T jor components: primary hemostasis, secondary hemostasis,

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1 Hemostatic Disorders in Cats: A Retrospective Study and Review of the Literature Janet L. Peterson, C. Guillermo Couto, and Maxey L. Wellrnan Hemostasis profiles from 101 cats presented for medical or surgical evaluation to The Ohio State University Veterinary Teaching Hospital from 1986 through 1991 were reviewed retrospectively; 69% were abnormal. Commonly identified abnormalities included a mixed hemostatic defect compatible with disseminated intravascular coagulation, thrombocytopenia, isolated prolongation of the acti- he hemostatic system is traditionally divided into 3 ma- T jor components: primary hemostasis, secondary hemostasis, and fibrinolysis.' Primary hemostasis refers to the interaction between circulating platelets and the vessel wall, whereas secondary hemostasis refers to the activation of the coagulation cascade (ie, clotting factors), which results in fibrin formation. Fibrinolysis involves lysis of a clot or thrombus through activation of plasminogen to plasmin. The conventional coagulation cascade consists ofthe intrinsic, extrinsic, and common pathways.' The intrinsic pathway is initiated by contact with a disrupted vascular surface, causing activation of factors XII, XI, IX, and VIII. Complexing of tissue factor with factor VII results in activation of the extrinsic pathway through formation of activated factor VII (factor VIIa). The common pathway includes fibrinogen and factors 11, V, and x. Both factor VIII/IX complex and factor VIIa activate factor X, initiating the common pathway. Abnormalities in any of these pathways can be detected using specific diagnostic tests. Primary hemostasis can be evaluated by determination of platelet numbers and by performing a buccal mucosal bleeding time to evaluate plateletvessel interaction.' Secondary hemostasis can be evaluated by the activated clotting time (ACT) or activated partial thromboplastin time (APTT) for intrinsic and common pathway abnormalities, fibrinogen quantification (common pathway abnormality), and the one-stage prothrombin time (OSPT) for extrinsic and common pathway abnormalities. The presence of fibrin degradation products suggests active systemic fibrinolysis (ie; circulating plasmin).' Hemostatic abnormalities can be classified into 4 main categories. Primary hemostatic disorders result from either thrombocytopenia or platelet dysfunction or, less frequently, from vasculopathies. Secondary hemostatic disorders result from low concentration or activity of coagulation factors. Mixed hemostatic disorders occur when both primary and secondary disorders coexist, such as in dissemi- From the Departments of Veterinary Clinical Sciences [Peterson and Couto) and Veterinary Biosciences (Wellman), College of Veterinary Medicine, The Ohio State University, Columbus, OH Accepted June 6, Reprint requests: Janet L. Peterson, D VM, 2005 Mull St, Collinsville, IL Copyright 0 f 99.5 bv the American College of Veterinary Internal Medicine /9S/0~ $3.0O/0 vated partial thromboplastin time (APTT). and prolongation of both the APTT and one-stage prothrombin time. The most common disorders associated with abnormal hemostasis profiles in this study were liver disease, neoplasia, and feline infectious peritonitis. J Vetlntern Med 1995;9: Copyright by the American College of Veterinary Internal Medicine. nated intravascular coagulation (DIC). To our knowledge, pure fibrinolytic disorders have not been documented in cats. Hemostatic abnormalities can also be characterized as either congenital or acquired. A limited number of congenital and acquired coagulation abnormalities have been reported in cats."18 Congenital abnormalities of primary hemostasis are rare and include Chediak-Higashi syndrome, an autosoma1 recessive platelet storage pool defect,18-'0 and von Willebrand's di~ease.