Hematology/Coagulation Flashcards
How is iron absorbed in the duodenum?
DMT1 transporter on duodenal enterocytes
What form is iron stored as in the cell?
Ferritin
What transports iron across the basement membrane?
Ferroportin
What is iron bound to in the plasma?
Tranferrin
How is transferrin measured?
- Indirectly
2. Reported as total iron binding capacity
What transports iron into the target cell?
- Transferrin receptor 1
What is the major form of stored iron in the body?
- Ferritin
* >95% of iron in the body
* Mostly in cytoplasm of hepatocytes
How is iron uptake systemically regulated?
- “Dietary regulator” - uptake by duodenal enterocytes is affected by amount of iron recently consumed.
- “Stores regulator” - uptake by duodenal enterocytes is affected by body iron in circulation.
- “Erythropoietic regulator” - uptake by duodenal enterocytes is increased according to erythropoietic demands.
- “Inflammatory regulator” - iron is sequestered in cells in response to systemic inflammation.
What is the most important regulator of iron homeostasis? What does it do?
- Hepcidin
- Binds to FERROPORTIN and triggers internalization of ferroportin → inhibits export from duodenal enterocytes
- Also inhibits DMT1 expression
How long do RBCs circulate?
100 days
How is hemoglobin broken down?
- Hemoglobin → iron and biliverdin
2. Biliverdin → reduced to bilirubin → binds to albumin in plasma for transport to liver → excreted in bile
Serum ferritin (does/does not) correlate well with tissue iron stores
Does
How long does the regenerative response take from onset of bone marrow response?
3 days
Why does anemia of inflammatory disease occur?
Cytokine derangements decrease EPO production, alter iron metabolism, and shorten RBC lifespan
How does inflammatory disease cause a relative iron deficiency?
L-6 and LPS → increased hepcidin → increased degradation of ferroportin → iron sequestered in enterocytes, macrophages, and hepatocytes → iron not available for systemic use → cant be used for erythropoiesis
Why does iron deficiency anemia occur?
- There is an absolute iron deficiency → either from chronic external blood loss, decreased iron dietary uptake, or decreased iron uptake
- Metarubricytes stay in bone marrow and divide continually, waiting for completion of Hb synthesis which is dependent on iron
- Results in a microcytosis
What are the common lab findings for an iron deficiency anemia?
- Microcytic, hypochromic anemia
2. Low ferritin with high-normal to high transferrin
Why does anemia of chronic disease occur?
- Decreased renal mass → decreased EPO production → decreased RBC production in the bone marrow
What is the most common syndrome associated with FeLV infection?
- Anemia
What is the most common type of FeLV associated anemia?
- Pure red cell aplasia
How does immune mediated hemolytic anemia occur?
Antibody mediated destruction of RBCs
- Antibody binds to RBC → Fc fragment of antibody binds to receptors on splenic macrophages
- Either complete phagocytosis occurs or partial phagocytosis of the RBC membrane, leading to formation of spherocytes
How does oxidant-mediated hemolytic anemia occur?
Oxidation exceeds reductive capacity of RBC
1. Hemoglobin precipitates as Heinz bodies in erythrocyte membrane
Why is polycythemia a problem?
- Increased blood viscosity
- Decreased venous return
- Sludging of blood in capillaries - Increased blood volume
- Increased venous return
What is the most common cause for a relative polycythemia?
- Dehydration
* EPO production is not altered
What does it mean if there is an appropriate secondary polycythemia?
Hypoxemia is present
- Congenital heart defects with right to left shunting of blood
- Chronic pulmonary disease due to V/Q mismatch
- Chronic upper airway obstruction
- High altitude
- Defective O2 carrying capacity of Hb
What does it mean if there is an inappropriate secondary polycythemia?
Hypoxemia is NOT present
- Usually due to renal neoplasia
What is primary polycythemia?
- Acquired myeloproliferative disorder leading to clonal expansion of sing hematopoietic stem cell
- RBC production proceeds without regard for EPO level
- Expected to have low plasma EPO due to negative feedback mechanism
How does primary hemostasis occur?
