DVT and Coagulation Flashcards
What is haemostasis?
How the body prevents blood loss when a blood vessel is injured/broken
What are the 3 stages of haemostasis?
PRIMARY HAEMOSTASIS
Vasoconstriction (immediate)
Platelet adhesion (within seconds)
Platelet aggregation and contraction (within minutes)
SECONDARY HAEMOSTASIS
Activation of coagulation factors (within seconds)
Formation of fibrin (within minutes)
FIBRINOLYSIS
Activation of fibrinolysis (within minutes)
Lysis of the plug (within hours)
In haemostasis how does the smooth muscle prevent blood leaking out due to tissue damage?
VASCULAR SPASM: SM cells contract
Endothelin is released by damage cells that binds to the smooth muscle cells causing contraction.
Direct injury to smooth muscle causes it to contract - myogenic mechanism.
Nociceptor activation by inflammation from tissue damage that causes pain response which leads to contraction of smooth muscle cells.
In haemostasis, how does platelet plug formation occur?
Damage to endothelial cells causes secretion of Von Wilderbrand factor (vWF).
Damaged endothelial cells can no longer inhibit platelet aggregation.
Platelets bind to vWF.
Platelets release granules, recruiting other platelets and forming the plug.
Granules also bind to smooth muscle causing contraction and vasoconstriction.
Why does the platelet plug need secondary haemostasis?
Unstable, needs to be stabilised
How is the platelet plug stabilised?
Fibrin forms a mesh over it
Thrombin activated via coagulation cascade which converts fibrinogen to fibirn
What clotting tests are there?
aPTT – Playing Table Tennis
Intrinsic (inside) pathway
PT – Playing Tennis
Extrinsic (outside) pathway
TT – Same letters
Common pathway
Mixing studies
Performed after finding error in aPTT or PT to determine cause
What is PT
PT (playing tennis)
What is aPTT
aPTT (playing table tennis)
What is TT
TT [thrombin time]: fibrinogen to fibrin time. Increased when def in fibrinogen i.e in liver failure
What happens in mixing studies
Mixing studies: if prolonged PT or PTT. Look to see if there is a deficiency in clotting factor or an inhibitor of factor activity. 50:50 plasma from patient and normal plasma.
If clotting normalises = factor deficiency (normal blood adds the missing factor). If does not normalise, there may be a clotting inhibitor in the patients blood, i.e antiphospholipid antibodies
In haemostasis, what happens in fibrinolysis?
Fibrinolysis is how the body limits clots and completes repair.
Tissue plasminogen activator (tPA) on endothelial cells converts plasminogen to plasmin.
Plasmin degrades the fibrin clot.
Fibrin mesh degrades to FDPs (fibrin degradation products) and d-dimer.
What factor is vital for coagulation, without which you can’t form clots?
Factor 7
DiSCo 1972
Factors S, C 10, 9, 7 & 2 require Vit K
What tests measure intrinsic and extrinsic pathways?
aPTT measures the intrinsic pathway – Playing table tennis (intrinsic indoors)
PT measures extrinsic pathway – Playing tennis (extrinsic outdoors)
What is another name for factor 3
Tissue factor (released from damaged endothelium)
Why does clotting occur in a test tube?
Factor 12 reacts with the rough chraged wall of the glass
Which coagulation pathway is slow?
Intrinsic (5 mins)
Extrinsic is fast (30s)
Embolus
An unattached mass that travels through the bloodstream and is capable of creating blockages
Embolism
An embolism is the lodigning of an embolus, a blockage-causing piece of material, inside a blood vessel
Thrombus
Blood clot, final product of the blood coagulation step in haemostasis
A thrombus is aggregated platelets and red blood cells that form a plug, and a mesh of cross-linked fibrin protein.
Thrombosis
Formation of blood clot inside a blood vessel obstructing the flow of blood through the circulatory system
Venus Thromboembolism (VTE)
A combined term for the linked conditions DVT (deep vein thrombosis) and PE (pulmonary embolism)
What are the types of emboli?
Fat Air Thrombus Bacteria Amniotic fluid Tumour
FATBAT
What happens to a thrombus if it doesn’t resolve?
Normally it lyses away and disappears
Or can propogate (grow down blood vessel) and cause damage later
Break off as an embolism
Sucked isnide blood vessel (organisation)
Holes punched through it so blood flows through it (recanulisation)
What causes thrombosis?
