key: cord-0010081-ob7ondas
authors: Edwards, David F.; Russell, Robert G.
title: Probable Vitamin K‐Deficient Bleeding in Two Cats With Malabsorption Syndrome Secondary to Lymphocytic Plasmacytic Enteritis
date: 2008-06-28
journal: J Vet Intern Med
DOI: 10.1111/j.1939-1676.1987.tb01995.x
sha: 5f160f402fef72c3443582b4f63eadc464e90489
doc_id: 10081
cord_uid: ob7ondas

Two cats with intestinal malabsorption developed a hemorrhagic diathesis. Although unsubstantiated, the probable cause of bleeding was a chronic malabsorption of fat and the fat‐soluble vitamin K. When treated_with vitamin Ki per os, one cat's clotting times were only partially corrected. Since vitamin K, is actively absorbed in the proximal small intestine, the incomplete response of this case to orally administered vitamin K, was predictable. The infrequent occurrence of bleeding in animals with malabsorption is, in part, attributable to the ileal and colonic absorption of bacterially derived vitamin K(2). For this reason, nonspecific use of antibiotics in these animals is contraindicated. Since long‐chain, polyunsaturated fats impair vitamin K absorption, dietary fat given to animals with malasorption should be restricted to medium‐ and short‐chain, saturated fats. Vitamin K should be administered subcutaneously to these animals if prolonged clotting times or active bleeding is present, and routinely prior to surgery. Oral supplementation with vitamin K(3), which is absorbed in the colon and less lipid soluble than vitamin Ki, should be given to animals with malabsorption that are maintained as outpatients. Adequate dosage levels of vitamin K(3), however, are yet to be established for the cat, and dose‐dependent hemolytic anemia is a probable toxic manifestation.

VITAMIN K is a generic term for lipid-soluble compounds required in the hepatic synthesis of specific proteins (i.e., factors 11, VII, IX, and X, and proteins C and S) involved in the clotting process.' Vitamin K exists in three major forms. Phylloquinone (KJ, present in green leafy vegetables, is the primary source of vitamin K for mammak2 Menaquinone (K2) is produced by intestinal bacteria (especially Escherichia coli and Bacteroides spp.), and menadione (K3) is a chemically related synthetic c~m p o u n d .~

The mechanism and site of absorption of the different forms of vitamin K are variable. Vitamin K l uptake is a saturable, energy-dependent process requiring micellar solubilization and occurs only in the proximal small intestine.' Vitamins K2 and K3 are passively absorbed in the ileum and C O~O~.~-~ Vitamins Kl and K2 are primarily transported in the intestinal lymphatic^,^,^,' whereas the less fat-soluble vitamin K3 is absorbed into the portal blood.* All three forms of vitamin K function in the hepatic production of coagulation protein^.^ Vitamin K carboxylates glutamic acid residues on preformed vitamin Kdependent proteins.' The carboxyglutamate residues bind calcium, which is essential for adherence of these proteins to phospholipid-rich surfaces. Lack of vitamin K inhibits glutamate carboxylation, resulting in nonfunctional precursor proteins with fewer than the normal number of carboxyl groups. These under carboxylated proteins are referred to by the acronym PIVKA (proteins induced by vitamin K absencelantagonists K. Lipolysis, however, is usually not totally absent; therefore, bleeding is rare in affected patients.'~'~ With intestinal malabsorption, defects in absorption and transport of lipids lead to vitamin K deficiency. Bleeding is an uncommon, but well-documented, sequela of this disorder.14,15

The purpose of this report is to describe the clinical history, laboratory data, and pathologic features of two cats with chronic lymphocytic-plasmacytic enteritis and a probable vitamin K-deficient hemorrhagic diathesis.

