A rare blood clotting disease in Kerry Blue Terriers
This page contains:
- The authoritative article on Factor XI Deficiency in Kerry Blue Terriers by Clare Knowler, BVMS; Urs Giger, PD, Dr Med Vet; W. Jean Dodds, DVM; Marjory Brooks, DVM. This article is reprinted with permission from the Journal of American Veterinary Medical Association, Vol 205, No. 11, Pages 1557-1561. Copyrighted American Veterinary Medical Association, 1994. All Rights Reserved. Feel free to provide your vet a copy of the article.
- A layman's summary by Daryl Enstone (firstname.lastname@example.org)
- Recommended procedures before surgery of a Kerry Blue, are the same as for von Willebrand's
by Daryl Enstone
The article is a case study of a 9 year old female Kerry who was referred to the authors when she developed severe, prolonged bleeding after surgery.
Some key points:
- Kerry blues are the breed most commonly diagnosed with factor XI deficiency.
- Bleeding episodes in affected dogs can be delayed as much as 4 days after surgery or trauma (differs from both hemophilia and Von Willebrands, in which bleeding is immediate.)
- Treatment is transfusion of fresh frozen plasma; multiple transfusions may be required to stop bleeding.
The theory expressed in this paper is that Factor XI not only has a role in the initial clot formation, it has a role is maintaining coagulation. If an animal is deficient, the clot can break down and bleeding can start again. This is why bleeding may be delayed up to 4 days.
At the time the paper was written, Dr. Dodds had clinical records on 10 other Kerries identified with factor XI deficiency. There were 6 males and 4 females ranging in age from 8 months to 11 years.
Mode of transmission is apparently simple autosomal recessive genetic defect.
Factor XI deficiency in Kerry Blue Terriers
Clare Knowler, BVMS; Urs Giger, PD, Dr Med Vet; W. Jean Dodds, DVM; Marjory Brooks, DVM
- Deficiency of coagulation factor XI has been detected most commonly in Kerry Blue Terriers.
- Episodes of hemorrhage in dogs deficient in factor XI will often be delayed, developing up to 4 days after surgery or trauma.
- Transfusions of fresh-frozen plasma can return activated partial thromboplastin time and factor XI activity values to w~thin reference range limits.
- Multiple transfusions of fresh-frozen plasma may be needed to stop hemorrhage and to sustain hemostasis.
A 9-year-old 16-kg spayed female Kerry Blue Terrier was referred because of protracted bleeding from a surgical site. Medical history included that the dog had been ovariohysterectomized and 2 masses had been removed from the subcutaneous tissue (1 each from the mammary and cervical areas, respectively) without signs of excessive hemorrhage; however, wound healing after removal of the cervical mass was found to be poor At 6 years of age, the dog had been examined because of diarrhea and frank blood dripping copiously from the anus. After careful questioning, the owner also recalled that numerous bruises had developed when the dog once was kenneled; however, a bleeding disorder was not suspected.
A lipoma-like mass had been removed from the right flank of the dog by the referring veterinarian 4 days prior to referral. Bleeding problems had no! been noticed during or immediately after surgery. Two days after surgery, the dog was examined by the referring veterinarian, because the surgical site was swollen. Despite the application of hot compresses and bandages, the surgical site remained swollen and began to ooze blood. During the next 2 days, the dog was inappetent, vomited, and had diarrhea. Activated clotting time (ACT) was 360 seconds (reference range, < 120 seconds). The dog was given fluids IV and vitamin K1 SC and was referred.
Physical examination revealed that the dog was febrile (40 C), lethargic, and tachycardiac (160 beats/min). Mucous membranes were pale and dry, but the capillary refill time was < 2 seconds. The surgery site on the right flank was swollen, and hemorrhagic discharge oozed from the incision. The swollen area measured approximately 20 x 15 x 5 cm and extended into the inguinal region. Edema extended from the right flank to the tarsus of the right hind limb, and the surrounding skin appeared bruised. All other systems appeared grossly normal, except for the detection of immature cataracts.
The PCV was 33%, with total plasma protein concentration of 5.9 g/dl. All RBC indices were within reference range limits, with a mean corpuscular volume of 67 fl and mean corpuscular hemoglobin concentration of 34 g/dl. Anemia, which was initially nonregenerative, was attributed to acute blood loss. White blood cell counts were within reference range limits. Microscopic examination of a stained smear of a sample obtained from the swollen area by needle aspiration revealed numerous RBC, consistent with a hematoma. In addition, a few intracellular rods were seen in neutrophils, which was suggestive of an infection.
