Source: Problems in Veterinary Medicine - Vol. 4, No. 4, December 1992, TRANSFUSION MEDICINE pp. 636-646.
Von Willebrand’s disease (vWD) is the most common canine inherited bleeding disorder.1-3 It comprises a group of bleeding diseases; variations exist in genetic transmission, clinical severity, and diagnostic laboratory findings. Differences in underlying pathogenetic mechanisms cause this variable expression in affected breeds of dog. In addition to breed-specific variants of inherited vWD, there are apparent “acquired” forms of vWD in many breeds of dog.3,4,7,8 Because of the clinical variability of canine vWD, treatment must be tailored to meet each affected dog’s specific needs.
The common feature in all forms of vWD is reduction in the amount of functional von Willebrand’s factor (vWF), a large plasma glycoprotein 1,2,9,10 that is produced in endothelial cells and has a critical role in supporting platelet adhesion to sites of small vessel injury. The net result of interactions between damaged endothelium, platelets, and vWF is localized formation of a platelet plug. These interactions are called the primary phase of hemostasis. In larger vessels, activation of the clotting cascade results in formation of more permanent fibrin clots around the framework of platelet plugs. Interactions of the primary phase of hemostasis are distinct from enzymatic reactions of the clotting cascade, and vWF does not participate as a factor or cofactor in the coagulation cascade.10,11
In plasma, vWF molecules are bound together in series like links in a chain. The length of these chains, known as multimers, is variable. It appears that the longest chains, consisting of the largest multimers, are most active in supporting platelet adhesion. 10,11
Abnormal hemostasis in dogs with vWD results from quantitative and qualitative defects of vWF protein.1,2 The most severe hemostatic defect is seen in dogs having no detectable plasma vWF or having reduced concentrations of structurally abnormal vWF. Milder forms of vWD occur in dogs having reduced concentrations of a structurally normal protein.1-6
DIAGNOSIS OF VON WILLEBRAND’S DISEASE
In Vivo Tests
Bleeding time tests are in vivo measures of primary hemostasis and are useful screening tests for the identification of dogs with vWD.12-14 However, abnormal bleeding time is not specific for vWD. Thrombocytopenia, inherited thrombopathies, acquired platelet dysfunction, hemophilia, and anemia are causes of long bleeding times reported in human beings.15,16 Two relatively simple techniques have been described for measuring bleeding time in dogs: cuticle bleeding time (CBT) and buccal mucosa bleeding time (BMBT).12,13,17 These tests are performed by producing a standard wound; incising the toenail cuticle or buccal mucosa of upper lip; and recording the time from incision until cessation of blood flow from the wound. Cuticle bleeding time is sensitive to deficiencies of coagulation factors and defects of primary hemostasis.17 Buccal mucosa bleeding time appears to be more specific for primary hemostatic defects.12 Normal CBT for dogs is approximately 4-6 minutes, and normal BMBT is approximately 2-4 minutes.12-14,17 Dogs with severe cases of vWD have marked prolongation of bleeding time (more than 20 minutes) and steady bleeding from incised wounds. Dogs with less severe cases have bleeding times that are variably prolonged beyond normal range, with finite end points.12,14 Bleeding times should be considered rough estimates of in vivo hemostasis in patients with vWD. Clinical severity of bleeding, especially after surgical procedure or trauma, is dependent on vWF function and other factors, such as the anatomic site, type of insult, and amount of tissue injured.
