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Excerpt from a letter from the Dept. of Veterinary Clinical Studies, University of Edinburgh

 

Thrombocytopenia

 

“This condition is certainly recognized in Cavaliers in a number of countries, but the significance is still under dispute.  Some investigators believe it is a harmless anomaly seen in CKCS (is they have fewer platelets, but they are large and work just as well as larger numbers of smaller ones), whereas other investigators believe it is a significant problem and many CKCS live on a knife-edge and may develop a clinically-apparent bleeding disorder at any time.  Clearly more work is needed, and again, this will require a prospective study whereby large numbers of Cavaliers are followed over a period of time.”

 

Virginia Luis Fuentes MA VetMB CertVR DVC MRCVS

 

 

 

Idiopathic, Asymptomatic Thrombocytopenia in Cavalier King Charles Spaniels:  11 Cases (1983 - 1993)

 

The medical records of 11 Cavalier King Charles spaniels with idiopathic, asymptomatic thrombocytopenia and large-to-giant platelets were identified from a 10-year retrospective search using the Veterinary Medical Data Base at Purdue University.  Eight of the dogs had been treated with various immunosuppressive drugs.  Six of the treated dogs remained thrombocytopenic, one was not reevaluated, and one developed a normal platelet count.  The underlying etiology of idiopathic, asymptomatic thrombocytopenia in Cavalier King Charles spaniels has not been identified, but this condition could represent a congenital macrothrombocytopenic disorder. J Am Anim Hosp Assoc 1997;33:411-5.

 

From the Journal of the American Animal Hospital Association

 

Linda E. Smedile, DVM

Doreen M. Houston, DVM, DVSc

Susan M. Taylor, DVM

Klaas Post, DVM, MVSc

Gene P. Searcy, DVM, PhD

 

From the Departments of Veterinary Internal Medicine (Smedile, Houston, Taylor, Post) and Veterinary Pathology (Searcy), Western College of Veterinary Medicine, University of Saskatchewan, 52 Campus Drive, Saskatoon, Saskatchewan S7N 5B4, Canada.

 

Doctor Smedile’s current address is the Broadview Animal Hospital, 34 Ten Rod Road, Rochester, New Hampshire  03867

 

Doctor Houston’s current address is Veterinary Medical Diets, Inc., 67 Watson Road S, Unit 3, Guelph, Ontario N1H 6H8, Canada.

 

Introduction

Idiopathic, asymptomatic thrombocytopenia and enlarged platelets have been reported in Cavalier King Charles spaniels (CKCSs). (1.2)  Eksell reported a 31% incidence of thrombocytopenia (defined as a manual platelet count of less than 100x109/L) in 102 clinically normal CKCSs. (1)   Enlarged platelets were identified in an investigation of 10 clinically normal CKCSs. (2)  Platelet size in this investigation was determined by measuring the diameter of 100 consecutive platelets per dog with an eyepiece graticule using ethylenediaminetetraacetic acid (EDTA)-treated blood smears.l  A bimodal platelet-size distribution was observed , with 44.5% of the platelets being normal size and 30% being twice normal size.  The manula platelet counts (greater than 200x109/L) in these cases were normal, but the automated platelet counts were low; the authors postulated that the enlarged platelets may have resulted in the erroneously low automated platelet counts.  Buccal mucosal bleeding times were measured in two cases and were normal. (2)  The objective of this study was to describe the clinical and clinicopathological features of CKCSs presented to veterinary teaching hospitals with idiopathic, asymptomatic thrombocytopenia.

 

Criteria for Selection of Cases

A 10-year retrospective search of medical records from 29 North American veterinary colleges was conducted using the Veterinary Medical Data Base at Purdue University.  Selection criteria included any CKCS with thrombocytopenia (defined as a platelet count of less than 200x109/L) (3) seen between January 1, 1983 and July 31, 1993.  Specific diagnostic codes included in the search were thrombocytopenia, thrombocytopenia purpura, congenital thrombocytopenia, thrombocytopenia due to infection, thrombocytopenia due to drug, autoimmune thrombocytopenia, and thrombocytopenia due to unknown etiology.  The universities identified by the search were contacted, and copies of the medical records were requested.

 

Results

Eighteen cases of thrombocytopenia in CKCSs were identified.  The medical records for 12 of these 18 cases were obtained and reviewed.  Eleven of the cases were determined to have idiopathic, asymptomatic thrombocytopenia.  The criteria for selection of this diagnosis were that the thrombocytopenia had no identified etiology and there was no evidence of abnormal hemostasis.  The 12th case had been diagnosed with immune-mediated hemolytic anemia (IMHA) and experienced transient thrombocytopenia attributed to disseminated intravascular coagulation (DIC).  This case was not included in the retrospective study.