Virchow’s triad:
VESSEL INJURY
damage from smoking
VENOUS STASIS
atrial fibrillation, valvular heart disease, prolonged immobility
HYPERCOAGULABILITY
Pregnancy, medications, cancer, inherited thrombophilias
Thrombosis risk factors: continuing or intrinsic risk factors
A history of DVT. Cancer (known or undiagnosed). Age over 60 years. Being overweight or obese. Male sex. Heart failure. Acquired or familial thrombophilia. Inflammatory disorders (for example, vasculitis, inflammatory bowel disease). Varicose veins. Smoking.
Thrombosis risk factors: that temporarily increase likelihood of DVT
Significant immobility.
Significant trauma or direct trauma to a vein (for example, intravenous catheter).
Hormone treatment (for example hormone replacement therapy).
Pregnancy and the postpartum period.
Oral contraceptives (COCP only) & HRT
Dehydration.
Chemotherapy.
Recent trauma, major surgery or hospitalisation.
Thrombosis genetic risk factors
Factor V Leiden
Protein C or S deficiency
Prothrombin gene G20210A mutation
Antiphospholipid syndrome
Factor V Leiden
Coagulation factor 5 mutates and is not inhibited by protein C or S
Protein C or S Deficiency
Proteins that are involved in fibrinolysis – inactivating factor 5 & 8
Prothrombin gene G20210A mutation
Increased prothrombin production
Antiphospholipid syndrome
Increases risk of VTE
Deep vein thrombosis: definition and diagnostic factors
Definition:
Deep vein thrombosis (DVT) is the development of a blood clot within a vein deep to the muscular tissue planes. DVT most commonly affects the legs, but can also affect the arms, and other sites in the body.
Diagnostic factors:
DVTs commonly cause asymmetrical leg swelling, unilateral leg pain, dilation or distension of superficial veins, and red or discoloured skin, but can also be asymptomatic.
If suspected DVT use…
Well’s score
If they score 2 or more, DVT is likely.
1 or less, DVT is unlikely.
DVT Likely: Duplex US within 4 hours (gold standard)
(if not available then start on anticoagulation)
DVT Unlikely: D-dimer within 4 hours
(if not available then start on anticoagulation)
2 points or more = DVT likely: organise duplex ultrasound within 4 hrs. If there is a delay, give anticoagulation until the scan is performed
1 point or less = DVT unlikely: organise D-dimer -> if D-dimer is positive, arrange duplex ultrasound
Pulmonary embolism
PE is a life threatening condition caused by the obstruction of one or more pulmonary arteries by solid, liquid, or gaseous masses, leading to respiratory dysfunction.
In most cases, the embolism is caused by blood thrombi, which arise from DVT and embolize to the lungs.
Suspect PE in a person with…
Dyspnoea (SOB) shortness of breath
Tachypnoea
Pleuritic chest pain (pain on inspiration and expiration)
Features of DVT (unilateral leg pain and swelling)
Additional symptoms of PE
Cough and haemoptysis
Dizziness and syncope (due to right ventricular failure in severe cases)
Retrosternal chest pain (due to right ventricular ischaemia)
Clinical signs of PE
Tachycardia (>100bpm) Hypoxia Pyrexia Elevated JVP Gallop rhythm (extra heart sound) Pleural rib Hypotension and cardiogenic shock (rare)
What respiratory issues can occur in PE?
V/Q Mismatch and PE Obstruction
V/Q MISMATCH
Dead space ventilation: reduced perfusion but normal ventilation -> high V/Q (no blood present)
Severity of V/Q mismatch depends on the number, size and location of the embolus
Reduced perfusion reduced O2 exchange
PE OBSTRUCTION
Infarction and inflammation of lungs and pleura
Pleuritic chest pain and haemoptysis
Cytokines released bronchoconstriction decrease in inspired O2
What is the result of reduced perfusion and cytokine release in the lungs?
Reduced O2 exchange due to reduced perfusion
Bronchoconstriction due to cytokine release leading to decrease in inspired O2
BOTH -> hypoxaemia (decreased PaO2) = type 1 resp failure
- > hyperventilation
- > hypocapnia (respiratory alkalosis)
How does an embolism in PE lead to compensatory tachycardia?
Embolism in pulmonary arteries ↓ Increased pulmonary vascular pressure ↓ Backflow of blood to the right side of the heart ↓ Pulmonary hypertension ↓ Right ventricular hypertrophy Right sided heart failure ↓ Decreased SV decreased CO decreased BP ↓ Compensatory tachycardia
Whatever happens on RHS affects LHS Decreased CO from left ventricle detected by baroreceptors ↓ Stimulates sympathetic response ↓ Tachycardia and vasoconstriction
What are the possible ABG changes in PE?
