- Email: [email protected]
Vitamin K deficiency with hemorrhage after kidney and combined kidney–pancreas transplantation
Vitamin K Deficiency With Hemorrhage After Kidney and Combined Kidney–Pancreas Transplantation G. V. Ramesh Prasad, MBBS, FRCP(C), Syed M. Abidi, MD, Jerry McCauley, MD, and James R. Johnston, MD ● Vitamin K deficiency is a common occurrence in the surgical and intensive care unit population, but its incidence in kidney and combined kidney–pancreas allograft recipients has not been described. We report four patients who received cadaveric kidney or combined kidney–pancreas allografts and subsequently developed significant bleeding associated with deficiency of vitamin K. Their coagulopathy promptly resolved with the parenteral administration of vitamin K. Treatment with vitamin K should be considered in kidney or combined kidney–pancreas allograft recipients with a prolonged prothrombin or partial thromboplastin time during the first postoperative week to avoid hemorrhagic complications. 娀 1999 by the National Kidney Foundation, Inc. INDEX WORDS: Vitamin K deficiency; hemorrhage; kidney transplantation; kidney–pancreas transplantation; prothrombin time; partial thromboplastin time.
B
LEEDING from acquired coagulopathy is associated with high morbidity and mortality rates.1 When associated with vitamin K deficiency, significant bleeding can occur in hospitalized patients, especially in the postoperative period.2 Early recognition with appropriate replacement can be an effective means of reducing morbidity.3 During a 7-month period, approximately 130 kidney and 16 combined kidney–pancreas transplants were performed at our institution. We describe four of these patients who developed vitamin K deficiency–induced coagulopathy and bleeding, associated with prolongation of the prothrombin time (PT) and partial thromboplastin time (PTT) in postoperative week 1 after kidney or combined kidney–pancreas transplantation. All four patients had advanced renal insufficiency, with three on maintenance hemodialysis. None had received prolonged antibiotic therapy, were severely malnourished before transplantation, or had a history of liver disease or coagulopathy. Admission coagulation parameters were normal in all patients. CASE REPORTS
developed confusion, with the hematocrit decreasing from 23% to 15%. The PT reported as the international normalized ratio (INR) was 10.2 and PTT 42.9 seconds. The platelet count was normal. Computed tomography of the abdomen showed large intraperitoneal and retroperitoneal hematomas. These were surgically evacuated, and the patient received parenteral vitamin K, 10 mg/d for 3 days, with prompt resolution of the coagulopathy. The pancreatic allograft was found to be thrombosed, and allograft pancreatectomy was performed.
Case 2 A 58-year-old white man on maintenance hemodialysis for 7 years for end-stage renal disease caused by amyloidosis was admitted for his first cadaveric renal allograft. His medical history was significant for chronic lymphocytic leukemia for which he had received chemotherapy 17 years earlier, with no recent evidence for recurrence. Admission medications included CaCO3, folate, colchicine, ascorbic acid, NaHCO3, and captopril. The patient received a total of four doses of cefazolin 1 g intravenously in the hospital. He was started on tacrolimus, famotidine, sucralfate, trimethoprim-sulfamethoxazole, and acyclovir postoperatively. His course was complicated by primary allograft dysfunction and abdominal distension requiring nasogastric decompression. On postoperative day 3, he became obtunded. The INR was 1.4. The whole blood tacrolimus level was 44 ng/mL. Tacrolimus was discontinued for presumed toxicity, and the patient was dialyzed without heparin. On postoperative day 6, diffuse ecchymoses were noted over the extremities and
Case 1 A 37-year-old white man was admitted for combined kidney–pancreas transplantation. He was taking aspirin, 81 mg/d. Other admission medications included nifedipine, famotidine, and cisapride. Perioperatively and postoperatively, he was administered four doses of cefazolin 1 g intravenously. Postoperatively he was started on tacrolimus, methylprednisolone, mycophenolate mofetil, famotidine, trimethoprim-sulfamethoxazole, and nifedipine. Both grafts had excellent function in the immediate postoperative period, but the patient remained without oral intake for 5 days because of poor bowel motility. On postoperative day 6, he
From the Renal Electrolyte Division, Department of Medicine, University of Pittsburgh, Pittsburgh, PA. Received June 3, 1998; accepted in revised form September 25, 1998. Address reprint requests to G. V. Ramesh Prasad, MBBS, FRCP(C), Division of Nephrology, Department of Medicine, University of Toronto School of Medicine, 10-158 Norman Urquhart Wing, 621 University Ave, Toronto, Ontario M5G 2C4, Canada.
