Case 20- strokes Flashcards
1
Q
Renshaw cell
A
Inhibitory interneurone
2
Q
Classification of lipids: Simple lipids - esters of fatty acids with alcohols
A
- Fats & oils: Esters of fatty acids with glycerol. Fats –solid, oil-liquid
- Waxes: esters of fatty acids with alcohols other than glycerol. Aliphatic or alicyclic.
3
Q
Complex lipids
A
Esters of fatty acids with alcohol containing other groups such as protein, carbohydrate.
• Phospholipids: contain phosphoric acid and a nitrogenous base e.g. glycerophospholipid – lecithin or sphingophospholipid – sphingomyelin
• Glycolipids: contains fatty acids, carbohydrates and nitrogenous base
• Lipoproteins: macromolecular complexes of lipid and proteins
• Other: sulfolipid, aminolipid, liposaccharide. Derived lipids
4
Q
Lipoproteins as ‘Delivery vans’
A
Lipoproteins carry 1) Apolipoproteins 2) Free cholesterol 3) Cholesterol esters 4) Phosphlipids 5) Free soluble vitamines • Cholesterol-Functions= bile acids, steroid hormones, cell membrane • Triglycerides- energy production, energy storage
5
Q
Apolipoprotein roles
A
- Structural components of lipoproteins- ApoB100, apoB48, apoA1
- Ligand Binding, receptor recognition- ApoB100, apoE
- Activation/ inhibition of lipolysis- ApoCII, apoCIII
- Cholesterol Efflux- ApoAI, apoAII, apoAIV
- Polymorphic forms- ApoE, apoaIV, apoB
- Undefined physiological role- Apo(a), apoJ, apok
6
Q
Where the Apoliproproteins are found
A
- Cholesterol and triglyceride are transported in lipoproteins
- Apolipoproteins govern lipoprotein metabolism
- ApoB is the major apolipoprotein of VLDL, IDL and LDL
- ApoB48 is found only in lipoproteins of intestinal origin
- ApoA1 is the major apolipoprotein of HDL
- Apolipoproteins A, C and E move between HDL and TRLs
7
Q
Apolipoproteins found in Chylomicrons
A
C-III
B-48= exclusive to chylomicrons and their remnants
8
Q
Apolipoproteins found in VLDL
A
B-100
9
Q
Apolipoproteins found in IDL
A
B-100
10
Q
Apolipoproteins in LDL
A
B-100
11
Q
Apolipoproteins found in HDL
A
A-I
12
Q
LDLR, HTGL
A
LDLR- low density lipoprotein receptor
HTGL-hepatic triglyceride lipase
13
Q
LRP
A
LDL receptor-related protein. It has diverse biological roles which include functions in lipid metabolism, and also in the homeostasis of proteinases and proteinase inhibitors, cellular entry of viruses and toxins, activation of lysosomal enzymes, cellular signal transduction, and neurotransmission.
14
Q
The exogenous lipoprotein pathway
A
- Fat and cholesterol which have been absorbed from the gastrointestinal tract are assembled to form chylomicrons.
- The chylomicrons then travel in the bloodstream to peripheral tissues, the first part of their journey is through the lymph it then enters the circulation at the thoracic duct
- In the peripheral tissues (e.g. adipose tissues) chylomicrons release their fats when they meet tissue expressing lipoprotein lipase (LPL). This allows fats to be absorbed in the form of fatty acids and glycerol. The heart receives TG first
- After unloading their fats, chylomicrons become smaller and are then known as chylomicron remnants.
- Empty HDL is produced as a byproduct of steps 3 and 4.
- Chylomicron remnants then travel to the liver and are removed by the binding of apoE to their remnant receptor. Supplies TG for energy use and storage
15
Q
The endogenous lipoprotein pathway
A
- Fat and cholesterol arriving at the liver are repackaged into VLDLs.
- VLDLs enter the bloodstream between meals and travel to the peripheral tissues.
- VLDLs meet tissues expressing lipoprotein lipase (e.g. muscle and adipose tissue) and release their glycerol and fatty acids, it is then known as an IDL.
- Empty HDL is produced as a byproduct (which can then collect LDL from the periphery).
- IDLs are absorbed from the blood by the liver.