The number of platelets was moderately low at 68,000/microl, and buccal bleeding time was 3.5 minutes (reference range, < 4 minutes). The result of an ACT assay was severely prolonged at 300 seconds. The result of an activated partial thromboplastin time (APTT) assay (1) was prolonged at 37.4 seconds (control sample, 12.8 seconds), whereas the result for a one-stage prothrombin time assay was within acceptable limits (7.5 seconds; control sample, 11.4 seconds), which was suggestive of an intrinsic coagulation factor deficiency. Factor XI deficiency was suspected, because that disorder has been detected in a Kerry Blue Terrier, (2) whereas deficiencies in other intrinsic coagulation factors (VlII, IX) characteristically cause bleeding in males (3 ) or do not result in bleeding (Factor XII). (4)
A plasma sample was obtained, using citrate to prevent coagulation (1 part of 3.8% citrate solution to 9 parts of blood), and was shipped frozen on dry ice for analysis. (a) Coagulation studies conducted included APTT, one-stage prothrombin, and thrombin clotting time assays. (1) Specific assays for factor XI coagulant activity were performed, using kaolin (10 mg/ml) as an activator, phospholipid, (b) and factor XI-deficient plasma from cattle in an APTT assay. Results were reported as the percentage of factor XI activity in comparison with results obtained for a pool of plasma from clinically normal dogs, which was assigned an activity value of 100%. Results of the coagulation assays confirmed prolongation of APTT (80 seconds; reference range, 14 to 18 seconds) and substantiated a specific deficiency of factor XI activity (9% of the value determined for normal control dogs). Using the APTT assay technique, the reference range of factor XI activity in dogs was determined to be 60 to 150%.
Initially, the dog described here was given fluids containing crystalloids IV to correct hypovolemia. The surgical site was conservatively treated as an open wound with daily changes of compression bandages. Proteus mirabilis was isolated on bacteriologic culturing of the hemorrhagic discharge. On the basis of antibiotic susceptibility testing, cephalexin (20 mg/kg of body weight, IV, q 8 h) was administered for 10 days.
Because the wound continued to bleed, the dog also was treated with fresh-frozen plasma (FFP) obtained from clinically normal dogs that contained functional coagulation factors, including factor XI. After 125 ml (1 unit) of FFP was infused, hemorrhage from the wound ceased immediately. Thereafter, 1 unit of m was transfused each day for 3 additional days, which increased the plasma factor XI concentration to 95% and caused results of the ACT test on day 3 to be within reference range limits (Fig 1). The dog was examined regularly to monitor ACT results and the decline of plasma factor XI activity values and to determine whether bleeding redeveloped. Plasma factor XI concentrations decreased exponentially during the next 2 weeks, and the calculated half-life of the transfused factor XI was 72 hours in this dog. Sixteen days after referral, the surgical site had healed, leaving only a small scar. Three months later, plasma factor XI activity was only 11%; however, the dog did not have further bleeding episodes during 1 year of observation.
The fact that the APTT was prolonged but the prothrombin time was within the reference range was indicative of a defect in the intrinsic coagulation system of the affected dog reported here, such as a deficiency of factor VIII, IX, XI, or XII. Hemophilia A and B (factor VIII and factor IX deficiency, respectively), the most common, severe, inherited coagulopathies, are inherited in an x-linked recessive manner and, therefore, were considered unlikely because the dog was female.
Figure 1-Values for plasma factor XI activity (semilogarithmic plot; A) and activated clotting time (B) before and after transfusion of 125 ml of fresh-frozen plasma (arrows) daily for 4 days to a factor XI-deficient 9-year-old spayed female Kerry Blue Terrier that had hemorrhage after removal of a mass from the right flank. Reference range values (shaded areas) for factor XI activity are 60 to 150 % and for activated clotting time are < 120 seconds.
Factor XII deficiency, commonly detected in cats but rarely reported in dogs, is not associated with bleeding problems, although it causes a marked prolongation of APTT .(3) Thus, screening coagulation test results, signalment, and signs of bleeding strongly suggested factor XI deficiency in this dog, which was confirmed by analysis of specific coagulation factors.
