Exo- Blood, Anaemia, Haemostasis Flashcards
How much blood in L do adults have
5L
What % of blood is
- plasma
- Buffy coat (leukocytes, platelets)
- Erythrocytes (the haematocrit)
- Plasma 55%
- Buffy Coat (leukocytes and platelets) <1%
- Erythrocytes or “Haematocrit” 45%
What is haematopoiesis
formation of blood cells
Start as pluripotent hematopoietic stem cell “Hemocytoblast”
Pluripotent cells then differentiate into mature cells!
Mature blood cell examples
Platelets,
Erythrocytes,
White cells
lymphocytes.
Mature cells have a finite lifespan in the blood… how long for
- red
- platelets
- white cells
- Red cells= 120 days
- Platelets= 7-10 days
- White cells= 6 hours
What Hormones stimulate and control blood cell production?
- Red cells: erythropoietin (EPO)
- White cells: granulocyte colony stimulating factor (GCSF)
- Platelets: thrombopoietin (TPO)
Describe Red cells, Erythrocytes
• Simple cell; no nucleus or mitochondria
• Biconcave disc
- Maximises surface area to volume ratio, SA:V (Greater SA)
- Flexible (can move through capillary beds)
• 4 x 1012/L. (per L of blood)
• Contains haemoglobin, able to carry oxygen
What is • Haemoglobin?
contains iron which reversibly binds oxygen in lungs.
- This oxygen is then carried to and released to tissues
What is Anaemia?
Causes?
deficient haemoglobin levels (or red cells?)
- Acute: due to blood loss (e.g.)
- Chronic: due to vitamin deficiencies, sickle cell disease
Symptoms of anaemia?
- Fatigue
- Dizziness
- Pallor- pale appearance
- Headaches
What is polycythaemia?
Causes?
an increase in red cells (thick blood is hard to pump around the body!)
Causes:
- Raised levels of Erythropoietin (EPO) hormone levels due to hypoxia
- Reduction in plasma volume due to dehydration or smoking
What are platelets?
- Tiny anucleate cells
- Made from megakaryocytes in bone marrow
- Circulate in resting state
- Bind to damaged vessel wall to plug hole and stop bleeding (blood clotting)
- 140 – 400 x 109/L of blood
Name for low platelet count?
thrombocytopenia
- Platelets <80 increased risk of bleeding
- Platelets < 20 spontaneous bleeding / bruising
Name for high platelet count?
thrombocytosis
- Increased rates of arterial and venous thrombosis (obstructing blood flow in circulatory system)
What are neutrophils
- The most prevalent white cell in blood
- Phagocytose and kill bacteria
- Release cytokines/chemokines which cause an inflammatory response- temperature
- “Neutrophilia” Increased in bacterial infections
- Neutropenia” Low number after chemotherapy or frequent/severe infections
What are lymphocytes
- Fight viral infections
- “Lymphocytosis” high number in EBV infection (glandular fever)
- “Immunodeficiency” Lack of lymphocytes
- E.g. HIV virus infects CD4 T cells- Immunodeficiency virus
What are B Lymphocytes (made in bone marrow)
- Differentiate into plasma cells
- Produce immunoglobulins (antibodies) when stimulated by exposure to a foreign antigen
- Vital for immunity and response to vaccinations
What are T lymphocytes?
- CD4 (helper) cells
- CD8 (cytotoxic) cells
- Aid B cells in antibody generation and also responsible for cell mediated immunity
What is Leukaemia?
Leukaemia- Malignancy of white blood cells
Difference between acute and chronic leukaemia?
Acute leukaemia: proliferation of immature cells without differentiation
Chronic leukaemias: proliferation with differentiation
In leukaemia- Bone marrow is replaced by malignant cells, symptoms:
Anaemia (fatigue, pallor)
Neutropenia (infections)
Thrombocytopenia (bleeding & bruising)
4 Classifications of Leukaemia…
- Acute myeloid leukaemia- Myeloblast
- Acute lymphoblastic leukaemia- Common lymphoid progenitor
- Chronic myeloid leukaemia
- Chronic lymphocytic leukaemia- B lymphocytes
What is lymphoma?
