Blood Platelets and the Cavalier King Charles Spaniel

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Blood Platelets in Cavaliers:

Too Few (Thrombocytopenia) and

Too Large (Macrothrombocytopenia)

CavalierHealth.org Copyright © 2004 Blenheim Company As many as half of all Cavalier King Charles spaniels may have a congenital blood disorder called idiopathic asymptomatic thrombocytopenia, an abnormally low number of blood platelets, according to recent studies in Denmark and the United States. Blood platelets (also called thrombocytes) are disk-shaped blood elements which aid in blood clotting. Excessively low numbers are the most common cause of bleeding disorders in dogs.

The platelets in the blood of many Cavalier King Charles spaniels are a combination of those of normal size for dogs and others that are abnormally oversized. Cavaliers' oversized platelets are called macrothrombocytes. Macrothrombocytosis also is a congenital abnormality found in at least a third of CKCSs.

These large platelets function normally, and the typical Cavalier does not appear to experience any health problems due to either the size or fewer numbers of its platelets. There are, however, exceptions to this typical situation.

Research Studies' Findings

It has been shown in studies of humans that mitral valve regurgitation can cause a reduction in the quantity of platelets, as well as increase their size, and alter their aggregation. In a 2003 Danish study, researchers found that CKCSs with mild, moderate, and severe mitral valve regurgitation have decreased platelet function. So, mitral valve disease may be the underlying cause of both thrombocytopenia and macrothrombocytopenia in the Cavalier King Charles spaniel.

In the 2004 US study, led by Drs. Sara M. Cowan and Rebecca Gompf of the University of Tennessee, thrombocytopenia was present in 51.43% of the 69 CKCSs in the study, and macrothrombocytes were present in one third of the Cavaliers. Co-incidentally, 38% of the dogs in the US study had cardiac murmurs. The American researchers found platelet ultrastructure to be normal. They have identified the disorder as Benign Inherited Giant Platelet Disorder (IGPD).

The 2002 Danish study report (Drs. Henrik D. Pedersen, Jens Häggström, Lisbeth H. Olsen, and others) concluded that Cavaliers' oversized platelets could lead to erroneous diagnoses of thrombocytopenia when automated blood counters are used. An erroneous diagnosis of low platelet counts could result in unnecessary diagnostic tests for the Cavaliers.

A 2005 Australian study (Drs. M. K. Singh and W. A. Lamb) of 152 Cavalier King Charles spaniels, all from New South Wales, found that the platelet count of the Cavaliers, as a group, was only 32% that of the mixed breed control dogs, and that 30% of the CKCS in the study had macrothrombocytes. The Australian researchers concluded that the data supported an autosomal recessive inheritance pattern.

In a 2007 Italian study (Drs. W. Bertazzolo, S. Comazzi, L. Sesso, P. Scarpa, G. Ru, and S. Paltrinieri), the researchers compared platelet counts, platelet estimations and platelet parameters in 41 Cavaliers measured by different methods -- impedance cell counter, laser cell counter and microscopic estimation -- commonly used in veterinary hospitals and commercial laboratories. Quantitative buffy coat analysis was performed on 17 of the samples, selected from Cavaliers which had low platelet counts detected by the cell counters.CKCSs with macrothrombocytes had significantly lower counts on impedance cell counter (34.1% dogs below normal -- < 1003×109/l), laser cell counter (26.8%) and microscopic estimation (22.0%). The quantitative buffy coat analyser result was only 5.8% below normal.

In a 2008 study at Auburn University (Drs. B. Davis, M. Toivio-Kinnucan, S. Schuller, M.K. Boudreaux) determined that "a mutation in the gene encoding β1-tubulin correlated with macrothrombocytopenia in CKCS." They concluded that "this information will aid in distinguishing inherited from acquired thrombocytopenia. It also provides insight into the mechanism of platelet production by megakaryocytes, and also may prove useful in understanding heart-related changes in macrothrombocytopenic CKCS with concurrent mitral valve regurgitation."

