Diseases of RBC

Question 1

Pyruvate kinase hemolytic anemia

Answer 1

• Dogs and Cats
• Variable degrees of regenerative anemias.
• Progressive iron overload due to chronic hemolysis leads to hemosiderosis and liver fibrosis
• Dogs diagnosed young
• Cats can be older when first diagnosed

Question 2

Phosphofructokinase hemolytic anemia

Answer 2

dogs ONLY
– some have no clinical signs but most have persistent hemolytic anemia exacerbated by a sporadic hemolytic crises secondary to exercise-induced hyperventilation alkalemia

Question 3

Hemophagocytic anemia
- Predisposition
- Describe the mechanism
- CxS
- DDX and Dx
- Prognisis

Answer 3

• Predisposed in: Bernese Mountain Dog, Rottie, Golden, and Flat-Coated Retriever
• Erythrophagocytosis -> regen anemia
  Erythrophagocytic histiocytes demonstrate infiltrative growth patterns in the spleen, liver, lung, and bone marrow.
• Often have splenomegaly and hepatomegaly
• Clinical signs of weight loss, anorexia, and lethargy
• ~50% have thrombocytopenia <100k
• Splenic histiocytes typically show more atypia (atypical mononuclear cell and multinuclear giant cells)
• Can differentiate from other histiocytic proliferative disorders by immunophenotyping for the beta-2 integrins CD11/CD18.
• Grave prognosis, MST 4 weeks

Question 4

Antimicrobial that can cause non-regenerative anemia?

Answer 4

Chloramphenicol

Question 5

Binding of fibrinogen to what receptor is essential for aggregation and clot retraction?

Answer 5

Platelet integrins and nonintegrin glycoprotein receptors play a critical role in adhesion (platelet–subendothelial matrix interactions) and aggregation (platelet-platelet association). The alpha-IIb-beta-3 complex (GPIIb/IIIa Glanzmanns thromboasthenia, Great Pyrenese Otterdog) is the most abundant platelet integrin and functions as the activation-dependent receptor for fibrinogen, fibronectin, and VWF.

Question 6

Causes of prolonged BMBT?

Answer 6

Inherited thrombocytopathies:
- Impaired platelet adhesion and aggregation in vWD, a hereditary deficiency of vWF reported in various D breeds and rarely in cats. vWD can result in a bleeding time more than 3x normal.
- Disorders of platelet membranes (Glanzmann’s thrombathenia in Otterhounds and Great Pyrenees)
- Disorders of platelet secretion in Spitz and Basset thrombopathy and platelet granule storage pool deficiency in American Cocker Sp and feline Chediak-Higashi syndrome.

Question 7

vWF disease characteristics and RX

Answer 7

• Normal platelet counts, normal PT/PTT -> need to do BMBT to test for primary hemostasis
  BMBT prolonged – test VWF:Ag prior to testing for intrinsic platelet function defects
• A PFA-100 will also show prolongation in Type 1 when VWF <30%
• IF platelet count over >100k, and PCV >30% then a prolonged PFA-100 indicates vWF OR thrombopathia
• Type 1 and III quantitative (can measure VWG:Ag, DNA testing), Type II qualitative need to diagnosis via documentation of the absence of high molecular weight multimers of VWF through a functional assay or via SDS-agarose gel electrophoresis. An ELISA measures plasma VWF:collagen-binding activity (CBA) -> this can only be done with high molecular weight multimers. Therefore, dogs with Type II VWD will have decreased VWF:CBA relative to VWF:Ag, it will be >2. Normal dogs and dogs with Type 1 VWB, ratio is 1.
• Treat with – fresh whole blood, FFP 10-15 ml/kgh, and cryoprecipitate 1U/10kg (product of choice as it has conc VWF)

Question 8

Breed predispositions for type 1,2,3 VWD?

