Long-acting anticoagulant overdose: brodifacoum kinetics and optimal vitamin K dosing

Ingestion of long-acting anticoagulant rodenticides such as brodifacoum can lead to prolonged and life-threatening coagulopathy. A paucity of conflicting information is available on brodifacoum's half-life and elimination pharmacokinetics. In addition, the optimal dose, duration, and route of administration of vitamin K(1) therapy are unknown. We report the case of a 52-year-old man who ingested eight 43-g boxes of a rodenticide (d-Con Mouse-Prufe II; 0.005% brodifacoum; Reckitt & Colman, Wayne, NJ). This case demonstrates that after stabilization with fresh frozen plasma, high-dose oral vitamin K(1) therapy ( congruent with 7 mg/kg per 24 hours divided every 6 hours) was effective in treating brodifacoum-induced coagulopathy. The concentration of vitamin K(1) required for normal coagulation in this case was less than the accepted value of 1 microg/mL, which is derived from a rabbit model. In this case, brodifacoum appears to follow zero-order elimination pharmacokinetics. In future cases of patients with ingestions of long-acting anticoagulants who present with coagulopathy, it may be useful to obtain serial brodifacoum concentrations to determine elimination curves to help predict the duration of oral vitamin K(1) therapy.     

Dietary fish lipids do not diminish platelet adhesion to subendothelium

There is a discrepancy in the results of reported studies of levels of vitamin K dependent coagulation factors in patients on warfarin therapy. This may have arisen partly because of the problem of assuring compliance with therapy in outpatients. The plasma concentrations of the vitamin K dependent clotting factors II, VII, IX and X were studied in 23 outpatients whose adherence to prescribed warfarin therapy was determined using a pharmacological indicator of compliance. In these patients, who were shown to have consistently good compliance and stable anticoagulant control over a period of 3-6 months, the activities in plasma of the four coagulation factors were not equally suppressed. Factor IX levels were significantly greater than those of factor VII (P less than 0.0001) which in turn were significantly greater than the levels of factor II (P less than 0.0001) or factor X (P less than 0.0001). There was no significant difference between the levels of factors II and X which were depressed to a similar extent. The proportion of variability of the International Normalized Ratio (INR) explained by linear regression was 51-77% and a model was derived to predict the INR from the mean of the levels of the four clotting factors. The concentrations of the coagulation factors II, VII, IX and X are likely to be highly dependent on the degree of compliance with warfarin therapy which should be taken into account when investigating the behaviour of these factors.     

Acquired isolated factor VII deficiency associated with severe bleeding and successful treatment with recombinant FVIIa (NovoSeven).

Acquired isolated FVII deficiency not due to vitamin K deficiency or liver disease is rare and often associated with severe bleeding. We present a case of transient acquired factor VII deficiency associated with major bleeding, successfully treated with twice daily intermittent intravenous recombinant activated factor VII (rFVIIa) (NovoSeven; Novo Nordisk). The severe transient reduction in factor VII coagulant activity (FVII:C) levels, unresponsive to fresh frozen plasma and vitamin K administration, raise the possibility of an acquired inhibitor to factor VII. However, no inhibitor to factor VII could be demonstrated using protein G sepharose adsorption, or a Bethesda assay using IgG purified from patient plasma. There are few reports of the use of rFVIIa in this setting and this case suggests that rFVIIa is effective therapy, and should be considered early when acquired factor VII deficiency is associated with severe bleeding.     

Vitamin K1 levels and coagulation factors in healthy term newborns till 4 weeks after birth

Vitamin K1 serum levels were assessed by means of an off-line multidimensional liquid chromatography in 18 mothers, shortly after delivery, and in their healthy term infants. Umbilical cord and venous blood samples were assayed up to 4 weeks of life. Concurrently, levels of coagulation factors II and X, antithrombin III and platelets were established. Although the detection limit of the assay was as low as 22 pg/ml, vitamin K1 concentration appeared to be still beyond that level in cord blood or in newborn serum within 30 min after birth, whereas vitamin-K-dependent coagulation factors are already at a level of 40%, without evidence for the presence of descarboxy prothrombin, in any of the investigated neonates. After 3 days, breast-fed neonates had lower vitamin K1 levels than formula-fed infants (0.76 and 1.44 ng/ml, respectively). The levels of the vitamin-K-dependent coagulation factors II and X, however, were comparable, regardless of the kind of feeding. After 28 days, breast-fed neonates had even lower vitamin K1 levels (0.49 ng/ml, while the formula-fed infants showed higher vitamin K1 levels (4.45 ng/ml). But even then, the levels of vitamin-K-dependent coagulation factors II and X were comparable, regardless of the kind of feeding. From this we conclude that the serum levels of vitamin K1 in formula-fed neonates exceed those of breast-fed infants from the moment of feeding (24 h and later) without a concomitant rise in vitamin-K-dependent coagulation factors. A relationship between vitamin K1 levels and vitamin-K-dependent coagulation factors could not be established in healthy term breast-fed or formula-fed infants.     