娀 1999 by the National Kidney Foundation, Inc. 0272-6386/99/3305-0022$3.00/0
American Journal of Kidney Diseases, Vol 33, No 5 (May), 1999: pp 963-965
963
964
PRASAD ET AL
incision site. Ultrasonography showed an allograft perinephric hematoma. At this point, the INR was 4.2 and PTT was 36.4 seconds. Administration of parenteral vitamin K, 5 mg/d for 3 days, corrected the coagulopathy, but he remained dialysis dependent.
Case 3 A 47-year-old white woman was admitted for combined kidney–pancreas transplantation. Two previous pancreatic transplants were removed because of severe pancreatitis. A first kidney transplant failed from chronic rejection, and she had been on maintenance hemodialysis for 10 months before this admission. She was taking aspirin, 81 mg/d, and erythropoietin, 4,000 units intravenously thrice weekly. Other medications included cyclosporine and insulin. She received four doses of cefazolin 1 g intravenously during her hospital stay. Postoperative medications included tacrolimus, methylprednisolone, trimethoprim-sulfamethoxazole, acyclovir, sucralfate, and famotidine. Postoperatively, she experienced a prolonged ileus and remained without oral intake for 3 days. Over the next 2 days, the INR increased to 10.8. The platelet count remained normal. Parenteral vitamin K, 10 mg/d, resulted in complete correction of the coagulopathy over the next 3 days.
Case 4 A 71-year-old white woman on maintenance hemodialysis for 4 years for end-stage renal disease due to hypertension was admitted for her first cadaveric renal allograft. Admission medications included doxazosin, pilocarpine eye drops, multivitamins, and CaCO3. She received a total of four doses of cefazolin 1 g intravenously during hospitalization. Postoperatively she received tacrolimus, acyclovir, methylprednisolone, trimethoprim-sulfamethoxazole, sucralfate, and famotidine. The postoperative course was complicated by primary allograft nonfunction. On postoperative day 3, the hematocrit declined from 30% to 21%, with prolongation of the INR to 1.7. Ultrasonography showed a subincisional hematoma. On postoperative day 6, active gastrointestinal bleeding occurred with an INR of 10.2 and PTT of 60.2 seconds. The platelet count was within the normal range. Packed red cells were administered along with parenteral vitamin K, 5 mg/d for 3 days. The bleeding resolved with correction of the coagulopathy. Patient characteristics are summarized in Table 1. The three patients on hemodialysis were adequately dialyzed based on current guidelines as indicated by the urea reduc-
Table 1. Clinical Features of Patients Before Admission Case No.
Age/Sex
Serum Albumin Level (g/dL)
Dialysis Pre/Post BUN (mg/dL)
Kt/V Urea
1 2 3 4
37/M 58/M 47/F 71/F
3.0 4.4 3.4 4.1
NA 63/15 56/12 47/16
NA 1.8 1.8 1.3
Abbreviation: NA, patient not on hemodialysis.
Table 2. Coagulation Parameters During Hospitalization
Case No.
Coagulation Parameter
1
INR PTT (seconds) INR PTT (seconds) INR PTT (seconds) INR PTT (seconds)
2 3 4
Value at Value After Admission Time of Treatment Value Hemorrhage With Vitamin K
1.1 26.2 1.0 24.8 0.9 27.0 1.0 21.5
10.2 42.9 4.2 36.4 10.8 38.4 10.2 60.2
1.4 21.8 1.2 24.1 1.0 24.6 1.2 22.8
Abbreviations: INR, prothrombin time reported as the international normalized ratio; PTT, partial thromboplastin time.
tion ratio and Kt/V urea. Elevation of the PT and PTT during the first week for the four patients along with their values after correction with vitamin K is shown in Table 2.