Answer 8

Type 1: Dorbie, Bernie, Corgi, Dutch Partridge, German Pincher, Goldendoodle, Irish Setter, Kerry Blue Terrier, Manchester Terrier, Papillon Poodle, Westie

Type 2: German Shorthaired pointer, German Wirehaired Pointer

Type 3: Dutch Kooiker, Scottish Terrier, Sheltie

Question 9

Glazmann thrombathenia
-Specific defect
-Breed affected
-Diagnosis

Answer 9

Specific defect: absence of deficiency of the fibrinogen receptor GPLLb- IIIa
Breed affected: Otterhounds, Great pyrenees
Diagnosis: DNA testing

Question 10

Chediak-Higashi syndrome
-Specific defect
-Breed affected
-Diagnosis

Answer 10

Specific defect: Associated with leukocyte and melanocyte abnormalities. Platelet storage pool disorder associated with lack of discernable dense granules and deficiency of ATP, ADP, serotonin, Ca2+ and Mg2=.
Breed affected: Persian
Diagnosis: Presence of characteristic granules in leukocytes (smear) and melanocytes (skin biopsy).

Question 11

Drugs that cause acquired thtombocytopenia?

Answer 11

hydroxyethyl starch, NSAIDs, and cephalosporins

Question 12

Clopidegrel:
MOA

Answer 12

– an irreversible platelet P2Y12 ADP receptor antagonist (ADP cannot bind to its site). Clopidogrel’s active metabolite irreversibly alters the ADP receptor causing the platelet to be affected for its lifespan (5-7 days)! Aka platelet function returns to normal by 7 days, important for patients that need surgery!
SE: GI (v, d, anorexia; decreases with giving at mealtimes) and non-regenerative anemias in cats receiving longterm, and obvi bleeding

Question 13

Aspirin: MOA

Answer 13

irreversible inhibitor of COX-1, reducing prostaglandin and thromboxane synthesis. Thromboxane is a vasoconstrictor, facilitates platelet aggregation, and is a potent hypertensive agent.

Question 14

Chediak-Higashi Syndrome 　(again)

Answer 14

• primary immunodeficiency with recurrent neutropenia and neutrophil function defects, as well as platelet function defects
• Persians with the blue smoke coat color
• Neuts, eos, and other cells contain abnormally fused
  granules
• G-CSF can partially correct Neutrophil function defects

Question 15

Pelger-Huet Anomaly

Answer 15

• defective terminal granulocyte maturation (neuts and eos).
• Australian Shepherds overrepresented
• Function of granulocytes are NORMAL

Question 16

Leukocyte Adhesion Deficiency (LAD)
- Type 1LAD
- Canine LAD

Answer 16

• mutations in leukocyte adhesion proteins that prevent the normal adherence and migration of WBC through luminal endothelium
• Type 1 LAD of Irish Setters – defect in beta-2 subunit, aka CD18
• Canine LAD – CD18 transcription reduced and other neutrophils defects noted
• Markered peripheral neutrophilia with nuclear hypersegmentation, along with absence of neuts in the tissues
• Pups gets omphlitis (infection of umbilical stump), lymphadenopathy, low BW, and febrile infections. Antibiotics cannot prolong life and most die by 2-3 months of age. **Some dogs can live with this for years

Question 17

Trapped Neutrophil Syndrome

Answer 17

• autosomal recessive neutropenia in Border Collies.
• Peripheral neutropenia with a degenerative left shift, marked monocytosis, and myeloid hyperplasia in the BM with increased mature neutrophils.
• Craniofacial development can be abnormal in severely affected dogs, small size, and they present with recurrent infections.

Question 18

PK deficiency
(Congenital White Blood Cell Disorders)

Answer 18

dogs and cats - develop progressive myelofibrosis, with time failure and decreased production in all cell lines

Question 19

X-linked Severe Combined Immunodeficiency (X-SCID)

Answer 19

• Congenital White Blood Cell Disorders.
• mutations in the gene encoding the IL-2 receptor gamma chain. Affects developing CD4 and CD8 thymocytes.
  Cardigan Welsh Corgis and Basset Hounds
  Pups have stunted growth, chronic infections, and as maternal Ab wanes they rarely
  live past 4 months. Hypoplastic thymus, increased circulating B lymphs, no T lymphs
  Females need 2 copies of X mutation, males only need one

Question 20

Autosomal Recessive Severe Combined Immunodeficiency

Answer 20

-defective recombination events during T and B lymphocyte maturation. Point mutation in the catalytic subunit of DNA-dependent protein kinase
-Pups have severe lymphopenia, decreased serum globulins, and marked lymphoid hypoplasia in the spleen, thymus, and other lymphoid tissues. Opportunistic infections or MLV cause of death
-Jack Russel Terriers!

