blood Flashcards
what are the two major lineages of blood cell?
myeloid and lymphoid
how many different types of blood cell are there?
11
which cells come from the lymphoid lineage?
natural killer cell, t lymphocyte, b lymphocyte, plasma cell
which cells come from the myeloid lineage?
erythrocyte, mast cell, basophil, neutrophil, eosinophil, macrophage (from monocytes), thrombocytes (from megakaryocyte)
which blood cell types end up in the tissue?
mast cells and macrophages
what proportion of the blood is plasma?
55%
what does the plasma of blood contain?
many important components of the blood coagulation (clotting) and immune (fighting infection) systems
Most abundant blood plasma proteins are:
albumin (35-50 g/L), “filler”
Immunoglobulins (15 g/L), involved in fighting infection
fibrinogen (3-5 g/L), involved in clotting
what is the difference between blood serum and blood plasma?
in blood serum the blood is allowed to coagulate before it is centrifuged
Serum = Plasma – Clotting Factors
Plasma = Serum + Clotting Factors (+ clotting inhibitor)
what happens when incompatible blood types are mixed?
antibodies react with antigens on the red blood cell (RBC) membrane, causing haemolysis (RBC rupture)
how are blood groups classified?
based on different antigens (sugars, transmembrane proteins, glycolipids) present on the RBC membrane
what are the most important systems in blood type?
ABO and Rh systems
how is the ABO group classified?
Based on carbohydrate (sugar) antigen present on the RBC membrane
what are the main types of blood group?
AB, A, B, O
which blood type is universal blood donor?
O
which blood type is universal blood recipient?
AB
what happens to the compatibility of blood plasma?
opposite of RBCs
because antibodies are in the plasma
what are the key feature of haemolytic reaction?
Hypotension
Kidney failure
DIC (Bleeding)
what is the Rhesus blood group categorised on?
Based on a transmembrane protein (ion-channel) antigen present on the RBC membrane
what are the two types of rhesus blood group?
Rh+ and Rh-
which rhesus blood group is more common?
Rh+
Ethnicity: Rh- more common in the West (15%) than in Asia or Africa (1%)
what is the most common cause of haemolytic syndrome in newborns and how does it happen?
difference in rhesus blood type
Antibodies from Rh- mother cross placental barrier and cause haemolysis and potentially lethal anaemia in Rh+ foetus/newborn
what are the main causes of thrombosis?
Hypercoagulability Thrombocythaemia (high platelets level) Factor V Leiden Atherosclerosis Cancer
what is neoplasia?
Process of uncontrolled cell growth
what are the two classes of genes implicated with neoplasia?
oncogenes and tumour suppressor genes
how are haematological malignancies classified?
by cell lineage and by location
Leukaemia (blood)
Lymphoma (lymph nodes)
what is polycythaemia?
increased red blood cells
what is Thrombocythaemia?
increased platelets
what is Myelofibrosis?
increased megakaryocytes
what does leukaemia cause?
Accumulation of white blood cells in the bone marrow and blood
bone marrow failure
what effects happen because of bone marrow failure?
Blood hyperviscosity due to increased white cells causing respiratory or neurological symptoms Infection if decreased white cells Tiredness/anaemia Bleeding Bone pain in children
how can lymphoma be classified?
affect T or B lymphocyte
Non-Hodgkin or Hodgkin
(Hodgkin Lymphoma characterised by Reed-Sternberg cells Reed-Sternberg cells generally originate from B lymphocytes, which become enlarged and are multinucleate or have a bilobed nucleus.)
what are the role of growth factors?
direct the transformation of multipotential stem cell into colony forming units (CFU), burst-forming units (BFU) and ultimately specialised blood cells.
what is the role of Colony-stimulating factors?
haemopoiesis of myeloid cells including RBCs
what is the role of lymphokines?
haemopoiesis of lymphocytes and NK cells.
what does iron deficiency cause?
microcytic anaemia Leads to microcytic anaemia (pale and small RBCs) production
what does microcytic anaemia do to RBCs?
smaller than normal and have an increased zone of central pallor increased anisocytosis (variation in size) and poikilocytosis (variation in shape).
what does a B12 or folate deficiency cause?
Megaloblastic anaemia
what does Megaloblastic anaemia do to RBCs?
larger than normal RBCs and includes the formation of macroovalocytes and also may lead to hypersegmented neutrophils
what type of anaemia does blood loss cause?
normocytic anaemia
what does epo do?
It stimulates haemopoiesis of stem cells into erythrocytes (BFU production) in the bone marrow
what causes haemolytic anaemia?
RBC lifespan down from 120 to as little as 20 days
Bone marrow unable to replace sufficient RBCs
how can you get haemolytic anaemia?
either acquired or inherited
acquired can be immune or non-immune
what causes sickle cell anaemia?
