Haematology Physiology Flashcards
What is the role of hepcidin
It is a negative feedback protein that inhibits intestinal absorption of iron and release of iron from intracellular stores
What factors influence hepcidin production
- Increased by inflammatory cytokines (IL6, TNF, IL1)
- Increased by elevated serum iron levels and iron stores
- Inhibited by erythropoiesis (overrides high iron stores but not inflammatory stimuli)
Outline Iron Homeostasis
Absorbed from GIT as Fe2+
Intracellular modification to Fe3+
Stored intracellularly in enterocytes as ferritin
Released from intracellular stores via ferroportin
Bound to transferrin in blood for transport
Transferrin receptors in BM (70%) and liver/spleen (20%) phagocytose the laden protein and release the Fe (also recycling transferrin)
BM macrophages release Fe3+ from stores using cerumoplasmin (Cu dependent) for use by maturing erythrocytes in erythroblastic clusters
Liver/spleen cells store Fe as ferritin
Regulators of Erythropoeisis
- EPO production from peritubular interstitial cells in kidneys. Stimulated by local tissue hypoxia
- Local tissue hypoxia also increases expression of hypoxia inducible protein (HIF) which potentiates EPO production in kidney (and liver)
- EPO binds to receptors on Rubriblasts (CFU-E) stimulating their differentiation
- Thyroid hormone and growth hormone both promote increased numbers of progenitor stem cells
- Cortisol has a synergistic effect with HIF resulting in burst activity of erythropoiesis
- Inflammatory cytokines (IL1, IL6, TNF) inhibit EPO production
Causes of reduced EPO production
Kidney disease
PTH
Low albumin
Ferritin
Transferrin
Low cortisol/thyroxine
Inhibitors of erythropoeisis
Cytotoxic drugs: chemo, phenobarbital, FBZ, cephalosporins, chloramphenicol
Endogenous: oestrogens, ferritin/transferrin, Auto-AB for EPO; Cu deficiency; B12 deficiency
Order of Red cell maturation
Rubriblast/CFU-E
Prorubricyte
Rubricyte
Metarubricyte
Reticulocyte/polychromatophil
Erythrocyte
Recent evidence for B12 and folate effect on RBC
JVIM 2019 in dogs -Retrospective comparison of anaemia prevalence in dogs with known B12/folate deficiency and anaemic dogs.
No significant differences in the prevalence of anaemia b/w dogs with or without B12/folate deficiencies.
Though high prevalence of B12 deficiency in anaemic dogs. Did not measure MMA
The macrocytic nonregenerative anaemia reported in humans was not evident.
JVIM 2021 - cats with chronic GI disease, prospective cross-sectional study. Functional iron deficiency was common. 3 of 8 cats with elevated MMA had normal B12. All cats with low B12 had higher MMA.
Iron deficiency present in 35% - malabsorptive vs functional. Based on iron parameters was functional
There was a negative correlation for TIBC and MMA. Which may be due to concurrent malabsorption of both vs functional Fe reduction due to inflammation
The cause of anaemia could be one or both factors - alterations of B12 and Fe occurred with and without concurrent anaemia
Pathogenesis/Pathophysiology of DIC
Initiation - an inciting cause results in 0one or more of increased tissue factor exposure, endothelial injury, platelet or complement activation. The result is generation of thrombin and activation of platelets which is compensated for by endogenous inhibitors (heparin, anti-thrombin, prostacyclin, NO, TFPI, Protein C and S)
Amplification - thrombin generation proceeds perpetually exhausting/overwhelming innate inhibitors. This is a result of coagulation mediated inflammation stimulus and inflammation mediated coagulation (a vicious cycle involving DAMPS, inflammation induced endothelial dysfunction and platelet release of proinflammatory cytokines).
Fulminant/Uncompensated - ongoing consumption of anticoagulant factors as well as coagulation factors and platelets. Eventually there is increased levels of tPA and urokinase along with reduction in PAI and TAFI which results in hyperfibrinolysis and a haemorrhagic phenotype.
Diagnosis of DIC
For compensated disease there is no sensitive and specific test, monitoring of trends in thrombin-antithrombin and D-dimers is useful as an indicator of syndrome progression. Also assessing for evidence of target organ microthrombosis such as increasing lactate, azotaemia or dyspnoea.
In Uncompensated phase there is a decrease in platelets and prolonged PT/APTT in 75% of dogs (50% of cats) as well as decreasing antithrombin and marked increases in D dimers (85% of dogs and 50% of cats). Additional findings may include schistocytes and decreasing fibrin/fibrinogen levels.
TEG studies can be helpful in determining where on the coagulation spectrum a patient is but changes are not sensitive/specific for DIC. In one prospective study 44% of dogs were hypercoagulable, 34% normal, 22% hypocoagulable.
