Companion animal medicine 2

Jaundice

Yellow staining of serum/ tissue caused by excess bilirubin

Large, sustained increase in bilirubin production or a major impairment of bile excretion

Normal bilirubin metabolism

1. Old RBCs are phagocytosed

2. Haem > biliverdin > unconjugated (fat-soluble) bilirubin

3. Unconjugated bilirubin binds albumin and travels to the liver

4. Hepatocytes conjugate bilirubin, making it water-soluble

5. Bilirubin is excreted into the bile - this step is rate-limiting

6. Bile is stored in the gallbladder or passes directly to the duodenum

7. Bacteria deconjugate bilirubin to urobilinogen - most is reabsorbed, some is excreted

Pre-hepatic (haemolytic) jaundice mechanism

Massive red cell destruction (intravascular or extravascular) overwhelms the liver’s substantial capacity to take up, conjugate and excrete bilirubin

Produces predominantly unconjugated hyperbilirubinaemia

Implies a marked, ongoing haemolysis

Pre-hepatic (haemolytic) jaundice causes

IMHA, babesiosis, cytauxzoonosis, oxidant toxicity, zinc toxicity

Pre-hepatic (haemolytic) jaundice clinically

Moderate to severe regenerative anaemia

Normal to high plasma protein

Minimally deranged liver enzymes

Normal to enlarged spleen/ liver

Intra-hepatic (hepatocellular) jaundice mechanism

Biliary disease impairs uptake, intracellular processing or canalicular excretion of bilirubin (true cholestasis with regurgitation of bile into sinusoidal blood)

Jaundice is more likely when disease primarily affect periportal hepatocytes

Intra-hepatic (hepatocellular) jaundice causes

Chronic hepatitis, hepatic lipidosis, cirrhosis/ fibrosis, acute hepatotoxicity, neoplasia (primary or infiltrative), cholangitis

Sepsis/ endotoxaemia can interfere with bile flow

Intra-hepatic (hepatocellular) jaundice clinicaly

High ALT (hepatocellular damage) with high ALP/ GGT (cholestasis)

Hypoalbuminaemia

Coagulopathy

Post-hepatic (obstructive) jaundice mechanism

Physical obstruction of bile flow distal to the liver, causing conjugated hyperbilirubinaemia

Post-hepatic (obstructive) jaundice causes

Extrahepatic bile duct obstruction

• Intraluminal - choleliths, biliary mucocele, neoplasia, parasites, foreign body

• Extraluminal - pancreatitis (most common)

Biliary rupture (trauma/ necrotising cholecystitis) causing bile to leak into peritoneal cavity

Post-hepatic (obstructive) jaundice clinically

Markedly elevated ALP/ GGT

Pale

Dilated bile duct/ gallbladder and possible obstructing mass/ choleliths on imaging

Primary haemostasis

Platelet plug formation through platelet adhesion via vWF causing aggregation

Forms a short-lived unstable plug

Secondary haemostasis

The coagulation cascade stabilising the initial plug with fibrin, producing a durable clot

Primary haemostatic disorders

Behave like a garden hose punctured with many small holes

Either thrombocytopenia or platelet dysfunction (where platelet numbers are normal)

Primary haemostatic disorders clinical signs

Petechiae and ecchymoses (multiple, small, short-lived bleeds)

Mucosal/ surface bleeding - epistaxis, melena, haematochezia, haematuria

Bleeding begins immediately after venipuncture or minor trauma

Thrombocytopenia aetiology

Decreased production

Increased destruction

Increased consumption

Increased sequestration

Decreased production of platelets causes

Immune-mediated megakaryocytic hypoplasia, marrow aplasia, myelophthisis, drugs (e.g. oestrogens), retroviral infection (cats)

Increased destruction of platelets causes

Immune-mediated thrombocytopenia, drug-induced, infectious, vaccine-associated

Increased consumption of platelets causes

DIC, microangiopathy, vasculitis

Increased sequestration of platelets causes

Splenomegaly, splenic torsion

Platelet dysfunction (thrombocytopathia) aetiology

Congenital

• von Willebrand disease (most common in dogs)

• Breed-specific thrombopathias

• Scott syndrome

Acquired: NSAIDs, uraemia, monoclonal gammopathies, vector-borne disease

Secondary haemostatic disorders

Behave like a hose with one large hole

Either congenital clotting factor deficiencies or vitamin K deficiency/ antagonism

Secondary haemostatic disorders clinical signs

Petechiae/ ecchymoses rare

Haematoma formation, bleeding into muscles, joints (lameness) and body cavities

Haemothorax/ hemiabomen leading to collapse, dyspnoea, abdominal distension

Bleeding after venipuncture is typically delayed, not immediate

Congenital clotting factor deficiencies aetiology

Haemophilia A and B (rare in cats, slightly more common in dogs)

Vitamin K deficiency/ antagonism aetiology

Rodenticide (anticoagulant) toxicity - inhibits vitamin K epoxide reductase

Cholestatic/ EBDO disease - fat malabsorption limits vitamin K uptake

Severe hepatic disease - most coagulation factors are hepatically synthesised

Diagnostic approach to haemostatic disorders

1. History

2. Physical examination - classify the bleeding pattern

3. Further testing

Causes of regenerative anaemia

Blood loss

Haemolysis (extravascular or intravascular)

