Physiology Flashcards
Coombs test
antoglobulin testing
aetiology of positive Coombs test
haemolytic anaemia
haemolytic transfusion reactions
haemolytic disease of newborn
indirect antiglobulin testing (IAT)
+ uses
detects antibodies present in the patient’s plasma
can be used in cross-matching or to detect maternal anti-D IgG
coagulation
formation of a blood clot.
Essential to Haemostasis
Process is characterised by a cascade of events which lead to formation of a blood clot.
Pathways of coagulation
Extrinsic: triggered by trauma which causes blood to escape circulation
Intrinsic: triggered by internal damage to vessel all
extrinsic pathway- clotting factors
VII, III TF-VIIa complex X -> Xa Va Thrombin (XIII)
extrinsic pathway of clotting
Damage to blood vessel - > Factor VII exits the circulation into surrounding tissues.
Tissue factor (III) is released by damaged cells outside the circulation
Factor VII and III form TF-VIIa complex
TF-VIIa then activates factor X into active Factor Xa
Xa+ Va trigger formation of thrombin
Responsible for initial generation of activated Factor X
intrinsic pathway- clotting factors
XII VIII IX + VIII -> Enzyme complex Factor X activated Factor Va
intrinsic pathway
Factor XII activated when it comes into contact with negatively charge collagen on the damaged endothelium, triggering cascade.
Along with clotting factors, platelets form a cellular ‘Plug’ at site of injury.
Platelets also release mediators that facilitate further clotting, including factor VIII.
Factor IX combines with Factor VIII to form enzyme complex that activates factor X, which along with factor Va, stimulates production of thrombin
Common pathway of clotting
intrinsic and extrinsic pathways converge.
Activated factor X -> inactive enzyme prothrombin (II) converted to its active form thrombin (IIa) by prothrombinase
Thrombin then converts soluble fibrinogens into insoluble fibrin strands.
Fibrin strands are further stabilised by factor XIII
regulation of clotting
Negative feedback on coagulation cascade
- Protein C and protein S
Antithrombin
protease inhibitor that degrades thrombin, factor IXa, factor Xa, factor XIa and factor XIIa
Constantly active, but can be activated further by heparins
protein S
activated following contact by thrombomodulin (activated by thrombin)
Along with co-factors (including protein S), activated protein C degrades factor V and factor VIIa, thus slowing rate of clotting.
protein C deficiency
Inherited or acquired (sepsis & liver disease)
Due to reduction in protein C, clotting cascade is under less inhibition.
patient care pre-disposed to abnormal and excessive clotting, leading to illnesses including DVT and stroke
fibrinolysis
fibrin is dissolved - leading to consequent dissolution of the clot.
Endothelial cells of blood vessel wall secrete tissue plasminogen activators (tPA) which convert precursor plasminogen to plasmin.
Plasmin then cleaves fibrin within the thrombus.
haemophilia
inherited bleeding disorder caused by partial or total deficiency in specific clotting factors.
Haemophilia A
deficiency in factor VIII
Haemophilia B
deficiency in factor IX
Haemophilia C
deficiency in factor XI
presentation of haemophilia
bruise easily.
Bleed spontaneously
Bleed for longer
haematopoiesis
production of cells that circulate in the bloodstream.
erythropoiesis
process by which RBCs are produced
sites of erythropoiesis
very early foetus: yolk sac
2-5 months gestation: liver and spleen
5 months gestation; bone marrow
Children- bone marrow of most bones
Adults- bone marrow of vertebrae, ribs, sternum, sacrum, pelvic and proximal femur
inadequate erythropoiesis in bone marrow
can trigger extra medullary hematopoiesis
commonly seen in haemoglobinopathies (thalassaemia’s and myelofibrosis
stages of erythropoiesis
begins with the haemocytoblast.
Some differentiate into common myeloid progenitor cells.
Go onto produce erythrocytes, mast cells , megakaryocytic and myeloblasts
Some differentiate into common lymphoid progenitor.
Go onto produce NKCs and lymphocytes
process of myeloid progenitor cells to fully mature RBCs
Myeloid progenitor cells become normoblasts (erythroblasts) Present in bone marrow only.
Lose organelles and nucleus to mature into reticulocytes.
Some reticulocytes released into peripheral circulation.
Nuclear extrusion: mature erythrocytes have no nucleus
Reticulocytes lose remaining organelles as they mature into erythrocytes
Nucleated RBCs present in sample of bone marrow
indicates release of incompletely developed cells.