In Vitro Tests
Definitive diagnosis of canine vWD requires specific measurement of canine vWF protein. 1-3 Routine hemostatic screening tests, such as platelet count, coagulation assays (activated clotting time, activated partial thromboplastin time, prothrombin time, thrombin time, and fibrinogen concentration) and titers of fibrin split products are not sensitive to deficiencies or dysfunction of vWF.1 Although vWF circulates in plasma bound to coagulation Factor VIII, measurements of Factor VIII are neither specific nor sensitive enough to substitute for direct measurement of vWF.3,9,10
Canine vWF is antigenically, functionally, and structurally distinct from human vWF.18-22 Samples should be submitted to laboratories that have specifically validated canine vWF assays. Sample quality is critical for accurate measurement of vWF. Plasma samples for routine vWF assays should be prepared from blood collected in citrate or ethylenediamin-etetraacetic acid (EDTA) anticoagulant. Serum samples and plasma containing clots or severe hemolysis are invalid for measurement of canine vWF.3,23
The von Willebrand factor antigen (vWF:Ag ) assay is routinely performed as a quantitative measure of canine vWF.18-19 Antibodies directed against antigens present on canine vWF protein are used to determine concentration of vWF in a sample. Concentration is reported as percentage of vWF:Ag or units/deciliter vWF:Ag compared with a control standard plasma. Test results should be interpreted relative to each laboratory’s established normal range of canine plasma vWF:Ag. Results from different laboratories are not directly comparable because plasma standards, assay techniques, and normal ranges vary among laboratories.1-3,23 Measurements of plasma vWF:Ag concentration are used as predictors of genetic status for the vWD trait and for the diagnosis of vWD in dogs with bleeding diatheses.1-4,24
The following ranges, using an ELISA assay technique for measurement of canine plasma vWF:Ag, have been established at the Comparative Hematology Laboratory 18,24: normal range, 70-180% vWF:Ag; borderline range, 50-69% vWF:Ag; and abnormal range, 0-49% vWF:Ag.
Dogs that test in the normal range are considered to not have the vWD trait and are considered to be a low risk for expressing or transmitting the disease.
Dogs that test in the borderline range can not be accurately classified as carriers or as clear of vWD on the basis of the measurement. This is an overlap region of plasma percentage vWF:Ag for which some dogs are genetically clear and some are carriers of vWD. It is unusual for dogs with more than 50% vWF:Ag to express the vWD trait and to exhibit a clinically significant bleeding diathesis.
Dogs that test in the abnormal range are considered carriers of vWD and are at risk for transmitting an abnormal vWF gene to offspring. Carriers that have no plasma vWF (0% vWF:Ag) invariably express a bleeding tendency. However, severity of bleeding diathesis for carriers having low plasma vWF is not necessarily proportional to a reduction in plasma vWF:Ag concentration. Inheritance and expression pattern of vWD within each breed and the presence or absence of concurrent disorders may influence severity of bleeding tendency in individual carriers.2-6
Functional vWF assays, known as cofactor assays, are performed by combining normal platelets with an agglutinating reagent that is dependent on vWF for activity.9,10 Comparisons are made between the agglutination response obtained using patient plasma as the source of vWF versus dilutions of normal canine plasma. The antibiotic ristocetin is used routinely in human vWF cofactor assays, but it is difficult to use in canine test systems.20 Botrocetin, a protein derived from snake venom, is more commonly used in canine vWF cofactor assays.21,24 Botrocetin cofactor (BCf) assays are semiquantitative measures of vWF and are dependent on concentration and function of vWF in test plasma. BCf assays are relatively imprecise compared with vWF:Ag assays and are somewhat difficult to standardize. Cofactor assays usually are performed when evaluating patients with a bleeding diathesis; they are used as a screening test to identify dogs with low plasma vWF.23 However, predictions of clinical severity of vWD that are based solely on abnormal BCf activity are not accurate. In general, the results of BCf assays provide no more clinical information than do results of vWF:Ag assays.
Structural vWF assays measure vWF multimer size distribution.10,11,22 Multimer assays are technically complex and are not routinely performed when screening for canine vWD. In research laboratories measurements of plasma vWF concentration and multimer size are used, making it possible or enabling differention of certain types of vWD in affected breeds of dogs. These canine variants are comparable to three broad categories used to describe vWD in humans.9,10 Type I vWD is characterized by low concentration of structurally normal vWF protein. This form is the most common in human and canine medicine, and severity of bleeding diathesis is variable in affected individuals.1-4,9 Type II vWD is characterized by low concentration of abnormal vWF (i.e., specifically deficient of the largest vWF multimers). Most affected individuals have a moderate to severe bleeding diathesis.2-4,9 Type III vWD is characterized by virtual absence of vWF in quantitative or qualitative assays. Type III vWD invariably is a severe bleeding diathesis.1-4,9 Table 1 presents a summary of characteristics of dogs with Types I, II, and III vWD.