DISCUSSION
The most common causes of acquired coagulation disorders are liver disease, disseminated intravascular coagulation (DIC), and vitamin K deficiency.4 Traditionally, prolongation of the PT with correction by vitamin K administration has been used for the diagnosis of vitamin K deficiency, although serum levels may be helpful. Vitamin K deficiency leads to low factor VII levels, but with more severe deficiency low levels of factors IX and X lead to prolongation of the PTT as well. Acquired deficiency can be associated with primary biliary cirrhosis, cholestatic hepatitis, and intestinal malabsorption.5 Drugs that can lead to vitamin K deficiency or a vitamin K deficiency–like state include warfarin, aspirin, and certain antibiotics such as moxalactam and cefamandole.5 Hypoprothrombinemia may be produced by antibiotics through mechanisms other than destruction of intestinal flora, such as inhibition of the gamma carboxylation of glutamic acid by N-methylthiotetrazole groups in cephalosporins.6,7 Old age, major surgery, and total parenteral nutrition are risk factors for vitamin K deficiency but are poor predictors in an intensive care unit population.8 Renal failure is associated with an abnormal PT,9 but in the absence of direct evidence that renal failure per se causes impaired absorption or utilization of vitamin K, routine supplementation is not recommended.10 To our knowledge, there is no definite
VITAMIN K DEFICIENCY AFTER TRANSPLANTATION
relationship between duration of dialytic care and the risk for PT prolongation from vitamin K deficiency. Vitamin K deficiency in these patients was probably multifactorial. Poor oral intake, preexisting renal failure, and the use of cefazolin may have been causative to varying degrees. Unfortunately, we did not have available to us preoperative serum prealbumin values, serum total protein levels, or body mass indices, which might have provided additional data on nutritional state. There was no evidence for loss of dry weight or diarrhea before transplantation. Specifically, cefazolin possesses a 2-methyl1,3,4-thiadiazole-5-thiol group7 and has been linked to coagulopathy.11 There is no reported association of vitamin K deficiency with the use of tacrolimus, whereas cyclosporine has been linked to thrombosis.12 Amyloidosis has been associated with coagulation abnormalities and bleeding from factor X deficiency, prolongation of thrombin time, or the presence of an inhibitor.13 Although amyloidosis was the cause for renal failure in case 2, his thrombin time was normal, and no inhibitor was present on mixing with normal plasma. Coagulation profiles were ordered for cases 2 and 4 because of their critical condition, and they showed normal values for fibrinogen, D-dimer, and plasma fibrin degradation products, making the probability of DIC very low. Although vitamin K deficiency usually develops 1 to 3 weeks after cessation of oral intake in combination with antibiotics,5 it may occur earlier in patients with marginal preoperative reserves whose coagulation profiles may be normal, but who are subjected to the added stress of surgery. Early recognition and treatment is therefore crucial in preventing excessive morbidity. It has been recommended that all intensive care unit patients with a prothrombin ratio exceeding 2.0 receive vitamin K regardless of risk.8 Three of our four patients manifested an abnormal PT by postoperative day 3 but did not receive specific treatment. They then developed severe bleeding requiring transfusions and surgical intervention, and one patient lost his pancreatic graft. In conclusion, neither the incidence nor severity of vitamin K deficiency in the perioperative or postoperative periods in kidney and combined kidney–pancreas allograft recipients has been described, and further elucidation is needed. It is
965
