VTE Part 1 Flashcards
General Background
Hemostasis vs Thrombosis
Arteries vs Veins
• Hemostasis
– Physiologic
– Process causing bleeding tostop, meaning to keep blood within a damaged blood vessel
• Thrombosis
– Pathologic
– Formation of a blood clot within a blood vessel,
obstructing blood flow through the circulatory system
Arteries vs Veins • Blood flow in the circulatory system • Arteries – High flow / pressure – Carry oxygenated blood – Generally smaller lumen with thicker (more muscular) walls
• Veins
– Low flow / pressure
– Carry deoxygenated blood
- Generally larger lumen with thinner walls
White vs Red Clot:
Oversimplified
clot location flow in vessel composition of clot culprit tx of choice
see slide 7
WHITE Clot “Atherosclerotic” RED Clot “Thrombus” or “Thromboembolic”
Clot location: Arterial Venous
Flow in vessel: High flow / pressure (atherosclerosis)
Low flow / pressure (stasis)
Composition of Clot” Platelets
Red blood cells trapped with fibrin
Culprit” Platelets
Clotting Factors / Fibrin
Treatment of Choice: Antiplatelet Anticoagulant
Factors Contributing to & Clinical Conditions
of Thrombosis
virchow\s triad
hypercoagulable state
endothelial injury
circulatory stasis
Abnormality of the blood (hypercoagulable state) -causing “overactive” clotting factors (hypercoagulable states) -increase estrogen -cancer
Abnormality of blood vessel (endothelial injury_
- disruption of atherosclerotic plaque (MI, cerebrovascular stroke)
- injury (trauma – fractures, surgery)
- change in “tissue” (heart valve replacement)
Abnormality of blood flow (“sluggish” flow) (circulatory stasis)
- Venous blood flow is a relatively low pressure (versus arterial),stasis may occur (prevent clearing of clotting factors).
- Risk includes: immobilization (bed rest, paralysis → VTE), disease states (CHF, AF → embolic stroke)
What is Venous Thromboembolism (VTE)?
VTE occurs in 1-2 per 1000 person years in general population
• Annual incidence of symptomatic DVT ~ 145/100,000
• Annual incidence PE ~ 66/100,000
• Incidence increases with age
• Mortality from PE occurs early
VTE = general term encompassing a blood clot that forms in a vein and may/may not embolize; Captures both DVT and PE
Deep Vein Thrombosis (DVT):
• Thrombosis occurring in the deep veins
• Most commonly in leg, may occur in other
veins (arms, mesenteric, cerebral)
Pulmonary Embolism (PE):
• Blockage of lung artery by a clot that has traveled from elsewhere in bloodstream
• Most commonly from deep veins of leg or pelvis
see slide 10-11 for clotting cascade
k
Antithrombotic Agents=
antiplatelet, anticoagulant, fibrinolytic
oral antiplatelets
injectable antiplatelets
antiplatelets and coagulants
Stabilizes Clot
Prevents Clot Growth
Prevents New Clot Formation
oral antiplatelets: Acetylsalicylic Acid (ASA) Ticlopidine Clopidogrel Dipyridamole Prasugrel Ticagrelor
injectable antiplatelets: Abciximab Eptifibatide Tirofiban (GP IIb/IIIa Inhibitors)
oral anti-coagulants: Warfarin Dabigatran Rivaroxaban Apixaban Edoxaban
injectable anti-coagulants: LMWH Fondaparinux UFH Lepirudin Bivalirudin
Fibrinolytics -Breaks down
the clot
Antifibrinolytic - Prevents clot
break down
fibrinolytics Streptokinase Alteplase Tenecteplase Reteplase
anti-fibrinolytic
Tranexamic acid
Aminocaproic acid
Leg Deep Venous Thrombosis:
Proximal vs Distal DVT
Proximal DVT
– Anything above the knee / located in the popliteal vein or above
– Larger veins, larger clots
– 70-80% of DVTs
– Larger clots, increased likelihood of embolization to the lungs
• Distal DVT – Anything below the knee – Smaller veins, smaller clots – 20-30% of DVTs – Likelihood of clot growth/extension into the proximal system (~15% will extend)
Misnomer … the Superficial femoral vein is NOT superficial ….