Differences in reactivity to vitamin K administration of the vitamin K-dependent procoagulant factors, protein C and S, and osteocalcin

Vitamin K is a trace nutrient necessary not only for the synthesis of four plasma clotting factors but also the production of two important anticlotting factors, protein C and protein S, and the synthesis of two bone proteins. If protein C and protein S are produced more quickly and/or in higher quantities than four plasma coagulation factors after vitamin K administration, then the result is unfavorable for stopping of hemorrhage. We therefore studied the difference of time dependence of prothrombin procoagulant factors, protein C and S and bone Gla protein after the administration of vitamin K in normal and vitamin K-deficient neonates. Results of our study showed that, on the whole, coagulation factors increased markedly more than anticlotting factors after vitamin K administration. Furthermore, the increase in bone Gla protein was also higher compared with protein C activity, although the detailed mechanism of the difference in reactivity of prothrombin procoagulant factors, protein C and S and bone Gla protein to vitamin K administration is not clear.     

Platelet-dependent coagulation assays for factor VIII efficacy measurement after substitution therapy in patients with haemophilia A

FVIII therapy for haemophilia A is safe and effective, with the problem of individually sufficient efficacy unsettled. Routine one-stage clotting assays and tests employing chromogenic substrates poorly detect individual haemostatic effects of FVIII due to artificial test conditions. In particular, the use of cell-free and diluted plasma samples neglect the crucial role of platelets for thrombin and fibrin formation. To optimize FVIII substitution therapy, we measured in 40 patients with severe to mild haemophilia A before and after FVIII substitution the FVIII activity in cell-free plasma samples using a one-stage clotting assay as well a chromogenic substrate assay and compared the data with those obtained with cell-based coagulation tests, i.e. thrombin generation in platelet-rich plasma (PRP) and thromboelastography (TEG) in samples of citrated whole blood (WB). To determine the maximum ex vivo haemostatic effect we added 1 unit/ml of FVIII to samples of PRP and WB and measured the maximum thrombin generation in the thrombin generation test (TGT) and the maximum clot firmness (MCF) in TEG. After FVIII substitution we observed a nearly linear relation between the individual FVIII activities administered to the patients and the activities measured in the plasma samples. However, data obtained with TGT and TEG revealed a high inter-individual variation and a very poor correlation to the administered FVIII activity. Actually, it could be shown that FVIII substitution yielding in a FVIII plasma activity of about 30% is sufficient to get an ex vivo haemostatic effect of more that 90% as measured by maximum thrombin generation and MCF. FVIII substitution up to a plasma activity of more than 90% did not further enhance the haemostatic effect. Our data clearly demonstrate that the haemostatic effect of FVIII is not only dependent on the activity that is measured in plasma but also depends on the interplay between coagulation and blood cells, in particular with platelets. The use of cell-based coagulation tests such us TGT or TEG may help to optimize FVIII therapy by determining the individual FVIII dosage that produces a maximum haemostatic effect.     

Temporal variations in plasma vitamin K and lipid concentrations and clotting factor activity in humans.