CLINICAL FEATURES OF CANINE VON WILLEBRAND’S DISEASE
History and Signs
Typical signs of vWD include bleeding from mucosal surfaces (e.g., epistaxis, hematuria, melena) and excessive bleeding and bruising from sites of trauma or surgical procedure.1-4 Specific signs in a particular affected dog are dependent on a number of variables. Puppies with severe forms of vWD often have noticeable gingival bleeding when deciduous teeth are shed; local or systemic treatment to control hemorrhage is required.4-6 The urinary tract and oronasal cavities are rich in local fibrinolysins. Surgery or minor injury to these tissues may lead to severe bleeding in dogs with vWD, whereas skin incisions or superficial wounds heal without complication. Abnormal hemostasis may not be clinically apparent in dogs with mild cases until a critical anatomic site, such as the central nervous system is injured. Compared with normal dogs, dogs with vWD may exhibit exaggerated signs of bleeding if they develop concurrent disorders that affect hemostasis. Commonly encountered disorders include thrombocytopenia, drug administration, hypothyroidism, liver disease, and uremia.1-4
Table 1. Characterization of Canine von Willebrand’s Disease
Type I Low Normal Variable Doberman, Corgi, Sheltie,
German Shepherd, Akita, Poodle*
Type II Low Abnormal(large Severe German Shorthaired Pointer
Type III Undetectable Undetectectable Severe Scottie, Sheltie, Chesapeake
Retriever, German Wirehaired
* Type I vWD has been identified in most common purebreeds.
Rarely is vWD the sole cause of petechiae, hemarthroses, or hematoma formation. Thrombocytopenia is by far the most common cause of petechiae in dogs. Acquired or inherited coagulation factor deficiencies are the usual cause of bleeding into body cavities, subcutaneous tissues, or muscles.1,2
Prevalence of Von Willebrand’s Disease
vWD has been identified in more than 50 different breeds of dog.1,3,24 Genetic screening programs for the vWD trait have been established in many of these breeds.3,4,24 Data for the six breeds with the largest testing programs for a 3-year period (1988-1990) is presented in Table 2. The information was compiled through the Comparative Hematology Laboratory’s nationwide vWD testing program.
Table 2. Prevalence of the von Willebrand’s Disease Trait in Six Breeds (1988-1990)*
Breed Average Number of Dogs
Average Percentage of Dogs
Tested in Carrier Range+
Doberman Pinscher 1625 75
Pembroke Welsh Corgi 181 43
Shetland Sheepdog 824 35
Scottish Terrier 343 30
Golden Retriever 644 30
Poodle (Standard and Miniature) 476 30
* Based on data from the Comparative Hematology Laboratory.
+ Carrier range defined as plasma vWF:Ag<50%
Within these six breeds and in other breeds with less extensive testing programs, there are variations in the proportion of carriers expressing the vWD trait and the severity of their bleeding diathesis.1-4 Doberman Pinschers, Scottish Terriers, and Shetland Sheepdogs are the breeds most often affected with clinical signs of vWD.4 Affected lines or severe forms of vWD also have been identified in Akitas, Old English Sheepdogs, German Shorthaired Pointers, Schnauzers, Rough Coasted Collies, and Basset Hounds.1-4 All purebred, as well as mixed breed, dogs have some apparent risk for expressing vWD. Within the last few years, sporadic cases of severe forms of vWD have been diagnosed in Pomeranians, Fox Terriers, Alaskan Huskies, and German Wirehaired Pointers (Comparative Hematology Laboratory, unpublished data).