clearly associated with high morbidity if not recognized and treated early. Although it is difficult to make definitive recommendations based on our experience with four patients, we suggest obtaining daily PT and PTT values in kidney and combined kidney–pancreas allograft recipients at least from postoperative days 3 through 7. Likewise, azotemic patients receiving prophylactic antibiotics such as cefazolin should be screened routinely. Administration of vitamin K should be considered in those with prolonged values to potentially prevent the hemorrhagic complications seen in these patients. REFERENCES 1. Alperin JB: Coagulopathy caused by vitamin K deficiency in critically ill, hospitalized patients. JAMA 258:19161919, 1987 2. Pineo GF, Gallus AS, Hirsh J: Unexpected vitamin K deficiency in hospitalized patients. Can Med Assoc J 109:880883, 1973 3. Ansell JE, Kumar R, Deykin D: The spectrum of vitamin K deficiency. JAMA 238:40-42, 1977 4. Staudinger T, Locker GJ, Frass M: Management of acquired coagulation disorders in emergency and intensive care medicine. Semin Thromb Hemost 22:93-104, 1996 5. Furie BC, Furie B: Vitamin K: Metabolism and disorders, in Hoffman R, Benz EJ, Shattil SJ, Furie B, Cohen HJ, Silberstein LE (eds): Hematology: Basic Principles and Practice. New York, NY, Churchill Livingstone, 1995, pp 1737-1741 6. Lipsky JJ: Antibiotic associated hypoprothrombinemia. J Antimicrob Chemother 21:281-300, 1988 7. Kerremans AL, Lipsky JJ, Van Loon J, Gallego MO, Weinshilboum RM: Cephalosporin-induced hypoprothrombinemia: Possible role for thiol methylation of 1-methyltetrazole-5-thiol and 2-methyl-1,3,4-thiadiazole-5-thiol. J Pharmacol Exp Ther 235:382-388, 1985 8. Chakraverty R, Davidson S, Peggs K, Stross P, Garrard C, Littlewood TJ: The incidence and cause of coagulopathies in an intensive care population. Br J Haematol 93:460463, 1996 9. Rabiner SF: Bleeding in uremia. Med Clin North Am 56:221-233, 1972 10. Kopple JD, Hirschberg R: Nutrition and peritoneal dialysis, in Mitch E, Klahr S (eds): Nutrition and the Kidney (ed 2). Boston, MA, Little, Brown, and Company, 1993, pp 290-313 11. Dupuis LL, Paton TW, Suttie JW, Thiessen JJ, Rachlis A: Cefazolin-induced coagulopathy. Clin Pharmacol Ther 35:237, 1984 12. Muraki T, Sasaki Y, Gidding JC, Ishii H, Kaneko T, Yamamoto J: Antithrombotic effect of FK506 versus prothrombotic effect of cyclosporine in vivo. Transplantation 60:308-310, 1995 13. Gastineau DA, Gertz MA, Daniels TM, Kyle RA, Bowie EJW: Inhibitor of the thrombin time in systemic amyloidosis: A common coagulation abnormality. Blood 77:2637-2640, 1991
B
LEEDING from acquired coagulopathy is associated with high morbidity and mortality rates.1 When associated with vitamin K deficiency, significant bleeding can occur in hospitalized patients, especially in the postoperative period.2 Early recognition with appropriate replacement can be an effective means of reducing morbidity.3 During a 7-month period, approximately 130 kidney and 16 combined kidney–pancreas transplants were performed at our institution. We describe four of these patients who developed vitamin K deficiency–induced coagulopathy and bleeding, associated with prolongation of the prothrombin time (PT) and partial thromboplastin time (PTT) in postoperative week 1 after kidney or combined kidney–pancreas transplantation. All four patients had advanced renal insufficiency, with three on maintenance hemodialysis. None had received prolonged antibiotic therapy, were severely malnourished before transplantation, or had a history of liver disease or coagulopathy. Admission coagulation parameters were normal in all patients. CASE REPORTS
developed confusion, with the hematocrit decreasing from 23% to 15%. The PT reported as the international normalized ratio (INR) was 10.2 and PTT 42.9 seconds. The platelet count was normal. Computed tomography of the abdomen showed large intraperitoneal and retroperitoneal hematomas. These were surgically evacuated, and the patient received parenteral vitamin K, 10 mg/d for 3 days, with prompt resolution of the coagulopathy. The pancreatic allograft was found to be thrombosed, and allograft pancreatectomy was performed.