There is no information available on temporal variability in plasma vitamin K concentrations and its relationship to coagulation processes. We investigated the possible existence of temporal changes in plasma vitamin K and lipid concentrations and activity of clotting factors II, VII, IX, and X and relationships between these variables. Plasma vitamin K and lipid concentrations and clotting factor activity were measured at four-hour intervals for 28 hours in a group of healthy volunteers. Temporal variations existed in plasma vitamin K concentrations, with a mean maximum at 22:00 hr and a mean minimum (32% of the maximum) at 10:00 hr. Plasma triglycerol concentrations mirrored the changes in vitamin K concentrations. Mean factor VII activity was positively correlated with mean total plasma cholesterol concentrations (r = 0.714; P < 0.0001) and with mean plasma low density lipoprotein (LDL) cholesterol concentrations (r = 0.461; P < 0.0001). No distinct correlations were found between plasma vitamin K concentrations and either high density lipoprotein (HDL) or LDL cholesterol concentrations, or between triglycerol, HDL, or LDL cholesterol concentrations and functional activity of factors II, IX, and X. Plasma vitamin K concentrations did not correlate with the functional activity of any of the clotting factors. The presence of a correlation between plasma cholesterol concentrations and factor VII activity for blood samples collected at four-hour intervals suggests that plasma cholesterol concentrations may have a more acute effect on factor VII activity. Temporal variations in plasma vitamin K concentrations indicate that a single time point measurement may be an inappropriate method of establishing vitamin K status in an individual.     

Efficacy of Argon Plasma Coagulation for Bleeding Gastroduodenal Ulcers

Background: Argon plasma coagulation (APC) can achieve an effective coagulation of large areas with a relatively shallow but well‐controlled and uniform coagulation depth. There are only a few reports of APC therapy applied to bleeding peptic ulcers, especially ulcers with exposed vessels. Methods: The aim of this study is to evaluate the usefulness of APC as a means of achieving endoscopic hemostasis for bleeding gastroduodenal ulcers. Thirty‐nine patients having these ulcers were treated with APC. Results: The success rates for initial hemostasis and complete hemostasis with APC are 87% and 97.4%, respectively. These results are almost equal to those of injection therapy and hemoclip. Six cases that re‐bled after other hemostatic procedures obtained complete hemostasis finally with APC. In one ineffective case of APC, complete endoscopic hemostasis was achieved with hemoclip. Conclusion: Argon plasma coagulation therapy is an effective therapeutic alternative in endoscopic hemostasis for bleeding peptic ulcers.     

Antikoagulation bei Vorhofflimmern

According to new criteria based on the CHAD(2)DS(2)-VASc score, the threshold for administering anticoagulation therapy for atrial fibrillation patients is being increasingly lowered. With the development of new anticoagulants, more therapy options are available. Currently, vitamin K antagonists are still the standard treatment. However, this therapy is problematic for some patients. Because of the increased bleeding risk and need for continuous blood tests to monitor coagulation, many patients needing anticoagulation therapy are not treated. The new anticoagulants apixaban, rivaroxaban and dabigatran were developed with the goal of avoiding these problems. Dabigatran has already been approved for thromboembolism prophylaxis for patients with atrial fibrillation. All three substances do not require routine control blood tests. Whether the costs saved by this together with the prevention of ischemic and bleeding events justify the higher price of these drugs compared to vitamin K antagonists needs to be examined by socioeconomic studies.     

Vitamin K metabolism and nutriture.

Vitamin K functions as a co-factor for the post-translational carboxylation of specific glutamate residues to gamma-carboxyglutamate (Gla) residues in several blood coagulation factors (II, VII, IX and X) and coagulation inhibitors (proteins C and S) in the liver; as well as a variety of extrahepatic proteins such as the bone protein osteocalcin. This review outlines some recent advances in our understanding of the metabolism of vitamin K and its role in human nutriture. The introduction of new methodologies to measure the low endogenous tissue concentrations of K vitamins and circulating plasma levels of des-gamma-carboxyprothrombin (PIVKA-II) have provided correspondingly more refined indices for the assessment of human vitamin K status. The assays for vitamin K have also been used to study the sources, intestinal absorption, plasma transport, storage and transplacental transfer of K vitamins and the importance of phylloquinone (vitamin K1) versus menaquinones (vitamins K2) to human needs. The ability to biochemically monitor subclinical vitamin K deficiency has reaffirmed the precarious vitamin K status of the newborn and led to an increased appreciation of the risk factors leading to haemorrhagic disease of the newborn and how this may be prevented. Biochemical studies are leading to an increased knowledge of the mode of action of traditional coumarin anticoagulants and how some unrelated compounds (e.g. antibiotics) may also antagonize vitamin K and cause bleeding. There is also an awareness of the possible deleterious effects of vitamin K antagonism or deficiency on non-hepatic Gla-proteins which may play some subtle role in calcium homeostasis.     

