Blood Pressure & Hypertension Flashcards

Question

What are some endocrine, medical and renal/vascular causes of hypertension?

Answer 1

**Endocrine** - primary Aldosteronism, phaeochromocytoma /paraganglioma (nerve cells regulating blood pressure) **Medical** - Oestrogen oral contraceptives, Non-steroidal anti-inflammatory drugs (NSAIDs) and Alcohol **Renal/vascular** - Renal artery stenosis (atheroma/fibromuscular) and Glomerulonephritis/pyelonephritis/vasculitis (inflammation of the kidney)

Answer 2

Blood pressure gradients a) Oncotic pressure - moves fluid into capillaries b) Hydrostatic pressure - moves fluid out into the tissue Balance of these forces dictate whether fluid moves in/out of the capillaries Arterial end - fluid moves out of the capillaries Venous end - fluid moves back into the capillaries

Answer 3

**Blood pressure** - must be maintained to provide perfusion of all the body organs **Blood volume**- must be maintained to provide the venous return necessary for adequate cardiac output and blood pressure generation Challenges 1. Fluid deprivation 2. Fluid overload 3. Fluid depletion 4. Meals 5. Exercise 6. Temperature changes 7. Postural changes 8. Zero gravity/acceleration

Answer 4

Sensing - arterial baroreceptors Effectors NS - Symapthetic & parasympathetic Hormones - RAAS, adrenaline and vasopressin Local factors - NO, endothelin, kinins, prostaglandins, renin-angiotensin Effector organs 1. heart 2. arterioles Response time - seconds/minutes

Answer 5

ARTERIAL BLOOD PRESSURE (ABP) measured in mmHg - typical brachial ABP in a young adult ~ 120/80 mmHg ABP = CO x SVR CARDIAC OUTPUT (CO) - output from ventricle in 1 minute CO = stroke volume (~70 mL) x heart rate (60-80/min) cardiac output ~ 5 L/min SYSTEMIC VASCULAR RESISTANCE (SVR) - majority of vascular resistance is provided by arterioles - note significantly effected by blood vessel radius Conclusion: arterial blood pressure will be dependent on **heart rate, cardiac contractility and arteriolar tone**

Answer 6

More research

Answer 7

Baroreceptor reflex - defense of blood pressure and cerebral blood flow Blood pressure sensed by baroreceptors – carotid arteries and in aortic arch – stretch allows the body to gain information of the blood pressure state Signal send to vasomotor centre of the brain If blood pressure drops... 1. Sympathetic NS activation (Alpha 1 and beta 1) - effects on the heart, blood vessels, adrenals and kidney - Note both the arteriolar and venous system constrict upon sympathetic NS activaion, to ensure that blood doesn’t pool in one system 2. Parasympathetic NS activation - heart - bradycardia (muscarinic receptr) Note - as we age we tend to lose our baroreflex

Answer 8

70kg man: Blood (intravascular) volume - 4 L Extracellular (interstitial) fluid - 12 L Intracellular fluid - 32 L Blood volume is dependent on the overall hydration of the body which is regulated by the kidney (level of reabsorption/excretion)

Answer 9

Blood volume is required to maintain venous return to the heart to enable it to produce an adequate cardiac output Sensors 1. Kidneys - juxtaglomerular cells sense low Na+ delivery and urine flow 2. Heart - low pressure stretch receptors in atria Efferent signals 1. Renin-angiotensin system 2. Sympathetic nerves 3. Other mechanisms

Answer 10

1. Blood volume sensed by juxtaglomerular cells in the kidney 2. Release renin 3. Renin converts angiotensinogen into angiotensin I 4. Angiotensin converting enzymes converts angiotensin I into angiotensin II 5. Angiotensin II - wide range of impacts a) Increases efferent arteriolar constriction - increasing GF b) Arteriole vasoconstriction - increasing blood pressure c) Stimulate posterior pituatary - thirst and vasopressin (increase H20 reabsoprtion) d) Aldosterone release - increase Na+ reasborption - increase H20 absorption

Answer 11

1. Decrease in intravascular volume 2. Decreased return to heart 3. Decreased ventricular filling 4. Cardiac output decreases 5. Blood pressure decreases 6. Renal perfusion decreases 7. Decrease capillary hydrostatic pressure

