DVTs related to erratic anticoagulation control. A thrombophilia screen performed in 1996 confirmed heterozygous type 1 protein C deficiency. Reinvestigation following this admission identified an additional thrombophilic defect, the prothrombin 20210 mutation. His baseline protein C antigen and activity levels, when not on warfarin, were reduced at 0.39 and 0.35 IU/ml, respectively (normal range 0.71–1.42). Family studies had shown that both his son and daughter were similarly affected though asymptomatic. Neither his parents nor his siblings had been tested for thrombophilic defects. Because of recurrent thrombotic events he had been maintained on long-term warfarin since 1993, but on the day of admission his anticoagulation was subtherapeutic with an international normalised ratio (INR) of 1.3. Clinical examination demonstrated diffuse abdominal tenderness only. Investigations revealed a raised white blood cell count of 11.8 × 109/l with a neutrophilia, normal chest and abdominal radiology, biochemical screens and serum amylase. A gastroscopy demonstrated bile reflux and minimal gastric ulceration without bleeding. He continued to deteriorate despite full supportive care with increasing abdominal distention, absent bowel sounds and guarding. In view of these findings, in the context of a thrombophilic disorder, a small bowel infarction was suspected and a mesenteric angiogram confirmed extensive portal, splenic and proximal superior plus inferior mesenteric venous thromboses. Pre-operatively he was treated with 2850 units (40 units/kg) of intravenous protein C concentrate (Immuno, Vienna) by bolus injection which increased his levels from 0.1 to 0.57 IU/ml.

At operation, extensive venous infarction of most of the small bowel was noted, requiring resection, together with anastomosis of the remaining viable 4.5 cm of jejenum and 7.5 cm of ileum. Postoperatively he was treated with once daily protein C concentrate, by bolus injection aiming for a protein C level of greater than 0.50 IU/ml, from day +1 to + 4 (table) and intravenous heparin, until the activated partial thromboplastin time ratio was stably maintained at 1.5–2.5. There were no further thromboembolic events. The half-life of the infused protein C concentrate was calculated at 16.2 h on day +1 and 13.6 h on day + 4. The longer than anticipated half-life, normally 6 h, probably reflected recovery of endogenous protein C levels whilst not receiving warfarin. Conversion to subcutaneous low molecular weight heparin occurred on day +13 and he was discharged home on day +17. Warfarin was restarted some 6 weeks postoperatively with erratic anticoagulation control initially as a result of impaired absorption. Currently, he remains well on life-long anticoagulation, with no further thrombotic complications, aiming for a target INR of 2.5.1

Table  The use of protein C concentrate and protein C levels achieved in a congenitally deficient patient with mesenteric venous thrombosis

Discussion

Mesenteric venous thrombosis (MVT) causing small bowel infarction is an extremely rare cause of an acute surgical abdomen and often difficult to diagnose. Predisposing factors include acquired conditions such as congestive cardiac failure, atrial fibrillation, myeloproliferative disorders, oral contraceptive use and abdominal infections. Our patient had no acquired risk factors. MVT has also been described in inherited thrombophilias (box 1), including antithrombin deficiency2 and the factor V Leiden mutation.3

Genetic factors predisposing to venous thrombosis

  • antithrombin deficiency

  • protein C deficiency

  • protein S deficiency

  • factor V Leiden mutation

  • prothrombin 20210A mutation

The prothrombin gene mutation 20210A is a recently described additional thrombophilic risk factor with an incidence of 2.3% in healthy control subjects and 18% in patients with a personal or family history of DVT.4 It is now recognised that some thrombophilic patients can be double heterozygotes for two inherited conditions with an increased relative risk for venous thromboembolic disease.5 Our patient had combined heterozygous type 1 protein C deficiency and the prothrombin 20210A mutation, which probably accounts for the severity of his thromboembolic complications. Additionally, on admission to hospital he had a subtherapeutic INR which would have provided inadequate protection combined with the fact that warfarin further lowers the levels of vitamin-K-dependent protein C, which was intrinsically reduced in this patient. The importance of strict anticoagulation control cannot be overstated and it is possible that this case may have been avoided if his INR had not been allowed to fall to 1.3. The severe protein C deficiency was corrected by the use of intravenous protein C concentrate. Prior to the commercial availability of protein C concentrate, fresh frozen plasma was traditionally used to raise protein C levels in cases of both inherited and acquired deficiencies with variable but generally poor therapeutic results.6

Summary points

  • inherited thrombophilia has an incidence of at least 5% in the general population

  • combined defects are being increasingly recognised and associated with an increased relative risk of venous thromboembolic disease

  • thrombophilic screening should be undertaken in patients presenting with mesenteric venous infarction

  • protein C concentrate is available and should be considered for congenitally deficient patients presenting with major venous thromboembolic complications

Intravenous protein C concentrate has been successfully used in cases of purpura fulminans in congenital homozygous deficient neonates7 and during pregnancy in a patient with a history of previous venous thrombosis and foetal loss8 with successful outcomes. Our case is the first to use protein C concentrate successfully in the context of established massive MVT and it is noteworthy that there were no postoperative thromboembolic problems. In the three years since his bowel resection he has had no further thrombotic events whilst on long-term warfarin. In addition to screening patients with MVT for thrombophilia,9 we feel protein C concentrate should be considered in congenitally deficient patients with major venous thromboembolic complications.

References

View Abstract

Request permissions

If you wish to reuse any or all of this article please use the link below which will take you to the Copyright Clearance Center’s RightsLink service. You will be able to get a quick price and instant permission to reuse the content in many different ways.