Review of medical records obtained from our laboratory (a) revealed an additional 10 Kerry Blue Terriers that had been identified as factor XI deficient during the past decade. This included 6 males and 4 females, ranging from 8 months to 11 years of age. Eight of these dogs had a history of postoperative bleeding. Two dogs did not have a history of abnormal bleeding, but were tested because they were related to clinically affected dogs. Plasma factor XI activity values of deficient dogs (homozygotes) ranged from 2.5 to 11% of the values for control dogs. In addition, the 2 dogs that were related to an affected dog had factor XI concentrations of 45 and 36%, respectively, and each had had a single episode of excessive bleeding after surgery, despite the fact that their APTT values were only slightly higher than the upper end of reference range values. Both of these dogs had developed hematomas at the surgical site after removal of a cutaneous or perianal mass.
Analysis of the available pedigrees-of the 10 dogs that were factor XI deficient as well as a few other related dogs revealed that severely deficient male and female offspring had been produced by clinically normal as well as by affected dams and sires. Although 1 affected sire had extremely low values for factor XI activity and 1 clinically normal dam had intermediate values for factor XI activity, other clinically normal dams and sires had factor XI activity values that ranged from 36 to 97%, which overlapped with the reference range values for plasma factor XI activity. Similar results have been detected for factor XI-deficient human beings, with clinically affected persons having low or intermediate values for factor XI plasma activity. (4)
The reason that factor XI deficiency leads to a hemorrhagic diathesis, whereas factor XII deficiency does not, has been debated for many years, because both factors are part of the contact phase of coagulation.. On the basis of earlier in vitro studies, it was believed that factor XI was primarily activated by factor XII; however, more recent in vitro studies indicate that thrombin is approximately 10 times more effective than factor XIIa in activating factor XI to factor XIa.(5) When blood vessel walls are injured, the extrinsic coagulation system is initially activated by tissue factor produced in the subendothelium, which combines with factor VIIa in plasma, thereby resulting in a small amount of factor VIIa-tissue factor complex. Factor VIIa-tissue factor complex activates factors IX and X (6)and then is rapidly inhibited by lipoprotein-associated coagulation inhibitor. (7)Nevertheless, the small amount of thrombin produced appears sufficient to activate factor XI to factor XIa and also to activate other cofactors (factors V, VIII, and XIII). Through the action of factor XIa on factor IX, thrombin formation is continued. Therefore, rather than merely initiating coagulation, factor XI has a pivotal role in sustaining coagulation (Fig 2). This may also explain why bleeding as a result of factor XI deficiency is often delayed for up to 4 days after surgery.(8)
Factor XI deficiency is a rare bleeding disorder in human beings and is characterized by mild bleeding (9) (10), however, the risk of severe hemorrhage after surgery is considerable. (4) The disorder is reported to be inherited as an autosomal trait in which homozygotes and heterozygotes have an excessive bleeding tendency. (4) (11-15) Homozygotes have prolonged times for APTT and values for plasma factor XI activity of < 20%, whereas heterozygotes usually have APTT that are within reference range limits or are slightly prolonged. (4) (6)
Figure 2 - Schematic of the coagulation pathways and factors activated by thrombin.
Interestingly, only 10 to 15% of obligate heterozygous human beings have plasma factor XI activity values within reference range limits, rather than the anticipated 40 to 60%, and up to half of the heterozygotes may have a history of episodes of increased bleeding, similar to the frequency of bleeding episodes reported for homozygotes.(4)
As in human beings, factor XI deficiency in Holstein cattle is inherited as an autosomal trait. (17-19) Homozygotes and heterozygotes have an increased bleeding tendency caused by an absolute deficiency of factor XI protein.(20 ) Affected cattle bleed after trauma or surgery, such as dehorning. (19) (20)
In 1971, factor XI deficiency in dogs was first described in a female English Springer Spaniel.(22) The dog of that report had severe hemorrhage after a routine ovariohysterectomy, and had a history of epistaxis, hematuria, and evidence of spontaneous development and resolution of lumps in the subcutaneous tissues, which were presumed to be hematomas. Factor XI activity for that dog ranged from 3 to 10% of the values for control dogs. Related dogs were clinically normal, despite the fact that they had intermediate factor XI activity values that ranged from 23 to 40%. Factor XI deficiency has also been described in 1 report of a Great Pyrenees and a Kerry Blue Terrier. (2)
Although the pedigree information of the affected Kerry Blue Terriers of our study was incomplete, our results were consistent with findings for human beings (11-15) and cattle (19) with factor XI deficiency. The high proportion of factor XI deficiency in this breed, the fact that dogs of both genders were affected, and evidence of a specific protein deficiency indicated a single autosomal gene defect. Some deficient dogs did not have an increase in bleeding tendency. Dogs with an increase in bleeding tendency had low (< 20%) or intermediate values for plasma factor XI activity; however, some obligate heterozygote dogs had factor XI activity within reference range limits. Results of assays performed on samples of frozen plasma may vary, as freezing plasma partially deficient in factor XI apparently may augment factor XI activity.(23 )Severely deficient homozygous dogs may have more clinical signs of bleeding than heterozygous dogs.