- Platelets adhere to damaged vessel wall (vWF is important here)
- Platelets are activated and release granules
- Platelets aggregate
Which clotting factors are vitamin K dependent? Why are they dependent on vitamin K?
- Factors II, VI, IX, and X
2. Must be carboxylated to become active → requires vitamin K
What is the most important initiator of coagulation?
Tissue factor
What occurs in the initiation phase of coagulation?
- Flowing blood contacts exposed TF on damaged cell → generates factor IX and thrombin on the surface of the damaged cell
- Thrombin and factor IXa diffuse from cell surface
What occurs in the amplification phase of coagulation?
- Thrombin that was generated during initiation phase
- Activates platelets
- Releases vWF
- Generates active factors V, VIII, and XI - Calcium may induce clustering of phosphitidylserine on platelet surface and facilitate binding of coagulation factors → promotes clotting formation
What occurs in the propagation phase of coagulation?
- Factors II, V, VIII, IX, X, and XI generated in earlier steps on procoagulant surface assemble into intrinsic tenase
- This causes factor Xa to form on the platelet surface → leads to thrombin generation directly on the platelet
- Thrombin cleaves fibrinogen to fibrinopeptide A → insoluble matrix forms
How does inhibition of coagulation occur?
Factor Xa that dissociates from procoagulant cell membranes is inactivated by antithrombin or TFPI
What does an abnormal buccal mucosal bleeding time tell you?
- Abnormality of platelet function
2. Von Willebrand disease
What is the most common hereditary bleeding disorder in dogs?
Von Willebrand disease
*Disorder of platelet adhesion resulting from qualitative or quantitative deficiency of von willebrand factor
What is the treatment for von Willebrands disease?
Desmopression
- MOA: Enhanced release of vWF from storage sites
Which blood products contain vWF? Which is the blood product of choice for bleeding dogs with von willebrands disease?
- Fresh whole blood, fresh frozen plasma, and cryoprecipitate
- Cryoprecipitate
Which antibiotics are most likely to cause secondary immune mediated thrombocytopenia?
- Beta lactams
2. Sulfas
What are diseases associated with acquired platelet dysfunction?
- Uremia
- Hepatobiliary disease
- Paraproteinemias
How do rodenticides cause coagulopathies?
- Inhibition of vitamin K epoxide reductase
When does the coagulopathy occur after exposure to anticoagulant rodenticide?
2-5 days after exposure
The (PT/PTT) is prolonged first after exposure to anticoagulant rodenticide
PT
- Factor VII has the shortest half life
What deficiencies are present in
- Hemophilia A
- Hemophilia B
- Factor VIII
- Factor IX
* Lack of either factor inhibits formation of the tenase complex which inhibits thrombin formation which prevents clot formation
What is the treatment for hemophilia?
- Plasma or whole blood to replace clotting factors
2. pRBCs or whole blood to correct anemia
What is the most common deficiency of the intrinsic pathway in cats?
Hageman trait
*Factor XII deficiency
What is found clinically in cats with Hageman trait?
- Prolonged PTT but no clinical signs of bleeding
- Clot formation is not dependent on factor XII
Which is the last cell in erythrocyte development that has the ability to divide?
Rubricyte
What breed can have pseudohyperkalemia? Why?
- Akitas
- The maintain the Na/K ATPase in the mature red cell which results in elevated intracellular K
- Pseudohyperkalemia can occur in a serum sample that was not immediately separated from forming a clot
Where is most iron in the body?
Hemoglobin (70%)
What is the function of ceruloplasmin?
Oxidized Fe2 to Fe3 to be transported by transferrin
*Copper dependent
IL-1 and TNF-α will (increase/decrease) hepatic synthesis of apolactoferritin
Increase
* This protein binds a lot of iron, especially in low pH areas with inflammation
INF-γ, LPS, and TNF-α (increase/decrease) expression of ferroportin
Decrease
Erythrocytes derive all of their energy from what?