A 9-year-old, neutered female, 2-kg, domestic shorthair cat was presented to the referral veterinarian for progressive weakness of 2 days' duration. The cat was in lateral recumbency and hypothermic (36.5"C), and had pale mucous membranes and a 9% PCV. Dramatic improvement followed intravenous fluid therapy (200 ml lactated Ringer's solution). Three days after the initial examination, the cat was referred to the University of Tennessee Veterinary Teaching Hospital for evaluation of its anemia. Historically, the cat was always small and had recently lost weight despite a good appetite. It was kept strictly indoors with two other cats, which were healthy. On examination, the cat was thin but alert and active. The rectal temperature was 38.3"C, and the heart rate was 160 beats/minute. Mucous membranes were pale with a capillary refill time of 2 seconds.

Abnormal results on a hemogram included a normocytic, normochromic anemia (PCV, 2 1 %). Platelet number was judged to be adequate from a blood smear. Urinalysis and serum chemistry values were unremarkable except for hyperglobulinemia (total protein, 7.7 g/dl; globulin, 5.2 g/dl). Results of indirect immunofluorescent antibody tests for coronavirus antibody and feline leukemia virus were negative. A small amount of free fluid in the abdomen was suspected on the basis of radiographically indistinct serosal margins.

A saline lavage was used to recover abdominal fluid following multiple unsuccessful needle aspirates. During the abdominal lavage, excessive and unrelenting bleeding occurred from the skin and subcutaneous tissue at the puncture site. A pressure bandage and transfusion of freshly obtained blood was required to stop the hemorrhaging. Clotting times on venous blood obtained prior to the transfusion were prolonged (OSPT, >60 sec, control, 9.5 sec; APTT, 44 sec, control, 13.9 sec). Treatment with vitamin K, (5 mg, PO, bid) and hetacillin (50 mg, PO, tid) was initiated. The owner denied any possible exposure of the cat to poisons, specifically dicoumarols or indandiones.

The following day the cat had a large, malodorous bowel movement, which was pasty and slate-grey in appearance. Fecal analysis was negative for parasites and starch, but positive for trypsin, muscle fibers, and split fat. After Dxylose was given orally (500 mg/kg in 5% solution), serum values peaked at 5.7 mg/dl in 2 hours (normal, >17 mg/dlI6).

Two weeks after hospitalization, the cat had an exploratory laparotomy. Preoperative clotting times were still prolonged (OSPT, 16.2 sec, control, 9.7 sec; APTT, 19.7 sec, control, 15.9 sec; platelets, adequate) despite continuous oral vitamin K, therapy. At surgery, biopsy specimens were taken from the small intestine, liver, and a mesenteric lymph node. Bleeding was not excessive, but fresh blood was transfused before and during the procedure. Recovery from anesthesia was uneventful, but 2 days postoperatively the cat was found dead in its cage.

At gross examination, the cat was emaciated and the liver enlarged. Histologically, there was marked villous atrophy. The lamina propria of the duodenum and proximal jejunum was diffusely infiltrated by small lymphocytes. Lesser numbers of plasma cells were present. In localized areas of the jejunum, lymphocytes had infiltrated the muscularis mucosa and at one site involved the submucosa, muscular layers, and serosa. The muscularis mucosa was covered with a cuboidal luminal epithelium in areas of healed ulceration. In the ileum, the lymphocytic infiltrate extended into the submucosa. The stomach was unremarkable, but the colon had a mild lymphocytic infiltrate restricted to the lamina propria. Many lipofuscin-laden macrophages were observed in the medullary sinusoids of the mesenteric lymph nodes. Follicular hyperplasia was present in the spleen. Swollen hepatocytes with marked cytoplasmic lipofuscin pigmentation were present throughout the liver, sometimes occumng in clumps of 6-10 cells. The cause of death was not determined.

A 10-year-old, neutered male, 3.6-kg, domestic shorthair cat was presented to the University of Tennessee Veterinary Teaching Hospital because of frequent, malodorous gray-colored bowel movements and weight loss of 4 months' duration. The cat was kept strictly indoors. Appetite was excellent. Physical findings were unremarkable. Abnormal results on a hemogram included an eosinophilia (4,4 1 O/pl). Platelet number was judged to be adequate from a blood smear. Urinalysis and serum chemistry values were unremarkable except for hyperglobulinemia (total protein, 7.8 g/dl; globulin, 5.3 g/dl) and increased ALT activity (220 IU/L; normal, <70 IU/L). Results of indirect immunofluorescent antibody tests for feline leukemia virus and for antibodies to coronavirus and Toxoplasma gondii were negative. Fecal analysis was negative for parasites and starch, but positive for trypsin, muscle fibers, and split fat. D-Xylose administered orally produced peak serum values of 27 mg/dl at 2 hours. Abdominal radiographs were unremarkable. At explbratory laparotomy, the abdominal viscera a p peared grossly normal, but histologic findings in biopsy specimens from the small intestine were consistent with a diagnosis of lymphocytic-plasmacytic enteritis.