~ The most common congenital coagulopathy recognized in cats is factor XI1 (Hageman) deficiency, an autosomal recessive disorder that results in delayed activation of the intrinsic system in vitro and, therefore, prolongation of the APTT and ACT. However, factor XI1 deficiency does not result in spontaneous bleeding.8~"-'32'8 Spontaneous bleeding may occur if other hemostatic abnormalities develop, as described in 1 cat with factor XI1 deficiency that was vaccinated with a modified live virus vaccine and was in estrus? This cat developed clinical signs of bleeding after a routine ovariohysterectomy, probably as a consequence of thrombocytopenia. Platelet function might also have been affected; however, it was not evaluated.' A combination of factors IX and XI1 deficiencies was documented in a family of Siamese mixed breed cats' in which the affected male kittens had intermittent bleeding and lameness? Coexistence of factors VIII and XI1 deficiencies have also been described in domestic shorthair cats.i4 Of the confirmed affected male kittens, at least 1 bled spontaneously. Hemophilia A or classical hemophilia (factor VIII deficiency), a sex-linked recessive disorder that is well documented in humans, several dog breeds, and horses, has also been reported in the cat.4~103's Hemophilia B or Christmas disease, a recessive sex-linked deficiency of functional factor IX, has been recognized in 2 unrelated male domestic shorthair cats,2 as well as in 1 family of British shorthair cak6,17 As mentioned above, coexistence of hemophilia A or B with factor XI1 deficiency has also been reported in domestic cats. A family of Devon Rex cats with a vitamin K-responsive multifactor coagulopathy was recently reported.16 Affected cats had a moderate to marked decrease of factors 11, VII, IX, and X activities. Two of the cats had clinical evidence of spontaneous deep bleeding.16 Vitamin K therapy PO resulted in normalization of clinical and laboratory hemostatic abnormalities in the affected cats. There are multiple causes of acquired hemostatic abnor- 298 Journal of Veterinary Internal Medicine, Vol9, No 5 (September-October), 1995: pp

2 HEMOSTATIC DISORDERS IN CATS 299 malities, although very few have been recognized in cat^.^,^'-'^ Primary hemostatic defects due to vascular causes have not been well documented, except for vasculitis in cats with feline infectious peritonitis (FIP).28 In contrast to dog~,*~,~o immune-mediated thrombocytopenia (IMT) appears to be rare in ~ ats.~,~~ One of 2 reported cats with IMT developed thrombocytopenia and immune-mediated hemolytic anemia after undergoing bone marrow tran~plantation.~ Probable IMT has also been described in 2 feline leukemia virus (FeLV)-negative cats3' Drugs associated with thrombocytopenia in cats include methimazole, propylthiouracil, griseofulvin, and chemo- therapeutic agents.2'.23-2s*27*32 Griseofulvin-induced cytopenias appear to be more common and severe in cats infected with feline immunodeficiency virus (FIV).33 Povey26 described thrombocytopenia in a group of cats with feline calicivirus infection treated with ribavirin. However, it was unclear whether the virus, the drug, or both caused the thrombocytopenia. Thrombocytopenia due to decreased megakaryopoiesis appears to be common in cats with retroviral infections (FIV and FeLV) due to virus-associated myelodysplasia or myeloproliferative disorder^.^^-^' Cats with myelophthisis due to neoplasia or granulomatous diseases can also develop thrombocyt~penia.~~~~~~~~ Acquired disorders of secondary hemostasis have been reported in cats. In contrast to dogs, cats with snake bites caused by tiger snakes (Notechis scutatus) and brown snakes (Pseudonuju textillis) have minimal prolongations in the APTT and OSPT, and do not bleed spontaneou~ly.~~ Prolongations of APTT and OSPT were observed after infusion of venom from the oriental hornet in normal Impaired absorption of vitamin K in a cat with exocrine pancreatic insufficiency lead to prolongations in both OSPT and APTT, which normalized after supplementation with pancreatic enzymes.43 Vitamin K deficiency secondary to warfarin and other rodenticides has been rarely reported in cats.3' Cats may either consume smaller amounts of bait given their finicky appetite or they may be more resistant to the effects of warfarin than dogs.44 The other possibility is that the disease has just been rarely recognized in cats as compared with dogs. Two cats with warfarin poisoning have been reported3'; 1 cat presented with severe intra-abdominal and subcutaneous bleeding, and another presented with persistent bleeding from a nasal bite wound. Phenobarbital has been shown to decrease the activities ofthe vitamin K- dependent factors I1 and VII in a dose-related manner in cats45; administration of vitamin K to affected cats resulted in resolution of this coagulopathy. Circulating anticoagulants, which act as inhibitors of coagulation, have been reported in a cat.46 This cat had spontaneous bleeding secondary to inhibition of factor XI by a circulating anti~oagulant.