Platelet Counting Procedures

Most commercial laboratories use an automated counting system for blood cells, which determine cell types on the basis of their size and volume. Because Cavaliers' platelets are so large, automated blood cell counters may not recognize platelets as being platelets and undercount them, thereby inaccurately lowering the platelet count. In a 2004 Danish study and the 2007 Italian study, the researchers found that all of their CKCS platelet counts using three different automated systems underestimated the actual counts determined manually. Antech Diagnostics, the largest veterinary diagnostic laboratory, specifically states on its website that "Platelets in this breed should be counted manually, because automated blood cell counters cannot distinguish the large platelets from erythrocytes and therefore underestimate the true platelet count."

An accurate platelet count can be obtained by visually counting the cells. Also, because the large platelets are so fragile, any blood samples should be extracted very carefully. Therefore, all blood samples from Cavaliers should be taken in a very careful manner and preferably only from the dog's jugular vein, using a large bore needle, and then should be examined only under a microscope by an experienced clinical pathologist before making a diagnosis of low platelet count. The 2004 US study report recommends that the blood be anticoagulated with ethylenediamine-tetraacetic acid (EDTA) and citrate.

Treatment

The typical CKCS does not appear to experience any health problems due to either the size or fewer numbers of its platelets. There are, however, exceptions to this typical situation. No treatment is recommended unless the dog shows other symptoms of a blood-related disorder, such as petechia, which are small red or purple spots on the dog, caused by broken capillary blood vessels.

Related Link: Mitral Valve Disease

Current Research:

4Dr. Inge Tarnow, at the University of Copenhagen's Department of Animal and Veterinary Basic Sciences, heads a group of specialists studying pathophysiological aspects of early mitral valve diseases in Cavaliers, including changes in platelet function, hemostatic changes, and prognostic factors. They currently are performing a large longitudinal study of 100 Cavaliers with examinations (echocardiographic and blood tests) at ages 2, 4, and 8 years.

Veterinary Resources:

Macrothrombocytosis in cavalier King Charles spaniels. Brown SJ, Simpson KW, Baker S, Spagnoletti MA, Elwood CM. Vet Rec. 1994 Sep 17;135(12):281-3.

Thrombocytopenia in the Cavalier King Charles Spaniel, Eskell P, Häggström J, Kvart C, Karlsson A. J Small Anim Pract 1994; 35:153-155.

Idiopathic, asymptomatic thrombocytopenia in Cavalier King Charles spaniels: 11 cases (1983-1993), Smedile LE, Houston DM, Taylor SM, Post K, Searcy GP. J Am Anim Hosp Assoc. 1997 Sep-Oct;33(5):411-5.

Macrothrombocytosis in a Cavalier King Charles Spaniel. Kraus MS. Veterinary Forum, May, 1997.

Platelet Counts in Cavalier King Charles Spaniels; Antech Diagnostics News, July 1998.

Control of Canine Genetic Diseases, Padgett, G. A., Howell Book House 1998, pp. 198-199, 223.

Increased platelet aggregation response in Cavalier King Charles spaniels with mitral valve prolapse, Olsen,L.H., Kristensen, A. T., Häggström, J., Jensen, A. L., Klitgaard, B., Hansson, H., Pedersen, H. D. J. Vet. Internal Med. 2001;15:209-216. Quote: "In Cavalier King Charles Spaniels (CKCS), a breed predisposed to myxomatous mitral valve disease, there is a high prevalence of hypomagnesemia and platelet anomalies, such as thrombocytopenia and macrothrombocytosis. The objective of this study was to evaluate platelet aggregation responses in CKCS and to determine the relationship between the platelet aggregation response and serum magnesium concentration, MVP, mitral regurgitation (MR), and platelet count. ... In conclusion, CKCS with MVP appeared to separate into 2 groups—1 group with <100,000 platelets/μL, normal platelet aggregation, low serum magnesium concentration, and enlarged platelets, and another group with >100,000 platelets/μL, increased platelet aggregation, and normal serum magnesium concentration and platelet size."

Idiopathic asymptomatic thrombocytopenia in Cavalier King Charles Spaniels is an autosomal recessive trait. Pedersen HD, Häggström J, Olsen LH, Christensen K, Selin A, Burmeister ML, Larsen H. J Vet Intern Med 2002;16(2):169-73.

Quantitative, functional, and morphologic characterization of platelets in the Cavalier King Charles spaniel. Cowan SM, Carroll RC, Gerard D, Bartges JW, et al. J Vet Intern Med 2002;16:349.