Question 21

Cyclic Hematopoiesis in Gray Collies

Answer 21

-cyclic neutropenia from a defect in trafficking of lysosomal membrane proteins. Cycles neuts every 2 weeks.
-Neuts are deficient in elastase and myeloperoxidase – aka frequent infections, must succumb by 6 months of age
-G-CSF eliminated neutropenic episodes, but didn’t correct functional defects
-The gray coat color results from the defect in melanocytes
Insertional mutations in the AP3B1 gene

Question 22

Common Variable Immunodeficiency

Answer 22

lymphocyte functions deficits, including hypogammaglobulinemia and absence of B cells in LN.
Miniature Dachshunds and Cavalier King Charles with Pneumocystis carinii

Question 23

Lysosomal Storage Disorders

Answer 23

abnormal granules accumulate in the cytoplasm of neuts, monocytes, and lymphocytes
Mucopolysaccharidosis type VI and type VII in dogs and cats
Manifests in neurologic signs
GM2 gangliosidosis results in abnormal vacuolation in the cytoplasm of peripheral leukocytes

Question 24

Pemphigus Foliaceus

Answer 24

-Autoantibodies disrupt desmosomal adhesion between keratinocytes, inducing subcorneal pustules
-Dog autoantibodies against desmocollin-1
Signalment – Akitas and Chow Chows are predisposed.
- Reported in other breeds like English Bulldog, Dobie, Collie, and Australian Sheepdog
- Clinical signs – subcorneal pustule that can progress to secondary erosions/crusts.
- Initial lesions usually on face (esp nasal planum, dorsal aspect of nose, periocular region, and concave pinnae.
- More than half will progress toward the generalized phenotype that involve the trunk and paw pads
Dx: Acantholytic keratinocytes with non-degenerated neuts or eos (acantholysis unfortunately not specific for PF, can be seen with pyoderma or pustular dermatophytosis)
Dx based on a combo of 1)skin lesion type and distribution 2)exclusion of an infection 3) supportive histopath findings
Other dx testing – IHC demonstrating antikeratinocyte Abs but this also detected in other dermatoses, serum antikeratinocyte Abs however this is also detected in low levels in healthy dogs, and finally anti- desmocollin-1 Abs but not commercially available
Tx: Steroids 2-4 mg/kg, and secondary immunosuppressives in some like cyclosporine

Question 25

Mucous Membrane Pemphigoid (MMP)

Answer 25

• Subepidermal blistering skin disease recognized in humans, dogs and cats in which autoantibodies target collagen XVII or laminin-332 (laminin 5) of the basement membrane.
  -Although rare, MMP is the most common autoimmune subepidermal blistering dermatosis (AISBD) recognized in veterinary medicine.
  -Usually dx in adult dogs (median age 5 years) and males > females. It affects a variety of breeds, but German Shepherd dogs are the most common (29%).
  -MMP is a chronic mucosal and mucocutaneous blistering disease with a tendency to form scars. Deep erosions and ulcers are the most common lesions, while intact vesicles are seen only rarely. Scarring in chronic cases.
  -Characteristic of this disease is the remarkable predilection of lesions for the oral cavity, other mucosae (eyes, genitalia, anus), perimucosal areas (mucocutaneous junctions) as well as the nose and concave pinnae. Truly cutaneous, not perimucosal, skin lesions are rare.
  Dx: Biopsy or if available, anti-collagen XVII or laminin-332 antibodies
  Tx: Tetracycline, niacinamide, and +/- immunosuppressives

Question 26

Epidermolysis Bullosa Acquisita (EBA)

Answer 26

• diagnosis of EBA is given to approximately 25% of dogs with autoimmune subepidermal blistering dermatosis (AISBD), making it the second most common AISBD in this species.
• Autoantibodies against collagen VII (basement membrane zone)
• Signalment – more often in young Great Danes, males > females
• Clinical signs: In contrast to MMP, EBA is a haired-skin–predominant disease with concurrent mucosal lesions.
• Early lesions present as erythematous and urticarial patches, usually on the face, axillae, abdomen, and inguinal region. Oral epithelial sloughing is a common feature. Skin ulceration is most prominent in areas of friction such as axillae, inguinal region, and paw pads.
• Dx: Biopsy, Demonstration of tissue-bound and/or circulating anti-BMZ antibodies, and/or anti-collagen VII antibodies
• Tx: Immunosuppressives