Malignancy of lymphoid cells, predominantly in lymph nodes
• Hodgkin’s lymphoma
• Non Hodgkin lymphoma
What is myeloma?
Malignant proliferation of plasma cells
Produces monoclonal immunoglobulin (paraprotein)
Clinical features:
Calcium (hypercalcaemia – bone pain, constipation)
Renal failure
Anaemia
Bone lesions (lytic lesions, fractures, pain)
Treatment – outpatient, mainly oral chemotherapy
Name some Plasma proteins and their functions?
Albumin- regulate the oncotic pressure of blood
- Carrier proteins for nutrients or hormones etc.
- Coagulation proteins
- Series of proteins that circulate in an inactive form
- Function= make blood clot
- Convert soluble fibrinogen-> insoluble fibrin polymer
- Overactivity= thrombosis
- Failure= bleeding
• Immunoglobins (Antibodies)
- Produced by plasma cells in response to exposure to foreign substance
- Different classes (IgG, IgA, IgM, IgE)
- Basis of vaccination
Red cells carry proteins on their surface (antigens) which differ between individuals
- Over 400 different systems of red cell antigens
What are the 2 main ones?
2 most important systems:
ABO and Rhesus
- Donors must be compatible in both systems!
How does the ABO blood group system work…
Inheritance pattern=
- O is recessive, so O = O,O
- A = AA or AO,
- B = BB or BO,
- AB = AB
UK population: O= 45%, A= 40%,B=12%, AB= 3%
Who can O receive/give blood to?
O blood has neither A or B antigens, has Antibodies against both!
Can receive blood from only O (Universal donors) but can give blood to all 3 other types.
What can A give/receive blood to?
- Give to A or AB
- Receive from A or O
Have A antigens and antibodies against B.
What can AB give/receive blood to?
Both A and B antigens but no antibodies
- Can receive from everyone (Universal recipients)
- Only give blood to AB
How does Rhesus system work?
Rh system
- if Rh antigen is present on surface of RBC= Rh positive +
- if Rh antigen is NOT present on surface of RBC= Rh negative +
85% of population D positive.
If you are D negative you can make anti D.
o Pregnancy- women given anti D to prevent sensitisation
Indications for a blood transfusion
- Hypovolaemia/ blood loss
- Severe anaemia
- Anaemia that cannot be corrected by bone marrow function
Contradictions to blood transfusions
- Iron deficiency or B12/folate def
- Minor blood loss
- Asymptomatic anaemia
A blood transfusion can also have serious, life-threatening complications- RISKS
• ABO incompatibility reaction – can be rapidly fatal
• Delayed transfusion reactions
• Febrile (fever) reactions, urticarial reactions (hives/ skin rash)
• Fluid overload, pulmonary oedema
• Infections:
- Bacterial
- Viral (HIV, hepatitis B and C)
- Malaria
- Prions (vCJD)
• Long term – iron overload: damage to heart, liver
Definition of anaemia?
Haemoglobin concentration below normal range ‘grams per litre’
Symptoms of Anaemia- what the px complains
- Fatigue
- Reduced exercise tolerance
- Shortness of breath on exertion and at rest
- Postural hypotension
- Dizziness
- Palpitations
- Angina- when anaemia is very severe
- Heart failure- shortness of breath (SOB) (anaemia is very severe)
Signs of Anaemia- what is found when examining the px
- Pallor- pale
- Tachycardia
- Heart murmurs
- Koilonychia (iron deficiency)- finger nails go the opposite way
- Angular stomatitis
- Glossitis (B12/ folate deficiency)
What is • Mean cell volume (MCV)?