~~ The presence of a circulating inhibitor is determined by the inability of normal plasma to correct screening coagulation tests when mixed with an equal volume of patient's plasma, or by an in vitro coagulation test (ie, APTT) that becomes progressively lengthened over 1 to 2 hours.46 DIC, a mixed hemostatic disorder, has been reported infrequently in cat^.*'.^'-^' One report described 15 cats with congestive heart failure secondary to dilated or hypertrophic cardiomyopathy and accompanying aortic thromboembolism that fulfilled diagnostic criteria for DIC.47 One of 8 cats experimentally inoculated with FeLV and treated with dextran sulfate as a potential antiviral agent also fulfilled diagnostic criteria for DIC.23 A cat with a mesothelioma, nonsuppurative cholangiohepatitis, hyperthyroidism, and chronic DIC was also de~cribed.~' Additionally, 8 kittens and 6 adult specific pathogen-free cats expenmentally inoculated with FIP virus exhibited laboratory abnormalities and histopathologic lesions of DIC Clinical signs in cats with coagulopathies appear less severe than those of dogs with similar hemostatic abnormalities. For example, while it is very common for hemophiliac dogs to present with spontaneous bleeding or to manifest severe bleeding during teething or vaccinations, hemophiliac cats rarely develop detectable spontaneous bleeding. A coagulopathy is usually suspected in cats when prolonged intraoperative bleeding is dete~ted.~ Materials and Methods All hemostasis profiles from cats performed at The Ohio State University Veterinary Teaching Hospital from 1986 through 1991 were retrospectively reviewed. One hundred and seven profiles from 107 cats were initially evaluated, but profiles from 6 of these cats were not included in the study because ofinsufficient data. With the exception of 4 cats with experimental FeLV infection treated with dextran sulfate as a potential antiretroviral drug, 2 blood donors, and 1 dental patient, all cats were symptomatic (ie, sick) patients presented to the VTH-OSU for medical or surgical evaluation. All hemostasis profiles consisted of an APTT, OSPT, platelet count, fibrinogen concentration, determination of fibrin degradation products (FDPs), and a blood smear evaluation for red blood cell (RBC) fragments." In selected patients, analysis for individual factors was performed on citrated plasma by the New York State Diagnostic Laboratory (New York State Department of Health, Comparative Hematology Laboratory, Albany, NY). Blood was collected into plastic syringes by direct atraumatic jugular venipuncture. Samples for determination of APTT, OSPT, and fibrinogen were collected into Vacutainer tubes (Beckton Dickinson, Rutherford, NJ) containing 3.8% buffered citrate solution, at a ratio of 2.7 ml of blood and 0.3 ml of anticoagulant. Samples for platelet counts and blood smears were collected into 3-mL Vacutainer tubes (Beckton Dickinson) containing 4.5 mg of EDTA. Samples for determination of FDPs were collected in 2-mL tubes containing thrombin and soybean trypsin inhibitor (Wellcome Reagents Ltd, Beckenham, England). Blood samples for APTT and OSPT determinations were collected from healthy blood donor cats and were used as controls each time a hemostasis profile was performed. From January I986 to June of 199 I, OSPT and APTT were determined by clot formation using a fibrometer (BBL Microbiology System, Becton Dickenson Co, Cockeysville, MD), and fibrinogen was quantified by heat pre~ipitation.~~ After June 199 I, chromogenic substrate assays were used to determine both the OSPT and APTT and to quantify fibrinogen (ACL 200, Instrumentation Laboratory, Lexington, MA). FDPs were measured using a latex agglutination test (Wellcome Reagents Ltd). Platelet counts were performed using the Unopette technique (Unopette; Becton, Dickinson, & Company. Rutherford, NJ) by Rees and E ~ker.~~,~~ The APTT and OSPT were considered abnormal if they were more than 25% above or below the concurrent controls. Thrombocytopenia was diagnosed if the platelet count was below 150,OOO/pL and