- IDLs are then broken down by hepatic lipase into LDLs (triglycerides are removed in this process).
- LDLs have relatively high cholesterol content whilst having minimal fatty acids and glycerol content.
- LDL circulates and is absorbed by various tissues via binding to LDL receptors.
- Excess LDL is absorbed by the liver via LDL receptors through ApoB100
16
Q
ABCA1
A
ATP-binding cassette transporter, also known as the cholesterol/phospholipid efflux regulatory protein (CERP) is a protein which in humans is encoded by the ABCA1 gene. It is defective in patients with Tangier disease and familial HDL deficiency. These patients cannot form HDL, and therefore have a defect in reverse cholesterol transport.
17
Q
SR-B1
A
Scavenger receptor, class B type 1 (SR-B1), is a multiligand membrane receptor protein that functions as a physiologically relevant high-density lipoprotein (HDL) receptor whose primary role is to mediate selective uptake or influx of HDL-derived cholesteryl esters into cells and tissues.
18
Q
HTGL, RLP, LDLR
A
HTGL = hepatic triglyceride lipase
RLP – remnant lipoprotein
LDLR = low density lipoprotein receptor
19
Q
LRP
A
LDL receptor-related protein It has diverse biological roles which include functions in lipid metabolism, and also in the homeostasis of proteinases and proteinase inhibitors, cellular entry of viruses and toxins, activation of lysosomal enzymes, cellular signal transduction, and neurotransmission.
20
Q
Recycling LDL receptors
A
You can recycle LDL receptors for reuse. LDL is released at low pH in the lysosome allowing LDLR to be recycled while LDL is completely broken down. PCSK9 prevents release of LDL so both LDL and LDLR are broken down in the lysosome so LDLR numbers are reduced
21
Q
Cholesterol transport pathway
A
- The Exogenous pathway delivers triglyceride from the gut to adipose tissue and muscle, and cholesterol to the liver
- The Endogenous pathway delivers triglyceride and cholesterol from the liver to adipose tissue, muscle and other tissues
- Lipoprotein lipase (LPL) offloads triglyceride into the tissues
- The liver is responsible for clearance of remaining cholesterol and triglyceride from the plasma via enzymes and receptors
- ApoB and ApoE are the major ligands for the hepatic receptors
- PCSK9 is an important regulator of LDLR
22
Q
Reverse cholesterol transport pathway
A
- When there is too much cholesterol in the peripheral tissues the ABCA1 receptor is activated.
- HDL then interacts with this receptor and collects cholesterol returning it to the liver, it is then excreted as bile. An empty HDL molecule is then released
- This pathway can help prevent the development of atherosclerosis.
23
Q
SREBP
A
In humans there are two SREBP genes, SREBP1 and SREBP2. SREBP1 is expressed primarily in the liver while SREBP2 is ubiquitously expressed
24
Q
Intracellular cholesterol homeostasis
A
- SREBPs are synthesized as ER membrane proteins where they bind with SREBP cleavage-activating protein (SCAP), an important cholesterol sensor and transporter.
- This association with SCAP retains SREBP in the ER. Under low sterol conditions the SREBP-SCAP complex is transported to the Golgi where proteolytic cleavage of SREBP releases the N-terminal bHLH domain, allowing increased expression of target gene e.g. squalene synthase and HMG-Co A reductase. More cholesterol is also taken up by the cells, reduced production of VLDL and bile acids. Decreased levels of cholesterol in hepatocytes
- In increased cholesterol- The sterol-sensing domain of HMG-CoA reductase regulates its association with INSIG in response to levels of lanosterol, a cholesterol precursor.
- INSIG binds the E3-ubiquitin ligase, gp78, which polyubiquitinates HMG-CoA reductase resulting in its degradation. Thus, sterols regulate the retention of SREBPs in the ER and the degradation of HMG-CoA reductase.