Case 2 A 58-year-old white man on maintenance hemodialysis for 7 years for end-stage renal disease caused by amyloidosis was admitted for his first cadaveric renal allograft. His medical history was significant for chronic lymphocytic leukemia for which he had received chemotherapy 17 years earlier, with no recent evidence for recurrence. Admission medications included CaCO3, folate, colchicine, ascorbic acid, NaHCO3, and captopril. The patient received a total of four doses of cefazolin 1 g intravenously in the hospital. He was started on tacrolimus, famotidine, sucralfate, trimethoprim-sulfamethoxazole, and acyclovir postoperatively. His course was complicated by primary allograft dysfunction and abdominal distension requiring nasogastric decompression. On postoperative day 3, he became obtunded. The INR was 1.4. The whole blood tacrolimus level was 44 ng/mL. Tacrolimus was discontinued for presumed toxicity, and the patient was dialyzed without heparin. On postoperative day 6, diffuse ecchymoses were noted over the extremities and
Case 1 A 37-year-old white man was admitted for combined kidney–pancreas transplantation. He was taking aspirin, 81 mg/d. Other admission medications included nifedipine, famotidine, and cisapride. Perioperatively and postoperatively, he was administered four doses of cefazolin 1 g intravenously. Postoperatively he was started on tacrolimus, methylprednisolone, mycophenolate mofetil, famotidine, trimethoprim-sulfamethoxazole, and nifedipine. Both grafts had excellent function in the immediate postoperative period, but the patient remained without oral intake for 5 days because of poor bowel motility. On postoperative day 6, he
From the Renal Electrolyte Division, Department of Medicine, University of Pittsburgh, Pittsburgh, PA. Received June 3, 1998; accepted in revised form September 25, 1998. Address reprint requests to G. V. Ramesh Prasad, MBBS, FRCP(C), Division of Nephrology, Department of Medicine, University of Toronto School of Medicine, 10-158 Norman Urquhart Wing, 621 University Ave, Toronto, Ontario M5G 2C4, Canada.
娀 1999 by the National Kidney Foundation, Inc. 0272-6386/99/3305-0022$3.00/0
American Journal of Kidney Diseases, Vol 33, No 5 (May), 1999: pp 963-965
963
964
PRASAD ET AL
incision site. Ultrasonography showed an allograft perinephric hematoma. At this point, the INR was 4.2 and PTT was 36.4 seconds. Administration of parenteral vitamin K, 5 mg/d for 3 days, corrected the coagulopathy, but he remained dialysis dependent.
Case 3 A 47-year-old white woman was admitted for combined kidney–pancreas transplantation. Two previous pancreatic transplants were removed because of severe pancreatitis. A first kidney transplant failed from chronic rejection, and she had been on maintenance hemodialysis for 10 months before this admission. She was taking aspirin, 81 mg/d, and erythropoietin, 4,000 units intravenously thrice weekly. Other medications included cyclosporine and insulin. She received four doses of cefazolin 1 g intravenously during her hospital stay. Postoperative medications included tacrolimus, methylprednisolone, trimethoprim-sulfamethoxazole, acyclovir, sucralfate, and famotidine. Postoperatively, she experienced a prolonged ileus and remained without oral intake for 3 days. Over the next 2 days, the INR increased to 10.8. The platelet count remained normal. Parenteral vitamin K, 10 mg/d, resulted in complete correction of the coagulopathy over the next 3 days.
Case 4 A 71-year-old white woman on maintenance hemodialysis for 4 years for end-stage renal disease due to hypertension was admitted for her first cadaveric renal allograft. Admission medications included doxazosin, pilocarpine eye drops, multivitamins, and CaCO3. She received a total of four doses of cefazolin 1 g intravenously during hospitalization. Postoperatively she received tacrolimus, acyclovir, methylprednisolone, trimethoprim-sulfamethoxazole, sucralfate, and famotidine. The postoperative course was complicated by primary allograft nonfunction. On postoperative day 3, the hematocrit declined from 30% to 21%, with prolongation of the INR to 1.7. Ultrasonography showed a subincisional hematoma. On postoperative day 6, active gastrointestinal bleeding occurred with an INR of 10.2 and PTT of 60.2 seconds. The platelet count was within the normal range. Packed red cells were administered along with parenteral vitamin K, 5 mg/d for 3 days. The bleeding resolved with correction of the coagulopathy. Patient characteristics are summarized in Table 1. The three patients on hemodialysis were adequately dialyzed based on current guidelines as indicated by the urea reduc-
Table 1. Clinical Features of Patients Before Admission Case No.