3 300 PETERSON, COUTO, AND WELLMAN thrombocytosis if the platelet count was above 500,OOO/pL. Hypofibrinogenemia was diagnosed if the fibrinogen concentration was below 50 mg/dl. Evaluation for FDPs was considered positive if agglutination was observed at any dilution, and reported as negative, positive at 1.5 dilution, or positive at 1:20 dilution. Blood smears with more than l+rbc fragments/high power field were considered positive. All smears were retrospectively reviewed. Criteria for diagnosis of DIC included the presence of 3 or more of the following abnormalities: 225% prolongation of APTT or 225% prolongation of OSPT as compared with controls, thrombocytopenia, hypofibrinogenemia, presence of FDPs, and RBC fragments. Neoplastic disorders were diagnosed by cytological or histopathological study of affected tissues; hepatic lesions were classified histopathologically in most cats. FIP was diagnosed on the basis of pyogranulomatous lesions in organs commonly affected by this disease (eg, liver, lungs, lymph nodes). Results Sixty-nine hemostasis profiles were abnormal. Hemostatic abnormalities were classified into 5 groups: thrombocytopenia (n = 6), abnormalities of the intrinsic system (ie, prolongation of APTT) (n = 9), abnormalities of the intrinsic and extrinsic systems (ie, prolongation of both APTT and ospt) (n = 8), mixed hemostatic disorders compatible with DIC (n = 21), and miscellaneous coagulopathies (n = 25) (Tables 1 and 2). Thrombocytopenia alone (n = 3) or in association with FDPs or fragments (n = 3) was found in 6 cats. Two of the cats were presumed to have IMT, because both responded to immunosuppressive doses of corticosteroids with an increase in the platelet count; 1 cat with FeLV infection had both thrombocytopenia and RBC fragments. One cat with hepatic lymphoma and a mast cell tumor had thrombocytopenia and FDPs; another cat had thrombocytopenia in association with neutropenia, anemia, and sepsis. Two cats had cardiac disease; 1 of these cats also had RBC fragments. Abnormalities of the intrinsic system were observed in 9 cats. One cat had factor XI1 deficiency. Two sibling Maine Coon cats had hepatic lymphoma and systemic immunemediated disease, respectively. Factor XI and XI1 deficiencies were documented twice in the cat with immune-mediated disease, both times while he was symptomatic. Two cats had hepatic lipidosis, 1 had FIP, 1 had chronic renal failure and lymphocytic enteritis, 1 was a prospective blood donor, and 1 had urethral obstruction. Specific factor analysis was not performed on the 7 cats where it was not mentioned, and none of the 9 cats was further evaluated. Combined abnormalities of the intrinsic and extrinsic Intrinsic and extrinsic Miscellaneous Table 1. Hemostatic Abnormalities (Except DIC) in 48 Cats System Abnormality Number Disease (no. of affected cats) Thrombocytopenia 6 Immune-mediated thrombocytopenia (1); immune-mediated thrombocytopenia/felv (1); hepatic lymphoma/mast cell tumor (1); sepsis/cholestasis/pancytopenia (1); cardiac disease (with fragments) (1); cardiac disease (without fragments (1) Intrinsic f APTT 9 Factor XI1 deficiency (1); hepatic lymphoma (1); immunemediated disease (1); hepatic lipidosis (2); feline infectious peritonitis (11; chronic renal failure/lymphocytic plasmacytic enteritis (1); blood donor (1); urethral obstruction (1) t APTT/OSPT Liver disease-unspecified (1); cholangiocarcinoma (1); hepatic lipidosis (2); FeLV positive receiving Dextran SO, infusion (3); intestinal obstruction/ulcer (1) t APTT/thrombocytopenia Hepatic lipidosis (1); hypertrophic cardiomyopathy (1); toxoplasmosis (1); mammary carcinoma (1); hepatic and renal lymphoma (1); immune-mediated hemolytic anemia (1); acute myelogenous leukemia (1); pneumonia/ cholangiohepatitis/sepsis (1) f APTT, 4 fibrinogen 1 Organophosphate toxicity (1) f APTT, FDPs 2 Feline infectious peritonitis (1); cholangiohepatitis/hepatic f APTT, Fragments 2 lipidosis (1) Cholangiohepatitis (1); hypertrophic cardiomyopathy (1) f APTT, fragments, thrombocytosis 2 Hyperthyroidism, hypertrophic cardiomyopathy (1); epilepsy (1) t APTT, thrombocytosis 1 Hyperthyroidism f OSPT, fragments, thrombocytosis 1 Hepatic lymphoma t OSPT, thrombocytosis 1 Hepatic lipidosis f OSPT, fragments 1 Hepatic lymphoma t OSPT 2 Kidney donor (1); diabetes mellitus/pancreatitis (1) Thrombocytosis 3 Blood donor (2); dental prophylaxis (1) FDPs, fragments 1 Hepatic lipidosis (1) Abbreviations: APTT. activated partial thromboplastin time; OSPT, one-stage prothrombin time; FDPs, fibrin degradation products; FeLV, feline leukemia virus; f, prolonged; 4- shortened.