TYPE 1 HYPOXIC RESP FAILURE
pO2 < 8kPa (increased alveolar-arterial gradient (> 10kPa difference)
pCO2 < 6.5kPa (respiratory alkalosis)
What are the possible ECG changes in PE?
SINUS TACHYCARDIA
McGinn-White sign
Right heart strain pattern- complete or incomplete right bundle branch block (RBBB), right axis deviation or T-wave inversion
What would the points in a two-level PE Well’s score indicate?
5 points or more = PE likely: organise immediate CTPA. If there is a delay, give anticoagulation until the scan is performed
4 points or less = PE unlikely: organise D-dimer -> if D-dimer is positive, arrange immediate CTPA and give anticoagulation until scan is performed
3 points = an alt diagnosis is less likely than PE
If patient has renal impairment or contrast allergy: V/Q scan
What investigations would you do for a suspected PE?
CT pulmonary angiography (CTPA)
Chest x ray (CXR)
Radionucleotide imaging (V/Q scan)
CT pulmonary angiography for PE
Radio-dense contrast delivered via IV allowing visualisation of arterial and venous blood vessels
CXR for PE
Usually normal – used to rule out other pathology, e.g. pneumonia
Pleural effusion
Atelectasis (collapse of small area of lung tissue)
Can see Fleischner sign (enlarged pulmonary artery), Hampton hump (peripheral wedge of airspace opacity and implies lung infarction) or Westermark sign.
Radionucleotide imaging (V/A scan) for PE
Scintigraphic examination of the lung using gamma radioisotopes.
Ventilation scan: Radio-isotope aerosols are inhaled by the patient small enough to reach distal tracheobronchial tree
Perfusion scan: Tc-99m MAA is given intravenously small enough to become lodged in arterioles of lungs.
What are the MoA, contraindications and side effects of warfarin?
MoA:
Inhibits production of vitamin K dependent coagulation factors (II, VII, IX and X and proteins C and S) by inhibiting epoxide reductase, the enzyme responsible for restoring vitamin K to its reduced form, which is needed for the synthesis of clotting factors
diSCo 1972
Contraindications:
Pregnancy
Liver disease
Caution when taking CYP inhibitors/inducers as they may increase or decrease warfarin metabolism
Certain antibiotics kill gut flora that synthesise vitamin K (increases warfarin’s effect
Side effects:
Haemorrhage
Many patients not sufficiently anticoagulated
Must be co-prescribed heparin for bridging during hypercoagulable phase* of treatment
Needs regular monitoring (aim for INR of 2.5).
What are the MoA, contraindications and side effects of Low molecular weight heparin (LMWH)?
Dalteparin
Enoxparin
MoA: Direct factor Xa inhibitor
Contrainidications:
Safe for pregnancy!
Severe hypertension
Recent surgery/trauma
Side effects:
Heparin induced thrombocytopaenia at S/C injection site (less common than UFH)
What are the MoA, contraindications and side effects of unfractionated heparin (UFH)?
MoA:
Inhibits factors Iia and Xa
Contraindications:
Severe hypertension
Recent surgery/trauma
Side effects:
Heparin Induced thrombocytopaenia (HIT) at S/C injection site (more common than LMWH)
Requires monitoring (aim for PTT of 1.5-2.5)
Warfarin induced clotting
As well as blocking vitamin K recycling, warfarin also inhibits proteins C and S (anticoagulants).
The half life of protein C is shorter than the clotting factors that it inhibits so protein C levels decrease more quickly than clotting factors.
For the first 2 days the patient can be pro-coagulant.
DOACs (Direct oral anticoagulant)
Don’t Ruin All Evils
Dabigatran (thrombin inhibitor, factor 2)
RivaroXaban
ApiXaban
EdoXaban
^ R, A and E all factor 10a inhibitors
Contraindications of DOACs
Active bleeding
Significant risk of major bleeding
Prosthetic heart valve
BUT GOOD THING: Less monitoring due to little or no food/drug interactions
Why are anticoagulants like warfarin, heparin and DOACs not good for removing the clot?
