DVT and PE Flashcards
Prevalence of DVT
1:1000 annual incidence DVT Importance is above knee DVT 8:100 Inherited thrombophilia Multifactorial risk
DVT is a thrombus in a vein
Thrombus in deep vein of calf or beyond – common problem – most are calf only but common and incidence of above knee is sig
20% of untreated calf dvt progress to prox veins – 50% risk of PE
Heritance plus external factors
Process of DVT and PE formation
Thrombus in deep vein around valves
Multiple triggers – finely balanced system is destabilised
50% of above knee DVTs will embolise
Pulmonary embolus -fragmentation of proximal clot which travels in venous system until it lodges in the pulmonary circulation
Consequences locally in source limb and/or in heart or lungs after embolisation
Stasis turbulence and reduced flow – key is fine balance between coagulation and lysis – trigger destabilises the equilibrium
What is Virchows triad- factors contributing to thrombosis
Endothelial injury
Stasis
Blood components Platelets Coagulation factors Coagulation inhibitors Fibrinolytic factors
Virchow’s triad of vessel wall injury, blood clotting components and blood flow remains accurate in describing the important factors involved. More is now understood about the interaction between the different elements. Importance of each factor varies depending on the site, eg vessel wall damage is important in arterial thrombosis whereas stasis plays an important part in the development of venous thrombosis.
Virchow 1856
Vessel wall is naturally antithrombotic and inhibits clotting – disturbance leads to clotting
Local accumulation of clotting factors is the mechanism in stasis - endothelial hypoxia impairs vascular antithrombotic mechanisms
Thrombosis is multi-factorialgenetic and acquired risk factors
ageing is a risk
throw in extra risk like long flight (stasis) or a new hip (endothelial injury
Impact of vessel injury on the clotting cascade
Vessel injury can go into 2 directions:
1) Collagen exposure– platelet release reaction– thromboxane A2, ADP, primary haemostatic plug, platelet fusion– stable haemostatic plug
2) vasoconstriction- reduced blood flow- primary haemostatic plug- platelet fusion, stable haemostatic plug
3) Tissue factor- coagulation cascade- thrombin- fibrin- stable haemostatic plug
The endothelial cell forms a barrier between platelets and plasma clotting factors and the sub- endothelial tissues. These connective tissues include collagen, basement membrane, von Willebrand factor, microfibrils, elastin, mucoploysaccharides and fibronectin. Endothelial cells produce substances which can initiate coagulation, cause vasodilatation, inhibit platelet aggregation or haemostasis and can activate fibrinolysis; such substances include, tissue factor, prostacyclin, nitric oxide, antithrombin, tissue factor pathway inhibitor , protein S and tissue plasminogen activator.
Vasoconstriction reduces flow, allows contact and the activation of platelets and coagulation factors
Thromboxane A2 leads to vasoconstriction and release of granules and thus ADP and increased aggregation
describe the cell based model of coagulation
Initiation of coagulation occurs when sub-endothelial tissue is exposed to the circulation at a site of injury. These tissues express tissue factor at their surface, which binds to endogenous activated FVII
This complex binds small amounts of FX and FV to the exposed endothelial surface, which produce small quantities of thrombin
The thrombin activates platelets that are attracted to the site by the process, as well as other plasma-borne clotting factors
The activated factors (among them FVIII and FIX) enable the binding of activated FX and FV to the surface of platelets whose activation has produce conformational changes in their surface membranes to expose the ‘reaction sites’ necessary for continuation of the process
This leads to the ‘thrombin burst’ that is necessary for the large-scale production of fibrin and so the development of an effective clot
These three stages are called the initiation, amplification and propagation phases of coagulation
Platelets adhere and aggregate and are activated on procoagulant surface
Thrombin fibrin plug
More granules and accelerate
2 roles for thrombin crosslinking of XIII and fibrinogen to fibrin
(search up coagulation cascade and draw)
Haemostatic plug formation
Response to injury
Vessel constriction
Formation of unstable platelet plug
- platelet adhesion - platelet aggregation
Fibrin stabilisation of the plug with fibrin
- blood coagulation
Dissolution of clot and vessel repair
- fibrinolysis
Describe fibrinolysis
tPA breaks down plasminogen into plasmin
Plasmin converts fibrin into D dimer
Plasmin breaks down clot
FDP binds fibrin and stops clot
D dimer tells us there is clot breakdown and by default that there is clot formation
thrombin time tells us the time converting from fibrinogen to fibrin
prothrombin time measures time from tissue factor activation all the way to fibrin (if you have an abnormal prothrombin time you don’t really know where the problem is on its own)
partial thromboplastin time- looking at intrinsic pathway
where are clotting factors synthesised and how are they measured
Synthesised in
liver
endothelium
megakaryocytes (platelets)
most synthesis is in the liver but some proteins produced in high local concentration in endothelium (eg vWF) in megakaryocyte (eg factor V)
Measurements
Prothrombin time – PT = PTR
Partial thromboplastin time – APTT =APTTR
Thrombin time - TT
The aPTT test is used to measure and evaluate all the clotting factors of the intrinsic and common pathways of the clotting cascade by measuring the time (in seconds) it takes a clot to form after adding calcium and phospholipid emulsion to a plasma sample
The prothrombin time is a measure of the integrity of the extrinsic and final common pathways of the coagulation cascade. This consists of tissue factor and factors VII, II (prothrombin), V, X, and fibrinogen.