In addition to the genetic cause for factor XI deficiency, it has been reported that human beings with systemic lupus erythematosus may acquire factor XI inhibitor (autoantibody against factor XI), which may result in an acquired factor XI deficiency state.(24) (25) This acquired deficiency state also has been reported in a cat that was believed to have had systemic lupus erythematosus.(26)
Transfusion with FFP or cryoprecipitate supernatants (cryo-poor plasma) is the treatment of choice for factor XI- deficient human beings and dogs with severe bleeding. (8) Severely anemic dogs may require additional transfusions of packed RBC or, altenatively, may receive fresh blood to provide plasma and RBC. Multiple transfusions (5 to 10 ml FFP/kg) may be required to return APTT and factor XI activity values to within reference range limits, to stop hemorrhage, and, in particular, to sustain hemostasis during the healing process. Fortunately, compared with factors VIII and IX, factor XI has a longer half-life (30 to 84 hours).(23) Thus, transfused factor XI lasts longer in the circulation than factors VIII and IX and provides for a prolonged period of hemostasis and healing of surgical sites. In the dog described here, 8 ml of FFP/kg arrested hemorrhage at the surgical site. A total of 30 ml of FFP/kg completely returned plasma factor XI concentration to within reference range values, as evidenced by a calculated half-life of 3 days for factor XI.
For minor surgeries, factor XI-deficient dogs do not need to be treated before surgery, but particular attention to surgical hemostasis is necessary. Fresh-frozen plasma or cryoprecipitate supernatants should be available if protracted postoperative hemorrhage is observed. Procedures involving tissues that are rich in local fibrinolysins, such as in the oronasal cavity and urogenital tract, are most often associated with excessive hemorrhage in human beings, (13) and, therefore, may warrant prophylactic and postoperative transfusions.
If major surgery is.required in an animal known to be factor XI deficient or hemostasis is further compromised by an acquired disorder such as hepatic disease, treatment prior to surgery with FFP or cryoprecipitate supernatant may be necessary to reduce the likelihood of postoperative hemorrhage. However, human beings may develop antibodies against homologous factor XI that will neutralize transfused factor XI, and, therefore, it is possible that hemorrhage may develop during subsequent surgeries, despite plasma transfusion.(27)(28) If a factor XI-deficient dog has been treated with FFP, it may be advisable to test for plasma factor XI inhibitors (antibodies) prior to surgeries and transfusions. In the dog of this report, factor XI antibodies were not detected in blood samples obtained 3 months after treatment with FFP.
(a) Comparative Hematology Laboratory, New York State Department of Health, Albany, NY.
(b) Dade Actin, B~Baxter Healthcare Corp, Dade Division. Miami, Fla.
1. Triplett DA, Harms CS Coagulation screening assays. In: Procedures for the coagulation laboratory. Chicago: Educational Products Division ASCP, 1981;1-21.
2. Dodds WJ. Third international registry on animal models or thrombosis and haemorrhagic diseases In: ILAR News. Washington DC: National Academy Press, 1988;130:R3-R32.
3. Fogh JM, fogh IT. Inherited coagulation disorders. Vet Clin North Am Small Anim Pract 1988;18:231-243.
4. Kitchens C. Factor XI: a review of its biochemistry and deficiency. Semin Thromb Hemost 1991;17:55-72.
5. Gailani D, Broze GJ. Factor XI activation in a revised model of blood coagulation. Science 1991;253:909-912.
6. Osterud B, Rapaport SI. Activation of factor IX by the reaction product of tissue factor and factor VII: additional pathway for initiating coagulation. Proc Natl Acad Sci U S A 1977; 74:5260-5264.
7. Broze GJ, Girard TJ, Novotny WF. Regulation of coagulation by a multivalent Kunitz-type inhibitor. Biochemistry 1990;29:7539- 7546.