Causes on non-regenerative anaemia

Anaemia of chronic disease

Anaemia of renal disease

Bone marrow disorders

Anaemia of endocrine disease

Peracute blood loss/ haemolysis

Blood loss anaemia

Acute or chronic external/ internal haemorrhage - trauma, GI ulceration/ neoplasia, coagulopathy, parasitism

Typically normal to low plasma protein

Progresses to iron deficiency anaemia

Extravascular haemolytic anaemia

RBCs phagocytosed by the mononuclear-phagocytic system in spleen/ liver/ marrow

Most common mechanism in small animals

IMHA, RBC parasites, Heinz bodies

Spherocytes are the hallmark finding

Intravascular haemolytic anaemia

Direct lysis in circulation

Caused by complement-fixing antibody, infectious agents, oxidative/ zinc toxicity, hypophosphataemia or mechanical shearing

Immune-mediated haemolytic anaemia

Primary/ idiopathic or secondary to drugs, infection, neoplasia

Diagnosed by spherocytosis, saline autoagglutination and/ or a positive direct Coombs’ test

Can be peracute and life-threatening

Anaemia of chronic disease

Most common non-regenerative anaemia

Mild, normocytic, normochromic, secondary to chronic inflammation/ infection/ neoplasia

Sequestration of iron making it unavailable for erythropoiesis

Usually resolves with treatment of underlying disease

Anaemia of renal disease

Due to reduced renal erythropoietin production

Normocytic, normochromic, poorly/ non-regenerative

Bone marrow disorders

Aplasia/ hypoplasia (e.g. FeLV)

Myelophthisis - marrow ‘crowding out’ by neoplastic cells

Myelodysplastic syndrome

Myelofibrosis/ osteosclerosis

Anaemia of endocrine disease

Mild and often incidental - hypothyroidism and hypoadrenocorticism

Iron-deficiency anaemia

Mild-moderate regeneration, becomes non-regenerative

Microcytic and hypochromic

In dogs - usually due to chronic GI blood loss (neoplasia, ulceration) or severe flea burden

In cats - rare in adults, seen mainly in kittens or with chronic GI blood loss

Torocytes

RBC with increased central pallor and a normal cell wall - looks punched out

Torocytes causes

Artefact with no clinical significance

Poikilocytosis

Increase in the number of abnormal RBCs of any shape

Poikilocytosis causes

Any condition disrupting normal RBC membrane integrity or production

Spherocytes

Small, spherical, densely-staining RBCs with little/ no central pallor

Spherocytes causes

Removal of membrane by macrophages - IMHA, oxidative damage, microangiopathic disease, toxicoses

Schistocytes

Small, irregularly shaped RBC fragments with sharp angles or points

Schistocytes causes

Shearing of RBC in circulation due to vasculature abnormalities

MAHA, DIC, haemangiosarcoma, iron deficiency, vasculitis, heartworm

Acanthocytes

RBCs with irregular, unevenly spaced, blunt membrane projections of varying length

Acanthocytes causes

Potentially fragmentation injury

Hepatic disease, haemangiosarcoma, DIC, glomerulonephritis, lipid disorders

Anisocytosis

Variation in RBC size within the same smear

Anisocytosis causes

Regenerative anaemia (macrocytes from reticulocytosis), any active/ compensating erythropoiesis, some breed variation

Microcytes

RBCs smaller than the normal reference size

Microcytes causes

Iron deficiency anaemia, portosystemic shunts, some breeds

Polychromatophils

Immature RBCs staining blue-grey/ purple due to residual ribosomal RNA - usually larger

Polychromatophils causes

Regenerative anaemia and release of reticulocytes

Hypochromia

RBCs with an enlarged area of central pallor and a thin rim of haemoglobin, giving a pale appearance

Hypochromia causes

Decreased Hb production - iron deficiency anaemia, chronic external blood loss

Ghost cells

RBC membranes with little to no visible haemoglobin - appear as pale, empty outlines

Ghost cells causes

Intravascular haemolysis (IMHA, oxidative injury, other haemolytic disease)

Can also be an artefact

Howell-Jolly bodies

Small, round, dark purple nuclear remnants within RBCs, usually single

Howell-Jolly bodies causes

Increased RBC production or decreased removal by splenic macrophages

Regenerative anaemia, splenectomy, glucocorticoids

Normal in cats

Metarubicytes

Most mature form of a nucleated RBC. Condensed, pyknotic nucleus still present within the cell, cytoplasm ranging from basophilic to orange depending on maturity

Metarubicytes causes

Strong regenerative anaemia, bone marrow disease, lead toxicity, splenic disease, extramedullary haematopoiesis, sepsis/ endotoxaemia