Thrombin time (TT) measures fibrin formation caused by the action of thrombin—the last step in the coagulation cascade. The principle of the test is that a standardized concentration of thrombin is added to citrated plasma and time to fibrin clot formation recorded in seconds
Risk factors for venous thromboembolism
STASIS: Prolonged immobility eg surgery, travel Stroke Cardiac failure Pelvic obstruction Dehydration Hyperviscosity Polycythaemia
COAGULATION ABNORMALITY Surgery or major trauma Pregnancy and puerperium Oestrogen medication Malignancy Antiphospholipid antibodies Hereditary or acquired thrombophilia Thrombocytosis Heparin induced thrombocytopenia
OTHERS Age Past history or family history of VTE Obesity Sepsis Nephrotic syndrome Paroxysmal nocturnal haemoglobinuria Behçet's disease
What are some clinical features of DVT
Pain, tenderness of veins
Limb swelling
Superficial venous distension
Increased skin temperature
Skin discoloration
All reflect obstruction to the venous drainage
There are multiple differential diagnoses for these presenting features
DVT diagnosis and PE diagnosis
DVT: Risk assessment Evidence based pre test probability score D dimer for exclusion Diagnostic tests Compression ultrasonography Venography
Risk assessment and diagnostic algorithm D – dimer for exclusion in low risk cases only Mortality stratification - PESI score Assessment of compromise - Pa02 + D dimer + ECG + troponin and BNP Consider echo Diagnostic tests CT pulmonary arteries – CTPA Ventilation Perfusion Scan
Long term consequences of VTE
10% of all hospital deaths
30% recurrence at 10 years
30% post phlebitic syndrome at 10 years
Chronic thromboembolic pulmonary hypertension (CTEPH)
50% ileofemoral DVT if the tghrombus doesn't dissolve, further thrombus formation in lungs lose pulmonary capillary vascular bed pressure in lungs goes up
scarring, damage to venous system, hyperpigmentation
Hospital acquired thrombosis
Top priority for NHS since 2010 (NICE)
Assessing the risks of VTE and bleeding
Reducing the risk of VTE
Patient information and planning for discharge – extended prophylaxis
Treatment of VTE
Why and how do we treat?
Best care is prevention ! This is our aim
Anticoagulants
Thrombolysis
Surgery
Compression hosiery????? evidence
Problem is thrombus
Two approaches
Lyse the thrombus
Prevent further thrombus formation
What we do reflects a risk benefit analysis
Lysis has the problem that if given systemically it lyses all thrombus everywhere……
Most treatment aims to prevent thrombus propagation and formation of new thrombus while allowing the body to concentrate lysis in the place where it is required
Risks are short term impact of thrombus burden and damage to vessels while thrombus remains
If cardiovascularly stable with acute VTE – Anticoagulate
Immediate anticoagulant effect
Heparin then warfarin/DOAC or immediate DOAC- Rivaroxaban or apixaban
Circulatory collapse due to PE Thrombolysis Alteplase (tissue plasminogen activator) Streptokinase Followed by heparin and warfarin or other – prevent recurrence
Investigations needed pre-treatment
Clotting screen Prothrombin time (INR) Partial thromboplastin time Thrombin time Full blood count Urea and electrolytes usually part of routine screen – to know creatinine clearance Liver function tests If clinical suspicion of liver disease
Extrinsic pathway – liver disease, warfarin and vitamin K deficiency
Time to clot after addition of tissue factor
Lab control of UFH
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
Challenge – actually difficult to achieve reliable anticoagulation
Heparin discovered by chance when attempting to obtain phospholipid extracts from the liver and heart. Commercial preparation improved using beef lung.