Details of age, sex, presenting complaint, initial platelet count, quantity of megakaryocytes in the bone marrow, and diagnoses made are summarized in Table 1.  The platelet counts ranged from 34 to 121x109/L (mean platelet count, 68.9x109/L).  Vaccination status was reported to be current in five cases and was unknown in six cases.  None of the cases were known to have been vaccinated within two months of the thrombocytopenia diagnosis.  At initial and subsequent evaluation, 10 of the cases had no history or clinical signs suggestive of a bleeding disorder.  Case no. 9 developed transient petechiation for five weeks after initial presentation (platelet count, less than 10x109/L).  Platelet counts were performed manually in nine cases, with an automated counter used in one case (case no. 8) and an estimation made from a blood smear in one cases (case no. 5).  In all 11 cases, the platelets were described as large or giant, based on subjective assessment of size on microscopic examination of air-dried EDTA whole blood smears.  In the initial complete blood cell counts, other cell lines were normal in all cases except case no. 8, which had a mild, nonregenerative anemia (hematocrit of 29%).  Bone-marrow cytology was performed in five cases, and the results are reported in Table 1.  Various additional diagnostic tests were performed to investigate the presenting complaints as well as to explore the etiology of thrombocytopenia [Table 2].  Abnormal test results are reported in the diagnosis column of Table 1.  All other test results were within normal limits.  No underlying etiology for the thrombocytopenia was identified in any one of the 11 cases.

 

 


 

Table 1

Idiopathic, Asymptomatic Thrombocytopenia in 11 Cavalier King Charles Spaniels

Case No.

Age (yrs)*

Sex

Presenting Complaint

Initial Platelet Count (x109/L)

Bone-Marrow Megakaryocytes

Diagnoses

1

NR

NR

Back Pain

71

Decreased

Lumbosacral pain; idiopathic thrombocytopenia

2

NR

NR

Dental

83

NE

Mitral insufficiency; idiopathic thrombocytopenia

 

3

 

1

F

Vomiting, Diarrhea

69

Normal

Idiopathic thrombocytopenia

4

1.3

M

NR

34

NE

Idiopathic thrombocytopenia

5

2

FS

Chronic vomiting

Decreased

NE

Eosinophilic, lymphocytic gastritis; idiopathic thrombocytopenia

6

2

FS

Lethargy

42

INCREASED

Cardiomegaly; Idiopathic thrombocytopenia

7

2

M

Neck pain, ataxia

54

NE

Degenerative disk disease; Idiopathic thrombocytopenia

8

2

M

Seizures

121

NE

Mild, mononuclear cerebrospinal fluid inflammation; Idiopathic thrombocytopenia

9

4

MC

Back pain, pruritus

110

NORMAL

Pemphigus foliaceous; mitral insufficiency; idiopathic thrombocytopenia

10

8

M

Cough

54

NE

Mitral endocardiosis; congestive heart failure; Idiopathic thrombocytopenia

11

8

MC

Dental

48

INCREASED

Mitral endocardiosis; left atrial and ventricular dilatation; Idiopathic thrombocytopenia

* NR=not reported

F=female; M=male; FS=spayed female; MC=castrated male

Quantity of megakaryocytes in the bone marrow; NE=not evaluated

 

 

 

 

Eight cases were treated with prednisone alone or in combination with other drugs for suspected immune-mediated thrombocytopenia (ITP) [Table 3].  Seven of the treated cases were reevaluated at various times for periods ranging from 10 days to three years.  The platelet counts in six of the cases fluctuated but remained below normal.  Case no. 9 had a normal platelet count (by estimation from a blood smear) three weeks after the addition of weekly gold salt (i.e., aurothioglucose; 1 mg/kg body weight) injections to the dog’s oral prednisone (0.5 mg/kg body weight, once daily) therapy.  Gold salts and prednisone were continued, and the platelet count fell to 105x109/L five months later; 10 months later, it was estimated to be within normal range.  After three months of medical therapy, a splenectomy was performed on case no. 3.  Histopathological examination of the spleen revealed extramedullary hematopoiesis and moderate lymphoid depletion.  The postsplenectomy platelet count increased to 185x109/L, but it decreased to less than 100x109/L one week later and remained low at subsequent rechecks.  Five (case nos. 3, 4, 6, 9, 11) of the treated cases developed mild-to-severe, nonregenerative anemias (hematocrit range, 15% to 35%) during treatment.