Age/Sex
Serum Albumin Level (g/dL)
Dialysis Pre/Post BUN (mg/dL)
Kt/V Urea
1 2 3 4
37/M 58/M 47/F 71/F
3.0 4.4 3.4 4.1
NA 63/15 56/12 47/16
NA 1.8 1.8 1.3
Abbreviation: NA, patient not on hemodialysis.
Table 2. Coagulation Parameters During Hospitalization
Case No.
Coagulation Parameter
1
INR PTT (seconds) INR PTT (seconds) INR PTT (seconds) INR PTT (seconds)
2 3 4
Value at Value After Admission Time of Treatment Value Hemorrhage With Vitamin K
1.1 26.2 1.0 24.8 0.9 27.0 1.0 21.5
10.2 42.9 4.2 36.4 10.8 38.4 10.2 60.2
1.4 21.8 1.2 24.1 1.0 24.6 1.2 22.8
Abbreviations: INR, prothrombin time reported as the international normalized ratio; PTT, partial thromboplastin time.
tion ratio and Kt/V urea. Elevation of the PT and PTT during the first week for the four patients along with their values after correction with vitamin K is shown in Table 2.
DISCUSSION
The most common causes of acquired coagulation disorders are liver disease, disseminated intravascular coagulation (DIC), and vitamin K deficiency.4 Traditionally, prolongation of the PT with correction by vitamin K administration has been used for the diagnosis of vitamin K deficiency, although serum levels may be helpful. Vitamin K deficiency leads to low factor VII levels, but with more severe deficiency low levels of factors IX and X lead to prolongation of the PTT as well. Acquired deficiency can be associated with primary biliary cirrhosis, cholestatic hepatitis, and intestinal malabsorption.5 Drugs that can lead to vitamin K deficiency or a vitamin K deficiency–like state include warfarin, aspirin, and certain antibiotics such as moxalactam and cefamandole.5 Hypoprothrombinemia may be produced by antibiotics through mechanisms other than destruction of intestinal flora, such as inhibition of the gamma carboxylation of glutamic acid by N-methylthiotetrazole groups in cephalosporins.6,7 Old age, major surgery, and total parenteral nutrition are risk factors for vitamin K deficiency but are poor predictors in an intensive care unit population.8 Renal failure is associated with an abnormal PT,9 but in the absence of direct evidence that renal failure per se causes impaired absorption or utilization of vitamin K, routine supplementation is not recommended.10 To our knowledge, there is no definite
VITAMIN K DEFICIENCY AFTER TRANSPLANTATION
relationship between duration of dialytic care and the risk for PT prolongation from vitamin K deficiency. Vitamin K deficiency in these patients was probably multifactorial. Poor oral intake, preexisting renal failure, and the use of cefazolin may have been causative to varying degrees. Unfortunately, we did not have available to us preoperative serum prealbumin values, serum total protein levels, or body mass indices, which might have provided additional data on nutritional state. There was no evidence for loss of dry weight or diarrhea before transplantation. Specifically, cefazolin possesses a 2-methyl1,3,4-thiadiazole-5-thiol group7 and has been linked to coagulopathy.11 There is no reported association of vitamin K deficiency with the use of tacrolimus, whereas cyclosporine has been linked to thrombosis.12 Amyloidosis has been associated with coagulation abnormalities and bleeding from factor X deficiency, prolongation of thrombin time, or the presence of an inhibitor.13 Although amyloidosis was the cause for renal failure in case 2, his thrombin time was normal, and no inhibitor was present on mixing with normal plasma. Coagulation profiles were ordered for cases 2 and 4 because of their critical condition, and they showed normal values for fibrinogen, D-dimer, and plasma fibrin degradation products, making