Answer 12

Blood volume and blood pressure receptors

Answer 13

Treatment - Intravenous fluid infusion and blood transfusion

Answer 14

Basically the systems that normally correct for decrease blood pressure/volume are activated during heart failure leading to extra stress that can overwhelm the heart

Answer 15

Work further down on the angiotensin system – blocking at the receptor level – actions and indications are similar Usually used for people on ACE inhibitors that develop and dry cough

Answer 16

Reducing the reabsorption of sodium and chloride

Answer 17

Aldosterone receptor antagonists - decrease in Na+/K+ exchanger - less re-absorption Sodium channel blockers - block sodium channels in luminal membrane

Answer 18

Decreased activation of B1 - inhibits cAMP formation and PKA activation - leading to a variety of downstream effects - decreased contractility of muscle cell, decreased calcium availability, etc. 1. Vasodilation 2. Decrease ventricular response rate 3. Decrease excitability of the conduction system 4. Decreased ventricular contractility

Answer 19

Cholesterol and triglycerides transported in lipoprotein

Answer 20

Lipoproteins - Transport cholesterol & triglycerides around the body via the circulation Main types: 1. Chylomicrons 2. Very Low Density Lipoprotein (VLDL) 3. Intermediate Density Lipoprotein (IDL) 4. Low Density Lipoprotein (LDL) 5. High Density Lipoprotein (HDL) Classification by size and density - decreasing size and increasing density

Answer 21

Sources - Lipids absorbed from the gut (exogenous lipid pathway) or created in the liver (endogenous lipid pathway) Lipids are transported across the body to different tissues Lipids can also be returned to the liver - reverse cholesterol transport - where they can be excreted

Answer 22

Dietary lipids – taken up in the small intestine – packaged in a chylomicron Chylomircons are transported to the liver but on their way there they are broken down by Lipoprotein lipase (releasing glycerol and non-essential fatty acids), which are absorbed by targets (muscle and adipose) Chylomircon remanent - left behind - absorbed by the liver

Answer 23

No dietary source of lipids – can be obtained from the liver 1. Liver produces VLDL (very triglyceride rich – low cholesterol) 2. Progressively broken down by LPL into glycerol and NEFA - taken up by tissues (muscle and adipose) 3. Also forms Intermediate density lipoproteins - can be taken up by the liver and converted into LDL by the liver (transports cholesterol around the body) 4. LDL has Apoe-B on it's surface allowing it to interact with LDL receptors, which is needed for transport of LDL into tissues

Answer 24

Reverse cholesterol transport system 1. HDL created both in the liver and gut – collects cholesterol 2. Free cholesterol is transported out via ABC-A1 transported and taken up by HDL using LCAT 3. HDL normally taken up by liver or sometimes taken up by VLDL

Answer 25

Chylomicrons - ApoB48 VLDL, IDL and LDL - ApoB100 HDL - ApoA1 Lipoprotein behaviour determine by proteins on their surface

Answer 26

LDL-Cholesterol is associated with increase rates of CV disease HDL-cholesterol is associated with decreased rates of CV disease Supported by the impact of statins (LDL lowering drugs) on reducing CV risk

Answer 27

Excessive LDL (not cleared by the liver) and damage to arterial walls (mechanical or chemical) leads to the accumulation of LDL in arterial walls - leading to the formation of fatty streaks Note - that any of the ApoB carrying lipoproteins (chylomicron remnants, VLDL, IDL, LDL can be taken up by arterial walls) LDLs are relatively long-lived (~9x lifetime of a VLDL)

Answer 28

1. **Formation of fatty streaks:** LDL + monocytes + O-free radicals - accumulation of lipids in the arterial wall - reacts with oxygen free-radiacals - consumed by macrophages to form foam cells - collection of foam cells = fatty streak - Inflammatory process 2. **Atheromatous plaque formation** - smooth muscles cells stimulated by macrophages to migrate, proliferate, differentiate (fibroblasts) - producing collagen cap - Foam cells undergo necrosis or apoptosis to leave a pool of extracellular cholesterol - pool of cholesterol = atheroma 3. **Plaque rupture** - Occludes blood flow – plaque remains stable – stable angina - Unstable/clot formation/thrombosis – full blockage - unstable angina/MI