 

DISCUSSION           

The 11 cases in this study initially were presented for a variety of clinical problems and had idiopathic, asymptomatic thrombocytopenia with large-to-giant platelets identified during routine laboratory evaluation.  There was no apparent age or sex predilection.  No temporal correlation between vaccination and thrombocytopenia was established.  Four cases had evidence of mitral valvular endocardiosis, a commonly recognized problem in

the CKCS; (4) no correlation between mitral valve endocardiosis and thrombocytopenia has been established.  Five of the cases developed nonregenerative anemias which were assessed to be secondary to immunosuppressive therapy.  Prior to therapy, bone-marrow erythropoiesis was evaluated in four cases and was normal.  Concurrent IMHA was not identified in any of these cases.

 

The etiology of the thrombocytopenia identified in CKCSs is unknown. Thrombocytopenia in dogs can result from platelet sequestration, increased platelet consumption, decreased platelet production, or increased platelet destruction. (5)  Platelet sequestration is relatively uncommon and is considered unlikely in these CKCSs, as non of the dogs had detectable splenomegaly. (5)  Platelet consumption due to DIC

was considered unlikely in the CKCSs evaluated since there was no evidence of severe, progressive, systemic disease.(5)  Only one of the five CKCSs which had bone-marrow analyses performed had megakaryocyte hypoplasia, making decreased platelet production an unlikely mechanism for the thrombocytopenia. (5) 

 


 

Table 2

Additional Diagnostic Tests Performed on 11 Thrombocytopenic Cavalier King Charles Spaniels

Case No.                                             Other Diagnostic Tests

1          Serum biochemistry profile, urinalysis, heartworm antigen test, antinuclear

            antibody (ANA) titer, synovial fluid analysis.

 

2          Serum biochemistry profile, thoracic and abdominal radiographs

 

3          Serum biochemistry profile, urinalysis, serum thyroxine, Ehrlichia canis

(E.  canis) titer, Rickettisia rickettsii titer (for Rocky Mountain spotted

fever [RMSF]), direct antiglobulin test, ANA titer, fibrin degradation

products (FDPs) titer, abdominal radiographs

 

 

4          sonography, heartworm antigen test, E. canis titer, RMSF titer, Borrelia

            burgdorferi titer, FDPs titer, thyroid-stimulating hormone stimulation test,

            Serum biochemistry profile, E. Canis titer, RMSF titer, ANA titer

 

5          Serum biochemistry profile, abdominal radiographs, upper gastrointestinal series,

            ammonia tolerance test, bile acid assay, gastric biopsy

 

6          Serum biochemistry profile, urinalysis, thoracic radiographs, abdominal ultra-

prothrombin time, partial thromboplastin time

 

7          Serum biochemistry profile, urinalysis, E. canis titer, RMSF titer, cervical

            radiographs

 

8          Serum biochemistry profile, E. canis titer, resting ammonia, Toxoplasma

            gondii titer, cerebrospinal fluid analysis

 

9          Serum biochemistry profile, urinalysis, abdominal radiographs, skin biopsy

 

10        Serum biochemistry profile, urinalysis, thoracic radiographs, ANA titer,

            lupus erythmatosus cell preparation

 

11        Serum biochemistry profile, urinalysis, thoracic radiographs, echocardiogram,

            buccal mucosal bleeding time


 

Platelet destruction due to ITP is a common cause of thrombocytopenia in dogs; definite diagnosis of ITP is difficult and frequently is made by exclusion of other conditions. (6)  Immune-mediated thrombocytopenia is suspected when there is a normal-to-increased number of megakaryocytes in the bone marrow and when potential causes of platelet sequestration, consumption, and decreased production have been eliminated systematically. (5)  Several assays have been designed to attempt to detect canine antiplatelet antibody and confirm immune-mediated destruction of platelets, but the low specificity of the available assays makes them of limited use in clinical practice. (7,8) Shortened platelet life span has been documented in many human patients with ITP, but platelet life span is not evaluated routinely in dogs. (9)  Immune-mediated thrombocytopenia  was suspected in several cases in this study when no underlying etiology could be identified and when bone-marrow analyses in four of five cases evaluated revealed normal or increased numbers of megakaryocytes.  Seven of eight CKCSs in this study did not respond to immunosuppressive therapy, however, making a diagnosis of ITP less likely.  The role of gold salt therapy in the resolution of the thrombocytopenia in case no. 9 is not known.  Gold salts are not used routinely in the treatment of ITP, and thrombocytopenia has been reported to develop in dogs receiving long-term (45 to 72 months), high-dose (2.4 to 3.6 mg/kg body weight per day) gold salt therapy. (10)