25
Key information about reverse cholesterol transport
* The Reverse cholesterol transport pathway removes cholesterol from many tissues via membrane bound transporters and returning it to the liver via HDL
* Reverse cholesterol transport mediated by HDL is important in preventing atheroma
* Cholesterol is carried in the core of mature HDL and returned to the liver directly or following transfer via CETP to TRLs
* In the liver, cholesterol exerts negative feedback regulation on cholesterol biosynthesis, by binding the “sterol sensor protein”, SREBP2, thereby preventing transcription of HMG-CoA reductase
26
Stroke
1. Sudden onset
2. Neurological symptoms- FAST (Face, Arm, Speech, Time)
3. Vascular origin
4. Risk factors
5. No clear prodrome
6. Lasting >24h or interrupted by death
27
Types of stroke
• Haemorrhagic stroke- 15%
• Ischemic stroke- 85%
Classification- TACS, PACS, LACS, POCS
28
Initial imaging in a stroke
CT head, within an hour possibly a CT angiogram
29
CTA
* Look for occlusion and access
* Stenosis, dissection, variation
* However- contrast use, take time, training to interpret
30
Thrombolysis treatment
* Recombinant Tissue Plasminogen Activator- rTPA (alteplase)
* 0.9mg/kg (max 90mg)- 10% bolus and 90% infusion over 1 hour
* Medically: tPA (intravenous tissue plasminogen activator)
* NIHSS >4
* Administer within 4.5 hrs
* The earlier tPA is administered, the higher the likelihood of a positive neurologic outcome
31
Thrombolysis mechanism of action
Activates blood clot removal system. Helps rapidly restore blood supply, reducing number of dead neurons
32
Risks vs Benefits of TPA
* Benefits include an absolute increase in the odds of an outcome with neurologic improvements at 90 days of 11 to 13 percentage points.
* Risk for intracerebral haemorrhage possibly causing neurologic worsening or death is 6%.
33
Treatment for Thrombolysis within 4.5 hours
* On CT- no established infarcts, no bleeding
* Mild-Moderate or higher severity strokes
* 15-20% of patients are eligible for thrombolysis
* No upper age limit
* Less pre-morbid disability
34
Time period for tPA
Give it within 4.5 hours of onsett of symptoms/last known normal
35
Absolute contra-intradictions of tPa
* Major surgery in last 14 days
* GI or urinary tract bleeding in last 21 days
* Stroke < 3 months ago
* Platelets <100
* Symptoms suggestive of subarachnoid bleed (even if CT Head clear)
* BP greater than >185 systolic or >110 diastolic unresponsive to medical treatment
* INR >1.7 or NOAC (novel oral anticoagulant) within 24-48 hours
36
tPA relative exclusion criteria
* Minor stroke symptoms or rapidly resolving symptoms
* Major surgery or trauma in the last 14 days
* GI or GU bleeding in last 14 days
* MI in last 3 months
* Seizure at onset of stroke symptoms
* Pregnancy
37
Problems with tPA
* Thrombolysis in cases with contra-indications
* Only 30% recanalization in LVO (large vessel occlusion) strokes
* Time window is restrictive (4.5hrs from known onset)
* Difficult with wake up strokes/aphasic/unknown onset time as you don't know when they started
* BP drop with alteplase
* Complications
38
Relative exclusion criteria for stroke
* Minor stroke symptoms or rapidly resolving symptoms
* Major surgery or trauma in last 14 days
* GI or GU bleeding in last 21 days
* MI in last 3 months
* Seizure at onset of stroke symptoms
* Pregnancy
39
Endovascular treatment of stroke
The clot is caught in a stent and removed. Its used for moderate or severe strokes, when the CTA shows proximal large vessel occlusion. Must be administered within 6 hours of the patient last seen normal. Can follow tPA administration or can be done when tPA is contraindicated.