Duncan & Prasse’s Veterinary Laboratory Medicine: Clinical Pathology. 4th ed. Latimer KS, Mahaffey EA, Prasse KW (eds). Iowa State Press, 2003, pp. 101-102, 114-116.

Decreased Platelet Function in Cavalier King Charles Spaniels with Mitral Valve Regurgitation, Tarnow I., Kristensen A. T., Texel H., Olsen L. H., Pedersen H. D.; Vol. 17, No. 5, pp. 680–686. J Vet Intern Med. 2003;17(5):680-686. Quote: "With aggregometry, increased platelet activity has been reported in Cavalier King Charles Spaniels (CKCS) without mitral regurgitation (MR). In contrast, dogs with MR have been found to have decreased platelet activity. The purpose of this study was to test an easy bedside test of platelet function (the Platelet Function Analyzer [PFA-100®]) to see if it could detect an increase in platelet activity in CKCS without MR and a decrease in platelet activity in CKCS with MR. ... CKCS with mild, moderate, and severe, clinically inapparent MR have decreased platelet function. The previous finding of increased platelet reactivity in nonthrombocytopenic CKCS without MR could not be reproduced with the PFA-100 device."

Platelet Counts in Cavalier King Charles Spaniels; Antech Diagnostics News Lab Tips, Oct 2003.

Guide to Congenital and Heritable Disorders in Dogs, Dodds WJ, Hall S, Inks K, A.V.A.R., Jan 2004, Section II(311a).

Breed Predispositions to Disease in Dogs & Cats, Alex Gough, Alison Thomas. 2004; Blackwell Publ. 44-45.

Comparison of manual and automated methods for determining platelet counts in dogs with macrothrombocytopenia, Olsen LH, Kristensen AT, Qvortrup K, Pedersen HD; J Vet Diagn Invest, March 2004; 16:167-170. Quote: "Platelet counts were performed in 43 Cavalier King Charles Spaniels (CKCS, a breed predisposed to macrothrombocytopenia) and in 10 control dogs using 3 automated systems and 3 manual methods (erythrocyte-lysing agents + counting chamber or evaluation of blood smear). Good correlations were found between platelet counts using all methods (all P < 0.0001; R2 = 0.71-0.85). Best correlations were found between the manual methods. Significantly larger platelets were found in CKCS with platelet count < or = 100,000/microl when compared with control dogs and CKCS with platelet count > 100,000/microl (both P < 0.0001). All platelet counts--except when made with the 2 counting chamber methods--were underestimated at platelet counts < or = 100,000/microl."

Giant platelet disorder in the Cavalier King Charles Spaniel, Cowan SM, Bartges JW, Gompf RE, et al.; Exp Hem, April 2004; 32:344-350. Quote: "A benign inherited giant platelet disorder affects approximately 50% of Cavalier King Charles Spaniels. It is characterized by thrombocytopenia, macrothrombocytes, or decreased platelet aggregation in response to ADP. Platelet ultrastructure is normal. Citrated or EDTA blood provides accurate platelet counts. Further studies are indicated to determine platelet glycoprotein structure and any association with mitral endocardiosis. Cavaliers may be useful models of inherited giant platelet disorders."

Assessment of changes in hemostatic markers in Cavalier King Charles Spaniels with myxomatous mitral valve disease. Tarnow I, Kristensen AT, Olsen LH, Pedersen HD. Am J Vet Res. 2004 Dec;65(12):1644-52. Quote: "Objective - To evaluate markers of haemostasis and their relationship to the degree of mitral regurgitation (MR) and platelet function in Cavalier King Charles Spaniels (CKCSs) with myxomatous mitral valve disease. ... Conclusions and Clinical Relevance - In CKCSs, MR appeared to be associated with a low plasma vWF concentration and likely a loss of vWF HMWMs (possibly through their destruction via shear stress to the blood). The importance of the changes in plasma fibrinogen concentration and the thromboembolic risk in dogs with MR remain to be investigated."

Biomarkers of Platelet Activation in Cavalier King Charles Spaniels. D.F. Hogan, D.J. Weiss, C.A. Thompson, M.P. Ward. J Vet Intern Med; May/June 2005;19(3) (ACVIM 23rd Ann. Vet. Med. Forum Abstract Program: Abstract 175).