 

The asymptomatic nature of the thrombocytopenia in the CKCSs in this report suggest adequate platelet function.  Clinical evidence of hemorrhage commonly does not occur until the platelet count is less than 50 x 109/L. (6) Perhaps the larger-than-normal platelets in the dogs with platelet numbers less than 50x109/L had increased functional capacity; platelet function has been speculated to depend more on total platelet mass (i.e., platelet number x platelet volume) than on actual platelet number. (11)  Mucosal bleeding time was evaluated in case no. 11 (platelet count, 48x109/L) and was normal.

 

The large-to-giant platelets subjectively identified in CKCSs have been measured manually in one report and confirmed to be enlarged. (2)  Increases in platelet size can be artifactual or real.  Artifactual changes in platelet size and shape can occur when anticoagulant, temperature, storage time, osmotic conditions, and degree of activation are varied. (12,13)  Platelet size is increased during accelerated thrombopoiesis, as seen during recovery from experimentally induced thrombocytopenia disorders are thought to arise from abnormal megakaryocytopoiesis. (16)

 

A congenital macrothrombocytopenic disorder could explain the thrombocytopenia and the enlarged platelets observed in the CKCSs in this study.  Congenital macrothrombocytopenia has not been reported in dogs, but several rare, congenital macrothrombocytopenic disorders have been described in humans. (16)  Well-recognized disorders include the Bernard-Soulier syndrome, (17) Fechtner syndrome, (18) May-Hegglin anomaly, (19) Montreal platelet syndrome, (20) gray platelet disorder, (21) and Mediterranean macrothrombocytopenia. (22)  Individuals with these syndromes may have prolonged bleeding times and can be asymptomatic (22) or experience mild-to-severe hemorrhagic episodes. (16, 21)  An asymptomatic congenital macrothrombocytopenia also has been reported in the Wistar Furth rat. (23)

 

Conclusion

The recognition of idiopathic, asymptomatic thrombocytopenia in the CKCS is important.  Although the number of cases identified in this study is low, previous reports indicated that the incidence of idiopathic, asymptomatic thrombocytopenia may be as high as 31% in this breed. (1) Determination of the prevalence of the disorder and investigation of the possible mode of inheritance are indicated.  Most affected dogs have remained asymptomatic with no clinical evidence of abnormal hemostasis.  Therapeutic intervention may not be warranted when a case is identified; certainly treatment with immunosuppressive agents has not been effective in most cases.  Further studies, such as investigations of platelet structure, function and life span, and megakaryocyte structure, should help to define the underlying pathophysiology of idiopathic, asymptomatic thrombocytopenia in this breed.

 

Acknowledgments

This study was part of the M.Vet.Sc. degree requirement for Dr. Smedile and was funded by the Companion Animal Health Fund at the Western College of Veterinary Medicine.  The medical records search was performed by the Veterinary Medical Data Base at Purdue University.

 

References

1.     Eksell P. Haggstrom J. Kvart C. Karlsson A. Thrombocytopenia in the

Cavalier King Charles spaniel. J Sm Anim Pract 1994;35:153-5

2.     Brown SJ,Simpson KW, Baker S, et al. Macrothrombocytosis in Cavalier

      King Charles spaniels. Vet Rec 1994;135:281-3

3.   Jain NC. Qualitative and quantitative disorders of platelets. In: Jain NC,

      ed. Schalm’s veterinary hematology.  4th ed. Philadelphia: Lea & Febiger,

      l986:469

4.   Beardow AW, Buchanan JW. Chronic mitral valve disease in Cavalier

      King Charles spaniels: 95 cases (1987-1991). J Am Vet Med Assoc

      l993;203:1023-9

5.   Feldman BF, Thomason KJ, Jain NC. Quantitative platelet disorders. Vet

      Clin N Am Sm Anim Pract 1988;18:35-49.

6.   Mackin A. Canine immune-mediated thrombocytopenia-Part II. Comp

      Cont Ed Vet Pract 1995;17:515-34.

7.   Kristensen AT, Weiss DJ Klausner JS, et al. Comparison of microscopic

      and flow cytometric detection of platelet antibody in dogs suspected of

      having immune-mediated thrombocytopenia.  Am J Vet Res 1994;55-1111-4.