4 HEMOSTATIC DISORDERS IN CATS 30 1 Table 2. Disseminated Intravascular Coagulation in 21 Cats Disease Disease Coagulation Abnormalities Neoplasia Infectious Liver disease Miscellaneous Hepatic and pancreatic carcinoma (biopsy) Biliary adenocarcinoma (biopsy) Lymphoma (necropsy) Lymphoma (cytology)/sepsis Lymphoma/leukemia Splenic hemangiosarcoma, chylothorax, chyloabdomen Hepatic lipidosis (biopsy) Hepatic lipidosis (biopsy) Hepatic Iipidosis, mild pancreatitis (biopsy) Hepatic lipidosis (necropsy), CNS signs, vitamin K responsive Hepatic lipidosis (cytology) Liver disease, Heinz body anemia Liver disease; chronic renal failure; urolithiasis Hyperthyroidism, methimazole therapy FeLV, dextran sulfate Chronic renal failure; hypokalemia Cardiac conduction disturbance, chronic passive liver congestion; chronic interstitial nephritis APTT, FDPs, fragments APTT, OSPT, FDPs, fragments APTT, thrombocytopenia, fragments APTT, thrombocytopenia, FDPs APTT, OSPT, thrombocytopenia APTT, OSPT. fragments APTT, OSPT, FDPs APTT, thrombocytopenia, fragments APTT, OSPT, FDPs thrombocytopenia APTT, fragments, hypofibrinogenemia APTT, OSPT, fragments APTT, OSPT, fragments APTT, thrombocytopenia, fragments APTT, OSPT, fragments APTT, OSPT, thrombocytopenia APTT, OSPT, FDPs APTT, OSPT, thrombocytopenia Abbreviations: FIP, feline infectious peritonitis; CNS, central nervous system; FeLV, feline leukemia virus; APTT, activated partial thromboplastin time; FDPs, fibrin degradation products; OSPT, one-stage prothrombin time. systems were detected in 8 cats; they were associated with liver disease in 4 cats. There were 3 cats experimentally inoculated with FeLV and treated with dextran sulfate, and 1 cat with intestinal obstruction and gastrointestinal ulceration. DIC was documented in 2 i cats (Table 2). Neoplasia was diagnosed in 6 cats; 3 cats had lymphoma, 1 had pancreatic carcinoma, 1 had splenic hemangiosarcoma, and another cat had biliary adenocarcinoma. Five cats had hepatic lipidosis, 2 cats had other types of liver disease, and 4 cats had FIP. Other cases of DIC included 1 cat with hyperthyroidism on methimazole therapy, 1 cat with heart disease, 1 cat experimentally inoculated with FeLV and treated with dextran sulfate, and 1 cat with hypokalemia and chronic renal failure. Twenty-five cats were placed in a group of miscellaneous coagulation abnormalities; 17 of these cats fulfilled 2 criteria for the diagnosis of DIC (Table 1). Overall, there were 16 cats with a variety of hepatic disorders (lipidosis, n = 13; cholangiohepatitis, n = 2; not specified, n = l),accounting for 23% of the abnormal hemostatic profiles. There were 14 cats with malignant neoplasms (lymphoma, n = 8; carcinoma and adenocarcinoma, n = 4; acute myeloid leukemia, n = 1; hemangiosarcoma, n = l), representing 20% of all cats with laboratory evidence of hemostatic dysfunction; 8 of these cats had neoplastic involvement of the liver (3 with bile duct-derived carcinomas and 5 with lymphoma). Five cats had FIP, representing 7% of all the abnormal hemostatic profiles. Discussion Although spontaneous bleeding disorders appear to be rare in cats, based on this study it appears that subclinical hemostatic abnormalities are rather common, particularly in cats with cancer or hepatopathies. Sixty-nine percent of the hemostasis profiles evaluated were abnormal. This is in contrast to dogs in our clinic, where the prevalence of abnormalities in hemostatic profiles was 40% (data not shown). Also, spontaneous bleeding was extremely rare in this study, contrary to dogs, where evaluation of hemostatic function is frequently performed in patients with clinical evidence of hemostatic dysfunction. Clinically, evidence of spontaneous bleeding was documented in only 2 cats with thrombocytopenia and 1 cat with DIC (data not shown). However, based on the fact that this information was obtained retrospectively from the medical records, it may be a misrepresentation of the true prevalence of spontaneous bleeding