The cat was discharged on prednisone (2.5 mg, PO, qod) and with the recommendation that unconventional foods (e.g., lamb and turkey) be fed. Occasionally antibiotic therapy was used (hetacillin 50 mg, PO, tid). The cat was closely monitored over a 13-month period during which it maintained its body weight despite intermittent episodes of voluminous, gray-colored stools. One day the owner left the cat for a period of 2 hours only to find it dead upon return. Hematochezia was observed 2 days prior to the cat's death, but no other abnormalities were noted. The cat was never permitted outdoors, and the owner denied any possible exposure of the cat to poisons, specifically dicoumarols or indandiones.

Gross pathologic findings included extensive subcutaneous hemorrhages on both sides of the thorax and the ventral abdo-men. Histologically, there was severe villous atrophy and diffuse infiltration of small lymphocytes between glands in the lamina propria of the duodenum, jejunum, and ileum (Fig. 1) . The submucosa of the duodenum and ileum had a moderate infiltration of cells, whereas the submucosa of the jejunum was thickened by a marked cellular infiltrate, which extended between the muscularis layers and into the serosa (Fig. 2) . There was lymphoid hyperplasia of Peyer's patches. Scattered crypts were lined by flattened cuboidal epithelium and contained neutrophils and necrotic epithelial cells. Beneath the luminal epithelium there were many macrophages containing lipofuscin pigment. The colon was unremarkable. Mesenteric lymph nodes were characterized by paracortical and medullary hyperplasia and the presence of many hemosiderin-laden macrophages in the medullary sinusoids. Histologic changes in the liver were diffuse. In many areas, the entire acinar units were composed of swollen hepatocytes containing lipofuscin pigment in the cytoplasm. Variable numbers of neutrophils, lymphocytes, and macrophages were present. Vacuolated hepatocytes appeared to have hydropic degeneration. Few lymphocytes were present in the portal areas, and the hepatic sinusoids contained numerous hemosiderin-laden macrophages.

Clinically, human beings present with subcutaneous hematomas at pressure points, hemarthrosis, hematemesis, melena, epistaxis, and hematuria. On rare occasions, bleeding can be the primary symptom. The acquired hemorrhagic diathesis is characterized as a hypoprothrombinemic disorder secondary to malabsorption of the fat-soluble vitamin K. As with other causes of vitamin K deficiency or antagonism, the laboratory parameters of hemostasis include early and marked prolongation of the OSPT, and mild to moderate prolongation of the APTT. Typically, the thrombin clot time, fibrinogen concentration, and platelet number are normal; however, the fibrinogen concentration and platelet number can be transiently reduced during extensive hemorrhaging. "J* Vitamin K deficiency resulting from bile salt deficiency or intestinal malabsorption is confirmed by the shortening of clotting times following the parenteral administration of vitamins Kl or K3. Anticoagulant antagonism of vitamin K will respond only to vitamin K1. In human beings, measurement of PIVKA is the most sensitive assay of vitamin K deficiency." Normally, plasma does not contain PIVKA, but with liver disease or vitamin K deficiency due to maldigestion, malabsorption, or anticoagulants, these undercarboxylated vitamin K-dependent proteins are detected.