8.   Lewis DC Meyers KM, Callan MB, et al.  Detection of platelet-bound serum

      platelet-bindable antibodies for diagnosis of idiopathic thrombocytopenia

      purpura in dogs. J Am Vet Med Assoc 1995;206:47-52.

9.   Tomer A. Hanson SR, Harker LA. Autologous platelet kinetics in patients

      with severe thrombocytopenia: discrimination between disorders of production

      and destruction. J Lab Clin Med 1991;118:546-54.

10. Bloom JC, Blackmer SA, Bugelski PJ, et al.  Gold-induced immune           

      thrombocytopenia in the dog. Vet Path l985;22:492-9

11. Thompson CB Jakubowski JA.  The pathophysiology and clinical relevance

      of platelet heterogenicity.  Blood 1988;72:1-8

12. Handagama P, Feldman B, Kono C, Farver T. Mean platelet volume artifacts;

      artifacts: the effect of anticoagulants and temperature on canine platelets.

      Vet Clin Path 1986;15:13-7

13. Frojmovic MM, Milton JG. Physical, chemical and functional changes

      following platelet activation in normal and “giant” platelets.  Blood Cells

     1983;9:359-82

14. Tavassoli M. Megakaryocyte-platelet axis and the process of platelet formation

      and release.  Blood 1980;55:537-45

15. Levin J. Bessman JD. The inverse relation between platelet volume and platelet

      number. J Lab Clin Med 1983;101:295-307

16. Jantunen E.  Inherited giant platelet disorders.  Eur J Haematol 1994;53:191-6

17. Berndt MC, Fournier DJ, Castaldi PA.  Bernard-Soulier syndrome.  Baillier’s

      Clin Haemat 1989;2:585-607

18. Peterson LC, Rao KV, Crosson JT, White JG.  Fechtner syndrome-a variant of

      Alport’s syndrome with leukocyte inclusions and macrothrombocytopenia. 

      Blood 1985;65:397-406.

19. Hamilton RW, Shaikh BS, Ottie JN, et al.  Platelet function, ultrastructure,

      and survival in the May-Hegglin anomaly.  Am J Clin Path 1980;74:663-8

20. Milton JG, Frojmovic MM, Tang SS, White JG.  Spontaneous platelet

      aggregation in a hereditary giant platelet syndrome (MPS). AM J Path

      1984;114:336-45

21. White JG.  Structural defects in inherited and giant platelet disorders.  In: Harris

H.    Harschhorn K, eds. Advances in human genetics. Vol. 29. New York: Plenum

Press, 1990:1330234.

22. White JG, Sauk JJ.  The organization of microtubules and microtubule coils in

      giant platelet discorders. Am J Path 1984;116:514-22.

23. Jackson CW, Hutson NK, Steward SA, et al.  The Wistar Furth rate: an animal

      model of hereditary macrothrombocytopenia.  Blood 1988;7l:1676-86.


 

 

Table 3

 

Treatment, Outcome, and Documented Duration of Thrombocytopenia in 11

Cavalier King Charles Spaniels with Idiopathic, Asymptomatic Thrombocytopenia

 

Case No.

Treatment

Outcome

Documented Duration of Thrombocytopenia

 1

Prednisone; vincristine

Persistent thrombocytopenia

2 years

 2

None

Persistent thrombocytopenia

1.5 years

 3

Prednisone; dexamethasone; azathioprine; cyclophosphamide; danazol; tetracycline; splenectomy

Persistent thrombocytopenia; euthanized because of persistent lethargy

8 months

 4

Prednisone; azathioprine; doxycycline; thyroxine

Persistent thrombocytopenia

2 months

 5

None

Not applicable

One exam only

 6

Prednisone; azathioprine; cyclophosphamide; danazol; tetracycline; vincristine-loaded platelets

Persistent thrombocytopenia

3 years

 7

Prednisone; tetracycline

Not applicable

One exam only

 8

None

Not applicable

One exam only

 9

Prednisone; azathioprine; danazol; vincristine; tetracycline; gold salts

Thrombocytopenia resolved while on gold salts

3 years

10

Prednisone

Persistent thrombocytopenia; died of congestive heart failure (CHF)

10 days

11

Prednisone; azathioprine

Persistent thrombocytopenia; euthanized because of CHF

17 months

 

           

 

LOW PLATELETS

 

My understanding, from material available to me and from personal

experience, is as follows: A low platelet count is referred to as

Thrombocytopenia. Thrombocytes (or platelets) are a type of blood cell

that is essential in forming a blood clot. Thrombocytopenia is different

from Anemia in that anemia is a reduced level of red blood cells below

the norm of 37%-52%. Thrombocytopenia can occur in as much as 31% of

cavaliers according to a study conducted (on cavaliers) by Drs. Houston,

Searcy, Smedile, Taylor and Post (Canada) as well as a study conducted

by Drs.

