Int Canc Conf J DOI 10.1007/s13691-015-0210-1
CASE REPORT
Pancreaticoduodenectomy in a patient with protein C deficiency Yasuro Futagawa • Norimitsu Okui • Junichi Shimada • Hiroaki Shiba • Ken Kaito Katsuhiko Yanaga
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Received: 9 December 2014 / Accepted: 22 January 2015 Ó The Japan Society of Clinical Oncology 2015
Abstract Protein C (PC) deficiency is a rare disease with an incidence of 0.2 % in the general population. Because PC deficiency is likely to be thrombogenic, particularly in the venous system, continuous anticoagulant therapy is required, and when undergoing surgical treatment, such patients are considered a high-risk group. To our knowledge, the current case is the first report of successful pancreaticoduodenectomy for a patient with PC deficiency. A 46-year-old man with PC deficiency was referred to our hospital for cancer of the head of the pancreas. He had been managed with oral warfarin and baby-strength aspirin to prevent thrombotic disorders. A right adrenal pheochromocytoma was also diagnosed. Laparoscopic adrenalectomy was first performed. In spite of strict perioperative management with administration of heparin, deep venous thrombosis developed in the right femoral vein on postoperative day 8. On elective pancreaticoduodenectomy 19 days after the adrenalectomy, taking into account the postoperative course after the urological surgery, perioperative management of anticoagulant therapy was performed as follows: (1) preoperative intravenous administration of heparin up to 6 h before surgery; (2) on the day of the surgery, the heparin administration was discontinued, and dried concentrated human activated PC formulation (APC) was started intravenously from 6 h before the surgery at a dose of 210 U/kg/day. (3) Y. Futagawa (&) N. Okui J. Shimada H. Shiba K. Yanaga Department of Surgery, Jikei University School of Medicine, 3-25-8, Nishishinbashi, Minato-ku, Tokyo 105-8461, Japan e-mail:
[email protected] K. Kaito Central Clinical Laboratory, Jikei University Hospital, 3-25-8, Nishishinbashi, Minato-ku, Tokyo 105-8461, Japan
Postoperatively, after the confirmation of hemostasis, the heparin administration was resumed on day 2. APC administration was discontinued as soon as the ongoing administration of APC was completed on day 2. During operation, no abnormal findings pertaining to hemostasis or thrombosis were observed. On his postoperative course, no new thrombus formation was identified. For patients with PC deficiency, there has been no clear standardized regimen for antithrombotic prophylaxis in surgical procedures. The prophylactic administration of APC might ensure a higher level of safety than that offered by surgery with the intraoperative administration of heparin or without the intraoperative administration of anticoagulants. Keywords Protein C deficiency Pancreaticoduodenectomy Activated PC formulation
Introduction Protein C (PC) deficiency is a rare disease with an incidence of 0.2 % in the general population [1]. However, because PC deficiency is likely to be thrombogenic, particularly in the venous system, continuous anticoagulant therapy is required, and when undergoing surgical treatment, such patients are considered a high-risk group [2]. Herein, we report a case of carcinoma of the head of the pancreas in a patient with PC deficiency that was treated with pancreaticoduodenectomy.
Case report A 46-year-old man with PC deficiency was referred to our hospital for cancer of the head of the pancreas. Type I
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(heterozygous) PC deficiency was diagnosed from his history of myocardial infarction at 33 years of age with decreased PC activity of 46 %. He also had a history of von Recklinghausen disease (type I neurofibroma) and hemorrhagic stroke at 24 years of age. Thereafter, he had been managed with oral warfarin and baby-strength aspirin to prevent thrombotic disorders. Blood laboratory findings on admission were as follows: PC activity (while under treatment with oral warfarin potassium) was 10 % (normal range, 64–146 %), prothrombin time (PT) was 23 %, and PT-international normalized ratio (PT-INR) was 2.9. During a preoperative work-up, a right adrenal pheochromocytoma was also diagnosed. Due to concerns of fluctuations in hemodynamics (hypertension, hypotension) during or after surgical removal of the pheochromocytoma, the right adrenal pheochromocytoma was first treated by performing a laparoscopic right adrenalectomy in our hospital’s Department of Urology. The duration of surgery was 3 h 41 min, and the amount of intraoperative bleeding was 50 mL. The perioperative management of PC deficiency as a complication is considered in the ACCP guidelines to put patients at high risk; therefore, to prevent perioperative thrombosis, combined anticoagulant therapy with mechanical prophylaxis was performed [3]. The anticoagulant therapy consisted of the following. Up to 6 h before surgery, heparin was administered (after admission, warfarin potassium was replaced with heparin in preparation for surgical treatment). Heparin treatment was resumed on the day of the surgery (the initial doses were 1,000 U/h with a target APTT of approximately 50 s). On day 3 after surgery, warfarin potassium was started. In spite of strict perioperative management mentioned above, deep venous thrombosis developed in the right femoral vein on postoperative day 8 (Fig. 1), for which a temporary IVC filter was placed to prevent pulmonary embolism.