in fl= femtolitres
how big the red cells are
- Low <82 Microcytic anaemia- red cells are too small due to iron deficiency
- Normal= Normocytic
- High > 96 Macrocytic anaemia – big size, vitamin b12 and folic acid deficiency
Classification of Anaemia (3)
- Microcytic
- Macrocytic
- Normocytic
Causes of Microcytic anaemia
small RBCs
- Iron deficiency
- Thalassaemia; group of inherited conditions that affect haemoglobin- produce no/little haemaglobin
- Anaemia of chronic disease (rarely)
Causes of macrocytic anaemia (big RBCs)
- vit. B12 deficiency
- B9 deficiency
Causes of Macrocytic RBCs without anaemia
- Liver disease
- Hypothyroidism
- Alcohol
Causes of Normocytic anaemia- when BCs are normal sized
- Acute bleeding- lose lots of red cells
- Haemolysis: congenital, acquired
- Aplastic anaemia
- Anaemia of chronic disease
Physiological Adaptations to Anaemia-
- Tachycardia- pump blood around body faster to get more oxygen to tissues
- Cardiomegaly- abnormal enlargement of the heart
- Increased cardiac output
- Right shift oxygen dissociation curve- better delivery of oxygen to the tissues
Cause of iron deficiency:
- Reduced intake (almost impossible in the UK)
- Increased requirements e.g. pregnancy/ childbirth, malabsorption, coeliac disease
- Chronic blood loss- Menorrhagia (heavy menstrual bleeding), GI blood loss: Upper GI/ Lower GI
- Abnormal if food in men- investigate GI tract!! As they don’t have periods
How to do diagnose.. Diagnosis of Iron deficiency-
Full Blood Count (FBC): Hb, MCV, MCHC (all 3 parameters will be low)
• Main test used in UK= Serum Ferritin- measure amount of ferritin in the blood
Extra tests (not usually used)- • Fe and TIBC • Bone marrow or liver biopsy = tissue iron stores
Treatment of Iron deficiency
Treat the cause
Ferrous sulphate 200mg oral od, until haemoglobin normal and then further 3 months to rebuild stores
B12 and Folate deficiency- these are required by all cells!
For what? (2)
- Necessary for haematopoiesis
- Necessary for DNA synthesis of all cells
What does B12/folate deficiency cause? (4)
- Megaloblastic anaemia-
- Macrocytic anaemia (High MCV of >96 fl)
- leukopenia
- thrombocytopenia
What is megaloblastic anaemia?
Megaloblastic anemia is an anemia (of macrocytic classification) that results from inhibition of DNA synthesis during red blood cell production.
Where do we get B12 from?
- Bacterial fermentation, animal products
How is B12 metabolised?
Adsorption- intrinsic factor from stomach absorbed it in terminal ileum as complex
Stored in body for 4 years
Causes of B12 deficiency
Failure of absorption in terminal ileum due to resection, crohn’s, TB, lymphoma
Lack of intrinsic factor ‘IF’-
Dietary deficiency
What is pernicious anaemia?
Autoimmune disorder
Pernicious anemia is a condition in which the body can’t make enough healthy red blood cells because it doesn’t have enough vitamin B12. …
Technically, the term “pernicious anemia” refers to vitamin B12 deficiency due to a lack of intrinsic factor.
- Autoantibodies against intrinsic factor; blocks binding of IF to vitamin B12
- Associated with other autoimmune disorders especially thyroid disease and vitiligo
- No point of giving oral B12- only for vegans
- Injection of B12 every 3 months instead
What is a gastrectomy?
A gastrectomy is a medical procedure where all or part of the stomach is surgically removed.
What is Pancytopenia
Low WBC and platelet count
B12 Deficiency diagnosis?
- Serum B12 levels
- In pernicious anaemia
• Intrinsic factor antibodies 50%
• Parietal cell antibodies 80% but not very specific
B12 deficiency treatment
- Parenteral Hydroxycobalamin
- 1mg intramuscular every 2 days initially
- Give before folate if mixed/ unknown deficiency
- Reticulocyte response
- Hb increase 1-1.5g per week
- Risk of hypokalaemia
- 1mg every 3 months for life maintenance
Folate deficiency causes…
- Necessary for DNA synthesis
- Macrocytic anaemia
- Megaloblastic bone marrow
- Pancytopenia with low WBC and platelets
How to get folate?
- Dietary source: fresh fruit and vegetables
Causes of Folate deficiency:
- Dietary
- Malabsorption- coeliac disease
- Increased requirements: pregnancy, haemolysis- destruction of red cells, some drugs e.g. folate antagonists
Folate deficiency treatment-
Oral folate 5mg tablet daily (smallest tablet you can get but really only need 10th of this)
Works for all causes including malabsorption
What is Sickle cell disease?