tendencies in cats. The difference in the prevalence of hemostatic abnormalities between cats and dogs may be a true phenomenon (ie, subclinical coagulopathies are more common in cats) or it may represent a sampling artifact, because hemostasis profiles are frequently evaluated in dogs in our clinic prior to performing major surgery (even when they do not have spontaneous bleeding tendencies). The most common hemostatic abnormality identified in this study was a mixed hemostatic defect compatible with DIC, which occurred in 21% of the cats (30.5% of the cats with hemostatic abnormalities); 17 additional cats also fulfilled partial criteria for diagnosis of DIC. This would result in a total of 38 cats (representing 38% of all cats and 55% of the cats with coagulopathies) with highly suspected or confirmed DIC. The disorders most commonly associated with DIC were malignancy, liver disease, and FIP. Therefore, it is likely that DIC has a relatively high prevalence among cats with these disorders and should prompt clinicians to

5 302 PETERSON, COUTO, AND WELLMAN evaluate hemostatic function in affected cats, particularly in those that will undergo surgery, because therapeutic intervention (eg, blood products, heparin, other anticoagulants) may result in clinical benefit in these patients. In contrast to dogs, in which thrombocytopenia represented the most common abnormality in hemostatic profiles in our clinic (23% of hemostatic profiles, data not shown), decreased platelet counts were present in only 6 feline hemostasis profiles (6%). As with other coagulopathies, this may represent a sampling artifact (eg, the population of cats evaluated is at high risk for coagulopathies) or a true phenomenon. Based on the fact that evidence of spontaneous primary hemostatic bleeding was extremely uncommon in cats in this study and on our clinical experience, we believe that symptomatic thrombocytopenia is indeed rare in cats. Disorders commonly associated with laboratory evidence of hemostatic abnormalities included liver disease (mainly lipidosis), malignant neoplasms (mainly lymphoma), and FIP. Most of the clotting factors and many components of the fibrinolytic system are manufactured in the liver. Moreover, the liver exerts regulatory functions on some of these fact01-s.~~ Therefore, impaired hemostasis can be anticipated in some cats with liver disease. Humans and dogs with cancer have a relatively high prevalence of hemostatic Tumors may interact with the coagulation and the fibrinolytic systems through a variety of mechanisms, including induction of thrombocytopenia or platelet dysfunction, production of procoagulants, inhibition of anticoagulants, and inhibition of clotting factors, among others Based on these facts, it is not surprising that 20% of the cats in this study had malignant neoplasms. Several mechanisms may lead to the development of coagulopathies in cats with FIP, including increased platelet reactivity, widespread hepatic necrosis, and diffuse endothelial lesions leading to DIC.28,49 Most cats experimentally inoculated with FIP develop clinical DIC.28 In conclusion, it appears that even though clinical evidence of spontaneous bleeding is extremely rare in cats, laboratory evidence of hemostatic dysfunction is common. Whether abnormal hemostatic function in vitro has clinical relevance in cats cannot be determined in a retrospective study. Based on this information, it may be warranted to prospectively evaluate hemostatic function in both symptomatic and asymptomatic cats with liver disease, cancer, or FIP, because therapeutic intervention may decrease morbidity and mortality. References 1. Bick R. Disorders of Thrombosis and Hemostasis: Clinical and Laboratory Practice. Chicago, IL: American Society of Clinical Pathologists; 1992: Brooks MB, Dodds WJ. 