He was then transferred to our department, where he underwent elective pancreaticoduodenectomy 19 days after the adrenalectomy. Taking into account the postoperative course after the urological surgery, perioperative management of anticoagulant therapy was performed as follows: (1) preoperative intravenous administration of heparin up to 6 h before surgery; (2) on the day of the surgery, the heparin administration was discontinued, and dried concentrated human activated PC formulation (APC) was started intravenously from 6 h before the surgery at a dose of 210 U/kg/ day. (3) Postoperatively, after the confirmation of hemostasis, the heparin administration was resumed on day 2. APC administration was discontinued as soon as the ongoing administration of APC was completed on day 2. The pancreatic cancer was advanced T3 N1M0 stage IIb by TMN classification. The operation time was 9 h 31 min and the intraoperative blood loss was 1,220 mL. During operation, no abnormal findings pertaining to hemostasis or thrombosis were observed. No blood transfusion was needed. Postoperative course (Fig. 2): APC was administered from 6 h before the surgery until day 2 after the surgery; the heparin administration was resumed at day 2 (starting at doses of 15,000 U/day with a target APTT of 50–70 s). Warfarin potassium was started at day 9 after surgery; however, since melena was found on day 11 after surgery, there was no other choice but to temporarily discontinue the anticoagulant therapy. An H1-stage ulcer was noted at the site of the gastrojejunostomy. On day 14 after surgery, after confirmation that the melena had disappeared, heparin administration was resumed. The veins of the lower part of the thigh were screened to check the presence or absence of thrombus, but none was found. There was no pancreatic juice leakage and no bile leakage. On day 18 after the surgery, the IVC filter was removed. Twenty-three days after the surgery, the warfarin potassium administration was resumed, and after the results of the controls using
Fig. 1 Abdominal CT findings (day 8 after surgery). a Thrombi immediately after the branching of the right crural vein and at many sites inside the popliteal vein and peroneal vein (arrow). b Thrombi at many sites within the great saphenous vein (arrow)
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warfarin potassium were obtained, the patient was discharged from the hospital on day 30 after the surgery.
Discussion PC deficiency is found in 0.2 % of the general population and is an autosomal dominant genetic disease with point mutations in the PC gene on chromosome 2 [1, 2, 4]. PC inactivates the activated blood coagulation factors (factor Va and factor VIIIa) using protein S as a coenzyme and sends negative feedback to the coagulation cascade. Ninety-five percent of cases of PC deficiency are found in heterozygous individuals (in whom blood PC activity is reduced by 30–50 %) who develop thrombosis in adulthood. The onset of the disease occurs early in life (before 40 years of age) and mainly affects the venous system. Homozygous types (blood PC activity B 5 %) are extremely rare (one person in 500,000–700,000), and are known to cause the development of purpura fulminans during the neonatal period. In addition, other risk factors (such as surgery, traumatic injuries, infections, pregnancy, stress, and hyperlipidemia) are also presumed to contribute to the development of thrombosis in PC deficiency; and because it can easily cause repetitive thrombosis, it requires continuous anticoagulant therapy, and careful attention is needed when considering surgical treatment [1, 2, 4].
However, there has been no clear standardized regimen for antithrombotic prophylaxis in surgical procedures for patients with PC deficiency. While a number of reports have described cases that developed mesenteric vein or portal vein thrombosis as a result of PC deficiency, most cases were diagnosed with PC deficiency after the onset of thrombosis. We conducted a PubMed search using the keywords ‘‘PC deficiency’’ and ‘‘surgery’’, and found only a several case reports written in English subjected to elective surgery for patients with PC deficiency. Recently, successful preoperative administration of APC has been reported for renal transplantation, gastric surgery, and orthopedic surgery [5–7]. APC is also administered as a second-line treatment in pregnant women with heterozygous PC deficiency who, despite heparin treatment, develop purpura fulminans during the puerperal period or are faced with repeated cases of fetal death; this has resulted in favorable outcomes [8, 9]. Of course, the use of heparin in the perioperative management of PC deficiency has not necessarily been disproven. Intraoperative low-dose heparin administration should be considered as an option. The intraoperative administration of heparin at doses of 20 U/kg has been reported to inhibit the formation of fibrin clots and not have any effect on the amount of blood loss [10]. Regarding the case we experienced, our findings clearly showed thrombus formation on day 8 after surgery during the perioperative management period when heparin and warfarin potassium
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were used, despite the fact that walking was started 1 day after laparoscopic surgery. The thrombus formation period was unknown and it was possible that it might have already occurred during surgery. Logically, PC supplementation is possible through the administration of fresh frozen plasma (FFP). However, the concentration of PC contained inside the FFP was only 0.85 U/mL [7]. The standard dose derived from the optimal dosage of APC in the treatment of deep venous thrombosis is 200–300 U/kg/day in compliance with the guidelines of the Ministry of Health and Welfare in Japan. Regarding PC supplementation through FFP administration, the calculation of the APC dose (200 U/kg) showed that FFP needs to be administered continuously at a dose of approximately 200 U/day in our case and that in practice, this was difficult and accompanied by issues of excessive fluid administration, allergy, and infection. To our knowledge, the current case is the first report of successful pancreaticoduodenectomy for a patient with PC deficiency. In the event of cancer types (ovarian, pancreatic) that are known to ease the formation of thrombi and when the risk of thrombosis is predicted to increase further due to revascularization, emergency surgery, and infection, options such as APC administration might also need to be taken into consideration. The accumulation of additional cases will be important to the establishment of suitable perioperative management to ensure safety in the treatment of cases complicated by PC deficiency.
Conflict of interest of interest.
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The authors declare that they have no conflict
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