Inheritance and Expression Patterns
vWD is inherited as an autosomal trait; males and females have equal risk for transmitting the defect or expressing a bleeding diathesis.1-4,9 Heterozygous carriers of vWD usually are identified as having less than half the normal concentration of plasma vWF (i.e., < 50% vWF:Ag), and homozygous carriers produce virtually no vWF protein (0% vWF:Ag). 1-4,24
In most breeds, the vWD trait is incompletely dominant. Heterozygotes that have a penetrant form of the defect express a bleeding diathesis, whereas other heterozygotes that have an impenetrant form have no symptoms.2-4 Family studies and pedigree analysis of vWD-affected Doberman Pinschers, Pembroke Welsh Corgis, German Shepherds, and most other breeds have shown variable expression of a bleeding diathesis in heterozygotes; this expression is compatible with incomplete penetrance of the vWD defect.3,24, An abnormal vWF gene transmitted from either parent is sufficient to produce affected offspring. In these breeds, homozygosity for the vWD trait apparently is lethal. All affected dogs have low, but measurable, plasma vWF and normal vWF multimer structure; these characteristics are typical of Type I vWD.2-4,24 In vitro assays of plasma vWF can not reliably differentiate carriers that will express a bleeding diathesis from those that have low plasma vWF without clinically relevant impairment of hemostasis.1-4 Additional evidence of expression of vWD can be obtained from evaluation of history and in vivo bleeding time.1-4,23
A simple recessive pattern of expression is found in Scottish Terriers with vWD.1-4 In this breed, dogs with the disease are homozygous for the vWD trait, have no detectable plasma vWF, and invariably express a severe bleeding diathesis. These findings are typical of Type III vWD.2-4,24 In this form, both parents must transmit an abnormal gene to produce affected offspring. Heterozygous carriers have low plasma vWF concentration, but they do not experience abnormal hemostasis.2-4 An apparent recessive inheritance and expression pattern also has been reported in Chesapeake Bay Retrievers.5
Shetland Sheepdogs are believed to have an incompletely dominant inheritance pattern of vWD, with variable but relatively mild bleeding diathesis seen in some heterozygotes.3,6 In recent years, a severe form of Type III vWD has been identified in this breed; affected dogs have no detectable plasma vWF.6 Family studies of these dogs have shown them to be offspring of two carrier parents; these findings are compatible with a homozygous or doubly heterozygous state.
German Shorthaired Pointers with vWD express a severe bleeding diathesis.2,4,25 The inheritance pattern in this breed is not well defined. Affected dogs have been the offspring of two clinically normal parents, findings that are compatible with incompletely dominant or recessive inheritance. Results of in vitro vWF assays have shown low plasma concentration of vWF and relative deficiency of large vWF multimers; such findings are typical of Type II vWD.2,25 this form of vWD has not been identified in any breed other than the German Shorthaired Pointer.
Acquired von Willebrand’s Disease
A hemostatic defect, with signs typical of vWD, has been described in adult purebred and mixed breed dogs that had no prior or familial history of abnormal hemorrhage.1,7,8,26 Dogs usually had excessive mucosal or postoperative hemorrhage. Diagnostic evaluation of these dogs reveals abnormal bleeding time and low plasma vWF concentration; normal platelet count and normal clotting times were found in coagulation assays. Signs of a concurrent disease process, usually an endocrine disorder, often were present.1,7 Thyroid insufficiency is considered the most common associated clinical disorder, but hormonal changes associated with estrus, parturition, and Addison’s disease have been found.4,7,23,26 Correction of the underlying disorder is followed by resolution of bleeding diathesis within a few days. In some, but not all cases, plasma vWF concentration increases to within normal range.26 A similar hemorrhagic syndrome that is responsive to thyroid hormone supplementation has been described in hypothyroid humans.27,28
The pathogenetic mechanism of acquired vWD is not well defined in humans or dogs. Reversible impairment of hemostasis may be secondary to changes in intracellular or subendothelial vWF and in plasma vWF. The acquired defect may be attributable, in part, to abnormalities of platelet function or hemostatic proteins other than vWF. In vitro assays of plasma vWF in patients with acquired vWD reveal low concentration of structurally normal vWF protein; such findings are typical of patients with inherited Type I vWD.7,26-28 Until more specific diagnostic tests are found, dogs suspected of having acquired vWD should be evaluated to rule out other acquired bleeding disorders, including thrombocytopenia, metabolic disease or drugs causing platelet dysfunction, and defects of the coagulation cascade or fibrinolytic pathways.
MANAGEMENT OF DOGS WITH VON WILLEBRAND’S DISEASE
Successful management of dogs with vWD includes definitive diagnosis and specific treatment of affected dogs during a bleeding crisis and identification of carriers that express an abnormal bleeding diathesis before they undergo surgical procedures.