Sickle cell disease is a group of disorders that affects haemoglobin,
People with this disorder have atypical hemoglobin molecules called hemoglobin S, which can distort red blood cells into a sickle, or crescent, shape.
A. Recessive!
Single point mutation.
- Heterozygous patients protected from malaria
- Develop painful vaso-occlusive sickle cell crises
- Crises precipitated by infection, cold, hypoxia etc.
- Diagnose by requesting FBC, sickle cell test and haemoglobin electrophoresis
- Halflife of RBC is shorter e.g. 10 days!
Describe normal haemostasis
- Injury to blood vessel
- Localised vasoconstriction at site of injury
- Adhesion of platelets to damaged vessel wall and formation of platelet aggregate or plug
- Activation of the coagulation cascade leading to fibrin formation, reinforcing the platelet plug
- Activation of the fibrinolytic system which digests the haemostatic plug, re-establishing vascular patency
What is Secondary haemostasis?
the coagulation cascade
What does factor 7 do?
Factor 7a- activates 2 parts of the coagulation
Whole series of enzymes
End up with insoluble fibrin
Coagulation problems with primary haemostasis-
– Involves vessel wall, platelets, and von Willebrand factor
– Present with purpura (micro bleeding in skin),
- bruising,
- bleeding from cuts,
- heavy periods
- surgical bleeding
Coagulation problems with secondary haemostasis-
– Involves the coagulation cascade
– Presents with joint and muscle haematomas
- surgical bleeding.
- Bruising is not prominent
History Qs to ask someone with a bleeding disorder
– Easy bruising? spontaneous – Bleeding after cuts/minor injury – Epistaxis – Menorrhagia – Bleeding (overnight not the few mins after) after dental extractions – Bleeding after surgery – Family history of a bleeding disorder – Drugs eg aspirin, warfarin, cytotoxics – Alcohol
What is Menorrhagia?
Heavy menstrual periods
What is Epistaxis?
Nose bleed
What is Haemoptysis
Coughing blood
What is haematemesis
Vomiting blood
What is Haematuria?
Blood in urine
What is Melaena
Black stool due to bleeding from upper GI tract
Clinical signs of bleeding problem
– Ecchymoses (Bruises)- not always – Purpura – Haemarthrosis – Damaged joints – Anaemia (due to bleeding) – Signs of liver disease – Splenomegaly
Investigations that can be done for determining bleeding problems
– Full Blood Count - Platelet count – Clotting screen – Prothrombin time (PT) – APTT – Fibrinogen levels? – Bleeding time or PFA (automated Platelet Function Analysis)- how the platelets function
Depending on the above results, more specialised investigations can be performed.
Treatment of bleeding problems,
- Depends on diagnosis e.g.
– Haemophilia A - FVIII concentrate
– Haemophilia B – FIX concentrate
– Thrombocytopenia – Platelet transfusion
– Warfarin overdose – Vitamin K
Name some Vascular Bleeding Disorders
INHERITED=
• Hereditary Haemorrhagic Telangiectasia HHT
• Ehlers-Danlos Syndrome
ACQUIRED=
• Senile Purpura
• Scurvy (Vitamin C deficiency)
• Steroid Purpura
What is HHT?
• Hereditary Haemorrhagic Telangiectasia HHT- can be in gums, take a while for bleeding to stop
What is Ehlers-Danlos syndrome?
collagen disorder, vessels don’t vasoconstrict= excessive bleeding,
skin becomes very hyperelastic= saggy!,
joints hyperextend,
10 subtypes of E.D., most are mild.
Name some inherited coagulation factor disorders
Haemophilia A
• X-linked
Haemophilia B
• X-linked
Von Willebrand disease
• Autosomal dominant
Others
• Autosomal recessive
• Deficiency of fibrinogen, FII, FV, FVII, FX, FXI, FXIII
What is haemophilia?