Describe 2 forms of heparin and mechanism of action
acts on factor 11a, 9a, 10a
factor 7, thrombin 2a
Unfractionated heparin:
biosynthesis: mast cells
MW 5,000-40,000 daltons
bioavailability 30%
t ½ 1-2 hours
accelerates inhibition of thrombin (IIa) and Xa
Effect easy to measure with standard clotting screen
LOW MOLECULAR WEIGHT HEPARIN
fractionation from UFH
MW 4,000-6,500 daltons
bioavailability 90%
t ½ 4-12 hours
accelerates inhibition of Xa > thrombin (IIa)
Measurement of effect requires Xa level assay
Renally cleared
Half life 12 hours, peak activity 3-4hours
No monitoring required -Predictability means this is not routine
No reversal agent
Anti Xa monitoring performed under certain circumstances
Pregnancy Renal failure Obesity peak 4 hours post injection treatment 0.5 - 1.0 u/ml prophylaxis 0.2 - 0.6 u/ml more predictable than heparin, needs less monitoring can be giving subcutaneously- more practical
in pregnancy and obestiy etc. you have to change the dosing
Proximal dvt heparin first
we don’t use unfractioned heparin much
made in mast cells
many sizes
short half life- so you need to give it intravenously
accelerates inhibition of thrombin and factora 10a, can measure what it’s doing through appt
What are some side effects of heparin
Bleeding
LMWH vs UFH less major bleeding (more even control)
stop heparin
give protamine sulphate – LMWH is harder to reverse
Heparin induced thrombocytopenia (HIT)
minor platelet drop at 5 days
transient
HIT with thrombosis syndrome (HITTS)
Thrombocytopenia -IgG antibody to heparin + platelet factor 4 complexes
Thrombosis - venous and arterial and gangrene
Timing - 4-5 days after starting heparin
other cause for thrombocytopenia not found
more controlled in LMWH
you can reverse unfractionated heparin
can cause minor drop in platelets
you can get heparin induce thrombocytopenia- antibodies to the heparin are made
iodiopathic- you can’t tell who’s going to get it- if someone gets gangrene/drop in platelets 45 days after starting heparin that is a sign
Describe warfarin and its mechanism of action
Warfarin acts as an anticoagulant by blocking the ability of Vitamin K to carboxylate the Vitamin K dependent clotting factors, thereby reducing their coagulant activity.
Synthesis of Non Functional Coagulant and Anticoagulant Factors
2,7,9,10, along with proteins C and S
Active at multiple sites with different half lives – net effect takes time and can lead to problem protem – fully effective
Rapidly absorbed t½ 36 - 42 hours 97% albumin bound in plasma pharmacological effect due to unbound fraction Eliminated by liver Interindividual dose variation genetic factors CYP2C9 – ↑ sensitivity VKORC1 – principal genetic modulator Intraindividual dose variation compliance / comprehension diet co-morbid conditions eg right heart failure numerous drug interactions
Side effects:
Especially in protein c deficiency
warfarin can be pro-coagulant before it become anticoagulant so we always give heparin first before warfarin
otherwise u can get necrosis
Describe warfarin dosing
Tablets
Dosing -Loading algorithms and maintenance dose
Interruption necessary for surgical procedures
International Normalised Ratio = INR
prothrombin time ratio
international sensitivity index (ISI)
Different target range depending on context
Standardised results avoid normal range issue
give a dose for 3 days
then check w blood tests
establish what impact it’s had and adjust dose
How is the INR tested?
(international normalized ratio) stands for a way of standardizing the results of prothrombin time tests, no matter the testing method.