Initial Patient Assessment
Plasma samples for vWF assay should be drawn before extensive drug or transfusion therapy. Common causes of bleeding diatheses in dogs, including thrombocytopenia, coagulation factor deficiency, and acquired platelet dysfunction, should be ruled out. Slide estimates of platelet number and activated clotting time are useful quick assessment tests.1,29 Bleeding caused by thrombocytopenia usually is not expected if examination of a stained blood film under oil immersion reveals at least 7-10 platelets per field. Normal range of canine activated clotting time is 60-120 seconds. Abnormalities detected in quick assessment tests can be studied more closely with more definitive tests, including platelet count, coagulation screening assays, fibrinogen concentration, and fibrin (ogen) degradation product titers.29 Thorough drug history and metabolic profile usually reveal conditions that affect platelet function, especially therapy with nonsteroidal anti-inflammatory drugs, uremia, or hyperproteinemia.29,30 In some cases, additional diagnostic workup may be indicated to identify underlying endocrinopathies that influence expression of vWD.1-3,23
When measurement of plasma vWF is used as a prediction of genetic status for the vWD trait, the most accurate results are obtained during physiologic “quiet” times.23,24 vWF is a hemostatic protein and also acts as an acute-phase reactant protein.10,23 Concentration of plasma vWF tends to fluctuate in association with systemic infectious, inflammatory and neoplastic disorders, and hormonal changes that accompany heat cycles, pregnancy, and lactation. The magnitude and direction of change from baseline vWF concentration is unpredictable, and samples for vWF:Ag (used as genetic predictor) should be drawn at least 2 weeks after vaccination, medication, or resolution of systemic disease.3
Measurement of in vivo bleeding time is useful in the initial workup of dogs with bleeding diathesis (after platelet and clotting disorders have been ruled out).1,2,23,29 Prolongation of bleeding time (CBT or BMBT) is compatible with a diagnosis of vWD. Preoperative measurement of bleeding time also can be performed for Doberman Pinschers and other breeds that have a high prevalence of the vWD trait. In general, dogs having clinically significant expression of the trait have measurable prolongation of bleeding time. However, predictions of intraoperative or postoperative bleeding complications should not be based solely on bleeding time. In each case, the type of surgical procedure and overall status of the patient’s other hemostatic mechanisms should be considered.
Nontransfusion Supportive Care
Dogs with severe forms of vWD have a lifelong risk of experiencing serious bleeding episodes. For these dogs, avoidance of invasive diagnostic procedures or elective surgical procedures is recommended. If dogs with vWD undergo surgical procedure, close postoperative monitoring is required. Excessive bleeding may not be obvious during a procedure but may occur during anesthetic recovery. In some dogs with vWD, rebleeding from incised tissues has been observed as long as 24 hours after surgical procedure.
It is good practice in dogs with vWD to avoid drug or vaccine adminstration that might compromise normal platelet function.1,30 Vaccination with certain modified live vaccines causes transient thrombocytopenia within 1 week of administration. Surgery or other stressful situations should be eliminated or minimized until platelet numbers rebound, usually within 2 weeks.1,3 Nonsteroidal anti-inflammatory drugs (aspirin, phenylbutazone, actaminophen, and ibuprofen) impair platelet function.30 Administration of these drugs can cause or exacerbate a bleeding episode in dogs with vWD. In general, the use of anti-inflammatory doses or corticosteroids (dexamethasone, prednisone, and prednisolone) is preferable to any of the nonsteroidal anti-inflammatory drugs.
Other drugs that are associated with thrombocytopenia or impaired platelet function include most chemotherapeutic agents, sulfa and sulfa trimethoprim combination drugs, chloramphenicol, quinidine, phenobarbital, heparin, and estrogen.30 Use of these drugs should be avoided. If they are administered, the patient’s clinical status and platelet count should be monitored closely.
Local wound treatment at the site of surgical or traumatic tissue injury often reduces blood loss in patients with vWD.1,3,23 Useful procedures for improving local hemostasis include electrocautery, ligation of small subcutaneous vessels, multilayer closure of incisions, and application of pressure wraps. Orthopedic procedures and surgical procedures that involve mucosal surfaces represent severe hemostatic challenges. Bleeding from wounds in the oral cavity, including tooth extraction sites, often is encountered and may be difficult to control. Absorbable sponges can be packed into gingival defects and kept in place with sutures. Topical tissue adhesive is useful for controlling hemorrhage from small mucosal defects. Adhesives are most effective if applied to a wound after bleeding is controlled with direct pressure and the tissues are dry.