Eksell, Haggstom, Kvart and Karlsson (Sweden) . This condition is not

considered a "normal thing", but rather those who do have this condition

may still function normally - meaning showing no signs of bleeding

disorders. My question would be "for how long". This disorder is called

Idiopathic, Asymptomatic Thrombocytopenia. To break down this name -

Idiopathic means an obscure or unknown cause. Asymptomatic means showing

no signs of disease. Thrombocytopenia (explained above).

 

A low platelet count brings forward many considerations. The count

should be conducted using a manual counting method - not automated

because of the possibility of the platelets being larger than the normal

size callibrated for the machine. The considered normal range is between

175,000 - 500,000. Thrombocytopenia can be a result of a bone marrow

failure, genetic deficiency, autoimmune/immune-mediated disorders, drug,

vaccine or poison

toxicity, infections, bacterial/viral diseases or any stressful

condition which would tax the immune system, eg. abnormal pregnancy.

Severe Thrombocytopenia can lead to, or be in association with, other

disorders such as: IMHA (Immune-mediated Hemolytic Anemia, DIC

(Disseminated Intravascular Coagulation), Renal Failure, Respiratory

Arrest, Seizures.

 

The studies have failed to show any association between heart murmurs

and low platelet counts, although they both admit that more studies are

needed before such a connection can be excluded. The Canadian study

concluded by stating: "Further studies, such as investigations of

platelet structure, function and life span, and megakaryocyte structure,

should help to define

the underlying pathophysiology of idiopathic, asymptomatic

thrombocytopenia in this breed." The Swedish study concluded by stating:

"The clinical significance and pathogenesis of thrombocytopenia in the

Cavalier King Charles Spaniel is not yet understood."

 

 

THROMBOCYTOPENIA IN THE Cavalier King Charles Spaniel

P. Eksell. J. Haggstrom, C. Kvart and A. Karlesont

 

Departments of Radiology. Physiology and Clinical Chemistry, Swedish University of Agricultural Sciences, Box 7045, Uppsala, Sweden

 

Journal of Small Animal Practice (1994) 35.153.155

 

ABSTRACT

 

Blood samples were collected for the determination of platelet counts from 102 cavaliers which had no history of bleeding disorders.  Thrombocytopenia was found in 3l% of the samples when the lower reference limit was set at 100 x 10/litre.  The platelet count of the males (mean SD. 147 x 10/litre - 15 x 10/litre) was found to be significantly (P<0.05) lower than that of the females (mean SD. 202 x 10/litre - 13 x 10/litre)  The platelet counts from a reference group of 16 normal beagles, analyzed identically, were not lower than 189 x 10/litre and no significant difference was found between males (mean SD. 249 x 10/litre - 14 . 10/litre) and females (mean SD. 282 x 10/litre).

 

INTRODUCTION

 

Platelets are essential for haemostasis and the maintenance of vascular integrity (Johnson 1971).  In patients with bleeding disorders it is therefore necessary to examine the platelets for abnormalities in number and, or, function (Feldman and others 1988) and a platelet count is often included in a haematological screen.

 

During routine blood controls of clinically normal Cavaliers at the Veterinary College in Uppsala, Sweden, Thrombocytopenia was frequently found.  The present investigation was undertaken to determine the prevalence of Thrombocytopenia in Swedish cavaliers.

 

MATERIALS AND METHODS

 

Forty-four male and 58 female unselected cavaliers (mean age, 6.6 years {SD 2—7 years}) with no history of bleeding disorders were subjected to clinical examination.  Including auscultation of the heart and venous blood sampling.  The case history of each dog and the existence of cardiac murmurs and their grade (grade 1-6).  Character and site were recorded together with the age and sex.

 

Blood samples were collected by venepuncture of a cephalic vein using 1.25 x 38 mm needles 1 inch x 18 gauge  into 5 ml Vacutainer tubes coated with silicon and prepared with potassium-EDTA (Becton Dickinson).  Twenty microlitres of blood were mixed with 380 ul Stromatol stromatolytic agent (Semmelweis), in a 2 ml plastic Ellerman tube, 30 to 200 minutes after venepuncture, in order to fix the platelets.

 

The platelet count was determined manually using a Burker counting chamber and a light microscope.  All the samples were evaluated by the same technician within 6 hours but not earlier than 15 minutes of fixation.