Point mutation in the Hb b globin gene Glu 6 to Val
Polymerisation of Hb, distorting RBC
why does sickle cell anaemia cause sickle cell crises?
blockage of microvasculature
what are the two types of thalassemia and how are they caused?
alpha Thalassaemia
Generally large deletions of the a-globin (two a-genes on chrom 16)
beta thalassemia
Point mutations in the b-globin gene
If both genes are affected patient has HbF and b-thalassaemia major
what are the two types of thalassemia and how are they caused?
alpha Thalassaemia
Generally large deletions of the a-globin (two a-genes on chrom 16)
beta thalassemia
Point mutations in the b-globin gene
If both genes are affected patient has HbF and b-thalassaemia major
what does haemostasis prevent?
prevention of severe blood loss after injury
what are the two main processes involved in stopping bleeding?
vasoconstriction and haemostasis
what are the two types of haemostasis?
Primary haemostasis: Platelet activation and aggregation
Secondary haemostasis: Coagulation pathway activation
what are the main characteristics of the primary haemostatic response?
Platelets are activated by collagen and thrombin (amongst others)
Activated platelets undergo shape change (pseudopodia)
Activated platelets clump together (aggregate) to form coagulum
Platelet response alone insufficient to stem bleeds
what are the main features of the secondary haemostatic response?
takes longer time
Involves a “cascade” of proteolytic enzymes in the plasma that activate one another
Activated by tissue factor or contact activation
Produces fibrin clot network
Coagulation response alone insufficient to stem bleeds
what is coagulation triggered by?
tissue factor and drives the secondary haemostatic response through a series of enzymatic reactions
what enzymes make up the coagulation pathway?
serine proteases
what do coagulation factors normally circle in the blood as?
pro-enzymes
what is limited proteolysis?
protein cut by an enzyme that only makes one cut and induces a conformational change
what is the intrinsic pathway?
coagulation caused by something contained within the blood (FXII)
what is the extrinsic pathway?
coagulation triggered by something that had to be added (brain is rich in TF)
where is tissue factor found?
membrane of perivascular cells
what does tissue factor cause?
the auto activation of FVII when bound to it
what does factor VII cause?
the activation of FX to FXa
what does the activation of FX cause?
cleavage of prothrombin (II) to thrombin (IIa) which then causes the conversion of fibrinogen (I) to Fibrin (Ia)
how is the initial process amplified?
thrombin activates FVIII which is a co-factor of F IX which can cleave FX which cleaves prothrombin
thrombin activates FV which also can cleave prothrombin
thrombin activates FXI –> F IX –> FX –> prothrombin
how is the initial process amplified?
thrombin activates FVIII which is a co-factor of F IX which can cleave FX which cleaves prothrombin
thrombin activates FV which also can cleave prothrombin
thrombin activates FXI –> F IX –> FX –> prothrombin
what activates the intrinsic pathway?
contact activation - negatively charged surfaces allow FXII to activate itself which can then activate FXI
what activates the extrinsic pathway?
injury releases tissue factor which activates FVII
what does factor XIII do?
forms cross links on the fibrin clot with Ca++
what is the coagulation pathway powered by?
vitamin-K dependent enzyme-cofactor complexes assembled on phospholipid membranes
which pathway contributes most to the trigger?
extrinsic
TF, FVII
which pathway contributes most to the consolidation phase?
intrinsic
FIX, FVIII, FXI
which pathway contributes most to the clot formation phase?
Common pathway (thrombin, FX, fibrinogen)
what is the lifespan of a platelet?
5-9 days
what are platelets produced by?
megakaryocytes in the bone marrow
what happens to a platelet when it is activated?
gets pseudopaedia
what granules does a platelet contain and what are they used for
alpha granules - contain Fibrinogen, FV, vWF, growth factors
dense granules - contain ADP, ATP,Serotonin,
Calcium, Polyphosphate
what is thromboxane used for in platelets?
auto-activation loop with COX-1
how do platelets bind to collagen?
directly via GPVI and a2b1, and also via GPI and vWF, activating the platelets
how are platelets activated after binding to collagen?
Platelets release ADP (from dense granules) and thromboxane that further activate platelets
what binds fibrinogen to platelets?
aIIbB3 binds fibrinogen
what do fibrinogen and VWF do?
assist in platelet aggregation and holding the platelet plug together
what does AAA stand for?
Abdominal Aortic Aneurysm
what is does an AAA cause?
Progressive dilatation of the abdominal aorta inferior to the renal and above the iliac arteries
High risk of rupture if aneurysm becomes too large
AAA Rupture associated with major internal bleeding and 50% mortality
what is Disseminated intravascular coagulation?
Involves a systemic inflammatory response that leads to a complex picture of microvascular thrombosis and bleeding at the same time
which clotting factors are vitamin K dependent?
FVII, FIX, FX, prothrombin, protein C and protein S
what happens to vitamin K dependent factors and why is it important?