Answer 29

Inherited disorders of lipoprotein metabolism e.g. Familial Hypercholesterolaemia (FH) - Autosomal dominant - monogenic - Mutation in LDL receptor (or ApoB, PCSK9) - Common ~1:500 to 1:200 (heterozygotes) - High LDL-C levels (typically >4.9 mmol/L) - Untreated leads to premature CHD onset - Statin treatment shown to reduce CVD risk to that of general population Be suspicious if… - Family history of hyperlipidaemia / prem CVD - Unusually high LDL-C despite v. healthy lifestyle - History of hyperlipidaemia from young age Cholesterol in FH can deposit in other areas of the body – builds up at tendons and in eyes

Answer 30

Routine laboratory measurements of lipids: - Total cholesterol - HDL cholesterol (HDL-C) - Triglycerides LDL cholesterol (LDL-C) is calculated, not measured: Friedewald equation Specialist labs – more specific measures are also possible

Answer 31

Myocardial infarction: acute treatment Re-perfusion – opening up with a balloon like device (Percutaneous coronary intervention - PCI) and then introducing a stent to maintain the artery open longer term

Answer 32

Mainstay of primary prevention is lifestyle change Consensus: treat those at highest absolute risk - based on high risk (Diabetes over 40, Fam. hyperchol., Chronic kidney disease) or risk of CV event over 10 years - Use a risk calculator e.g. ASSIGN, QRISK etc. UK national guidelines say: Scotland - SIGN 149 (2017) - treat if >20% CV risk England - NICE CG181 (2014) treat if >10% CV risk Easy to predict for extreme risk-factors e.g. very high LDL-C in Familial Hypercholesterolaemia, or in severe hypertension... However, usually... CV risk = product of several risk-factors

Answer 33

Lifestyle advise + statins!

Answer 34

Statins - block cholesterol synthesis in the liver, resulting in increase uptake form the circulation to compensate (upregulate LDL receptors) Fibrates - increased LPL activity and hepatic fatty acid oxidation - reducing triglycerides & enhanced IDL, LDL uptake by liver as well as reduce VLDL synthesis

Answer 35

PCSK9-inhibitors - Monoclonal antibodies, delivered by fortnightly s/c injection - Alirocumab, Evolocumab - Capable of ~60% reduction of LDL-C (as adjunct to statin) - Increase LDL receptor levels in hepatocytes by suppresing activity of PCSK9 (drives degradation of receptor) - increasing uptake - PCSK9 have also been targetted by SI-RNA - 6 monthly injection

Answer 36

Fetus - Yolk sac - blood isalnds - Taken over by AGM - AGM turns into fetal liver - haematopoetic centre Infant - Cells move into the bone marrow - cells produced in all bone marrow Adult - Haematopoiesis focuses on adult centralized skeleton

Answer 37

~ 1 billion cells produced each day in healthy adult

Answer 38

Two main lineages 1. Common myleiod progenitor - RBCs and cells of the innate immune system 2. Common lymphoid progenitor - NK cells and cells of the adaptive immune system

Answer 39

**Extrinsic signalling** a) Growth Factors - influnece... - Cell survival/ proliferation - Differentiation - Maturation - Activation b) Adhesion molecules - Interact with extracellular matrix **Intrinsic signalling** - Transcription factors

Answer 40

**Erythropoiesis** Regulated by renal erythropoietin which is stimulated by tissue oxygen **Myelopoiesis** G-CSF – granulocytes M-CSF – macrophages IL-5 – eosinophils **Thrombopoiesis** Thrombopoietin from liver Feedback mechanism controls platelet count

Answer 41

White cells are in order of abundance in the blood – Neutrophils to Basophils

Answer 42

95% range (ref interval) = **mean +/- 2sd** Reference ranges for each parameter shown in the attached image – differ by age

Answer 43

**Too much** ( - cytosis) - too many * Erythrocytosis (or ‘polycythaemia’) * Leucocytosis - level of white blood cells * Thrombocytosis (or ‘thrombocythaemia) **Too little** (- cytopenia) * Anaemia (red) * Leucopenia (white) * Thrombocytopenia (platelets) * Pancytopenia (red, white & platelets) Are these changes malignant vs non-malignant