- Anaerobic glycolysis
- erythrocytes lack mitochondria
What is the end result of phosphofructokinase deficiency?
- Impaired synthesis of 2,3 DPG, alkalosis, and erythrocyte fragility
- Causes erythrocytes to bind oxygen more strongly than normal cells → Hb-O2 curve shifts LEFT
What breeds are predisposed to phosphofructokinase deficiency?
- English Springer Spaniels
2. Cocker Spaniels
What is the end result of pyruvate kinase deficiency?
- Impairs ATP generation from glucose
What are the clinical findings in dogs with pyruvate kinase deficiency?
- Intravascular hemolysis WITHOUT spherocytes
- Strongly macrocytic/hypochromic strongly regenerative anemia
- Osteosclerosis and myelofibrosis
What are the clinical findings with phosphofructokinase deficiency?
- Exertional myopathy
2. Episodic intravascular hemolytic crises
Which membrane bound receptors activate platelets?
- Collagen
- ADP
- Epinephrine
- PAF
- TXA2
- Thrombin
Prostacyclin (increases/decreases) platelet activity. How?
- Decreases
2. Decreases intraplatelet cAMP → decreases Ca and IP3 release
NO (increases/decreases) platelet reactivity. How?
- Decrease
2. Increase cGMP (inhibitory)
What is the MOA for use of NSAIDs in anti-platelet therapy?
- Irreversibly acetylate platelet COX site
2. Prevents formation of TXA2 and platelet activation
What is the MOA for use of thienopyridines (clopidogrel) in anti-platelet therapy?
- Block ADP receptors (P2Y12) → prevents a platelet plug from forming because platelets cant be activated
What are the contents of eosinophil granules?
- Major basic protein
- Eosinophilic cationic protein
- Eosinophil peroxidase
- Eosinophil derived neurotoxin
Which breed inherits canine leukocyte adhesion deficiency (CLAD)
Irish setters
What is the most antigenic DEA in dogs?
1.1
Which DEA is associated as the universal blood donor in dogs?
1.1 neg
What are the components of major crossmatching?
Patient plasma against donor RBCs
What are the components of minor crossmatching?
Donor plasma against patient RBCs
PT measures the (extrinsic/intrinsic)/common pathways and includes which factors?
- Extrinsic
2. Factors I (fibrinogen), II (thrombin), V, VII, and X
PTT measures the (extrinsic/intrinsic)/common pathways and includes which factors?
- Intrinsic
2. Factors I (fibrinogen), II (thrombin), V, VIII, IX, X, XI, and XII
The following increase/decrease in DIC:
- Platelets
- Fibrinogen
- PT
- PTT
- FDPs
- D-Dimers
- Decrease
- Decrease
- Increase
- Increase
- Increase
- Increase
What are the components of prothrombin activator?
- Factor X
- Factor V
- phosphotidylserine
- Calcium
What activates factor X?
- Tissue factor - Factor VIIa complex (extrinsic)
OR
- Factor IX, Factor VIII, Calcium, and phosphotidylserine (intrinsic)
What factor is used to cross-link fibrin?
- Factor XIII
* Must be activated by thrombin
What are the four steps to hemostasis?
- Vascular constriction
- Formation of primary platelet plug
- Stabilization of platelet plug by fibrin (clot formation)
- Contraction of clot
What is the rate limiting step from secondary hemostasis?
- prothrombin converted to thrombin by prothrombin activator
What are the inherent anti-coagulant factors of blood vessels?
- Smooth vessel walls
- Endothelial glycocalyx → has a negative charge which repels platelets and clotting factors unless disrupted
- Thrombomodulin → binds thrombin to prevent inappropriate clotting
- Tissue plasminogen activator (TPA) → causes delayed conversion of plasminogen to plasmin and results in fibrinolysis at sites of injury
What is the MOA of aminocaproic acid?
Inhibits plasminogen
What is the MOA of antithrombin III?
Combines with free thrombin and factor Xa and inactivates it
What is the effect of heparin on antithrombin III?
Makes it 1000x more potent