Undergo post-translational modification of glutamic acid (Glu) to g-carboxyglutamic acid (Gla)
Gla binds to negatively charged phospholipids (provided by activated platelets) via Ca2+
This increases the catalytic efficiency of the limited proteolysis dramatically
what is vitamin K deficiency caused by and what is it associated with?
fat malabsoption Associated with (severe) bleeding
Vitamin K is essential for normal haemostasis since it…
Plays a critical role in the formation of Gla-domains in key coagulation factors that bind negatively charged cell membranes
what are the two types of haemophilia?
A + B
what is Haemophilia A caused by?
Deficiency of FVIII
Cofactor for conversion of FX to FXa (intrinsic pathway)
Consolidation phase of thrombin generation
what is Haemophilia B caused by?
Deficiency of FIX (Christmas disease)
FIXa converts FX to FXa (intrinsic pathway)
Consolidation phase of thrombin generation
how is Haemophilia carried?
X-linked recessive
Female carrier, male offspring at risk
Relatively rare
what does prothrombin time measure and what is it prolonged by?
Measures factors in the extrinsic pathway
Prolonged in FVII deficiency
what does Activated Partial Thromboplastin time measure and what is it prolonged by?
Measures factors in the intrinsic pathway
Prolonged in FVIII, FIX, FXI and FXII deficiency
what kind of bleeding is associated with haemophilia?
Severe
“Spontaneous” bleeding into the muscle and joints in particular
Easy bruising
Risk for cerebral haemorrhage
what are the 4 types of von Willebrand disease
Type 1: heterozygous disease (autosomal dominant)
Type 2: functional deficiency (autosomal dominant)
Type 3: complete deficiency (autosomal recessive)
Platelet type: mutation in GP1 (pseudo vWD)
what is vWF?
Large, multimeric glycoprotein
Stabilises FVIII
Involved in platelet adhesion and aggregation
Deficiency is quantitative (type 1,3) or qualitative (2)
where is vWF produced?
Produced by endothelial cell in Weibel-Palade bodies
And by megakaryocytes
what type of bleeding is associated with vW disease?
Mild to severe (depending on type)
Menorrhagia, nose bleeds and bleeding after tooth extractions common
Easy bruising
Risk of gastrointestinal bleeding, petechiae (capillary bleeding in the skin), muscular or joint bleeds if more severe
which type of vW disease is the least serious?
1
what type of bleeding is associated with thrombocytopenia or thrombasthenia?
Generally milder than haemophilia Easy bruising Gum bleeds Epistaxis (nosebleeds) Menorrhagia Petechiae (bleeding from skin microvasculature)
what are the characteristics of veins?
Large diameter Thin wall Thin tunica media Low pressure Valves
what are the characteristics of arteries?
Small diameter Thick wall Thick tunica media High pressure No valves
what are the main causes of venous thrombosis?
Deep vein thrombosis (DVT; arm/leg) Pulmonary embolism (PE; lungs)
what are the main causes of arterial thrombosis?
Myocardial infarction (MI; heart)
Atrial fibrillation (AF; heart)
Peripheral vascular disease (PVD; leg)
Stroke (brain)
when do DVTs occur?
Occurs under low blood flow as opposed to arterial thrombosis which occurs under high flow.
Usually develops around the valves in the deep veins (legs, arms), may lead to pulmonary embolism
what are the characteristics of the thrombus in DVT?
fibrin- and erythrocyte-rich
what causes a PE?
A small part of a deep vein thrombus breaks off (embolus)
The embolus travels via the veins, right atrium and right ventricle to the lung
The embolus blocks an artery in the lung leading to lung tissue infarction
what are the main risk factors for venous thrombosis?
Stasis
endothelial dysfunction
Hypercoagulable state
what are the main risk factors for venous thrombosis?
Stasis
endothelial dysfunction
Hypercoagulable state
what is virchows triad?
circulatory stasis
endothelial injury
hypercoagulable state
what does antithrombin inhibit?
Direct inhibitor of thrombin, FXa and FIXa
what does Tissue Factor Pathway Inhibitor (TFPI) inhibit?
Direct inhibitor of FVIIa/TF and FXa
what does Activated Protein C (aPC) inhibit?
Proteolytically inactivates FVa and FVIIIa
what does Protein S (PS) inhibt?
Cofactor for aPC in the inactivation of FVa/FVIIIa
what is Factor V leiden?
Inherited Activated Protein C Resistance
Point mutation in the Factor V gene which increases the risk of deep venous thrombosis
what is the cause of arterial thrombosis?
atherosclerosis: inflammation of the vessel wall with infiltration of macrophages (> foam cells) and fat deposits > Atherosclerotic plaque
Triggered by rupture of the atherosclerotic plaque
what is the thrombus in arterial thrombosis like?
platelet-rich
where does an atherosclerotic plaque form?
in the tunica intima
what drugs are used to treat athero-thrombosis?
Statins Antiplatelets Fibrinolytics Warfarin/coumarins Direct thrombin inhibitors Direct Anti-Xa