Hormonal therapy is indicated for certain patients if differential diagnosis includes acquired vWD.1-4,23 Many of the same breeds with a high prevalence of the vWD trait also are at increased risk of developing thyroid insufficiency.31-33 For adult dogs that develop a bleeding tendency in association with hypothyroidism, supplementation with thyroid hormone often prevents or reverses significant bleeding episodes. Thyroid hormone should be given at a replacement dose of 0.02 mg/kg twice a day. The dose should be adjusted to maintain postpill T4 concentration near the high end of the normal canine range.7 Dogs that do not respond should be carefully reassessed to identify a focal source of hemorrhage (including occult neoplasia) or systemic bleeding diathesis other than vWD.
Table 3. Blood Products and Dosages to Supply von Willebrand Factor
Product Dose Frequency
Fresh* whole blood 12-25 mg/kg q 24 hr
Fresh* plasma 6-10 ml/kg q 8-12 hr
Fresh frozen plasma+ 6-10 ml/kg q 8-12 hr
Plasma cryoprecipitate 1 unito/10 kg q 6-8 hr
* Fresh indicates that the blood product was transfused within 6 hours of collection.
+ Fresh frozen plasma separated from whole blood and frozen within 6 hours of collection.
o 1 unit is the amount of cryoprecipitate produced from 150 ml of fresh frozen plasma.
Desmopressin acetate (DDAVP, deamino 8-D-arginine vasopressin) is a synthetic vasopressin analog that is used as pharmacologic treatment for some forms of vWD in humans.9,10 The drug is believed to stimulate release of intracellular stores of vWF, which results in increased concentrations of plasma vWF.34 It is not effective in patients who are genetically incapable of producing vWF or in those who produce certain dysfunctional forms of the protein. The duration of response to desmopressin is transient (hours), and there is a poor response to repeated doses given within a 24-hour period.9,10,34 A summary of trials evaluating the effect of desmopressin in healthy dogs with normal vWF concentration and Doberman Pinschers with vWD has been reported.23 In general, desmopressin caused an increase in plasma vWF concentration in healthy dogs. The magnitude of response was variable and was less than that seen in humans. Affected Dobermans had only nonrelevant increases of plasma vWF concentration after desmopressin administration. However, shortening of BMBT has been reported in some Dobermans with vWD one-half hour after subcutaneous administration of desmopressin at a dose of 1 ug/kg.35 Because of the unpredictable canine response to desmopressin, routine use of the agent in dogs with vWD is not recommended. Corrections of abnormal bleeding time should be demonstrated before desmopressin is used as preoperative prophylaxis. In addition, close intraoperative and postoperative monitoring is required to ensure adequate duration of response.
Transfusion to supply active vWF is needed to control hemorrhage in dogs with severe forms of vWD and dogs unresponsive to supportive care or hormonal therapy. Blood products that contain functional vWF include fresh whole blood, fresh plasma, fresh frozen plasma, and plasma cryoprecipitate.1,36-38 Table 3 presents dosage and frequency guidelines for transfusing these products.
Ideally, blood donors should have the same blood type and should have been found on crossmatch to be compatible donors for dogs with vWD that have received prior transfusions and dogs likely to receive multiple transfusions. Donor dogs negative for red blood cell antigens DEA 1.1, 1.2, and 7 usually are considered “universal” donors, those least likely to sensitize recipients to foreign antigens.1,37 Blood donors should be screened for the vWD trait to ensure that they have plasma vWF:Ag within the normal range.
Intravenous catheters for administering blood products to dogs with severe cases of vWD should be placed in a peripheral vein, rather than the jugular vein, to avoid perivascular hematoma or hemorrhage that might interfere with respiration. If intravenous catheterization is impossible, most red cells and plasma proteins transfused via the intraosseous route will gain access to the peripheral circulation.37 The intramedullary cavities of the femur, ilium, humerus, and tibia are potential sites of intraosseous transfusion.