Platelet clumping

Can cause a falsely low platelet count

Platelet clumping causes

Occurs during routine blood collection and indicates normal numbers of platelets

Macroplatelets

Larger than normal, immature platelets

Macroplatelets causes

Produced in response to peripheral thrombocytopenia

Fresh whole blood contents

RBC, WBC, platelets, all coagulation factors, albumin, globulin

Indications for fresh whole blood

Anaemia with coagulopathy/ platelet disorder

Severe haemorrhage requiring massive transfusion

Stored whole blood contents

RBC, WBC, albumin, globulin, non-viable platelets, coagulation factors

Indications for stored whole blood

Blood loss anaemia

Packed RBCs contents

RBC, WBC, non-viable platelets

Indications for packed RBCs

Symptomatic anaemia of any aetiology, especially those at risk of overload

Fresh frozen plasma contents

All coagulation factors, albumin, globulin

Indications for fresh frozen plasma

Coagulopathy

Benefits of component therapy

Allows for longer storage

>1 patient can benefit from one donation
Decreased risk of volume overload + transfusion reactions

Downsides of component therapy

Requires specialised equipment

Commercial availability can be inconsistent

Hard to get a stable source of platelets

Febrile non-haemolytic transfusion reaction

An increase of at least 1ºC from pre-transfusion values within 4 hours of the end of transfusion

Infection, acute haemolysis, TRALI and bacterial contamination have been ruled out

Possibly caused by transfer of inflammatory mediators by stored RBCs

Febrile non-haemolytic transfusion reaction treatment

Generally self-limiting and not life-threatening so no need for antipyretics

Continue transfusion at a slower rate?

Transfusion associated cardiac overload

Circulatory overload due to an increase in blood volume

Acute respiratory distress and pulmonary oedema within 6 hours of transfusion

Diagnosed with radiographic or ultrasonographic evidence

Allergic transfusion reaction

Type I hypersensitivity reaction to antigen within the blood product

Occurs within 4 hours of transfusion

Can be transient/ self-limiting or life-threatening

Allergic transfusion reaction clinical signs

Dogs: erythema, urticaria, pruritic, peripheral angioedema, GI signs (vomiting)

Cats: respiratory distress, GI signs (vomiting)

Allergic transfusion reaction treatment

Non-anaphylactic - antihistamine therapy, stop transfusion and assess patient for severity

Anaphylactic - adrenaline

Acute haemolytic transfusion reaction

Onset of haemolysis within 24 hours of transfusion

Inadequate increase in PCV post-transfusion

With or without new onset of fever, tachycardia or hypotension

Causes of acute haemolytic transfusion reaction

Immunologic - secondary to incompatibility of transfused product to recipient

Non-immunologic - damage to RBCs due to thermal, osmotic, mechanical or chemical factors

Delayed haemolytic transfusion reaction

Unexplained decrease in PCV/ Hb >24h - 28d post transfusion

Delayed onset of two indicators of RBC destruction

Causes of delayed haemolytic transfusion reaction

Xenotransfusion - usually within median 2 days, happens regardless of compatibility

Type A cats receiving type B blood - usually within 2 days

Auto-transfusion

Blood taken from a patient and re-transfused into the same patient

Reduces the risk of transfusion reactions, risk of contamination/ haemolysis

Macroscopic agglutination test

Fresh anticoagulated blood on a glass side - examine for visible clumping

Mix a drop of blood with 1-2 drops of saline - true agglutination persists despite this dilution, whereas rouleaux disperses into individual cells once diluted

Microscopic agglutination test

Saline-diluted blood on a slide and examined under a microscope within 1 minute

• True agglutination - irregular, 3D, grape like clustering

• Rouleaux - RBCs arranged in linear stacks resembling piles of coins

RBC autoagglutination

Occurs when large amounts of immunoglobulin coat the RBC surface, allowing antibody molecules on adjacent cells to cross-link and clump together

Definitive evidence of IMHA

Sensitivity of RBC autoagglutination test

Useful but incompletely sensitive - a negative result does not rule out IMHA (e.g. lower burden)

Specificity of RBC autoagglutination test

Highly specific - a positive result almost always indicates immune-mediated RBC destruction

Coombs test

Uses polyvalent antisera to detect immunoglobulin and/ or complement bound to the surface of the patient’s own RBCs

Sensitivity of the Coomb’s test

Not particularly sensitive for IMHA

Typically only detects RBC coating once >200-300 molecules per cell are present - lower numbers can still cause clinically important haemolysis

Specificity of the Coomb’s test

Poorly specific

A positive Coombs test can occur in a variety of other inflammatory and infecitous disease

Donor selection for blood

Healthy, calm temperament, age 1-8

No current medications, no prior transfusion, not pregnant

Canine blood types

DEA group system - 13 different DEAs, which dogs typically have a combination of

1.1 is most immunogenic - ‘universal donors’ - only thing we test for

DEA 1.1 donation and receiving rules

Can give 1.1- to 1.1+ and 1.1+ to 1.1+

CANNOT give 1.1+ to 1.1-

Feline blood types

AB system - type A most prevalent

Feline blood receiving rules

Type A should ideally get type A blood, if they get type B blood = mild reaction

Type B HAS TO get type B blood, if they get type A blood = death

Type AB have both antigens, but best to receive type A blood

Crossmatching

To see if donor blood samples are likely to cause a reaction in the recipient

Agglutination = transfusion reaction