 

The platelets from  a reference group of 7 male and 9 female beagles with a mean age of 3 years (SD=1.3) were also examined by the same method.

 

Validation of platelet quantification

 

Blood samples from 40 of the cavaliers were analyzed both by the described method and by an automated cell counting system (Sysmex F-800:  Toa Medical Electronics, Kobe, Japan).  A satisfactory 95 per cent limit of confidence (85 to 180 per cent) between automated and manual platelet counting was found among dogs with a platelet count greater than 100 x 10/litre.  However, in samples with low platelet counts the automated cell counting system failed to separate the large platelets from small erythrocytes and hence yielded an erroneously low platelet count.  The manual platelet counting procedure was therefore the method of choice, as recommended by Jain (1988).

 

Thrombocytopenia and reference values

 

Thrombocytopenia may be defined as any platelet count less than the normal reference range of 200 to 500 x 10/litre (Jain 1986, Feldman and others 1988).  In this laboratory the reference range has been set at 150 to 400 x 10/litre but, in order to define more rigorously those dogs with Thrombocytopenia in this study, the lower reference limit was set at 100 x 10/litre as recommended by Dodds (1988).

 

Statistical methods

 

All statistical calculations were performed on the 1989 SAS statistical program (JMP 2.0.2.).  Statistical analyses included one-way ANOVA and linear regression.  In cases where parametric tests were not applicable, the Wilcoxon rank sum test and rank correlation test were used.  The minimum level of significance was chosen as P<0.05.  Data are presented as means with standard deviation.

 

RESULTS

 

None of the cavaliers in this study had, according to their owners, shown any clinical signs of a bleeding disorder.  The dogs were all found to be free of any signs of systemic disease, except that a cardiac murmur was detected in 52 of the 102 subjects.  The clinical histories of these cases revealed that only tow of the dogs had received medication;  one dog captopril and one dog a combination of frusomide and digoxin.

 

The mean platelet count for all 102 cavaliers was 178 x 10/litre - 104 x 10/litre.  32 of these dogs had a platelet count less than 100 x 10/litre giving the prevalence of Thrombocytopenia as 31%.  Four dogs ( 4%) had a platelet count less than 50 x 10/litre.  The mean platelet count of the males (147 x 10/litre - 15 x 10/litre) was significantly lower (P<0.05) than that of the females (202 x 10/litres - 13 x 10/litre).  Circulating megathrombocytes were occasionally found in the Thrombocytopenia animals.

 

No difference was found in platelet counts between cavaliers with a detected cardiac murmur and those subjects free from a murmur.  No association was found between either weight or age of the animal and the platelet count.

 

DISCUSSION

 

Thrombocytopenia in the dog has been reported to be associated with many clinical disorders such as bone marrow failure, immune-mediated disorders, drug toxicity, infections and consumptive coagulopathies (Davenport and others 1982).  The high prevalence of Thrombocytopenia among unselected dogs of this breed which were free from any history or clinical signs of a bleeding disorder makes diagnoses such as bone marrow failure, infections, and acute consumptive coagulopathies less conceivable.  Autoimmune Thrombocytopenia cannot be excluded because the presence of antiplatelet antibodies was not investigated in this study.  As only two of the dogs received medical therapy, drug toxicity can be excluded as a causal factor of the low platelet counts.

 

Spontaneous bleeding due to Thrombocytopenia does not usually occur until the platelet count falls below 30 to 50 x 10/litres (Dodds 1988).  Some of the dogs n this study had platelet counts as low as 35 to 50 x 10/litres .  But none had any history or clinical signs of bleeding disorders.  A low platelet count does not necessarily lead to an haemostatic disorder as all processes engaged in haemostasis involving platelets must be taken into account.  In cases of platelet anisocytosis with many young, large and normally granulated megathrombocytes, clinical signs may be absent despite Thrombocytopenia.  This can be explained by the greater metabolic activity of the megathrombocytes (Karpatkin and others 1978).  The presence of megathrombocytes in the blood from some of the present cases might account for the lack of clinical signs.  Megathrombocytes may also be indicative of regenerative platelet disorders ( Corash 1983).