Answer 44

Anaemia Different symptoms but there are commonalities: 1. Lethargy 2. Breathlessness 3. Chest pain 4. Headache, dizziness 5. Pallor - pale Symptoms depend on degree of anaemia, speed and comorbidities

Answer 45

1. **Blood loss** 2. **Reduced RBC production** Deficiency - Iron, B12/folate Malignancy Chronic disease, kidney disease – low EPO Thalassaemia Bone marrow failure 3. **Increase RBC destruction** Haemolysis e.g. autoimmune Sickle cell disease

Answer 46

1. **Chronic blood loss** Menstruation Gastrointestinal bleeding 2. **Dietary** Vegetarian, vegan, toddlers 3. **Malabsorption** Coeliac disease, gastric surgery 4. **Increased requirements** Pregnancy, growth

Answer 47

Smaller, large central white areas, pale, pencil cells **Microcytic hypochromic anaemia** MCV < 80fl, MCH < 27 pg

Answer 48

Occurs when there is fefective DNA synthesis during RBC production causing cell growth without division Macrocytic anaemia - increased MCV Usually due to **B12/folate deficiency** Test levels of B12/folate in blood & replace (+ remove cause of deficiency) Example - RBCs as big as WBCs

Answer 49

**Dietary sources** Green vegetables Folate free diet causes deficiency in weeks **Deficiency** Inadequate intake Malabsorption – coeliac disease Excess consumption – pregnancy Drugs eg anticonvulsants

Answer 50

**Dietary** - Meat, dairy, fish **Deficiency** - Vegan diet - Autoimmune – pernicious anaemia - immune system attacks stomach cells that produce intrinsic factor - Malabsorption - gastric or ileal surgery

Answer 51

Normal: Old RBC (120 day lifespan) RES removal and recycling Haemolytic anaemia = Excessive/ premature RBC breakdown Results in: Spherocytes (RBCs that are more likely to get destroyed by the spleen) or fragments Anaemia and reticulocytosis Raised bilirubin and Lactate dehydrogenase Causes can be extravascular and intravascular Can be... 1. Inherited - e.g. Hereditary spherocytosis 2. Acquired - e.g. Autoimmune haemolytic anaemia

Answer 52

Too many red blood cells - elevated haematocrit (HCT) and haemoglobin Absolute (increased red cell mass) - Primary – Polycythaemia Rubra Vera - Secondary – Increased EPO – Chronic hypoxia (COPD, altitude) and renal tumours Relative/apparent Polycythaemia - Caused by reduced plasma volume - Acute dehydration, alcohol, diuretics

Answer 53

Leucocytosis (too many) vs Leucopenia (too few) Possible to have one cell type effected and also a combination Can be benign vs malignant Malignant cause of leucocytosis - Lymphoid – lymphoma/ leukaemia - Myeloid – myeloproliferative disorders/ leukaemia

Answer 54

Mainly neutropenia Causes = Infections 1. Recurrent bacterial skin infections 2. Mouth ulcers 3. Overwhelming sepsis 4. Unusual infections Common complication of chemotherapy

Answer 55

Thrombocytosis - Sustained rise in platelets levels - platelets > 450 x 10^9/L **Primary** (arising from bone marrow) - Essential thrombocytosis (ET) or another myeloproliferative disorder (MPD) **Secondary** Infection/ inflammation/ surgery Post-splenectomy Iron deficiency Malignancy

Answer 56

Platelets < 150 x 10^9/l Symptoms < 20x10^9/l 1. Bruising 2. Gum bleeding 3. Nose bleeds 4. Petechiae (skin rash) 5. Prolonged bleeding from cuts

Answer 57

**Increased destruction/consumption** *Immune - Immune thrombocytopenia purpura, drugs (e.g. heparin), autoimmune, infection *Non-immune - Hypersplenism, MAHA (e.g. DIC/ TTP/ HUS) **Decreased production** Bone marrow failure B12/folate deﬁciency Drugs/ alcohol Infection Liver disease

Answer 58

Pancytopenia - deficiency of all three cellular components of the blood (red cells, white cells, and platelets). 1. Severe infection 2. Hypersplenism 3. Megaloblastic anaemia 4. Myelosuppressive drugs 5. Bone marrow failure

Answer 59

1. Red cells, white cells, platelets or combination? 2. Too little or too much? 3. What is the context? 4. Benign condition or malignant? 5. Urgent attention required or ongoing monitoring?