Can occur in pathology such as thalaaemia, severe anaemia, or haematological malignancy
regulation of erythropoiesis
Erythropoietin (EPO )
erythropoietin
Glycoprotein cytokine
secreted by kidney
constantly secreted at a low level, sufficient for normal regulation of erythropoiesis
EPO feedback loop
reduced partial pressure of oxygen in the kidney is detected by renal interstitial peritubular cells.
In response: surge of EPO production, which acts in the bone marrow to stimulate increased RBC production
Causes pO2 to rise and EPO level to fall
CKD related to EPO
CKD often cause anaemia.
In damaged kidney, reduced basal level EPO production and a reduced response to hypoxia leading to anaemia.
Counteract with EPO injections as required
Underproduction of RBCs
Results in anaemia: low Hb concentration
Can be caused by decreased red cell production or increased red cell removal
Reduced RBC production
- luck of building block: iron, folate, B12 deficiency
- failure of stimuli: EPO deficiency due to CKD
-Bone marrow failure: aplastic anaemia
Overproduction of RBCs
Seen in polycythaemia rubra vera
polycythaemia rubra vera
Myeloproliferative disease which results from dysregulation at the level of the haematopoietic stem cell.
EPO production is switched off, but excess RBCs are continually produced.
JAK-2 mutation
Usually affects patients >60 years
Regular monitoring
Can cause increased risk of thrombin
iron absorption
occurs in duodenum and upper jejunum.
transporter protein DMT1
Located on apical surface of erythrocytes.
Facilitates uptake of non-harm ferrous iron from intestinal lumen
Ferric iron must be reduced to ferrous iron by duodenal cytochrome before uptake by DMT1
iron with erythrocytes
stored as ferritin
transferred into bloodstream via protein ferroportin
Bound iron
Mostly transported to bone marrow for erythropoiesis.
Some iron is taken up by macrophages in reticuloendothelial system as storage pool
regulation of iron absorption
Hepcidin
hepcidin
peptide
primary regulation of absorption of iron
expressed by the liver.
directly binds to ferroportin causing its degradation and preventing iron from leaving the cell.
Inhibits transcription of DMT1 gene.
free iron
toxic to cells as it acts as a catalyst in formation of free radicals
complex regulatory system to ensure safe absorption, transportation and utilisation of iron
iron excretion
no specific mechanism for iron excretion.
iron levels balanced by regulating iron absorption to match natural losses.
recommended iron dietary intake
10-20 mg per day
iron recycling
occurs within reticuloendothelial system.
Iron is freed from storage and returned to active pool
Iron storage
Ferritin
Haemosiderin (insoluble derivative)
Highest concentration of stored iron in the liver, spleen and bone marrow
hereditary haemochromatosis
autosomal recessive condition characterised by excessive absorption of iron.
Most susceptible organs: liver, adrenal glands, heart, joints and pancreas
Patient presentation: Cirrhosis, adrenal insufficiency, heart failure, arthritis and diabetes.
treatment: therapeutic phlebotomy
mononuclear phagocyte system
Network of phagocytic cells in the blood and lymphatic system.
Also called reticuloendothelial system
Function of mononuclear phagocyte system
identify foreign antigens and start appropriate immune response.
Antigens re phagocytosed
Also plays a role in destruction of old and dysfunctional cells.
Cells of MPS
Primary cell: Phagocyte
Common phagocytes: macrophages, dendritic cells and granulocyress
Monocytes
formed in bone marrow and circulated in blood.
Migrate into surrounding tissues.
In tissues, mature to become histiocytes or macrophages
macrophages
CNS: microglial cells
Liver: Kupffer cell
Lungss: Alveolar macrophage
Skin and mucosa: Langerhans Cells
Organs of mononuclear phagocyte system
spleen
lymphatic system
liver
Spleen
formed from red pulp and white pulp
Also serves as pool for platelets and RBCs
30% of platelet are sequestered within spleen- ready for rapid mobilisation
red pulp of spleen
contains endothelial macrophages
ensure defective or ageing red blood cells are Phagocytosed
allows any dysfunctional RBCs to be disposed of and the iron within them recycled.
white pulp of spleen
responsible for immunological function of spleen and contains B and T lymphocytes
lymphatic system
consists of lymphatic vessels and lymph nodes- filter tissue fluid from blood
Lymph nodes house b and T lymphocytes
Liver
contains Kupffer cells which reside in sinusoids.