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6 HEMOSTATIC DISORDERS IN CATS Rottman JB, English RV, Breitschwerdt EB, et al. Bone marrow hypoplasia in a cat treated with griseofulvin. J Am Vet Med ASSOC 1991; 198: Weiss RC, Dodds WJ, Scott FJ. Disseminated intravascular coagulation in experimentally induced feline infectious peritonitis. Am J VetRes 1980;41: Wilkins RJ, Hurvitz AI, Dodds-Laffin WJ. Immunologically mediated thrombocytopenia in the dog. J Am Vet Med Assoc 1973; Willard MD, Bailey MQ, Hauptman J, et al. Obstructed portal venous flow and portal vein thrombus in a dog. J Am Vet Med ASSOC 1989; 194: Pedersen NC. In: Holzworth J, ed. Diseases of the cat. Philadelphia, PA: WB Saunders, 1987: 146- I Couto CG. Oncology. In: Sherding RG, ed. The Cat: Diseases and Clinical Management. Philadelphia, PA: Churchill-Livingstone, 1993: Shelton GH, Grant CK, Lindenberger ML, et al. Severe neutropenia associated with griseofulvin therapy in cats with feline immunodeficiency virus infection. J Vet Int Med 1990;4: Boyce JT, Kociba GJ, Jacobs RM, et al. Feline leukemia virus-induced thrombocytopenia and macrothrombocytosis in cats. Vet Pathol 1986;23: Jacobs RM, Boyce JT, Kociba GJ. Flow cytometric and radioisotopic determinations of platelet survival time in normal cats and feline leukemia virus-infected cats. Cytometry 1986; 7: Shelton GH, Linenberger ML, Grant CK, et al. Hematologic manifestations of feline immunodeficiency virus infection. Blood 1990;76: Thomas JB, Robinson WF, Chadwick BJ, et al. Leukogram and biochemical abnormalities in naturally occumng feline immunodeficiency virus infection. J Am Anim Hosp Assoc 1993;29: Clinkenbeard KD, Cowell RL, Tyler RD. Disseminated histoplasmosis in cats: 12 cases ( ). J Am Vet Med Assoc 1987; 190: Gabbert NH, Campbell TW, Beiermann RL. Pancytopenia associated with disseminated histoplasmosis in a cat. J Am Anim HOSPASSOC 1984;20: Holloway SA, Parry BW. Observations on blood coagulation after snakebite in dogs and cats. Aust Vet J 1989;66: Kornberg A, Kaufman S, Silber L, et al. The effect of the venom of the oriental hornet [Vespa orientalis] on coagulation factors [in man and cats]. Thromb Haemost 1987;58: Kornberg A, Kaufman S, Silber L, et al. Effect of venom sac extract of the oriental hornet (Vespa orientalis) on coagulation factors. Toxicon 1988;26: Perry LA, Williams DA, Pidgeon G. Feline exocrine pancreatic insufficiency with associated coagulopathy in a cat. J Am Anim Hosp Assoc 199 I : Couto GC. Disorders of hemostasis. In: Sherding RG, ed. The Cat: Disease and Clinical Management. New York, NY: Churchill-Livingstone; 1993: Solomon GE, Hilgartner MW, Kutt H. Phenobarbital-induced coagulation defects in cats. Neurology. I974;24: Feldman BF, Soares CJ, Kitchell BE, et al. Hemorrhage in a cat caused by inhibition of factor XI (plasma thromboplastin antecedent). J Am Vet Med Assoc 1983; 182: Fox PR, Dodds WJ. Coagulopathies observed with spontaneous aortic thromboembolism in cardiomyopathic cats. ACVIM Proceedings 1982: Schaer M, Meyer D. Benign peritoneal mesothelioma, hyperthyroidism, nonsuppurative hepatitis, and chronic disseminated intravascular coagulation in a cat: a case report. J Am Anim Hosp Assoc 1988; 24: Boudreaux MK, Weiss RC, Cox N, et al. Evaluation of antithrombin-i11 activity as a coindicator of disseminated intravascular coagulation in cats with induced feline infectious peritonitis virus infection. Am J Vet Res 1989;50: Dodds WJ. Hemostasis and coagulation. In: Kaneko JJ, ed. Clinical biochemistry of domestic animals. New York, NY Academic Press; 1980: Weiss DJ. Uniform evaluation and semiquantitative reporting of hematologic data in veterinary laboratories. Vet Clin Pathol 1988; 13: Jain NC. Schalm s Veterinary Hematology. Philadelphia, PA: Lea and Febiger; 1986: I. 53. Rees HM, Ecker EE. An improved method for counting blood platelets. JAMA 1923; 80: Mammen E. Coagulation abnormalities in liver disease. Hematol Oncol Clin North Am 1992;6: Rosen P. Bleeding problems in the cancer patient. Hematol Oncol Clin North Am 1992;6: OKeefe DA, Couto CG. Coagulation abnormalities associated with neoplasia. Vet Clin North Am, Small Animal Practice 1988; 18: