Physiological Variations of Blood Coagulation and Coagulation Disorders in Animals - a Short Review

Wien. Tierärztl. Mschr. - Vet. Med. Austria 96 (2009), 78 - 86

From the Department Toxicology and Pharmacology, Octapharma Pharmazeutika Produktionsges.mbH

Physiological variations of blood coagulation and coagulation disorders in animals - a short review

L. PICHLER received March 25, 2008 accepted for publication December 18, 2008

Keywords: animals, bleeding disorders, inherited, Schlüsselwörter: Heim- und Nutztiere, Blutgerinnung, acquired, thrombophilia. Blutungsneigung, erblich, erworben, Thromboseneigung.

Summary Zusammenfassung This review covers pet and farm animals, occasionally Blutgerinnungsstörungen bei Tieren results of other species are mentioned. Der vorliegende Übersichtsartikel berücksichtigt Heim- The physiological variability of blood coagulation is dis- und Nutztiere, vereinzelt werden experimentelle Ergebnisse cussed: biological rhythmics, influence of age, influence of von anderen Tierarten erwähnt. gender, estrous cycle and pregnancy, influence of breed, Im ersten Abschnitt wird auf physiologische Schwan- and influence of feeding conditions and exercise. kungen der Blutgerinnung eingegangen, die durch biologi- The disseminated intravascular coagulation is described sche Rhythmen, das Alter, das Geschlecht, durch den as a special situation where thrombosis as well as hemor- Ovarialzyklus und die Trächtigkeit, durch die Rasse, die rhage occur. Fütterung und schließlich durch körperliche Belastung Bleeding disorders are classified as inherited or bedingt sind. acquired. Within both categories platelet disorders (pri- Die disseminierte intravaskuläre Koagulation wird als mary hemostasis) and coagulation factor disorder (sec- eigenes Kapitel behandelt, da es hier sowohl zu Thrombo- ondary hemostasis) are reviewed. sen als auch zu Blutungen kommt. Finally thrombophilia is discussed. Blutungsneigung wird in erbliche und erworbene Emphasis is put on diagnosis of bleeding disorders, Erkrankungen eingeteilt. Dabei wird jeweils zwischen Störun- therapy is not considered. gen der primären Hämostase (Plättchen) und der sekun- dären Hämostase (Gerinnungsfaktoren) unterschieden. Abbreviations: a = activated; ADP = adenosine diphosphate; ATP = Im letzten Abschnitt wird die Thromboseneigung adenosine triphosphate; CHS = Chediak-Higashi syndrome; DIC = (Thrombophilie) behandelt. disseminated intravascular coagulation; GP = glycoprotein; In der Einleitung, vor allem aber in der Diskussion wird HMWK = high molecular weight kininogen; p.m. = post meridiem; auf die Diagnose von Blutgerinnungsstörungen eingegan- PT = prothrombin time; PTT = partial thromboplastin time; SHT = gen, therapeutische Gesichtspunkte werden nicht berück- Simmental hereditary thrombopathy; TT = thrombin time; vWD = sichtigt. von Willebrand disease; vWF = von Willebrand factor

Introduction long in vivo bleeding time. The classic signs of coagulation factor deficiency (secondary hemostasis) include hemorrhage into joints, chest, or abdomen, and subcutaneous or Hemostasis is a highly complex defense mechanism of intramuscular hematoma formation. Signs common to both vertebrates, involving multiple interdependent interactions primary and secondary hemostatic defects include exces- among platelets, the vascular endothelium and plasma sive bleeding from sites of surgery or trauma and from proteins. Various components of this system have biologi- sites of tooth eruption (BROOKS, 1999). cal roles in other, non-coagulation reactions. The endothe- Bleeding time determination, global clotting tests and lium, not reviewed here, plays a pivotal role as a link single factor determination as diagnostic measures were between the coagulatory system and inflammation. Throm- recently reviewed by PICHLER (2008). An accurate phe- bin, factor Xa, and factor VIIa (all serine proteases) are notypic diagnosis, however, is required to ensure screen- involved in inflammation, tissue remodelling, and angio- ing for the relevant disease. genesis. Tissue factor may also have a role in embryonic and tumorigenic angiogenesis (see GENTRY, 2004). It is evident, that disorders in one or more components Physiological variability of this complex system can predispose animals to excessive bleeding or thrombotic disease. Biological rhythmic Disorders of primary hemostasis (platelets) and sec- BERTOLUCCI et al. (2005) tested the circadian rhythm ondary hemostasis (coagulation factors) will be covered by of the extent of factor Xa and thrombin generation (after this review. Neglecting thrombophilia, clinical signs of pri- artificial activation) in a mouse model. Generation of these mary hemostatic (= platelet) defects typically consist of activated factors was highest at 6 p.m. Taking into account bleeding from mucosal surfaces, cutaneous bruising, and the different behavioral habits between mice (nocturnal)

78 Wien. Tierärztl. Mschr. - Vet. Med. Austria 96 (2009) and humans (diurnal), authors conclude that the evening calves; GENTRY, 1984). peak observed in mice corresponds to the morning hyper- In the newborn foal the PT is slightly elevated (10.9 s) coagulability state in humans. but decreases during the first month of life towards adult COLOGNESI et al. (2007) showed (also in a mouse levels (9.5 s).(It should be mentioned, however, that the model) that variations of the photoperiod (winter or sum- total allowable error for functional coagulation tests might mer conditions) have a strong impact on plasma factor VII be as high as 20 %.) The PTT of the newborn is high (56.8 levels. Factor VII activity levels showed a clear 24 h rhyth- s), but on days 4 to 30 of life it is with approximately 40 s micity under both conditions, however, peak levels were close to the value of the adult horse (42.0 s). Platelets are reached at different times and mean daily activity levels markedly elevated in the neonatal period (245x103/μl vs. were significantly reduced in mice exposed to summer 153x103/μl). Fibrinogen (195.2 mg/dl in adults) is low in photoperiods. newborn foals (116.8 mg/dl), reaches adult levels at 4 to 14 days (196.8 and 199.6 mg/dl), but is increased after one Influence of age month of life (221.1 mg/dl). Antithrombin is low in newborns In the newborn rabbit (day 1) PT, PTT and TT are pro- (107.1 %) compared to adults (202.1 %) and shows a longed compared to adult animals according to MASSI- plateau between days 4 to 30 of approximately 165 %. The COTTE et al. (1986). Fibrinogen levels are in the adult protein C antigen is low (63.5 vs. 98.9 %) in newborn hors- range. Regarding the vitamin K-dependent factors, factors es, the protein C activity, however is higher in newborns II, VII, and X are elevated compared to adults. Factor IX than in adults (112.9 vs. 86.5 %). Plasminogen is low in levels are about 60 % of adult values. The “contact factor” newborns (82.3 %) but increases during the first month of (XI and XII) levels of the amplification pathway are compa- life towards adult levels (113.5 %). The tissue plasminogen rable to adult values in the rabbit pup. From the cofactors, activator is slightly lower in newborns than in adults (2.2 vs. factor VIII is slightly decreased, factor V slightly increased 2.8 U/ml) but elevated at 2 weeks and one month of life in the newborn. Regarding the inhibitor levels, antithrombin (5.4 and 8.9 U/ml). The levels of plasminogen activator is slightly decreased, alpha2-antiplasmin increased com- inhibitor is very high in the newborn foal (39.0 U/ml) but pared to adults. decreases towards adult levels (8.2 U/ml) during the first

In the newborn dog (Beagle, day 1) PT, PTT and TT are month of life. Alpha2-antiplasmin is approximately equal in prolonged compared to adult animals according to MASSI- newborn and one week old foals (197.3 and 206.8 %) and COTTE et al. (1986). Fibrinogen levels are in the adult range. relatively low in 2 weeks and one month old foals (174.7 The vitamin K-dependent factor levels are below 60 % of and 174.4 %) compared to adult horses (209.4 %) (BAR- adult values. The “contact factor” (XI, XII, and HMWK) lev- TON et al., 1995). els of the amplification pathway are lower than in adults. The studies of HATHAWAY et al. (1964) showed that the The cofactors VIII and V are decreased in the newborn. newborn guinea pig, rabbit cat, dog, pig, and cow are defi-

The inhibitors (antithrombin, alpha2-antiplasmin) are cient in the vitamin K dependent factors II, VII, IX, and X markedly reduced in the newborn Beagle. According to and additionally in factor V. However, a vitamin K deficien- MISCHKE (1994) activity of the coagulation factors II, V, cy bleeding (in the past: “hemorrhagic disease of the new- and X is lower during the first months of life compared to born”), as recently reviewed for humans by PICHLER and adult dogs. No such difference is seen regarding factor VII. PICHLER (2008) is not known in animals. There is a tendency towards elevation of factors II, V, VII, and X in dogs older than 8 years. Gender, estrous cycle and pregnancy In the newborn pig (day 1) PT and PTT are prolonged Male rats are more susceptible than female rats to compared to adult animals according to MASSICOTTE et hypoprothrombinemia due to vitamin K-deficiency (TABA- al. (1986). Fibrinogen levels are markedly lower than in TA et al., 1995). Female dogs have slightly higher factor II adults. The vitamin K-dependent factor levels are below 60 % and factor V levels than males, there is however, no gen- of adult values, except factor II which is markedly elevated. der difference regarding factors VII and X (MISCHKE, The “contact factor” (XI, XII, and HMWK) of the amplifica- 1994). Although not at all a “physiological variability”, it tion pathway are lower than in adults. From the cofactors, should be pointed out here, that sex-linked recessive factor VIII is markedly increased, factor V markedly bleeding disorders, such as classic hemophilia A or B , decreased in the newborn piglet. The inhibitor antithrombin occur almost exclusively in males. is lower, alpha2-antiplasmin higher in newborns compared Increasing oestradiol-17β concentrations during the to adults. estrous cycle of dogs were accompanied by a rise of PT In the newborn lamb (day 1) PT, PTT and TT are pro- and TT, pointing towards hypocoagulability. Increasing prolonged compared to adult animals according to MASSI- gesterone concentrations were associated with a shortening COTTE et al. (1986). Fibrinogen levels are in the adult of PT, PTT and TT, meaning an increased coagulation range. Regarding vitamin K-dependent factors, factor II is (RÜBERG et al., 1990). von Willebrand factor concentra- elevated compared to adults. The other factors of this tion did neither change significantly at any time during the group (VII, IX and X) are below 60 % of adult values. The estrous cycle in 6 nonpregnant mixed-breed dogs nor in 3 “contact factor” (XI, XII, and HMWK) levels of the amplifi- nonpregnant Doberman Pinschers with von Willebrand dis- cation pathway are lower than in adults. The cofactor VIII ease type 1 (MOSER et al. 1998). level is decreased, the factor V level markedly increased SIEME (1989) described in 48 estrous mares a short- compared to adult sheep. Inhibitor levels (antithrombin, termed significant increase in platelet counts before ovula- alpha2-antiplasmin) are nearly the same in newborn and tion, which was followed by a massive decrease after hem- adult animals. orrhage in the follicle cavity to levels below those prior to In cattle, factor XI activity increases with age (low in ovulation. Furthermore, a latent hypercoagulability in the

79 Wien. Tierärztl. Mschr. - Vet. Med. Austria 96 (2009) plasmatic coagulation system close to the ovulation could diphosphate (ADP) in racing Standardbred horses (JOHN- be demonstrated. In 4 mares (2 in the luteal phase, 2 STONE et al., 1991). ABILDGAARD and LINK (1965) were ovariectomized) experimental treatment with estradiolben- not able to show this rise in factor VIII in horses after run- zoate resulted in an increase in the activity of the extrinsic ning on-half to five-eights of a mile. Fibrinogen, however, and amplification pathway of coagulation and a constant was increased in their investigation by 38 %. decrease of antithrombin activity. In pregnant dogs, plasma concentration of fibrinogen Disseminated Intravascular and the biological activity of the coagulation factors VII, VIII, and IX increase. Plasma vWF concentration markedly Coagulation (DIC) increased during pregnancy and at parturation in healthy mongrel dogs (by 155 %) and in Doberman Pinschers with DIC, as an acquired disorder, is described as a separate vW disease type 1 (by 119 %), and decreased to prepreg- entity because it is characterized by thrombosis as well as nancy values within 14 days after delivery (MOSER et al., by hemorrhage. Several reviews discuss these pathologi- 1998). cal phenomena (WU, 1985; ROSENBERG and BAUER, In pigs, only fibrinogen concentration increases at par- 1986; VERSTRAETE and COLLEN 1986; SALEM et al., turition (see GENTRY and LIPTRAP, 1988). 1987) which are caused by an continuous activation of the In cattle, a clear decline in platelet counts was observed coagulation and fibrinolytic pathways secondary to several during the second trimester of pregnancy. An increase in diseases. Microvascular and large-vessel thrombosis fibrinogen was noted during the second trimester followed might lead to tissue hypoxia and to organ damage. Hem- by a slight decrease prior to calving. Factor VII activity orrhage is caused by consumption of platelets and coagu- increased (approx. 20 %) at parturition (GENTRY et al., lation factors. 1979). Many diseases and conditions are associated with DIC, In mares, fibrinogen and fibronectin concentrations and including inflammatory conditions, infectious diseases, liv- factor VIII activity as well as the concentration of vWF er disease, neoplasia, and other conditions such as shock, increase during pregnancy. In addition, there is a modest gastric dilatation/volvolus, obstetric disorders, congestive rise in antithrombin concentration (GENTRY et al., 1992). heart failure, venomous snake bites etc.(for references see The hemostatic changes during pregnancy may be WEISS et al., 1980, BADYLAK and VLEET, 1981, FELD- required to maintain the integrity of the placenta-uterine MANN et al., 1981; BADYLAK et al., 1983; GREEN, 1984; interface and ensure effective hemostasis in the uterus on DRAZNER, 1985; WELCH et al., 1992). DIC has been placental separation (MOSER et al., 1998). reported also in prozoan diseases: Plasmodium knowlesi malaria in monkeys, Trypanosoma brucei infected rabbits, Influence of breed and Trypanosoma simiae infections in pigs (see WRIGHT The difference in antithrombin activity (lower in Persian and GOODGER, 1977). and European Shorthair cats than in other breeds) seems DIC is a marked, life-threatening disorder with extreme- more of scientific interest than of practical impact (maxi- ly variable clinical signs. In small animals, fulminant DIC is mum difference 8.7 %; RIVERA RAMIREZ et al., 1997). often characterized by petechial and ecchymotic hemor- MISCHKE (1994) investigated 5 groups of dogs of dif- rhages in the skin and mucous membranes and sometime ferent breeds and 1 group of mongrel dogs. There was no overt hemorrhage from body orifices. race difference regarding the activity of the factors II, V, The typical laboratory findings in DIC are: thrombocy- and X. The activity of factor VII, however, was increased in topenia, increased concentration of fibrin degradation Swiss and Bernese mountain dogs as well as in Doberman products, hypofibrinogenemia, prolonged PTT and PT, and Pinschers. Plasma samples from Airdale Terriers contain decreased antithrombin activity. significantly lower concentrations of von Willebrand anti- For cats, a search of medical records (University of Min- gen than do plasma samples from normal dogs of other nesota Veterinary Medical Center) covering the period breeds (THOMAS, 1996). from January 1990 to April 2004 revealed 46 cases of DIC. Only 3 cats (7 %) survived (ESTRIN et al., 2006). From 59 Influence of feeding conditions and exercise critically ill dogs with clinical signs of diseases known to Overnight fasting produced a vitamin K-deficient syn- predispose to DIC, DIC was identified in 16 cases (27.1 %, drome in male rats, increasing PT and PTT (TABATA et al., BATEMAN et al., 1999). Mortality rates in dogs with DIC 1995). Clotting time was decreased in one dog (n = 1) from range from 50 to 77 % (BATEMAN et al., 1998). 11 min to 5 min after feeding 200 g raw lean meat. No such effects were seen after pork fat feeding (same dog) or Bleeding disorders steamed rice feeding (3 different dogs) (MILLS and NECHELES, 1928). Inherited disorders 21 cats were exercised in a treadmill (575 or 1,150 m). Inherited (congenital) coagulation disorders may arise Clotting time was determined (from an ear vein) ex vivo. 13 from either the absence of a normal clotting protein or the animals showed an exercise-induced decrease, 5 an presence of a defective molecule (regarding secondary increase and 3 an increase followed by a decrease in clot- hemostasis). ting time. The typical change therefore was a decrease in A positive family history is of great diagnostic impor- clotting time (HARTMAN, 1927). tance, a negative family history, however, does not rule out Exercise (15 min run on a 260 m oval track at an aver- the possibility of a heritable defect: a certain but unknown age speed of 10 m/s) increased factor VIII activity and percentage of congenital hemophilia is the result of spon- decreased platelet responses to the agonist adenosine taneous mutations (JOHNSTONE, 1988).

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Platelet disorders (primary hemostasis) enlarged granules in most granule-containing cells , and a Platelet disorders might be quantitative (thrombocy- bleeding tendency. In cattle affected with CHS, the most topenia) or qualitative (functional). important clinical manifestations are bleeding diatheses. Cyclic neutropenia in Gray Collies (an autosomal reces- Diathesis is caused by insufficient platelet aggregation as sive trait) is associated with thrombocytopenia noted every a result of depressed response to collagen. Contents in 11 to 13 days. The disease may be life threatening (DAV- dense granules (ADP, ATP, serotonin and Ca2+ ) of CHS ENPORT and CARAKOSTAS, 1982). platelets are greatly decreased. These findings justified Macrothrombocytopenia (i.e., enlarged platelets and the assessment of CHS as a “storage pool disease”. How- thrombocytopenia) was described in Cavalier King Charles ever, ADP and thromboxane A2 (like ADP a secondary ago- Spaniels by PEDERSEN et al. (2002) as an autosomal nist on platelets, the production of which is also impaired) recessive trait. A mutation in the gene encoding beta 1- play a minor role in collagen-induced aggregation of tubulin is responsible for this disorder (DAVIS et al., 2008). bovine platelets. Therefore, it was suggested that the pri- Approximately 50 % of all Cavalier King Charles Spaniels mary cause of the impaired response to collagen is not a are affected with this benign condition (PEDERSEN et al., decreased release of endogenous agonists. Recent data 2002 ; COWAN et al., 2004) which warrants no medical suggests that CHS platelet have a defect in a signal trans- treatment. duction; crosstalk among collagen receptors (glycoprotein A thrombastenic, inherited bleeding disorder was VI, glycoprotein Ia/IIa, and rhodocytin binding protein) is described in Otterhounds (DODDS, 1967) and in Great obviously impaired. The bleeding tendency in CHS cattle Pyrenees dogs (BOUDREAUX et al., 1996). The disease is often manifested clinically by fibrosis in resolution of resembles the Glanzmann´s thrombasthenia platelet disor- large subcutaneous accumulations of blood and by the der in humans and is due to a mutation in the gene encod- production of numerous, firm subcutaneous nodules at ing for platelet glycoprotein IIb (BOUDREAUX and CATAL- sites of previous trauma. Bleeding manifestations are FAMO, 2001). Platelet aggregation responses are minimal observed as excess bleeding during and after castration, or lacking and clot retraction is markedly impaired. The dis- development of superficial or intrapubic (or abdominal) ease follows an autosomal dominant trait with variable hematoma. expression. Spontaneous bleeding includes excessive gin- Finally, the Ehlers-Danlos syndrome should be men- gival bleeding during tooth eruption, nose bleedings, and tioned. This congenital disorders leads to a deficiency in superficial skin bleeds. collagen, type III. Although platelet function is intact, the Basset Hound thrombopathy is an autosomal recessive collagen deficiency does not permit physiologic platelet disorder characterized by failure of platelet aggregation in adhesion in affected animals (see DAVENPORT and response of ADP and collagen. In contrast to bleeding Sim- CARAKOSTAS, 1982). mental cattle (see below), however, thrombopathic Basset Hound platelets aggregate in response to thrombin (and Coagulation factors disorders (secondary hemostasis) have impaired secretion of serotonin; CATALFAMO et al., Hereditary fibrinogen deficiencies have been recog- 1986). nized in goats and dogs (see DODDS, 1989) as well as in A hemorrhagic diathesis associated with a hereditary calves (BENTINCK et al., 1960). Both autosomal recessive platelet disorder has been reported in Simmental cattle in and autosomal dominant inheritance have been docu- both Canada and the United States (KOCIBA, 1980; mented (FOGH and FOGH, 1988). We distinguish between SEARCY and PETRIE, 1990). A disease resembling this afibrinogenemia, hypofibrinogenemia and dysfibrinogene- “Simmental hereditary thrombopathy” (SHT) has also been mia. Mild to severe bleeding diathesis is observed. identified in a Simmental crossbred herd (GENTRY et al., Canine hypoprothrombinemia is the only (and rare) inher- 1997). SHT is an apparently autosomal recessive defect. ited prothrombin (factor II) abnormality in animals (autoso- Data of MAPLETOFT et al. (2000) suggests that the inher- mal recessive trait). Dysprothrombinemia, however, seems itance is not simple Mendelian recessive. It seems more not to be the only mechanism of this bleeding disorder, as likely that the defect is the result of the inheritance of at the turnover of all vitamin K-dependent clotting factors (VII, least 2 genes. Platelets from affected animals do not IX, and X) is affected (DODDS, 1989). Epistaxis and umbili- aggregate when stimulated with ADP or collagen. The cal bleeding is observed in newborn puppies and mild response to thrombin is markedly diminished (SEARCY et mucosal surface bleeding in young adults. In Devon Rex al., 1990). Aside from death (blood loss) resulting from sim- cats a congenital deficiency of all vitamin K-dependent fac- ple procedures such as dehorning or castration, clinical tors as the result of a defective gamma-glutamyl-carboxy- findings include spontaneous epistaxis, hematuria and lase has been described (SOUTE et al., 1992). superficial hematomas (STEFICEK et al., 1993; MAPLE- Factor VII deficiency (autosomal dominant trait) in Bea- TOFT et al., 2000). gle dogs was already described in 1971/72 (see GENTRY, The Chediak-Higashi syndrome (CHS; for references 2004). The disease was also described in Alaskan mala- see BELL et al., 1976 and SHIRAISHI et al., 2002) is mute, bull-dogs and mixed breeds (see DODDS, 1989). described in humans, cattle, minks, cats, mice, rats, fox, Considering the prominent role of factor VII in the coagula- and killer whales. CHS is an autosomal recessive genetic tion cascade, it is surprising that factor VII-homozygous disease. The gene associated with CHS in humans, mice deficient dogs, unlike dogs with an inherited defect of fac- and Japanese Black cattle encodes a novel 400-kDa pro- tor VIII or IX (see below), are usually clinically asympto- tein, LYST, which stands for lysosomal trafficking regulator matic (see GENTRY, 2004). Affected animals are prone to (function not completely understood). Patients suffering systemic demodecosis, because the defective extrinsic from CHS show a variable degree of partial oculocuta- clotting might provide an ideal environment for mange neous albinism, increased susceptibility to infections, mites (DODDS, 1989).

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Hemophilia A (factor VIII deficiency) is an X chromo- 1989), and cats (TROXEL et al., 2002). Typical symptom is some-linked recessive trait. Carrier females are heterozy- protracted bleeding after surgery. Results in cattle indicate, gous, affected males are hemizygous for the trait. Classi- that factor XI deficiency is related to the absence of a nor- cal hemophilia was diagnosed in dogs already 1946 mal clotting protein rather than to the presence of a defec- (FIELD et al.), long before the normal coagulation process tive protein (GENTRY, 1984). In the latter species homozy- in this species had been worked out. The disease is also gous individuals show delayed ovulation and increased described in cats (mild), pigs, sheep, cattle, and horses fetal loss (see GENTRY, 2004). (severe) (for references see MUCHITSCH et al., 1999). Deficiency of factor XII is the most common inherited Hemorrhage into joints, chest, or abdomen, and subcuta- coagulation factor deficiency in cats (autosomal recessive neous or intramuscular hematoma formation are observed. trait). Affected animals show an isolated prolongation of Hemophilia B (factor IX deficiency) is also an X chro- the PTT, but do not suffer from spontaneous bleeding (see mosome-linked recessive trait, but is much rarer than PETERSON et al., 1995). The situation in dogs is similar hemophilia A. Bleeding symptoms are the same. The dis- (see DODDS, 1989; GENTRY, 2004). ease has been identified in cats (less frequently), in dogs Deficiencies in factor V and XIII have not yet been (many breeds), cattle, and horses (for references see described in animals (FOGH and FOGH, 1988). GENTRY, 2004). Double hemophilia (hemophilia AB) has been described Acquired disorders in dogs (see FOGH and FOGH, 1988). In cats, coexistence Platelet disorders (primary hemostasis) of hemophilia A or B with factor XII deficiency has been This chapter will comprise quantitative (thrombocytope- reported (see PETERSON et al., 1995). nia) and qualitative (functional) disorders. It must not be Von Willebrand factor deficiency is an autosomal trait, overlooked, however, that qualitative defects are frequent- therefore males and females are at equal risk. Clinical and ly superimposed on thrombocytopenia or other hemor- laboratory expressions are variable. The disease is rough- rhagic disorders. ly classified into 3 types: type 1 (incompletely dominant Thrombocytopenia is considered to be the most com- trait; DODDS, 1989), characterized by a low plasma con- mon acquired coagulopathy encountered in small animal centration of structurally normal vWF; type 2, character- practice (PARRY, 1989). According to DAVENPORT and ized by qualitative abnormalities of vWF; and the autoso- CARAKOSTAS (1982) thrombocytopenia and the underly- mal recessive (DODDS, 1989) type 3, where vWF is ing diseases can be classified as follows: absent from plasma and platelets. The milder forms of vW # decreased platelet production: idiopathic bone marrow disease have the characteristics of a platelet disorder aplasia, drug-induced bone marrow hypoplasia, chronic (bleeding from mucosal surfaces), whereas in some of its infections, myeloproliferative diseases, and irradiation- more severe forms, it shows features more typical of a induced bone marrow aplasia, coagulopathy (hemarthosis, subcutaneous hematomas) # platelet sequestration: splenomegaly, hypersplenism, (JOHNSTONE, 1988). An inherited disorder closely hepatomegaly, endotoxemia, and hypothermia, resembling vW disease was first described in pigs by # increased platelet destruction: immune-mediated throm- HOGAN et al. (1941). vW disease is the most common bocytopenia (autoimmune or drug-associated), microan- bleeding disorder in dogs (over 50 breeds) and the differ- giopathy, infectious diseases, live virus vaccination, and ent types of the disease are spread over different breeds mechanical injury to platelets, (BROOKS, 1999). Type 1 vWD is very frequently diag- # increased platelet utilization: DIC, microangiopathy, pro- nosed in Doberman Pinschers were 73 % of the animals tracted hemorrhage, vasculitis, and septicemia/viremia. have vW antigen levels < 50 %. This figure is 43 % in the In addition, hypothyroidism may exhibit thrombocytope- Corgi, 35 % in the German Shepard dog, 30 % in the Gold- nia and associated mucosal bleeding in dogs (DODDS, en Retriever and Poodle, and 23 % in the Shetland Sheep- 1989). dog. Type 2 vWD is a very rare disorder, seen in German Severe platelet destruction may be caused by Ehrli- Shorthair Pointers. The very severe form (type 3) is found chioses. The causative bacteria belong to a subgroup of in the Scottish Terrier and the Shetland Sheepdog. 30 and the Proteobacteria, the family of the Anaplasmataceae. 3 23 % of the dogs, respectively, of these breeds have vW genera are recognized: Neorickettsia, Ehrlichia (e.g. antigen levels < 50 % . No figures are given for the also Ehrlichia canis), and Anaplasma (e.g. Anaplasma phago- affected Chesapeake Bay Retriever (THOMAS, 1996). The cytophilum) (BRANGER et al., 2004). Anaplasma phago- disease has also been reported in a number of other cytophilum is the causative agent of the granulocytic species such as mice, rabbits, cats, pigs, cattle, horses, and anaplasmosis of dogs (KOHN et al., 2008), sheep, goats, recently in a Rhesus monkey (PATTERSON et al., 2002). cattle, and man (WOLDEHIWET, 2006, 2008). Anaplasma Factor X deficiency (autosomal dominant) was phagocytophilum is distinct from Ehrlichia canis, the etio- described in dogs (see DODDS, 1989) and cats (GOOKIN logic agent of canine monocytic inclusions (POITOUT et et al., 1997). The severity of the resulting hemorrhagic dis- al., 2005). Ehrlichiosis (Anaplasmosis) is a wide spread ease depends on the amount of factor X present in disease, reported from the USA and Europe (POITOUT et homozygous or heterozygous individuals. The disease is al., 2005; BARUTZKI et al., 2006; KOHN et al., 2008). The well known as the cause of the “fading puppy syndrome” in bacteria are transmitted by ticks. There is an interesting dogs. Due to the central role of factor X in the coagulation paper of WIELINGA et al. (2006) investigating the Ehrlichia cascade, a complete absence of this factor is not compa- infections of Ixodes ricinus ticks in The Netherlands. tible with life. Canine babesiosis, caused by intraerythrocytic Babesia Congenital factor XI deficiency (transmitted as an auto- spp., is a tick.borne disease of worldwide importance. 2 somal recessive gene) occurs in cattle, dogs (see DODDS, subspecies, Babesia canis and Babesia gibsoni are recog-

82 Wien. Tierärztl. Mschr. - Vet. Med. Austria 96 (2009) nised as the main causative agents (see DUH et al., 2004). ciency, and even following exercise (JOHNSTONE, 1988) The latter one is considered endemic in the wild in Asia, or idiopathically in the course of neoplasias. Africa, the Middle-East, North America and Australia (see Hypercoagulability and suppression of fibrinolysis are MATSUU et al., 2004). The most common hematological characteristics of the early response to hemorrhage in abnormalities in canine babesiosis are anemia and throm- experimental hemorrhagic shock. The findings of bocytopenia (MANZILLO et al., 2006). Babesiosis is also YAMASHITA et al. (1995) suggest that an increase in plas- known from calves infected with Babesia bigemina or minogen activator inhibitor activity might be the underlying Babesia argentina (WRIGHT and GOODGER, 1977). mechanism for this phenomenon. The feline leukemia virus is recognized as a cause of Cats with cardiac dysfunction have an increased risk of thrombocytopenic states in the cat. Megakaryocytic thromboembolism (WELLES et al., 1994). Pathophysiology hypoplasia has been reported in association with a variety and symptoms were excellently reviewed by SCHOEMAN of myeloproliferative disorders and aplastic anemias sec- (1999) and RODRGUEZ and HARPSTER (2002): aortic ondary to feline leukemia virus (DAVENPORT and thromboembolism can occur with any form of cardiomyo- CARAKOSTAS, 1982). pathy, but is most commonly associated with hypertrophic The most prominent coagulation disorder in the course cardiomyopathy, and is the most common cause of of a hog cholera infection is thrombocytopenia already hindlimb paresis. Thrombus formation usually occurs in the exsitent on day 2 post infection (HEENE et al., 1971). left atrium with subsequent embolization into the systemic An acquired platelet adhesion (functional) disorder circulation. Although emboli most commonly lodge in the occurs in severe, end-stage uremic patients. Phenol and distal aortic trifurcation, they can also occlude cerebral, related substances are believed to inhibit the binding of col- renal, mesenteric, pulmonary or brachial arteries. Predis- lagen to GP I (DAVENPORT and CARAKOSTAS, 1982). posing factors for thrombus formation are endocardial Several drugs are implicated in the induction of acquired injury (due to enlargement), circulatory stasis and platelet aggregation disorders (e.g. dextrans, synthetic increased blood coagulability. Some of these cats may also penicillins; DAVENPORT and CARAKOSTAS, 1982). have hypercoagulable platelets. Aspirin (acetyl salicylic acid) is the most prominent exam- A hypercoagulable state has been described with ple for drugs which impair the release of secretory prod- nephrotic syndrome of dogs and cattle (MURRAY et al., ucts from the storage granules (DAVENPORT and 1972). Antithrombin - one of the endogenous anticoagu- CARAKOSTAS, 1982). lants - is similar in molecular size to albumin and is lost in the urine in moderate to marked amounts with this dis- Coagulation factor disorders (secondary hemostasis) ease. RIVERA RAMIREZ et al. (1997) described Liver disease is a common cause of hemostatic abnor- decreased antithrombin values in cats suffering from malities in several species because of impaired factor syn- chronic renal failure. Similarly, a hypercoagulable state can thesis, synthesis of abnormal factors, increased consump- exist in protein-losing intestinal diseases (WELLES, 1996). tion of coagulation factors, impaired clearance and Mortality in dogs suffering from canine parvoviral enteri- impaired fibrinolysis (LISCIANDRO et al., 1998). Diseases tis appears to result from secondary bacteremia and endo- causing biliary obstruction impede bile secretion into the toxemia. The initial response to endotoxin is activation of duodenum and thereby impair absorption of vitamin K coagulation (and this is in contrast to the experimental find- which is necessary for synthesis of factors of the so called ings of WEST et al., 1966; see above). And in fact, OTTO prothrombin complex. In cats there is a significant associ- et al. (2000) detected hypercoagulability in 9 affected dogs ation between coagulation test abnormalities and high by the thromboelastographic method. 4 of these dogs had alkaline phosphatase activity, indicative of cholestasis clinical evidence of venous thrombosis or phlebitis associ- (LISCIANDRO et al., 1998). ated with catheters. One dog showed multifocal splenic Experimental endotoxemia (injection of endotoxin from thrombosis at necropsy. E. coli) is known as cause of hemostatic disorders in dogs 4-6 hours after induction of an experimental pancreati- (WEST et al., 1966). tis, ENCKE et al. (1966) observed an hypercoagulable Vitamin K deficiency secondary to warfarin or other state, leading in some cases to DIC. rodenticide poisoning leading to a drop of the factors of the Malignancies may also lead to hypercoagulability. A prothrombin complex (II, VII, IX, and X) is much less study on hemostatic abnormalities in dogs with mammary reported in cats than in dogs (PETERSON et al., 1995). carcinoma (STOCKHAUS et al., 1999) showed thrombocy- Hypothyroidism suppresses the efficiency of the hemo- tosis, shortening of coagulation screening test results, ele- static mechanism (JOHNSTONE, 1988, see also above) vated plasma levels of single coagulation factors as well as and may thereby increase the clinical severity of vW dis- fibrin monomers in 56 % of the animals. ease in dogs (see DODDS, 1989). In pneumonic pasteurellosis tissue factor expression on the surface of cells is induced and platelets are activated Thrombophilia by Pasteurella mannheimia leading to fibrin deposition in the lung of cattle (GENTRY, 2004). Thrombophilia in animals is generally associated with Colic horses are prone to thrombophlebitis after long- pathophysiological conditions that cause alterations in term use of in-dwelling intravenous catheters. Authors con- blood flow, vascular disorders and/or hemostatic abnor- clude that the state of debilitation in these patients is the malities (GENTRY, 2004). most important determining factor (LANKVELD et al., Thrombocytosis is a rare syndrome (DAVENPORT and 2001). Antigen concentration and activity of protein C - one CARAKOSTAS, 1982) seen either as physiological of the endogenous anticoagulants - is decreased in horses response to acute hemorrhage, trauma, infection, iron defi- with acute gastrointestinal diseases. A case of acquired