Answer 60

Hemostasis is the mechanism that leads to cessation of bleeding from a blood vessel.

Answer 61

1. Platelets - normal number, normal function 2. Functional coagulation cascade 3. Normal vascular endothelium

Answer 62

1. PLATELET ADHESION 2. PLATELET ACTIVATION / SECRETION 3. PLATELET AGGREGATION Known as the primary hemostatic pathway

Answer 63

Secondary hemostatic pathway - formation of a fibrin mesh Secondary hemostatic process involving the clotting factors – thrombin – causes cross-linking of fibrin meshes around aggregated platelet

Answer 64

All defects - All give rise to a “prolonged bleeding time” 1. REDUCED NUMBER OF PLATELETS - Thrombocytopenia (TP): long list of causes - bone marrow failure - peripheral consumption (e.g. immune TP, disseminated intravascular coagulation (DIC), drug- induced) 2. ABNORMAL PLATELET FUNCTION - Most commonly drugs such as aspirin (interfers with prostaglandin function), clopidogrel - Renal failure: uraemia causes platelet dysfunction 3. ABNORMAL VESSEL WALL - Scurvy - Ehlers Danlos syndrome - Henoch Schӧnlein purpura - Hereditary Haemorrhagic Telangiectasia 4. ABNORMAL INTERACTION BETWEEN PLATELETS & VESSEL WALL - Von Willebrand disease

Answer 65

- Aspirin and COX inhibitors - Reversible COX inhibitors eg. NSAIDs - Dipyridamole - inhibits phosphodiesterase - Thienopyridines - inhibit ADP-mediated activation, eg clopidogrel - Integrin GPIIb/IIIa receptor antagonists abciximab, tirofaban, prevent Fgn binding

Answer 66

Purpuric Rashes - Bleeding into the skin

Answer 67

Intrinsic pathway responds to spontaneous, internal damage of the vascular endothelium, Extrinsic pathway becomes activated secondary to external trauma. Both intrinsic and extrinsic pathways meet at a shared point to continue coagulation, the common pathway

Answer 68

Waterfall theory Things to note... 1. there is a competing pathway that breaks clots via fibrinolysis 2. Reactions are catalysed by macromolecular complexes that sit on the surface of membranes - e.g. extrinsic tenase (VIIa + TF) and intrinsic tenase (VIIIa + IXa) convert factor X into Xa

Answer 69

Prevention of over-activity of the coag cascade by natural inhibitors 1. TF-VIIa complex/fXa inhibited by **TFPI**, tissue factor pathway inhibitor - extrinsic tenase 2. Thrombin, fXa and fIXa activity inhibited by **Antithrombin** 3. **Protein C pathway** inhibits fVa (required by Xa to convert prothrombin into thrombin) and fVIIIa

Answer 70

Commonest Hemophilia – A Willebrand – sex-linked to males

Answer 71

Haemarthrosis - a condition of articular bleeding, that is into the joint cavity - can cause athropathy of the joint

Answer 72

Most common hereditary condition for both men and women Autosomal dominant inheritance! Arises from a deficiency in the quality or quantity of von Willebrand factor (VWF), a multimeric protein that is required for platelet adhesion.

Answer 73

Liver disease 1. Reduced hepatic synthesis of clotting factors 2. Thrombocytopenia secondary to hypersplenism 3. Reduced vitamin K absorption due to cholestatic jaundice causing deficiencies of factors II, VII, IX & X Treat with plasma products and platelets to cover procedures, and vitamin K

Answer 74

EMICIZUMAB (ACE910) A humanised bi-specific antibody that binds to and bridges fIXa and fX Acts as a **FVIII-mimetic agent**

Answer 75

An acquired syndrome of systemic intravascular activation of coagulation – “thrombin explosion” - leading to widespread deposition of fibrin in circulation Associated with tissue ischaemia and multi-organ failure Furthermore, consumption of platelets and coagulation factors to generate thrombin, may induce severe bleeding (lack of them) To maintain vascular patency, plasmin generated in excess, leads to fibrinogenolysis Wide range of causes - infection (sepsis), tumours, etc.