They are preventative, prevent the clot from occuring whereas antiplatelets and thrombolytics act to breakdown the clot while its there
PE management if patient is haemodynamically stable
- Oxygen therapy if hypoxic
- Paracetamol if in pain
- DOAC’s (rivaroXaban or apiXaban) REMEMBER
Offer LMWH if breastfeeding, pregnant or has active cancer.
Continue anticoagulation for at least 3 months.
If PE was provoked: consider stopping treatment after 3 months
If PE was unprovoked: consider continuing treatment after 3 months
PE management if patient is haemodynamically unstable (massive PE – BP <90 systolic or drop >40mmHg in 15mins
- Continuous UFH infusion (unfactionated heparin)
- Thrombolysis (alteplase or streptokinase)
Surgical thombectomy in those with failed fibrinolysis or patients with a free-floating thrombus in the right atrium or ventricle
Types of hypoxia
An inadequate level of tissue oxygenation for cellular (aerobic) metabolism
- Hypoxic Hypoxia
- Hypoxemic Hypoxia
- Circulatory Hypoxia
- Histotoxic Hypoxia
Hypoxic hypoxia
Lung problems – low PaO2
- High altitude (low oxygen in air)
- Airway obstruction (any cause)
- Hypoventilation (any cause)
VQ Mismatches:
- Alveolar pathology
- Diffusion defects
- Vascular defects
Hypoxaemic hypoxia
(anaemic hypoxia)
Blood problems - PaO2 normal
- Low Hb content
- Abnormal Hb (e.g. sickle cell)
- Other stuff bound to Hb (e.g. Kai!)
Circulatory hypoxia
Circulation problems
- Shock
- Blockage
- Cardiac failure
Histotoxic hypoxia
Cells can not use the perfectly good oxygen that’s been delivered.
- Sepsis
- Drugs
- Cyanide
What contraceptive most increases risk of thrombosis?
COCP (bc oestrogen)
What is the first line treatment for someone diagnosed with a PE?
DOACs (DRAE)
A prolonged prothrombin time indicates a fault in which pathway?
Extrinsic and common
Why would a PE cause hypoxic hypoxia?
V/Q mismatch, blood circulation is fine but not getting oxygenated
What are anticoagulants?
Reduce the ability of the haemostatic system to respond to activation signals. They do not in fact thin the blood
These drugs will not dissolve clots that already have formed, but it will stop an existing clot from becoming worse and prevent future clots
Why do we need anticoagulants for:
a) Stroke prevention
b) Venous Thromboembolic disease (VTE)
c) Arterial Thrombotic disease ?
Stroke prevention 70% •Atrial fibrillation •Valvular heart disease •Mechanical heart valves •Cardiomyopathy •Intracardiac thrombus
Venous Thromboembolic disease (VTE) 20%
•Treatment
•Prophylaxis
Arterial Thrombotic disease 10% •Acute coronary syndrome (ACS) •Myocardial infarction (MI) •Failed arterial grafts •Haemodialysis access
What factor do most anticoagulants target nowadays?
Xa
What anticoagulants inhibit Xa?
Rivaroxaban
Fondaparinux- INDIRECT
Apixaban
What anticoagulants act on thrombin?
Dabigatran
Argatroban
UFH vs LMWH
Unfractionated (UFH)
- Standard UFH, derived from pig intestine or bovine lung tissue
- Heterogeneous mixture of polysaccharide chains of varying length
Low molecular weight (LMWH)
-Derived from chemical or enzymatic degradation of UFH into fragments approximately one-third the size of heparin
What does heparin target?
Antithrombin
Why does size of heparin molecule matter?
Has pentasaccharide sequence.
Binds directly to antithrombin and inhbits thrombin production
Sequence important in potentiating inhbition of active factor Xa
But need longer molecule to wrap around thrombin and do this so unfractionated can inhibit Xa AND thombin but LMWH mainly inhibits Xa (stopping conversion of prothrombin to thrombin)
Why still use unfractionated heparin?
Reticuloendothelial clearance- cleared by spleen and liver so used in patients with renal impairment, whereas LMWH cleared by kidneys (so wouldn’t be good for patients w renal issues)
Half life 1.5 hours- in IV infusion so if patient going to theatre, very easy to stop and start IV heparin
What are the cons of using unfractionated heparin?
APTR monitoring- activated partial thromboplastin time ratio, need to monitor activity and dose
Reversal agent protamine- too much of which can be procoagulant, but in small doses can inhibit unfractionated heparin
What setting is best for UFH?