Vitamin K2 (Menaquinone-7) supplementation does not affect vitamin K-dependent coagulation factors activity in healthy individuals

Background:Vitamin K has long been regarded as a procoagulant drug by physicians, and concerns have been raised with regard to its effects on hemostasis. Although many studies have shown that vitamin K supplementation is safe for thrombotic events, the effect of vitamin K supplementation on the activities of vitamin K dependent procoagulation factors in healthy individuals is not available.Objectives:This study aimed to investigate whether vitamin K2 supplementation at recommended doses affects the activity of vitamin K dependent procoagulation factors in healthy individuals without any anticoagulation treatment.Design:Forty healthy volunteers between 25 and 40 years of age were recruited. Menaquinone-7 (MK-7) was administrated at 90 μg for 30 days. Prothrombin time (PT), activated partial thromboplastin time (APTT), thrombin time (TT), and blood coagulation factors II, VII, IX, and X activities and Protein induced by vitamin K absence or antagonist-II (PIVKA-II) were measured on days 0 and 30 after MK-7 administration.Results:PT, APTT, and TT showed no significant differences on day 30 when compared with baseline. The activities of coagulation factors II, VII, IX, and X on day 30 showed no significant differences with those at baseline. PIVKA-II levels were unchanged after 30 days of MK-7 supplementation.Conclusions:MK-7 supplementation at recommended dosage does not affect vitamin K-dependent coagulation factors’ coagulation activity, and does not enhance the carboxylation of prothrombin in healthy individuals. This indicated that MK-7 administration does not alter hemostatic balance in healthy populations without anticoagulation treatment.     

Coagulopathy in liver disease

Opinion statement The liver plays a central role in hemostasis, as it is the site of synthesis of clotting factors, coagulation inhibitors, and fibrinolytic proteins. The most common coagulation disturbances occurring in liver disease include thrombocytopenia and impaired humoral coagulation. Therapy’s overall goal is not to achieve complete correction of laboratory value abnormalities but to gain hemostasis. Therapy with vitamin K may be a useful option in patients with increased prothrombin time due to vitamin K deficiency; in patients with malnutrition; in patients using antibiotics; and in patients with cholestatic liver disease, particularly prior to invasive procedures. Infusion of fresh frozen plasma is more often effective and is recommended in patients with liver disease before invasive procedures or surgery, as such patients require transient correction in their prothrombin time. Therapy with plasma exchange may be considered in patients who cannot be treated with fresh frozen plasma due to volume overload risk. In patients with severe coagulopathy and hypofibrinogenemia, cryoprecipitate therapy is ideal. Therapy with prothrombin-complex concentrate is seldom pursued in patients with liver disease due to high risk of thrombotic complications. Transfusions of platelets are appropriate for patients with thrombocytopenia (< 50,000/mm³) associated with active bleeding or before invasive procedures in which a short-term platelet count increase is noted. Trial with desmopressin may be considered before invasive procedures in patients with liver disease and with refractory and prolonged bleeding time. Recombinant activated factor VIIa administration is suggested for patients with significantly prolonged prothrombin time and contraindications to fresh frozen plasma therapy; however, this is expensive. Thrombopoietin and interleukin-11 are currently investigational for patients with thrombocytopenia of chronic liver disease. Liver transplantation completely restores impaired coagulation abnormalities and is the ultimate intervention that corrects coagulopathy of advanced liver disease and liver failure.     

The Effects of Vitamin K on the Generation of Des-γ-Carboxy Prothromhin (PIVKA-II) in Patients with Hepatocellular Carcinoma

The clinical significance of des-gamma-carboxy prothrombin (PIVKA-II) in hepatocellular carcinoma (HCC) was investigated in 112 patients with and without vitamin K administration. The positivity rate of PIVKA-II was significantly decreased in patients receiving vitamin K (28.5%), compared with those without vitamin K administration (54.5%, p less than 0.05). The plasma levels of vitamin K derivatives [phylloquinone (VK1), menaquinone-4 (MK4), and menaquinone-7 (MK7)] measured were not decreased in patients with HCC, but were significantly increased in MK4 and VK1 + MK4 + MK7. The amount of PIVKA-II in plasma did not correlate with the plasma levels of vitamin K derivatives. However, PIVKA-II was decreased by the administration of vitamin K, and all of the six patients with more than 5.0 ng/ml of VK1 + MK4 + MK7 were within normal limits, whereas half of 32 patients with less than that had abnormal levels of PIVKA-II. Thus, it was suggested that PIVKA-II was not elevated due to vitamin K deficiency, but might result from the impaired metabolism or availability of vitamin K in the tumor. Therefore, PIVKA-II should be measured without vitamin K administration.     