As blood enters the liver via the portal vein and drains into sinusoids, Kupffer cells remove foreign material through phagocytosis.
Also stimulate local inflammatory response using cytokines and oxygen radicals.
Bilirubin conjugated here and secreted in bile
Kupffer cells
involved in the metabolism of RBC and haemoglobin.
remove foreign material through phagocytosis
Haem portion: further broken down into iron for immediate reuse or for storage.
Globin chains are reused
Hyposplenism
Damage to spleen predisposes to infection by encapsulated bacteria.
Damage can occur directly following trauma, surgery or sickle cell anaemia.
Splenic macrophages responsible for the clearance of blood borne bacteria.
Encapsulated bacteria can only be phagocytosed following opsonisation, and are poorly cleared otherwise.
C3b is an opsonin which facilitates this clearance and is activated by IgM
if spleen is damaged or dysfunction, splenic macrophages are not present to remove opsonised encapsulated bacteria from circulation
Results in bacteria persisting in bloodstream.
structure of platelets
originate from megakaryocytes.
Contain 2 types of granules
Have abundant surface receptors, classified into agonist and adhesion receptors
granules in platelets
Alpha: contain proteins of high molecular weight including vWF, factor V and fibrinogen
Dense: contain low molecular weight molecules such as ATP, ADP, serotonin and calcium ions
Platelet: agonist receptors:
recognise stimulatory molecules (collagen, thrombin, ADP etc)
Platelet adhesion receptors
promote adhesion of platelet to other platelets, vessel wall or leukocytes
(vWF, GPIa-IIa collagen, GPIIb-IIIa fibrinogen)
function of platelets
participation in Haemostasis through formation of blood clots.
Main stages: adhesion , activation and aggregation
platelet adhesion
injury to vessel wall exposes endothelium and collagen fibres.
Exposed collagen fibres bind to vWF released from damaged endothelium, in turn binds to vWF receptors on platelets to promote adhesion.
Exposed collagen also promotes platelet binding
Exposed collagen triggers clotting cascade which generated thrombin (XIIa).
Thrombin converts fibrinogen (I) into fibrin, creating dense network of fibrin fibres.
Fibrin net meshes circulating platelets to form platelet plug
Factor VII not very stable and rapidly broken down.
vWF stabilises it by binding
platelet activation
Binding of platelet to collagen, activates glycoprotein IIb/IIIa pathway (controlled by G-protein coupled receptors).
Result: excretion of DP and thromboxane A2 -> activates other platelets.
Platelet activation results in a morphological change on membrane surface of platelet, increasing surface area and preparing it for aggregation.
platelet aggregation
once activated, platelets express GPIIb/IIIa receptors which can then bind with vWF or fibrinogen.
Fibrinogen facilitates formation of crosslinks between platelets, aiding platelet aggregation to form platelet plug.
fibrinolysis
breakdown of blood clots
Production of platelet plug- positive feedback
plasminogen
produced in the liver
activated to form plasmin by factors XI and XII.
Plasmin breaks down fibrin into fibrin degradation products (d-dimers)
Antiplatelets
Clopidogrel
Aspirin
clopidogrel
Often used as secondary prevention after stroke or MI
Primary MOA: prevention of clot formation through antagonism of agonistic ADP receptor
aspirin
irreversibly inhibits cyclo-oxygenase and blocks production of thromboxane, preventing platelet activation and further aggregation.
Management:
Acute coronary syndromes (unstable angina, NSTEMI, STEMI)
Pregnancy women with moderate/ high risk of pre-eclampia
von willebrand’s disease
Autosomal dominant disease
Very low levels of vWF resulting in reduced platelet adhesion and reduced factor VIII activity
Patient predisposed to bleeding
Presentation: frequent and long-lasting epistaxis, large and easy-bruising, bleeding gums.
Women can have heavy periods and possibly postpartum haemorrhage
Management of Von Willebrand’s Disease
Desmopressin
- release intrinsic stores of vWF and factor VIII
Tranexamic Acid (antifibrinolytic)
thrombocythaemia
Increased serum platelet count.
Primary or secondary (bleeding, infection, chronic inflammation from rheumatoid arthritis/ IBD, trauma/surgery or hyposplenism
Increased rusk of thrombosis (arterial and venous
Management: aspirin