40
Endovascular thrombectomy
Removal of a thrombus under guidance
• Inclusion- within 6 hours of onset of symptoms, good prior function (Mrs 0-2), there needs to be a clot to pull out
• Can be done with or without thrombolysis
• mRS = The Modified Rankin Scale (mRS), which is a tool used to assess and review degree of disability or dependence after a stroke
41
Who benefits from a Thrombectomy
* On CT- no established infarcts, no bleeding
* Mild-moderate or higher severity strokes
* 15-20% of patients are eligible for thrombolysis
* No upper age limit
* Less pre-morbid disability
42
Relative exclusion criteria for EVT
* Minor stroke symptoms or rapidly resolving symptoms
* Major surgery or trauma in the last 14 days
* GI or GU bleeding in the last 21 days
* MI in last 3 months
* Seizure at onset of stroke symptoms
* Pregnancy
43
MDT involvement- stroke
* Speech and language therapist- swallow assessment, risk of aspiration
* Nursing- monitoring, hygiene, pressure sores, IPC
* Physio- moving and handling review
* Occupational therapist- establish functional abilities
44
Secondary prevention
* Blood pressure <140/90 or <150/90 (lower if diabetic)
* Lipids- statins, diet
* Lifestyle- Healthy diet, Weight reduction, Smoking cessation, Decrease alcohol consumption, encourage physical activity
* Anti-platelets- Aspirin or clopidogrel, Anticoagulation for atrial fibrillation
45
Investigating the cause of stroke
* Modifiable risk factors- Hypertension, Diabetes, Smoking, Dyslipidemia, Obesity, Sedentary lifestyle, Sleep apnea
* Non-modifiable risk factors- Age, Prior stroke, History of vascular disease (CAD, PVD, stroke), family history of premature vascular disease
46
How to monitor risk factors for stroke
* BP monitoring
* BM
* Bloods- ESR, FBC, U&E, lipids
* Smoking advice
* Weight management
* Medications- CCP
* Carotid doppler
47
Non modifiable risk factors for stroke
* Genetic testing in selected cases i.e. CADASIL
* ECG/ambulatory monitoring +/- ECHO – PFO
* MRI/MRA- dissection
* Bloods- antiphospholipid
48
Strokes and driving
* DVLA states- no driving for 1 month following a stroke, no need to form DVLA
* Patients with persisting neurological deficits after 1 month- inform DVLA, no driving unless DVLA allows
* Following TIA- no driving for 1 month, maybe longer for multiple TIA’s
49
Role of endothelial cells
* Barrier
* Regulates fluid in tissues
* Controls inflammation
* Anticoagulant surface (thrombomodulin activated protein C receptor)
50
What causes thrombosis
Thrombosis is where coagulation (fibrin formation) is more then fibrinolysis (fibrin breakdown). Causes red blood cells and platelets to be trapped in the insoluble fibrin mesh. Platelets play a prominent role in arterial thrombosis and are full of vasoactive mediators
51
Stasis and turbulence
* Venous side- stasis is more common due to Gravity, Immobility, and Valve damage
* Arterial side- turbulence in the left atrium during atrial fibrillation
52
Ruptured plaque
* Thin fibrous cap
* Collagen poor fibrous cap
* Large lipid core
* Many Macrophages
* Fibrin rich thrombus
53
Causes of hypercoagulability
• Cancer i.e. pancreas, lung, brain, gastric, haem
• Oestrogen- pregnancy, post-partum, oestrogen-containing OCP
• Antiphospholipid syndrome (APLS)
• Hereditary thrombophilia
• Factor V Leiden
• Antithrombin III deficiency
• Protein C deficiency
• Protein S deficiency
• Prothrombin G20210A mutation
Commonly two or more elements of Virchow's triad occur simultaneously
54
Risk factors for hypercoagulability- Major trauma/lower limb fracture
* Stasis (inactivity and distally)
* Endothelial injury
* Trauma is hypercoagulable
55
Risk factors for hypercoagulability- Major (abdominal) surgery
* Stasis (post-op inactivity)
* Endothelial injury
* Trauma is hypercoagulable
56
DVT
* Blood clot formed in large veins of the lower limb
| * Diagnosis with duplex ultrasound, a non compressible vein is thrombosed
57
Symptoms of DVT
* Pain
* Swelling
* Sometimes erythema
* Warmth
* Shiny skin
58
DVT natural history
* Resolve (if fibrinolysis can catch up) OR
* Break off from leg and embolise OR
* Persist (and not break off)
59
Venous thrombosis
* Chronic venous insufficiency= common, get pain, swelling and pigmented skin
* Venous ulceration
* Upper limb thrombosis- rare, usually iatrogenic (related to LINES) but may be related to cancer
60
Rare types of Thrombosis
Portal vein thrombosis- rare, often asymptomatic but may cause abdo pain and swelling. Can lead to portal hypertension and to oesophageal varices
Cerebral venous sinus thrombosis- rare i.e. after pregnancy. Headache, blurred vision, ‘venous’ stroke