Platelets in Cavalier King Charles Spaniels; Antech Diagnostics News Lab Tips, June 2005.

Dogs with Heart Diseases Causing Turbulent High-Velocity Blood Flow Have Changes in Platelet Function and von Willebrand Factor Multimer Distribution, Tarnow I., Kristensen A. T., Olsen L. H., Falk T., Haubro L., Pedersen L. G., Pedersen H. G.; J Vet Intern Med. 2005 Jul;19(4):515-521.

Idiopathic thrombocytopenia in Cavalier King Charles Spaniels. Singh M. K., Lamb W. A. Aust Vet J. 2005 Nov;83(11):700-3.

Macrothrombocytopenia in the Cavalier King Charles Spaniel. Meg Carriere, DVM; Kenneth S. Latimer, DVM, PhD; Bruce E. LeRoy, DVM, PhD; Heather L. Tarpley, DVM. College of Veterinary Medicine, Univ. of Georgia. 2006. www.vet.uga.edu/vpp/clerk/carriere/index.php

Platelet function in dogs: breed differences and effect of acetylsalicylic acid administration. Nielsen LA, Zois NE, Pedersen HD, Olsen LH, Tarnow I. Vet Clin Pathol. 2007 Sep;36(3):267-73. Quote: "The objective of this study was to investigate platelet function in clinically healthy dogs of 4 different breeds by whole-blood aggregometry and with a point-of-care platelet function analyzer (PFA-100), and to evaluate the effect of acetylsalicylic acid (ASA) administration on the results from both methods. Forty-five clinically healthy dogs (12 Cavalier King Charles Spaniels [CKCS], ...) were included in the study. ... A higher platelet aggregation response was found in CKCS compared to the other breeds. ... Platelet function is influenced by breed, depending upon the methodology applied. However, the importance of these breed differences remains to be investigated."

Comparison of methods for determining platelet numbers and volume in cavalier King Charles spaniels. W. Bertazzolo, S. Comazzi, L. Sesso, P. Scarpa, G. Ru, S. Paltrinieri. J Small Animal Practice, Oct 2007;48(10):556-561. Quote: "CKCS with macrothrombocytosis have low platelet counts on impedance cell counters, laser cell counters and microscopic estimation. CKCS with low platelet counts may have a normal platelet crit detected by a quantitative buffy coat analyser and thus a normal circulating platelet mass."

Mutation in β1-Tubulin Correlates with Macrothrombocytopenia in Cavalier King Charles Spaniels. B. Davis, M. Toivio-Kinnucan, S. Schuller, M.K. Boudreaux. J.Vet.Int.Med. May-June 2008;22(3): 540-545. Quote: "Background: Cavalier King Charles Spaniels (CKCS) have a high prevalence of inherited macrothrombocytopenia. The purpose of this study was to determine if a mutation in β1-tubulin correlated with presumptive inherited macrothrombocytopenia. Hypothesis: A mutation in β1-tubulin results in synthesis of an altered β1-tubulin monomer. α-β tubulin dimers within microtubule protofilaments are unstable, resulting in altered megakaryocyte proplatelet formation. ... Methods: DNA was used in polymerase chain reaction (PCR) assays to evaluate β1-tubulin. Platelet numbers and mean platelet volume (MPV) were evaluated for a correlation with the presence or absence of a mutation identified in β1-tubulin. Platelets obtained from homozygous, heterozygous, and clear CKCS were further evaluated using electron microscopy and immunofluorescence. Results: A mutation in the gene encoding β1-tubulin correlated with macrothrombocytopenia in CKCS. Electron microscopy and immunofluorescence studies suggest that platelet microtubules are present but most likely are unstable and decreased in number. Conclusions and Clinical Importance: The macrothrombocytopenia of CKCS correlated with a mutation in β1-tubulin. α–β tubulin dimers within protofilaments most likely are unstable, leading to altered proplatelet formation by megakaryocytes. This information will aid in distinguishing inherited from acquired thrombocytopenia. It also provides insight into the mechanism of platelet production by megakaryocytes, and also may prove useful in understanding heart-related changes in macrothrombocytopenic CKCS with concurrent mitral valve regurgitation."

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