Incomplete gamma carboxylation of human coagulation factor VII: differential effects on tissue factor binding and enzymatic activity

The integrity of the γ-carboxylic glutamic acid (GLA) residues of coagulation factor VII are thought to be essential for both the interaction of factor VII with its cell-surface lipoprotein receptor tissue factor and for the activated protein to manifest its serine protease activity. During the course of transiently expressing recombinant human factor VII in monkey COS cells it was noted that the factor VII synthesized in the absence of added vitamin K had < 20% of expected procoagulant activity yet retained 65% of its binding activity to recombinant human tissue factor. Similar results were obtained when vitamin K was omitted from human 293 cell cultures permanently expressing recombinant factor VII. In contrast, both transient and permanent expression of factor VII in human 293 cell cultures containing physiological concentrations of vitamin K resulted in the synthesis of fully functional factor VII. Furthermore, factor VII in plasma samples from 24 patients undergoing warfarin therapy bound quantitatively to tissue factor whereas factor VII procoagulant activity averaged 65% of normal. Thus, data from both in vitro and in vivo situations indicated that factor VII molecules with suboptimal GLA content retained most of their ability to bind tissue factor but exhibited reduced procoagulant activity.     

Role of dietary vitamin K intake in chronic oral anticoagulation: prospective evidence from observational and randomized protocols

PURPOSE: The potential association between vitamin K intake and coagulation instability has been explored primarily in case reports and small, retrospective, uncontrolled studies. We prospectively evaluated the effects of dietary vitamin K intake on anticoagulation parameters. METHODS: In an observational protocol, clinical characteristics and vitamin K intake, assessed semiquantitatively, were evaluated in 39 outpatients who made 230 visits to our anticoagulation clinic. In a randomized crossover protocol, 12 patients with stable anticoagulation underwent 4-day in-hospital dietary interventions, 1 to 2 weeks apart, providing a 500% increase and an 80% decrease in vitamin K intake relative to the baseline level. RESULTS: Univariate analysis of the observational data demonstrated a progressive, statistically significant inverse association between the vitamin K intake score and different levels of anticoagulation. Multivariate logistic regression analysis showed that vitamin K intake was independently associated with both overcoagulation and undercoagulation. In the randomized protocol, the international normalized ratio increased from 2.6 +/- 0.5 at baseline to 3.3 +/- 0.9 at day 7 (P = 0.005) in subjects on the vitamin K-depleted diet and decreased from 3.1 +/- 0.8 at baseline to 2.8 +/- 0.6 at day 4 (P = 0.04) in those on the vitamin K-enriched diet. CONCLUSION: Our prospective data strengthen the concept that the interaction between vitamin K and coumarin is a clinically relevant, major independent factor that interferes with anticoagulation stability.     

Vitamin K deficiency amplifies anticoagulation response to ximelagatran: possible implications for direct thrombin inhibitors and their clinical safety

Dietary vitamin K is known to influence the anticoagulation response to warfarin. It is possible that dietary vitamin K availability also influences the pharmacological activity of other oral anticoagulants, which target the vitamin-K dependent clotting proteins in the coagulation cascade. This study examined whether vitamin K insufficiency affected anticoagulation response to the direct thrombin inhibitor, ximelagatran. Anticoagulation response to ximelagatran and warfarin in rats on a normal diet was compared to those on a vitamin K deficient diet. Ximelagatran and warfarin increased prothrombin time (PT) by 1.4- and 1.3-fold, activated partial thromboplastin time (APTT) by 1.8- and 1.4-fold and ecarin clotting time (ECT) by 6.8- and 1.2-fold, respectively, in rats on normal diet. Vitamin K deficient diet alone caused modest increases in PT, APTT and ECT. The anticoagulant activity of both ximelagatran and warfarin was significantly greater in rats on vitamin K deficient diet (6.1- and 12.3-fold for PT, 2.6- and 5.1-fold for APTT and 2.9- and 1.6-fold for ECT, respectively) compared to those on normal diet. Factor II activity was reduced by both ximelagatran (58%) and warfarin (44%) in rats on normal diet. However, factor II activity was virtually abolished (<0.1%) by both drugs in rats on vitamin K deficient diet. The results suggest that oral anticoagulant drugs, whose primary site of action is not within the vitamin K cycle, may also exhibit variability in clinical response due to dietary variation as the established coumarin drugs such as warfarin.     