• Haemophilia A – FVIII deficiency
• Haemophilia B – FIX deficiency
(factors 8 and 9)
- A and B are identical, have to measure levels in the blood to identify
- Identical clinical features
- Sex linked inheritance
• Sites of bleeding
– Joints, muscles, post trauma, post-operative
Haemophilia treatment?
If mild haemophilia A: Desmopressin (DDAVP)
• Releases FVIII from endothelium
For all severities: FVIII/IX concentrate
What is Von Willebrand disease?
- Commonest inherited bleeding disorder
- Affects up to 1 in 1000 of the population
- Autosomal dominant
- 3 main types with many subtypes
- In general, a milder bleeding disorder than haemophilia
- Clotting factor PLUS platelet abnormality
- Sites of bleeding: Bruising, cuts, gums, epistaxis, menorrhagia, post operative, post trauma
VWF protects factor 8 from being broken down
Tx for VW disease
– DDAVP
– Intermediate purity (plasma derived) FVIII
Platelet disorders- Reduced count
Platelet Number Abnormalities- Thrombocytopenia
Inherited
- MYH-9 related thrombocytopenia
- Another 32 other inherited causes
Acquired
- Failure of platelet production
- Increased consumption of platelets
- Hypersplenism
Platelet disorders- function abnormalities
Platelet Function Abnormalities:
Inherited
- Glanzmann’s thrombasthenia
- Storage pool disease
Acquired
- Aspirin or Clopidogrel usage
- Renal disease
- Liver disease
- DIC
What is Thrombosis?
blood coagulation (formation of a blood clot) inside a vessel
Causes of Arterial thrombosis?
- High pressure
- Platelet rich
- Examples: myocardial infarction (MI), stroke
- Treat with antiplatelet drugs
Causes of Venous thrombosis?
- Low pressure
- Fibrin rich
- Examples: deep vein thrombosis (DVT), pulmonary embolism (PE)
- Treat with anticoagulants
Risk factors of venous thrombosis-
Acquired
- Age, previous VTE
- Surgery/trauma, immobility, obesity
- Cancer, serious illness
- Pregnancy, contraceptive pill, HRT
Inherited (Thrombophilia)
- 5 known causes
Arterial Thrombosis Risk Factors
- Smoking
- Obesity
- Hypertension
- Diabetes mellitus
- Older age
- Not inherited thrombophilia
Name some Vascular Bleeding Disorders
Inherited - Hereditary Haemorrhagic Telangiectasia - Ehlers-Danlos Syndrome Acquired - Senile Purpura- bruising in the skin - Scurvy (Vitamin C deficiency) - Steroid Purpura
Causes of Thrombocytopenia
• Failure of platelet production
- Vitamin B12 or folate deficiency
- Bone marrow infiltration (leukaemia or metastases)
- Radiation, cytotoxic therapy
• Increased consumption of platelets
- Immune thrombocytopenia (ITP)
- Disseminated intravascular coagulation (DIC)
- HIV infection
• Hypersplenism
What is Immune thrombocytopenia (ITP)?
destruction of platelets
Children- usually follow acute infection, self-limiting so usually not treated
Adults- cause not clear, chronic, treat if there is bleeding
Diagnosis of ITP
- Thrombocytopenia
- Exclusion of other causes of thrombocytopenia
- Bone marrow examination
Treatment of ITP
- Steroids
- Intravenous immunoglobulin
- Splenectomy, removal of spleen
- Thrombopoietin receptor analogues
What is Disseminated intravascular coagulation (DIC)?
- Breakdown of haemostatic balance
- Simultaneous bleeding and microvascular thrombosis
- Life threatening condition
Causes of DIC?
– sepsis
– obstetric (childbirth)
– malignancy
Treatment of DIC?
– Remove underlying cause
– Give plasma and platelets if bleeding
What is Splenomegaly?
enlargement of the spleen, measured by size or weight
- can affect platelet distribution
Platelet Function Abnormalities?
• Inherited
- Glanzmann’s thrombasthenia
- Storage pool disease
• Acquired – Antiplatelet drugs – Renal disease – Liver disease – DIC
Name 3 Antiplatelet drugs?