83 Wien. Tierärztl. Mschr. - Vet. Med. Austria 96 (2009) protein C deficiency was associated with a hypercoagula- functional platelet defects or a vW disease. A normal ble state in a Thoroughbred colt (see WELLES, 1996). bleeding time, however, does not exclude a diagnosis of Blood vessels are the principle target of equine arteritis vW disease. If the bleeding time is within physiological virus. Vasculitis with associated thrombosis may inter alia ranges, PT and PTT should be measured. play a role inducing ischemia of the placenta resulting in A prolonged PT with normal PTT indicates usually fac- expulsion of the fetus (DEL PIERO, 2000). tor VII deficiency. A prolonged PTT with normal PT indi- According to the results of WEISS et al. (1998) platelet- cates deficiencies of the factors XI, IX, or VIII. Prolongation dependent thrombosis is involved in the pathogenesis of of both global screening tests is caused by deficiency of alimentary laminitis. Authors hypothesize that mucosal several factors and is seen most often in cases with vita- injury in alimentary laminitis results in endotoxin absorp- min K deficiency or antagonism. tion into the enterohepatic circulation. Local production of Tentative diagnoses can be verified by further labora- platelet-activating factor within the enterohepatic circulatory investigations (e.g. quantification of activity levels of tion may result in formation of platelet-platelet and platelet- specific coagulation factors). As recently mentioned by neutrophil aggregates that lodge in the microvasculature. PICHLER (2008), it is very important to pay attention to The situation (ischemia) might be aggravated by minimal pre-analytical aspects. Some clotting factors are quite collateral circulation and the large number of arteriovenous unstable and easily depleted or activated by inappropriate anastomoses within the hoof wall. handling. In some cases (e.g. platelet function evaluation), A hypercoagulable condition and poor perfusion to dis- it is necessary to submit the patient for testing. BOWIE and tal extremities might occur during equine endotoxemic or OWEN (1984) stated "when tests for hemostasis are per- septic shock, which could cause thrombosis of limb arter- formed, the patients are the best containers for their blood ies - especially in foals (TRIPLETT et al., 1996; BRI- samples". ANCEAU and DIVERS, 2001). This preference might be For therapeutic approaches (not topic of this review) explained by low fibrinogen and protein C antigen concen- see PICHLER (2006). tration, and by low antithrombin, plasminogen, alpha-2 antiplasmin, and tissue plasminogen activities during the Acknowledgement first month of life. The excellent literature service by Ms. Sonja Moser is gratefully acknowledged. Discussion References A thorough clinical examination of animals with a sus- pected hemorrhagic diathesis is the prerequisite for a prop- ABILDGAARD, C.F., LINK, R.P. (1965): Blood coagulation and er diagnosis. Sometimes bleeding may not be recognized hemostasis in Thoroughbred horses. Proc. Soc. Exp. Biol. Med. for what it is, as in the case of a haemophiliac dog with a 119, 212-215. history of recurring shifting lameness due to hemarthrosis BADYLAK, S.F., VLEET J.F. van (1981): Alteration of prothrombin time and activated partial thromboplastin time in dogs with (JOHNSTONE, 1988). hepatic disease. Am. J. Vet. Res. 42, 2053-2056. Race, gender and age may give first important informa- BADYLAK, S.F., DODDS, W.J., VLEET, J.F. van (1983): Plasma tions: vW disease is very common among Doberman Pin- coagulation factor abnormalities in dogs with naturally occur- schers, classical hemophilia A or B is rather exclusively ring hepatic disease. Am. J. Vet. Res. 44, 2336-2340. seen in males, inherited abnormalities are recognized nor- BARTON, M.H., MORRIS, D.D., CROWE, N., COLLATOS, C., mally within the first 6 months of life, whereas acquired PRASSE, K.W. (1995): Hemostatic indices in healthy foals from bleeding disorders are more common recognized in birth to one month of age. J. Vet. Diagn. Invest. 7, 380-385. mature or aged patients (JOHSTONE, 1988). BARUTZKI, D, NICOLA, A. de, ZEZIOLA, M., REULE, M. (2006): Seroprevalence of Anaplasma phagocytophilum in dogs in It is very important to distinguish between bleeding due Germany. Berl. Münch. Tierärztl. Wochenschr. 119, 342-347. to local factors (like infection or neoplasm in epistaxis, or BATEMAN, S.W., MATHEWS, K.A., ABRAMS-OGG, A.C.G. trauma in the case of hemarthrosis) or due to a systemic (1998): Disseminated intravascular coagulation in dogs: review coagulopathy caused by coagulation factor deficiencies or of the literature. J. Vet. Emerg. Crit. Care 8, 29-45. thrombocytopenia. If a systemic coagulopathy is evident, a BATEMAN, S.W., MATHEWS, K.A., ABRAMS-OGGS, A.C., family history might be helpful to distinguish between an LUMSDEN, J.H., JOHNSTONE, I.B., HILLERS, T.K., FOSTER, inherited and an acquired disease. R.A. (1999): Diagnosis of disseminated intravascular coagula- An inquiry should be made regarding uncontrolled food tion in dogs admitted to an intensive care unit. J. Am. Vet. Med. Assoc. 215, 798-804. intake (warfarin poisoning), drugs (in the course of treat- BELL, T.G., MEYERS, K.M., PRIEUR, D.J., FAUCI, A.S., WOLFF, ment or in an uncontrolled manner), vaccinations, infec- S.M., PADGETT, G.A. (1976): Decreased nucleotide and sero- tious or other pre-existing diseases. tonin storage associated with defective function in Chediak- PARRY (1989) suggested the protocol given below to Higashi syndrome cattle and human platelets. Blood 48, 175- be followed in small animal practice (in the case of a hem- 184. orrhagic disorder): BENTINCK, J., ROBERTS, J.S., KATZ, E.M. (1960): A bleeding As most of the acquired coagulopathies result from disease of new-born calves. Cornell Vet. 50, 15-25. thrombocytopenia, a platelet count is a useful first step. If BERTOLUCCI, C., PINOTTE, M., COLOGNESI, I., FOA, A., thrombocytopenia is shown, the most likely causes are BERNARDI, F., PORTALUPPI, F. (2005): Circadian rhythms in mouse blood coagulation. J. Biol. Rhythms 20, 219-224. immune-mediated destruction of platelets, DIC, or BOUDREAUX, M.K., CATALFAMO, J.L. (2001): Molecular and megakaryocytic hypoplasia. If the platelet count is normal, genetic basis for thrombasthenic thrombopathia in Otter- a bleeding time test is a useful second step. hounds. Am. J. Vet. Res. 62, 1797-1804. If the bleeding time is prolonged, most likely causes are BOUDREAUX, M.K., KVAM, K., DILLON, A.R., BOURNE, C.,