Short term, clinical setting as it’s a very controllable coagulant esp patients w renal impairment
How is UFH monitored?
Activated Partial Thromboplastin Time Ratio – APTTR
–therapeutic range varies with different reagents
•1.5 - 3.5 at SGH
•check local range
–baseline level prolonged by
•antiphospholipid antibodies
•combined Rx with warfarin or thrombolytics
•congenital factor deficiencies
–baseline level shortened by
•high Vlll
What are the benefits of using LMWH?
Renally cleared
Can just give once daily unlike UFH
Half life 12 hours, peak activity 3-4hours
No monitoring required
used for pregnant women and beastfeeding women
HOWEVER No reversal agent
Anti Xa monitoring performed under certain circumstances
Heparin side effects
Bleeding: stop heparin and give protamine sulphate 1mg/100units
Heparin induced thrombocytopenia (HIT): minor platelet drop at 5 days, transient, no treatment required
BUT HIT with thrombosis (HITT): stop heparin immediately + use danaparoid or hirudin
Osteoporosis: dose and duration related
Warfarin mechanism of action
Targets production of vitamin K dependant clotting factors (7, 9, 10 and 2)
Affects production of anticoagulants Protein S and C
Blocks recycling of vitamin K- so vit K cannot carboxylase proteins aka activate them, so these clotting factors do not work
Why can patients be procoagulant in the first few days of starting warfarin?
Becauase protein C has a short half life compared to other clotting factors, and so will drop and make patient pro-thrombotic. So must wait for other working clotting factors to come out of system which can take 2-3 days
Pharmacokinetics and dynamics of warfarin
Good bioavailability-rapidly absorbed Half life 36 - 42 hours 97% albumin bound in plasma Eliminated by liver Cytochrome p450 system metabolise it
Warfarin drug interactions
–impair absorption of vitamin K: increase anticoagulant effect
–compete for plasma protein binding sites: increase anticoagulant effect
–are hepatotoxic: increase anticoagulant effect
–induce hepatic enzymes: reduce anticoagulant effect
–have antiplatelet activity: cause increased bleeding
Consequences of warfarin pharmacology
Heparin must be used for initiation of warfarin in patients with thrombosis due to fall in protein C activity
Dose of warfarin required varies widely between individuals
Individual warfarin dose is sensitive to: – diet (Fat and Vitamin K intake) – other drugs (+/-) – ethnicity ( VKORC1 polymorphisms) – age
Warfarin needs monitoring
What test is used to monitor warfarin vs heparin?
PT prothrombin time to monitor warfarin
APTT to monitor heparin
What does INR measure?
Time it takes to form a clot in prothrombin assay, normally 2.5 if it takes longer then overcoagulated
Warfarin side effects
Skin necrosis
Protein C deficiency
give heparin firsr for VTE Rx
Bleeding
Crosses placenta, coumarin embryopathy 6-12 weeks, doses above 5mg SO NEVER USED IN PREGNANCY
Increased fetal loss: intracerebral haemorrhage, antepartum haemorrhage
Warfarin risk factors
Age over 70
INR above 4.9
first 3/12 of Rx
comorbid disease
Treatment of bleeding
Major bleed
–life or limb threatening
–fully reverse anticoagulation immediately: vit K konakion 5 -10mg iv
Prothrombin complex concentrate PCC
–20 – 30 u/kg
Fresh frozen plasma FFP–15ml/kg
Omit anticoagulation till bleeding controlled Beriplex® / Octaplex
Direct thrombin inhibitors, examples and what they act on
Hirudin: binds to exosite 1 and active site on thrombin
Melagatran and Dabigatran: bind to active site on thrombin
Rivaroxaban
Direct inhibitor of Xa Oral agent Once daily dosing Rapid onset of action Half life4-9 hours Monitoring not usually necessary Renal excretion Few food or drug interactions GI side effects
NOACs pros
Oral anticoagulant
Rapid onset/offset of action –No need for bridging
Short half life –Easy to control anticoagulant effect
Little or no food-drug interactions
Limited drug-drug interactions
Predictable anticoagulant effect –No need routine monitoring
DOACs in obese patients
Standard dose for BMI<40 <120kg
Suggest not used with BMI>40 >120kg
If used suggest drug specific peak and trough levels
Guidance on frequency of monitoring not given
Describe the intrinsic, extrinsic and common pathways
What ion is needed in activation stages of coagulation?
Calcium
What vitamin is required by factors 2,7,9 and 10?
Vitamin K