Aspirin
– Inhibits cyclo-oxygenase (platelet enzyme) irreversibly
– Act for lifetime of platelet ie 7-10 days
Clopidogrel
– Blocks ADP receptor (on platelet surface) irreversibly
– Acts for lifetime of platelet ie 7-10 days
Prasugrel
– Blocks ADP receptor irreversibly
– Acts for lifetime of platelet ie 7-10days
– More rapid and consistent inhibition than clopidogrel
What is Renal Disease?
• Increased bleeding… causing:
– Anaemia
– Thrombocytopenia in autoimmune renal disease
– Uraemia
Treat with DDAVP and/or dialysis
• Increased thrombotic risk
– In nephrotic syndrome (Acquired antithrombin deficiency)
What is Liver disease?
- Site of synthesis of coagulation factors and fibrinogen
- Liver disease often associated with bleeding and prolonged prothrombin time
• Often more than one cause for bleeding in liver disease
Causes of bleeding in liver disease
- Reduced clotting factors (poor synthesis or vit. K deficiency)
- Thrombocytopenia (due to hypersplenism)
- Platelet function defect
- Portal hypertension; bleeding from varices
- Dysfibrinogenemia
- Increased fibrinolysis
Vitamin K deficiency problems…
• Vitamin K necessary for the correct synthesis of coagulation factors II, VII, XI and X
Manifests as prolonged prothrombin time
Drugs as causes of acquired bleeding disorders
• Antiplatelet drugs such as aspirin
– Affect platelet function
• Anticoagulants such as heparin and warfarin
– Affect coagulation cascade
- Steroids make tissues thin and cause bruising and bleeding
- Many drugs can affect liver, kidneys and bone marrow
Thrombosis- Two types: depending on in which circulation…
1) In the arterial circulation (eg MI or Stroke):
– high pressure system
– platelet rich
2) In the venous circulation (eg DVT or PE):
– low pressure system
– fibrin rich
DVT= deep vein thromb. PE= pulmonary embolism
Thrombosis treatment
Arterial thrombosis – Antiplatelet drugs
Venous thrombosis – Anticoagulant drugs
Name Antiplatelet drugs (4)
- Aspirin
- Clopidogrel
- Prasugrel
- Ticagrelor
Name some Anticoagulants- 3 types: IV, Subcutans. ; Oral
• Intravenous
- Unfractionated heparin
• Subcutaneous
- Low molecular weight heparin
• Oral
- Warfarin,
- Dabigatran, rivaroxaban, apixaban, edoxaban
Name some Oral Anticoagulants ?
- vit.K antagonists (e.g. warfarin, acenocoumarol)
Direct oral anticoagulants:
- Dabigatran
- Rivaroxaban
- Apixaban
- Edoxaban
What is Heparin?
• Glycosaminoglycan
- Binds to antithrombin and increases its activity
- Indirect thrombin inhibitor
- Not absorbed from the gut so given iv or sc
- Monitor with the APTT test
What is Low molecular weight heparin
- Smaller molecule made from heparin
- Less variation in dose
- Given subcutaneously
- Renally excreted
- Given once daily
- Weight adjusted dosing
- Used for treatment and prophylaxis
What is Warfarin: Pharmacology
- Given by mouth completely and rapidly absorbed
* 99% plasma protein bound
What does warfarin act on?
• Inhibits the production of factors II, VII, IX, X
How long does effects of warfarin last?
Peak effects after 3-4 days after starting.
Effect still present 4-5 days after stopping.
– ie slow on and slow off action
Side effects of warfarin
Bleeding, embryopathy
Warfarin: Monitoring- how to??
- Measure the INR (International Normalised Ratio)
* Dose of warfarin is based on the INR
What are the Direct Oral Anticoagulants? “DOACs”
- Oral
- No monitor
- Aims to replace heparin and warfarin
- Few interactions with alcohol/food/drugs
- Short half life (10-15 hours)
- More expensive than warfarin
Advantages of DOACs
- Rapid onset of action
- Fixed oral dosing with predictable anticoagulant effect
- Low potential for food or alcohol interactions
- Low potential for drug interactions
- No need for blood monitoring
Disadvantages of DOACs
- Renal elimination
- No specific antidotes for the Xa inhibitors
- Licensed for only specific indications