84 Wien. Tierärztl. Mschr. - Vet. Med. Austria 96 (2009)

SCOTT, M., SCHWARTZ, K.A., TOIVIO-KINNUCAN, M. (1996): GENTRY, P.A., CHERYK, L.A., SHANKS, R.D., HEALY, R. (1997): Type I Glanzmann´s thrombasthenia in a Great Pyrenees dog. An inherited platelet function defect in an Simmental crossbred Vet. Pathol. 33, 503-511. herd. Can. J. Vet. Res. 61, 128-133. BOWIE, E.J.W., OWEN, C.A. (1984): The clinical and laboratory GENTRY, P.A., FELDMAN, B.F., O´NEILL, S.L. MADIGAN, J. E., diagnosis of hemorrhagic disorders. In: RATNOFF, O.D., ZINKL, J.G. (1992): Evaluation of the haemostatic profile in the FORBES, C.D. (eds.): Disorders of hemostasis. Grune and Strat- pre- and post parturient mare, with particular focus on the peri- ton, Orlando, p. 43-73 (cited according to JOHNSTONE, 1988). natal period. Equ. Vet. J. 24, 33-36. BRANGER, S., ROLAIN, J.M., RAOULT, D. (2004): Evaluation of GENTRY, P.A., LIPTRAP, R.M., BLACK, W.D. (1979): Changes in antibiotic susceptibilitie of Ehrlicheia canis, Ehrlichia chaffeensis, blood coagulation profiles of dairy cows during pregnancy and in and Anaplasma phagocytophilum by real-time PCR. Antimicr. heifer calves after hormone treatment. Can. J. Anim. Sci. 59, 503- Agent Chemother. 48, 4822-4828. 510. BRIANCEAU, P., DIVERS, T.J. (2001): Acute thrombosis of limb GOOKIN, J.L., BROOKS, M.B., CATALFAMO, J.L., BUNCH, S.E., arteries in horses with sepsis: five cases (1988-1998). Equ. Vet. MUNANA, K.R. (1997): Factor X deficiency in a cat. J. Am. Vet. J. 33, 105-109. Med. Assoc. 211, 576-579. BROOKS, M. (1999): A review of canine inherited bleeding disor- GREEN, R.A. (1984) Clinical implications of antithrombin III defi- ders: biochemical and molecular strategies for disease charac- ciency in animal diseases. Comp. Cont. Ed. Pract. Vet. 6, 537- terization and carrier detection. J. Heredity 90, 112-118. 545. CATALFAMO, J.L., RAYMOND, S.L., WHITE, J.G., DODDS, W.J. HARTMAN, F.A. (1927): Changes in the clotting time of the blood (1986): Defective platelet-fibrinogen interaction in hereditary of cats as a result of exercise. Amer. J. Physiol. 80, 716-718. canine thrombopathia. Blood 67, 1568-1577. HATHAWAY, W.E., HATHAWAY, H.S., BELHASEN, L.P. (1964): COLOGNESI, I., PASQUALI, V., FOA, A., RENZI, P., BERNARDI, F., Coagulation factors in newborn animals. J. Lab. Clin. Med. 63, BERTOLUCCI, C., PINOTTI, M. (2007): Temporal variations of 784-790. coagulation factor VII activity in mice are influenced by lighting HEENE, D., HOFFMANN-FEZER, G., HOFFMANN, R., WEISS, regime. Chronobiol. Intern. 24, 305-313. E., MÜLLER-BERGHAUS, G., LASCH, H.G. (1971): Coagula- COWAN, S.M., BARTGES, J.W., GOMPF, R.E., HAYES, T.D., tion disorders in acute hog cholera. Beitr. Path. 144, 259-271. SNIDER, C.C., GERARD, D.A., CRAFT, R.M., MUENCHEN, HOGAN, A.G., MUHRER, M.E., BOGART, R. (1941): A hemophil- R.A., CARROLL, R.C. (2004): Giant platelet disorder in the Cav- ia-like disease in swine. Proc. Soc. Exp. Biol. Med. 48, 217-219. alier King Charles Spaniel. Exp. Hematol. 32, 344-350. JOHNSTONE, I.B. (1988): Clinical and laboratory diagnosis of DAVENPORT, D.J., CARAKOSTAS, M.C. (1982): Platelet disorders bleeding disorders. Vet. Clin. North Am. Small Anim. Pract. 18, in the dog and cat. Part I: physiology and pathogenesis. Comp. 21-33. Contin. Ed. Pract. Vet. 4, 762-772. JOHNSTONE, I.B., VIEL, L., CRANE, S., WHITING, T. (1991): DAVIES, B., TOIVIO-KINNUCAN, M., SCHULLER, S., Hemostatic studies in racing Standardbred horses with exer- BOUDREAUX, M.K. (2008): Mutation in beta 1-tubulin correlates cise-induced pulmonary hemorrhage. Hemostatic parameters with macrothrombocytopenia in Cavalier King Charles Spaniels. at rest and after moderate exercise. Can. J. Vet. Res. 55, 101- J. Vet. Intern. Med. 22, 540-545. 106. DEL PIERO, F. (2000): Equine viral arteritis. Vet. Pathol. 37, 287- KOCIBA, G.J. (1980): Partial characterization of a hemostatic 296. defect in Simmental cattle. Vet. Clin. Pathol. 9, 46-47 (cited DODDS, W.J. (1967): Familial canine thrombocytopathy. Thromb. according to GENTRY et al., 1996). Diath. Haemorrh. 26 (Suppl.), 241-248. KOHN, B., GALKE, D., BEELITZ, P., PFISTER, K. (2008): Clinical DODDS, W.J. (1989): Hemostasis. In: KANEKO, J.J. (ed.): Clinical features of canine granulocytic anaplasmosis in 18 naturally biochemistry of domestic animals. 4th ed., Academic Press, San infected dogs. J. Vet. Intern. Med. 22, 1289-1295. Diego, p. 274-315. LANKVELD, D.P.K., ENSINK, J.M., DIJK, P. van, KLEIN, W.R. DRANZER, F.H. (1985): Clinical implications of disseminated (2001): Factors influencing the occurrence of thrombophlebitis intravascular coagulation. Comp. Cont. Educ. Pract. Vet. 4, 974. after post-surgical long-term intravenous catheterization of col- DUH, D., TOZON, N., PETROVEC, M., STRASEK, K., AVSIC- ic horses: a study of 38 cases. J. Vet. Med A 48, 545-552. ZUPANC, T. (2004): Canine babesiosis in Slovenia: molecular LISCIANDRO, S.C., HOHENHAUS, A., BROOKS, M. (1998): evidence of Babesia canis canis and Babesia canis vogeli. Vet. Coagulation disorders in 22 cats with naturally occurring liver Res. 35, 363-368. disease. J. Vet. Intern. Med. 12, 71-75. ENCKE, A., SCHIMPF, K., KOMMERELL, B., GRÖZINGER, K.H., MANZILLO, V.F., CAPPIELLO, S., OLIVA, G. (2006) Tick-transmit- GILSDROF, H., WANKE, M., LASCH, H.G. (1966): Veränderun- ted disease in dogs: clinicopathological findings.Parassitologia gen der Blutgerinnung bei der akuten experimentellen Pankreati- 48, 135-136. tis des Hundes. Klin. Wschr. 44, 90-95. MAPLETOFT, R.J., SCHMUTZ, S.M., SEARCY, G.P. (2000): A ESTRIN, M.A., WEHAUSEN, C.E., JESSEN, C.R., LEE, J.A. (2006): study of the inheritance of a bleeding disorder in Simmental Disseminated intravascular coagulation in cats. J. Vet. Intern. cattle. Can. Vet. J. 41, 791-793. Med. 20, 1334-1339. MASSICOTTE, P., MITCHELL, L., ANDREW, M. (1986): A com- FELDMAN, B.F., MADEWELL, B.R., O´NEILL, S. (1981): Dissemi- parative study of coagulation systems in newborn animals. nated intravascular coagulation: antithrombin, plasminogen, and Pediatr. Res. 20, 961-965. coagulation abnormalities in 41 dogs. Am. Vet. Med. Assoc. 179, MATSUU, A., KAWABE, A., KOSHIDA, Y., IKADAI, H., OKANO, S., 151-154. HIGUCHI, S. (2004): Incidence of canine Babesia gibsoni infec- FIELD, R.A., RICKARD, C.G., HUTT, F.B. (1946): Hemophilia in a tion and subclinical infection among Tosa dogs in Aomori Pre- family of dogs. Cornell Vet. 36, 285-300. fecture, Japan. J. Vet. Med. Sci. 66, 893-897. FOGH, J.M., FOGH, I.Z. (1988): Inherited coagulation disorders. MILLS, C.A., NECHELES, H. (1928): Variations in the coagulability Vet. Clin. North Am. Small Anim. Pract. 18, 231-243. of the blood normally and after food ingestion. Chin. J. Physiol. 2, GENTRY, P.A.(1984): The relationship between factor XI coagulant 19-24. and factor XI antigenetic activity in cattle. Can. J. Comp. Med. 48, MISCHKE, R. (1994): Aktivität der Gerinnungsfaktoren II, V, VII 58-62. und X beim gesunden Hund-Abhängigkeit von Alter, Ge- GENTRY, P.A. (2004): Comparative aspects of blood coagulation. schlecht und Rasse. Berl. Münch. Tierärztl. Wschr. 107, 289- Vet. J. 168, 238-251. 294. GENTRY, P.A., LIPTRAP, R.M.(1988): Comparative hemostatic pro- MOSER, J., MEYERS, K.M., RUSSON, R.H., REEVES, J.J. tein alterations accompanying pregnancy and parturition. Can. J. (1998): Plasma von Willebrand factor changes during various Physiol. Pharmacol. 66, 671-678. reproductive cycle stages in mixed-breed dogs with normal von