Intraventricular hemorrhage in preterm infants: coagulation perspectives

It has long been considered that a severe coagulation deficiency in premature newborns could be a major contributing factor in the occurrence of intraventricular hemorrhage (IVH). High-grade IVH has also been shown to coincide with severe derangement of coagulation in extremely low birth weight infants. This review focuses on the relevance of the physiologically developing immature hemostatic system to IVH, and the potential benefit of agents affecting hemostasis for IVH therapy or prevention in preterm infants. The findings of small, open-label interventional studies on the effect of ethamsylate, vitamin K, fresh frozen plasma, recombinant activated factor VII, and prothrombin complex concentrate on the premature coagulation system will be reviewed.     

A functional assay of protein C in human plasma

A three-step spectrophotometric assay was developed for measuring functional protein C (PC) in human plasma. The assay is based on: (1) adsorption of citrated platelet-poor plasma on barium citrate and elution of the vitamin K-dependent factors with EDTA; (2) activation of PC by incubation of the mixture of vitamin K-dependent factors with a complex of thrombin and its endothelial cell cofactor, thrombomodulin; (3) addition of antithrombin III and heparin to the system to inhibit thrombin and other coagulation enzymes generated during incubation and measurement of the activated PC with a synthetic (chromogenic) substrate. The assay appears to be specific for PC because: (a) PC- depleted plasma (by immunoadsorption) is inactive; (b) addition of purified PC to PC-depleted plasma reconstitutes its activity; and (c) no enzymatic activity is generated in the absence of the thrombin- thrombomodulin complex. Mixtures of a normal plasma pool with PC- depleted plasma yielded an amount of enzymatic activity proportional to the fraction of normal plasma. Using this as a standard curve, the amount of PC in the plasma of 23 normal subjects was 97% +/- 15%. The within-assay coefficient of variation was 3.5% and the between-assay coefficient 6.5%. A linear correlation (r = 0.86) was found between PC as measured with the functional assay and with a radioimmunoassay. In 3 patients with congenital PC deficiency, the functional PC level was 37% +/- 9% and the antigen level 64% +/- 11%. It is concluded that the present assay may be used for reliable and accurate estimation of activatable PC in human plasma.     

Compound heterozygous mutations in the gamma-glutamyl carboxylase gene cause combined deficiency of all vitamin K-dependent blood coagulation factors

Hereditary combined deficiency of the vitamin K-dependent coagulation factors II, VII, IX, X, protein C, S and protein Z (VKCFD) is a very rare autosomal recessive inherited bleeding disorder. The phenotype may result from functional deficiency of either the gamma-glutamyl carboxylase (GGCX) or the vitamin K epoxide reductase (VKOR) complex. We report on the third case of VKCFD1 with mutations in the gamma-glutamyl carboxylase gene, which is remarkable because of compound heterozygosity. Two mutations were identified: a splice site mutation of exon 3 and a point mutation in exon 11, resulting in the replacement of arginine 485 by proline. Screening of 100 unrelated normal chromosomes by restriction fragment length polymorphism and denaturing high-performance liquid chromatography analysis excluded either mutation as a frequent polymorphism. Substitution of vitamin K could only partially normalize the levels of coagulation factors. It is suggested that the missense mutation affects either the propeptide binding site or the vitamin K binding site of GGCX.     

Skin necrosis and protein C deficiency associated with vitamin K depletion in a patient with renal failure.

Skin necrosis similar to that induced by warfarin was seen in a patient who had never received the drug but who was vitamin K-deficient due to malnutrition and prolonged treatment with broad-spectrum antibiotics. He also had end-stage renal failure and was receiving prophylactic subcutaneous heparin therapy because of immobilization. His plasma protein C antigen level and, disproportionately, his plasma protein C functional activity were decreased. Both protein C values improved after vitamin K therapy, discontinuation of heparin, and initiation of hemodialysis. We surmise that skin necrosis occurred as a result of protein C deficiency caused by vitamin K depletion. Production of abnormal (descarboxy) protein C/protein S due to vitamin K deficiency and increased protein C inhibitory activity associated with renal failure and/or heparin administration may have contributed to the clinical picture. This rare but serious complication of a relatively common disorder, viz., vitamin K deficiency, reinforces the importance of vitamin K supplementation in malnourished patients who receive long-term antibiotic maintenance therapy.