Transfusions of blood products that contain red blood cells are indicated when patients with vWD have signs that are indicative of acute or chronic blood loss anemia. Stored whole blood and packed red blood cells do not contain relevant amounts of active vWF, but the plasma of fresh whole blood, transfused within 6 hours of collection, supplies some functional vWF.1,36 Transfusion of products that contain red blood cells, whether or not they contain active vWF, often stabilize the condition of dogs with vWD and allow time for nontransfusion supportive care to be initiated and take effect. However, repeated administration of these products puts the recipient at risk of adverse immunologic transfusion reactions and volume overload and does not supply sufficient vWF to improve hemostasis to a marked degree.1,36,37 For these reasons, dogs with vWD that have no clinical signs of anemia are best treated with blood components that more selectively supply vWF.
Plasma separated from whole blood and transfused within 6 hours of collection is considered fresh plasma (FP).1,36-38 Fresh frozen plasma (FFP) is produced by centrifuging whole blood within 6 hours of collection and separating and rapidly freezing the plasma supernatant. Storage of FFP at low temperatures (as low as -70o C) preserves the activity of hemostatic proteins, including vWF, for as long as 1 year.38 Transfusions of FP and FFP supply roughly an equivalent amount of active vWF (in half volume) as the whole blood from which they were prepared. In general, these products are transfused through 150 um blood filters at a rate of 6-10 ml/minute.1 Plasma can be administered prophylactically to patients with vWD within a few hours of invasive procedures; repeated transfusions (minimum interval, every 8 hours) can be given within a 24-hour period. However, there is some risk of volume overload with the administration of multiple plasma transfusions.23,36,37
Cryoprecipitate is a plasma concentrate prepared from FFP that is enriched in vWF, coagulation Factor VIII, fibrinogen, and fibronectin.1,36-38 The volume of cryoprecipitate that forms, when FFP is slowly thawed, is about one-tenth that of the initial plasma. One unit of cryoprecipitate (defined as that amount formed from approximately 150 ml plasma), is administered for each 10 kg of recipient body weight. Cryoprecipitates can be stored frozen at low temperatures for as long as 1 year.36-38 A major advantage of cryoprecipitate transfusion is the large amount of active vWF supplied in small volumes of infusate. Second or third doses of cryoprecipitate can be transfused in 1-2-hour intervals without causing volume overload.23 Maintenance transfusions (sometimes needed in dogs with severe cases of Type II or III vWD) can be given at 6 hour intervals. Cryoprecipitates also are convenient to transfuse preoperatively because the entire dose can be given during a period of 10-15 minutes. The dose can be repeated intraoperatively or postoperatively.
Transfusion of selected blood components, rather than whole blood, optimizes the benefit of transfusion and minimizes the risk of adverse reactions.36-38 Cryoprecipitate transfusions are the most reliable means of supplying active vWF to control hemorrhagic crises in dogs with vWD.1,23,37 Increased plasma vWF:Ag concentrations, in some cases as much as three to four times greater than pretreatment values, have been measured in dogs with vWD after cryoprecipitate transfusion (Comparative Hematology Laboratory, unpublished data). To improve efficacy of canine cryoprecipitates, some researchers recommend administration of desmopressin to donor dogs before blood collection.2,23 The expected increase in concentration or activity of vWF in products prepared from these donors or the specific beneficial response in a series of recipients have not been well described.
More widespread availability of blood components is expected as commercial companies and veterinary teaching hospitals develop canine donor programs and blood banking techniques. Controlled clinical trials are needed to determine the optimum treatment protocols for dogs with various forms of vWD. Clinical and laboratory characteristics of dogs with vWD and the specific hemostatic insult they encounter should be thoroughly defined in the comparisons of different treatment protocols. Objective measures of plasma vWF, bleeding time, and clinical response should be included in trials to clarify the effects of different transfusion and nontransfusion treatments.
Knowledge of the inheritance and expression pattern of vWD within different breeds of dog and the evaluation of clinical history, endocrine profile, plasma vWF, and bleeding time in individual dogs provide a good framework for choosing the appropriate treatment and effective management of canine vWD.
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