the probability of DIC very low. Although vitamin K deficiency usually develops 1 to 3 weeks after cessation of oral intake in combination with antibiotics,5 it may occur earlier in patients with marginal preoperative reserves whose coagulation profiles may be normal, but who are subjected to the added stress of surgery. Early recognition and treatment is therefore crucial in preventing excessive morbidity. It has been recommended that all intensive care unit patients with a prothrombin ratio exceeding 2.0 receive vitamin K regardless of risk.8 Three of our four patients manifested an abnormal PT by postoperative day 3 but did not receive specific treatment. They then developed severe bleeding requiring transfusions and surgical intervention, and one patient lost his pancreatic graft. In conclusion, neither the incidence nor severity of vitamin K deficiency in the perioperative or postoperative periods in kidney and combined kidney–pancreas allograft recipients has been described, and further elucidation is needed. It is
965
clearly associated with high morbidity if not recognized and treated early. Although it is difficult to make definitive recommendations based on our experience with four patients, we suggest obtaining daily PT and PTT values in kidney and combined kidney–pancreas allograft recipients at least from postoperative days 3 through 7. Likewise, azotemic patients receiving prophylactic antibiotics such as cefazolin should be screened routinely. Administration of vitamin K should be considered in those with prolonged values to potentially prevent the hemorrhagic complications seen in these patients. REFERENCES 1. Alperin JB: Coagulopathy caused by vitamin K deficiency in critically ill, hospitalized patients. JAMA 258:19161919, 1987 2. Pineo GF, Gallus AS, Hirsh J: Unexpected vitamin K deficiency in hospitalized patients. Can Med Assoc J 109:880883, 1973 3. Ansell JE, Kumar R, Deykin D: The spectrum of vitamin K deficiency. JAMA 238:40-42, 1977 4. Staudinger T, Locker GJ, Frass M: Management of acquired coagulation disorders in emergency and intensive care medicine. Semin Thromb Hemost 22:93-104, 1996 5. Furie BC, Furie B: Vitamin K: Metabolism and disorders, in Hoffman R, Benz EJ, Shattil SJ, Furie B, Cohen HJ, Silberstein LE (eds): Hematology: Basic Principles and Practice. New York, NY, Churchill Livingstone, 1995, pp 1737-1741 6. Lipsky JJ: Antibiotic associated hypoprothrombinemia. J Antimicrob Chemother 21:281-300, 1988 7. Kerremans AL, Lipsky JJ, Van Loon J, Gallego MO, Weinshilboum RM: Cephalosporin-induced hypoprothrombinemia: Possible role for thiol methylation of 1-methyltetrazole-5-thiol and 2-methyl-1,3,4-thiadiazole-5-thiol. J Pharmacol Exp Ther 235:382-388, 1985 8. Chakraverty R, Davidson S, Peggs K, Stross P, Garrard C, Littlewood TJ: The incidence and cause of coagulopathies in an intensive care population. Br J Haematol 93:460463, 1996 9. Rabiner SF: Bleeding in uremia. Med Clin North Am 56:221-233, 1972 10. Kopple JD, Hirschberg R: Nutrition and peritoneal dialysis, in Mitch E, Klahr S (eds): Nutrition and the Kidney (ed 2). Boston, MA, Little, Brown, and Company, 1993, pp 290-313 11. Dupuis LL, Paton TW, Suttie JW, Thiessen JJ, Rachlis A: Cefazolin-induced coagulopathy. Clin Pharmacol Ther 35:237, 1984 12. Muraki T, Sasaki Y, Gidding JC, Ishii H, Kaneko T, Yamamoto J: Antithrombotic effect of FK506 versus prothrombotic effect of cyclosporine in vivo. Transplantation 60:308-310, 1995 13. Gastineau DA, Gertz MA, Daniels TM, Kyle RA, Bowie EJW: Inhibitor of the thrombin time in systemic amyloidosis: A common coagulation abnormality. Blood 77:2637-2640, 1991