The sudden onset of bleeding in two cats with chronic intestinal malabsorption was consistent with observations in human patients. In case 1, an acute intra-abdominal bleeding episode would account for the sudden onset of weakness, rapid response to intravenous fluids, spontaneous rise of the PCV (i.e., 9-21% in 72 hours) and radiographic evidence of peritoneal effusion. The results of coagulation tests (OSPT, >60 sec; APTT, 44 sec; platelets, adequate) were suggestive of vitamin K deficiency. The incomplete response to oral vitamin Kl therapy can be attributed to the continued malabsorption of fat. Since vitamin Kl undergoes active transport in the proximal small intestine and has a high lipid solubility, the intestinal inflammation would disrupt the cellular uptake of vitamin KI , and it would be retained in the unabsorbed fats. In case 2, laboratory verification of hypoprothrombinemia is lacking, but the spontaneous and extensive subcutaneous hemorrhaging in a cat with chronic malabsorption that was kept strictly indoors and had no exposure to anticoagulant rodenticides is consistent with vitamin K deficiency. Similar   FIG. 2. Jejunum, Case 2. A marked infiltration of lymphocytes in the submucosa (large arrow) and between the circular and longitudinal muscularis layers (small arrow). Lymphocytes are also infiltrating the circular muscularis layer. (H&E; original magnification, X 120) 

Internal Medicine cases of spontaneous, lethal hemorrhaging have been reported in human beings with intestinal malabsorpt i~n . '~, '~ The pathogenesis of vitamin K-dependent bleeding associated with intestinal malabsorption is more complex than the simple malassimilation of dietary vitamin K. In human patients with malabsorption, acquired liver damage, antibiotic therapy, and dietary fat composition can accentuate the vitamin K deficiency.'' Hepatic lesions occur commonly in human beings with intestinal malabsorption.22 These degenerative and inflammatory lesions result from the chronic malnutrition and/or an extension of the intestinal disease. As observed in case 2, cats with lymphocytic-plasmacytic enteritis can have increased serum ALT activity and periportal mononuclear cell infiltrate^.^^,^^ Since the liver produces most coagulation proteins, the hepatic disease secondary to intestinal malabsorption may promote a bleeding diathesis.

Bacterially derived vitamin K2 represents a major source of vitamin K. Rats on vitamin K,-deficient diets rarely develop bleeding tendencies, but germ-free rats on the same diet develop fatal hemorrhages within 2-4 weeks.25 Vitamin K-responsive bleeding is common among anorectic human patients treated with antibi-otic~.'~,~' In many disorders causing malabsorption, duodenal and jejunal lesions predominate, with the colon being minimally affected. Hence, the absorption of bacterially derived vitamin K2 in the ileum and colon may account for the infrequent appearance of hypoprothrombinemic bleeding in human beings and animals with malabsorption. Under these circumstances, the use of antibiotics could precipitate bleeding by turning a hypovitaminosis into an avitaminosis. The intermittent use of antibiotics in case 2 may have contributed to the onset of bleeding.

The absorption of natural forms of vitamin K is affected by the amount and type of dietary fat. Severe dietary fat restriction in animals with malabsorption can aggrevate vitamin K deficiency because the uptake of vitamin K is dependent on fat absorption. Intestinal absorption of vitamin K is reduced by progressively longer-chain fatty acids and greater degrees of unsaturatherefore, dietary fat requirements of animals with malabsorption should be met by short-or medium-chain, saturated fatty acids.

Vitamin K treatment should be given to all animals with malabsorption, especially when abnormal clotting is detected or prior to surgery. Abnormal clotting may be present as a laboratory finding (i.e., prolonged OSPT) or as clinical bleeding. Routine clotting tests (OSPT and APTT) are insensitive indicators of vitamin K deficiency, and prolonged values occur only after vitamin K-dependent coagulation factors decrease to approximately 35% of normal activity. Therefore, a prolonged OSPT in an animal with malabsorption would warrant immediate parenteral vitamin Kl or K3 administration. Since intramuscular injections in a hypoprothrombinemic animal can produce hematomas and intravenous administration of vitamin K1 has been associated with anaphylaxis, subcutaneous injection of vitamin K preparations in normovolemic animals is the preferred parenteral route of administration. Because of the time required (4-8 hours) to increase clotting factor activity following vitamin K supplementation, animals with clinical bleeding should receive fresh plasma or blood transfusions prior to vitamin therapy.