Venous sample labour intensive accurate cheap Near patient testing (NPT) finger prick capillary whole blood quick patients prefer immediate advice 0.5 variation in INR expensive
Describe warfarin interactions and bleeding risk
Drugs can impair absorption of vitamin K increase anticoagulant effect compete for plasma protein binding sites increase anticoagulant effect be hepatotoxic increase anticoagulant effect induce hepatic enzymes reduce anticoagulant effect have antiplatelet activity cause increased bleeding
Bleeding Risk
Fatal 0.1 – 1% pa
Major/life threatening 0.5 – 6.5 % pa
ie Intracranial, GI bleed, fall in Hb, or transfusion or hospital admission
Minor 6.2 – 21.8% pa
eg all other bleeds
warfarin in pregnancy and other problems
crosses placenta coumarin embryopathy 6-12 weeks doses > 5mg increased fetal wastage intracerebral haemorrhage ante partum haemorrhage
Issues:
narrow therapeutic window
risk of bleeding– intracranial haemorrhage
lifestyle restrictions
poor compliance
leading to many patients not being sufficiently anticoagulated
Advantages of direct oral anticoagulant
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
Indirect Xa inhibitors - enhance antithrombin
Fondaparinux
Idraparinux
Direct Xa inhibitors ORAL
Rivaroxaban
Apixaban
Direct thrombin inhibitors ORAL
Ximelagatran
Dabigatran
Describe rivaroxaban
Direct inhibitor of Xa Oral agent ,once daily dosing Rapid onset of action and half life 4-9 hours Monitoring not usually necessary Renal excretion Few food or drug interactions GI side effects
NICE approved VTE prevention Post TKR , THR and hip # superior to LMWH VTE treatment and secondary prevention non inferior to LMWH and warfarin Now first line in many hospitals SPAF - Rocket AF vs warfarin in 16000 patients non inferior major bleeding rate similar but less IC bleeding
Rivaroxaban for VTE
Rivaroxaban Einstein PE/DVT Every patient received 15mg bd 21 days Standard dose 20mg od No dose reduction in the trial for age or CKD No patients enrolled with crcl<30 No increased risk of bleeding with CKD patients or elderly on subanalysis
Apixaban
Direct inhibitor of Xa Oral agent Twice daily dosing Rapid onset of action Half life 9-14hours Monitoring not usually necessary Biliary and renal excretion Few food or drug interactions GI side effects
Trial Data – NICE approved for SPAF
VTE prevention – approved in US and UK
Advance -1 failed to show non inferiority vs LMWH post surgery
Advance - 2 superior with less bleeding vs LMWH post TKR
SPAF Aristotle vs warfarin in 18,200 patients
5mg BD superior in preventing stroke or systemic embolism
less bleeding
lower mortality
Apixaban for VTE Apixaban 10mg bd one week 5mg bd till 6 months Excluded if crcl <25 No dose adjustment for CKD No difference in efficacy or safety compared to normal renal function group
Dabigatran etexilate
Direct thrombin inhibitor NICE approved for SPAF Oral, fixed doses Predictable anticoagulant response Monitoring not ususally necessary Rapid onset and offset of action Peak plasma level 0.5 -2 hrs Half life 12-17 hours Mininal food and drug interactions Renal excretion No agent available for reversal Reasonable cost No trials of use as first agent in VTE – need to give heparin first
Coagulation tests PT not affected APTT prolonged but not dose related TT prolonged excessively Haemoclot assay - a dilute calibrated TT Ecarin clotting time
How long should we give anticoagulants for?
VTE
Variable
Minimum 6 weeks
3-6 months for most indications – in unprovoked thrombosis
For period of risk
Practice has changed - increasingly unprovoked thromboses now result in lifelong treatment
Warfarin can be stopped abruptly
Secondary prevention in dosing VTE
Risk factors related to initial event
Idiopathic
The annual risk of recurrent VTE after a first idiopathic VTE
10% during the first 2 years then 3% per year
20 to 40% percent of those with an unprovoked venous thromboembolism (VTE) experience a recurrence within five years of the initial event
This is different in cancer
The future
VTE risk assessment as part of ‘health check’ of hospitals, CQUINs,
Oral anticoagulants that do not need monitoring – we are here but… adherence… over time more data can increase complexity
Targeted anticoagulants for different indications
Alternative means of reversal
recombinant clotting factors?