85 Wien. Tierärztl. Mschr. - Vet. Med. Austria 96 (2009)

Willebrand factor and in Doberman Pinschers with type-1 von of all vitamin K-dependent blood coagulation factors due to a Willebrand´s disease. Am. J. Vet. Res. 59, 111-118. defective vitamin K-dependent carboxylase in Devon Rex cats. MUCHITSCH, E.-M., PICHLER, L., TURECEK, P.L., GRITSCH, H., Thromb. Haemost. 68, 521-525. RICHTER, G., AUER, W., SCHWARZ, H.P. (1999): Charakter- STEFICEK, B.A., THOMAS, J.S., BAKER, J.C., BELL, T.G. (1993): isierung der Faktor VIII-knock out-Maus für den Einsatz in der Hemorrhagic diathesis associated with a hereditary platelet dis- biomedizinische Forschung. Wien. Tierärztl. Mschr. 86, 339-346. order in Simmental cattle. J. Vet. Diagn. Invest. 5, 202-207. MURRAY, M., RUSHTON, A., SELMAN, I. (1972): Bovine renal STOCKHAUS, C., KOHN, B., RUDOLPH, R., BRUNNBERG, L., amyloidosis: a clinicopathologic study. Vet. Rec. 90, 210-216. GIGER, U. (1999): Correlation of haemostatic abnormalities with OTTO, C.M., RIESER, T.M., BROOKS, M.B., RUSSELL, M.W. tumour stage and characteristics in dogs with mammary carci- (2000): Evidence of hypercoagulability in dogs with parvoviral noma. J. Small Anim. Pract. 40, 326-331. enteritis. JAVMA 217, 1500-1504. TABATA, H., NAKAMURA, S., MATSUZAWA, T. (1995): Some PARRY, B.W. (1989): Laboratory evaluation of hemorrhagic coagu- species differences in the false prolongation of prothrombin lopathies in small animal practice. Vet. Clin. North Am. Small times and activated partial thromboplastin times in toxicology. Anim. Pract. 19, 729-742. Comp. Haematol. Int. 5, 140-144. PATTERSON, M.M., JACKSON, L.R., BROOKS, M.B., CATAL- FAMO, J.L. (2002): Type-3 von Willebrand´s disease in a Rhesus THOMAS, J.S. (1996): von Willebrand´s disease in the dog and cat. monkey (Macaca mulatta). Comp. Med. 52, 368-371. Vet. Clin. North Am. Small Anim. Pract. 26, 1089-1110. PEDERSEN, H.D., HÄGGSTROM, J., OLSEN, L.H., CHRIS- TRIPLETT, E.A., O´BRIAN, R.T., WILSON, D.G., STEINBERG, H., TENSEN, K., BURMEISTER, M.L., LARSEN, H. (2002): Idio- DARIEN, B.J. (1996): Thrombosis of the brachial artery in a foal. pathic asymptomatic thrombocytopenia in Cavalier King Charles J. Vet. Int. Med. 10, 330-332. Spaniels is an autosomal recessive trait. J. Vet. Intern. Med. 16, TROXEL, M.T., BROOKS, M.B., ESTERLINE, M.L. (2002): Congen- 169-173. ital factor XI deficiency in a domestic shorthair cat. J. Am. Anim. PETERSON, J.L., COUTO, C.G., WELLMAN, M.L. (1995): Hemo- Hosp. Ass. 38, 549-553. static disorders in cats: a retrospective study and review of the lit- VERSTRAETE, M., COLLEN, D. (1986): Thrombolytic therapy in the erature. J. Vet. Int. Med. 9, 298-303. eighties. Blood 67, 1529-1541. PICHLER, L. (2006): Blut und Blutprodukte in der Veterinärmedi- WEISS, R.C., DODDS, W.J., SCOTT, F.W. (1980): Disseminated zin - eine Literaturübersicht. Vet. Med. Austria/Wien. Tierärztl. intravascular coagulation in experimentally induced feline infec- Mschr. 93, 127-136. tious peritonitis. Am. J. Vet. Res. 41, 663-671. PICHLER, L. (2008): Parameters of coagulation and fibrinolysis in WEISS, D.J., EVANSON, O.A., McCLENAHAN, D., FAGLIARI, J.J., different animal species - a literature based comparison. Vet. DUNNWIDDIE, C.T., WELLS, R.E. (1998): Effect of a competitive Med Austria/Wien. Tierärztl. Mschr. 95, 282-295. inhibitor of platelet aggregation on experimentally induced PICHLER, E., PICHLER, L.(2008): The neonatal coagulation sys- laminitis in ponies. Am. J. Vet. Res. 59, 814-817. tem and the vitamin K deficiency bleeding - a minireview. Wien. WELCH, R.D., WATKINS, J.P., TAYLOR, T.S., COHEN, N.D., Med. Wochenschr. 158, 385-395 . CARTER, G.K. (1992): Disseminated intravascular coagulation POITOUT, F.M., SHINOZAKI, J.K., STOCKWELL, P.J., HOLLAND, associated with colic in 23 horses (1984-1989). J. Vet. Intern. C.J., SHUKLA, S.K. (2005): Genetic vartiants of Anaplasma Med. 6, 29-35. phagocytophilum infecting dogs in Western Washington State. J. WELLES, E.G. (1996): Antithrombotic and fibrinolytic factors. Vet. Clin. Microbiol. 43, 796-801. RIVERA RAMIREZ, P.A., DENIZ, A., WIRTH, W., MISCHKE, R. Clin. North Am. Small Anim. Pract. 26, 111-1127. (1997): Antithrombin III-Aktivität bei der gesunden Katze und ihre WELLES, E., BOUDREAUX, M., CRAGER, C., TYLER, J.W. (1994): Veränderung bei ausgewählten Erkrankungen. Berl. Münch. Platelet function and antithrombin, plasminogen, and fibrinolytic Tierärztl. Wschr. 110, 440-444. activities in cats with heart disease. Am. J. Vet. Res. 55, 619-627. RODRIGUEZ, D.B., HARPSTER, N. (2002) : Aortic thromboem- WEST, R.L., ELOVITZ, M.J., HARDAWAY, R.M.(1966): Blood coag- bolism associated with feline hypertrophic cardiomyopathy. ulation factor activity in experimental endotoxemia. Ann. Surg. Comp. Contin. Educ.Pract.Vet. 24, 478-481. 163, 567-572. ROSENBERG, R.D., BAUER, K.A. (1986): New insights into hyper- WIELINGA, P.R., GAASENBEEK, C., FONVILLE, M., BOER, A. de, coagulable states. Hosp. Pract. 21, 131-138, 143, 147. VRIES, A. de, DIMMERS, W., AKKERHUIS OP JAGERS, G., RÜBERG, B., GÜNZEL-APEL, A.-R., WIRTH, W., HOPPEN, H.-O. SCHOULS, L.M., BORGSTEEDE, F., GIESSEN, J.W.B. van der (1990): Untersuchungen der Hämokoagulationsdynamik während (2006): Longitudinal analysis of tick densities and Borrelia, des Sexualzyklus der Hündin. Waltham Rep. Nr. 31, p. 39-49. Anaplasma, and Ehrlichia infections of Ixodes ricinus ticks in dif- SALEM, H.H., MITCHELL, C.A., FIRKIN, B.G. (1987): Current views ferent habitat areas in The Netherlands. Appl. Envir. Microbiol. on the pathohysiology and investigations of thrombotic disorders. 72, 7594-7601. Am. J. Hematol. 25, 463-474. WOLDEHIWET, Z. (2006): Anaplasma phagocytophilum in rumi- SCHOEMAN, J.P. (1999): Feline distal aortic thromboembolism: a nants in Europe. Ann. NY Acad. Sci. 1078, 446-460. review of 44 cases (1990 - 1998). J. Feline Med. Surg. 1, 221- WOLDEHIWET, Z. (2008): Immune evasion and immunosuppres- 231. sion by Anaplasma phagocytophilum, the causative agent of SEARCY, G.P., PETRIE, L. (1990): Clinical and laboratory findings tick-borne fever and human granulocytic anaplasmosis.Vet. J. of a bleeding disorder in eight Simmental cattle. Can. Vet. J. 31, 175, 37-44. 101-103. WRIGHT, I.G., GOODGER, B.V. (1977): Acute Babesia bigemina SEARCY, G.P., SHERDAN, D., DOBSON, K.A. (1990): Preliminary infection: changes in coagulation and kallikrein parameters. Z. studies of a platelet function disorder in Simmental cattle. Can. J. Vet. Res. 54, 394-396. Parasitenk. 53, 63-73. SHIRAISHI, M., OGAWA, H., IKEDA, M., KAWASHIMA, S., ITO, K. WU. K.K. (1985): Microvascular thrombosis: pathophysiology and (2002): Platelet dysfunction in Chediak-Higashi syndrome-affect- new strategies. Hosp. Pract. 20, 47-55. ed cattle. J. Vet. Med. Sci. 64, 751-760. YAMASHITA, M., DARLINGTON, D.N., WEEKS, E.J., JONES, SIEME, H. (1989): Bestimmung von Hämokoagulationsparametern R.O., GANN, D.S (1995): Plasminogen activator inhibitor-1 ris- im Blut zyklischer Stuten. (Untersuchungen zur diagnostischen es after hemorrhage in rats. Am. J. Physiol. 268, E1065-E1069. Terminierung praxisrelevanter Zyklusphasen). Diss., Tierärztl. Hochschule Hannover. Author´s address: SOUTE, B.A., ULRICH, M.M., WATSON, A.D., MADDISON, J.E., Univ. Prof. Dr. Ludwig Pichler, Gußhausstraße 24, A-1040 Wien. EBBERINK, R.H.,VERMEER, C. (1992): Congenital deficiency e-mail: [email protected]