 

Cavaliers have a marked tendency to develop valvular incompetence due to chronic valvular disease at a young age (Darke 1987, Haggstrom and others 1982).  The findings of a high prevalence of cardiac disease and Thrombocytopenia within this breed is interesting, as platelet action is well known to be essential in the pathogenesis for atherosclerosis and thrombosis in humans.  Pathological changes in the vascular wall have been reported to induce an increased consumption of platelets (Davenport and others 1982).  Chronic valvular disease and canine small vessel diseases have been compared to human atherosclerosis and arteriosclerosis (Schneider and others 1973, Schole and others 1982).  But there is no report showing that the conditions should be related to each other.  This investigation failed to show any association between heart murmurs and low platelet counts although more studies are needed before such a connection can be excluded.  The clinical significance and pathogenesis of Thrombocytopenia in the cavalier is not yet understood.

 

ACKNOWLEDGEMENTS

 

This study was supported by Agria Insurance and the Thure F. and Karin Forsbergs Fund.  The authors wish to thank Professor B. Jones and Professor K. Olsson for valuable advice and Professor P. Lord for assistance with the translation.

 

 

Low Platelet Counts in Cavaliers

by Bet Hargreaves

 

After reading Mr. Doyles’ letter in the winter edition of the Bulletin, I wondered whether the following comment would be of interest to some Cavalier owners who may not know of this condition affecting our breed.  In Sweden recently after research work centered out there, it was reported that 3l% of Cavaliers have Thrombocytopenia, a low platelet count.  Since Cavaliers would originate from the same basic stock, presumably Cavaliers in Britain and America will have the same condition.  Whether this has any bearing on the low platelet count in Cavaliers, but after the giving of the live parvo vaccination the platelet drops on the 3rd day, and then again around a month later.  I have pedigrees of Cavaliers already suffering from heart trouble and some did seem to have had an adverse reaction to their booster vaccination about a month later when their heart condition had deteriorated and they died shortly afterwards.

 

Yet other Cavaliers also with a heart condition, had their yearly boosters and lived on to a normal old age.  Could it be possible that the Cavaliers who seemed to have had an adverse reaction to their vaccinations from both Thrombocytopenia and a heart condition, and when the platelet count dropped because of the parvo vaccination something was happening to their heart problem?  A few vets here in Britain are now paying heed to Cavaliers with heart trouble and taking note of any who seem to be having an adverse reaction to their heart condition around a month after their booster.  It has now been published in a thesis in Sweden after 8 years research work carried out there on heart trouble in Cavaliers that the expression of C.U.D. is the result of summation of genetic and environmental factors, and is this all the more reason why Cavaliers who have lived to a normal old age show that they have been able to withstand whatever genetic and environmental factors are causing the heart trouble in our breed today, and it’s their offspring who could be of benefit to today’s Cavaliers breeding programmers.

            Boat Road, Thankerton, Biggar ML126NU, Scotland

 

 

PLATELET COUNTS IN CAVALIER KING CHARLES SPANIELS

 

Recent studies in Sweden, The United Kingdom and North America have established that many healthy Cavaliers have low circulating platelet counts, especially when measured with automated cell counters.  Manual counting usually reveals a higher number of platelets of relatively large size (megathrombocytes).  In the Swedish study, 102 healthy Cavaliers had mean platelet counts of 178,000/ul.  However, 32 (31%) of them had platelet counts below 100,000/ul and 4 dogs had counts between 30,000-50,000/ul.  The mean count for male dogs was significantly lower (147,000/ul) than that of females (202,000/ul).

 

In North America, many dogs of this breed are found to have thrombocytopenia during routine health profiling prior to elective procedures or at annual checkups.  Typical platelet counts range from 20,000-80,000/ul with some counts as low as 5,000/ul in clinically normal dogs.  This situation becomes complicated, however, when the dog has some illness and thrombocytopenia is noted, or in the case of immune-mediated thrombocytopenia which also occurs in this breed.  Dogs with thyroid disease, commonly seen in Cavaliers, can show a greater incidence of thrombocytopenia.  Whether the chronic cardiac valvular disease prevalent at a young age in this breed could be a contributing factor is unknown, although no association has been found between the presence of cardiac murmurs and low platelet counts.  Preliminary evaluation of bone marrow megakaryoctyes of severely thrombocytopenic, healthy dogs has shown no structural abnormalities but functional studies have yet to be performed.  Pedigree analysis revealed that the thrombocytopenic tendency can be transmitted to subsequent generations.

 

The clinical importance of these findings warrants comment.  Cavaliers that have thrombocytopenia as an incidental laboratory finding should have platelet counts rechecked by manual methods, and do not need treatment to attempt normalization of platelet numbers.  A complete health profile including thyroid function is advised to identify any concurrent abnormality that may need attention.

[Eksell, Pet al, J Sm Anim Pract 35:153-155, 1994; Dodds, WJ, unpubl. Observ.]

 

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