8. Lewis JH, Spero JA, Ragni MV, et al. Transfusion support for congenital clotting deficiencies other than haemophilia. Clin Haematol 1984;13:119-135.
9. Rosenthal RL, Dreskins OH, Rosenthal N. New hemophilia-like disease caused by deficiency of a third plasma thromboplastin factor. Proc Soc Exp Biol Med1953;82:171-174.
10. Seligsohn U. High gene frequency of Factor XI (PTA) deficiency in Ashkenazi Jews. Blood 1978;51:1223-1228.
11. Bolton-Maggs PHB, Young Wan-Yin B, McCraw AH, et al. Inheritance and bleeding in factor XI deficiency. Br J Haematol 1988;69:521-528.
12. Asakai R, Chung DW, Ratutff OD, et al. Factor XI (plasma thromboplastin antecedent) deficiency in Ashkenazi Jews is a bleeding disorder that can result from three types of point mutations. Proc Natl Arad Sci U S A 1989;86:7667-7671.
13. Asakai R, Chung DW, Davie EW, et al. Factor XI deficiency in Ashkenazi Jews in Israel. N Engl J Med 1991;325: 153-158.
14. Hancock JF, Wieland K, Pugh RE, et al. A molecular genetic study of factor XI deficiency. Blood 1991;77:1942-1948.
15. Ragni MV, Sinha D, Seaman F, et al. Comparison of bleeding tendency, factor XI coagulant activity, and factor XI antigen in 25 factor XI-deficiency kindreds.Blood 1985;65:719-724.
16. Seligsohn U, Modan M. Definition of the population at risk of bleeding due to factor XI deficiency in Ashkenazi Jews and value of the activated partial thromboplastin time in its detection. Isr J Med Sci 1981;17:413-415.
17. Kociba GJ, Ratnoff OD, Loeb WF, et al. Bovine plasma thromboplastin antecedent (factor XI) deficiency. J Lab Clin Med 1969;74:37- 41.
18. Brush PJ, Anderson PH, Gunning RF. Identification of factor XI deficiency in Holstein-Friesian cattle in Britain. Vet Rec 1987;121: 14-17.
19. Gentry PA, Black WD. Prevalence and inheritance of factor XI (plasma thromboplastin antecedent) deficiency in cattle. J Dairy Sci 1980;63:616-620.
20. Gentry PA. The relationship between factor XI coagulant and factor XI antigenic activity in cattle. Can J Comp Med 1984;48:58-62.
21. Brush PJ, Gentry PA. Bovine factor XI deficiency: relationships between heterozygotes in Canada and Britain. Vet Rec 1988;122:134
22. Dodds WJ, Kull JE. Canine factor XI (plasma thromboplastin antecedent) deficiency. J Lab Clin Med Med 1971;78:746-752.
23. Dodds WJ. Hemostasis. In: Kaneko JJ, ed. Clinical bio chemistry of domestic animals. 4th ed San Diego: Academic Press Inc, 1989;274-315.
24. De la Cadena RA, Baglia FA, Johnson CA, et al. Naturally occurring human antibodies against two distinct functional domains in the heavy chain of FXI/FXIa,Blood 1988,72: 1748-1754.
25. Reece EA, Clyne LP, Romero R, et al. Spontaneous factor XI inhibitors. Seven additional cases and a review of the literature. Arch Intern Med 1984;144:525-559.
26. 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 Assoc1983;182:589-591.
27. Musclow CE, Amato D, Ofosu F, et al. Transfusion induced specific anti-factor XI inhibitor in a patient with previously unrecognized factor XI deficiency. Am J ain Pathol 1988; 89:418-422.
28. Sehnall SF, Duffy IP, Clyne LP. Acquired factor XI inhibitors in congenitally deficient patients. Am J Hematol 1987; 26:323-328.
From the Department of Clinical Studies, School of Veterinary Medicine, University of Pennsylvania, 3900 Delancey St, Philadelphia, PA 19104-6010 (Knowler, Giger), and New York State Department of Health, Wadsworth Center for Laboratories and Research, Empire State Plaza, PO Box 509. Albany. NY 12201-0509 (Dodds, crooks).
Supported in pan by grants from the National Institutes of Health (HLO2355, RRO2512, and HL09902).
The authors thank Drs. M. Podolion and L Babbit for assistance with this dog.
Address reprint requests to Dr. Giger.