Surgical biopsy of the intestines is frequently used to make a specific diagnosis in animals with malabsorption. Since clotting parameters are a poor determinant of vitamin K levels, animals with intestinal malabsorption should routinely receive parenteral vitamin K prophylactically 8-12 hours before surgery. The time interval is critical because of the delay in carboxylation of vitamin K-dependent proteins and the relatively short half-lives of these proteins (e.g., factor VII, 6 hours) and vitamin K, especially vitamin K3.

Animals with malabsorption in a home environment should receive daily oral supplementation with vitamin K. Because of its colonic absorption and lower lipid solubility, vitamin K3 is the most effective oral form of vitamin K in these animals. Vitamin K3 is associated with a dose-dependent Heinz body hemolytic anemia and methemoglobinemia in human beings3' and dogs3' Reactions involving vitamin K3 and the metabolic intermediate, semiquinone, deplete RBC-glutathione and inhibit in vitro activity of hepatic glucuronyl transferase.31*32 Cats are very sensitive to oxidant drugs and have low levels of hepatic glucuronyl tran~ferase~~; therefore, hemolytic anemia and, possibly, hepatoxicity are anticipated with inappropriately high doses of vitamin K3 in this species. A safe but effective dose of vitamin K3 has not been established for the cat. Although massive doses of vitamin KI have been administered to infants without resultant hem~lysis,~* it should not be given indiscriminantly to cats because hemolytic anemia was produced in a dog that received an excessively large dose. 31 

Carboxylated calcium-binding proteins and vitamin K

Vifamin K, intestinal a b sorption in vivo: influence of luminal contents on transport

Production of menaquinones by intestinal anaerobes

Vitamin Kz colonic and ileal in vivo absorption: bile, fatty acids, and pH effects on transport

Mechanism and site of vitamin K3 small intestinal transport

Colonic absorption of vitamin K1

Metabolism of K-vitamins

Biological activity of the various vitamin K forms

Nature of prothrombin biosynthesis: preprothrombinanemia in vitamin K deficiency

Deficiency of fat-soluble vitamins in treated patients with pancreatic insufficiency

Vitamin K in medical practice: adults. Vitam Horm

Incidence and severity of nutritional deficiency states in chronic exocrine pancreatic insufficiency: comparison with non-tropical sprue

A haemorrhagic diathesis in idiopathic steatorrhoea: observations on its association with vitamin K deficiency

Sprue with bleeding from hypoprothrombinemia

Digestion of bentiromide and absorption of xylose in healthy cats and absorption of xylose in cats with infiltrative intestinal disease

Laboratory evaluation of coagulopathies due to vitamin K antagonism in the dog: three case reports

Hemorrhagic disease due to vitamin K deficiency in a premature infant: a syndrome which may resemble disseminated intravascular coagulation (DIC)

Acquired vitamin K dependent carboxylation deficiency in liver disease

normal) prothrombin: a new serum marker of primary hepatocellular carcinoma

The prevalence of vitamin K deficiency in chronic gastrointestinal disorders

Liver changes in malabsorption syndrome

Chronic feline inflammatory bowel disorders. Part 1. Idiopathic inflammatory bowel disease. Compendium on Continuing Education for the Practicing Veterinarian

Lymphocytic-plasmacytic enteritis in a cat

Effects of vitamin K-active compounds and intestinal microorganisms in vitamin K-deficient germ-free rats

Hypoprothrombinemia in febrile, neutropenic patients with cancer: association with antimicrobial suppression of intestinal microflora

Unexpected vitamin K deficiency in hospitalized patients

Intestinal absorption of vitamins A

Absorption mechanisms of fat-soluble vitamins and the effect of other food constituents

Vitamin K in medical practice: pediatrics. Vitam Horm

Vitamin K-induced Heinz body formation in dogs

The reaction of menadione with haemoglobin

Acetaminophen toxicosis in small animals: clinical signs, mode of action, and treatment. Compendium on Continuing Education for the Practicing Veterinarian

issue, an error occurred on page 92 in the first sentence of the second paragraph of the "Results" section. The sentence should read