Signs & Symptoms of DVT
• Pain and tenderness in the affected area
• Swelling (distal to clot)
• Discoloration
• Joint pain and soreness
• Warmth in the affected area
• Palpable Cord
• Superficial venous dilation
• Presentation is relatively non-specific, as signs/symptoms are not unique to DVT
• Objective testing is necessary to confirm / exclude the
diagnosis of DVT
Signs & Symptoms
of PE
• Shortness of breath, “breathlessness”
• Hypoxemia
• Tachycardia
• Sudden, unexplained cough
• Pleuritic Chest pain (=worsens with
breathing, coughing, sneezing) & Hemoptysis may occur
• Dyspnea, Fatigue
• Increase in pulmonary vascular resistance → right ventricular strain /enlargement / failure (Pulmonary Pattern on 12-lead ECG)
– Pulmonary embolism with cor pulmonale
• Syncope, confusion, coma/shock, hemodynamic instability
Clinical significance depends on:
- Size of embolus/emboli
- Patient’s cardiorespiratory reserve
Severity of PE
3 classes, which need hospitalization?
Massive: Unstable, in shock < 5% PEs, > 15% death
Sub-massive: No hypotension, beginning of right ventricular (RV) failure (large RV) or signs of RV strain,
positive biomarkers (troponin, BNP)
~ 15%, 3 - 15% death
Non-massive* Stable ~ 80%, < 1% death
*5-50% with PE are treated at home (as outpatients) vs admitted to hospital
• Non-massive patients are not required to be
admitted to hospital (=may be managed as an
outpatient - >40% in Edmonton Zone)
• Non-massive and sub-massive were studied in
clinical trials of DOACs vs LMWH/warfarin for PE
• Massive are all admitted
Clinical Consequences of VTE
VTE = DVT + PE
DVT Clot extension/embolization → PE Recurrence (20% will be PE) Post-thrombotic syndrome (legs/arms) Pain / Discomfort in limb
PE DEATH (3rd most common CV cause)* Prior to Presentation (within hours) Risk of early death (1st month) Recurrence (60% will be PE) Chronic thromboembolic pulmonary hypertension (CTEPH) Right ventricular failure *after MI and stroke
Death due to PE occurs early – implying:
• Early detection / treatment is important
• Identification and prophylaxis for those at risk of DVT/PE are key
• Prevention is the most effective approach
Goals of VTE Treatment
• Prevent death from PE • Reduce the symptoms of the clot • Prevent long-term complications – DVT – PE • Minimize adverse effects of medications • Longer Term: Prevent recurrence of VTE
Which of the following is correct?
1. Patients having a proximal DVT should be
counseled about their risk of also having an
embolic stroke (=clot traveling to the brain)
2. Clots occurring with VTE are red clots therefore
are best treated with antiplatelet drugs
3. Anticoagulants will help break down the clot
4. Pulmonary embolism is most concerning given
the risk of sudden death & proximal leg clots are
more likely to embolize compared to distal leg
clots
Pulmonary embolism is most concerning given
the risk of sudden death & proximal leg clots are
more likely to embolize compared to distal leg
clots
Diagnosis – Role of the Pharmacist
• Access to reports (NetCare) – read report / summary
• Confirmation (report) of the diagnosis
• Severity / Extensiveness of the clot - impacts care /
complications
Non-specific presentation mandates
objective testing:
Differential Diagnosis of a VTE
Deep Vein Thrombosis • Baker’s cyst • Cellulitis • Lymphedema • Chronic venous insufficiency • Aneurysm (venous or arterial) • Hematoma • Muscle Tears
Pulmonary Embolism • Angina / Myocardial Infarction • Musculoskeletal pain • Pleuritis • Pericarditis • Cardiac Tamponade • Pneumonia / acute Bronchitis • Asthma or COPD exacerbation • Heart failure exacerbation • Hyperventilation / Panic disorder • Lung trauma / pneumothorax • Mediasitinitis
Wells Criteria for Deep Vein Thrombosis
Wells Criteria for Pulmonary Embolism
• Probability of DVT: – Low, score of 0 – Intermediate, score of 1-2 – High, score > 3
• Probability of PE: – Low, score of 0-1 – Intermediate, score of 2-6 – High, score > 7 see slide 24-25
D-Dimer: Sensitive, but not Specific
what is it for?
(Fibrin Degradation Product)Fibrin split products
• Simple blood test • Elevated with VTE • Non-specific, also elevated if: – Malignancy – DIC – Pregnancy – Infection – Post-surgery / trauma – Inflammatory conditions
• If positive, not helpful
• If negative, helpful, rules
out VTE
DVT Diagnosis
Diagnostic Algorithm for DVT & PE
see slide 26
If high or moderate clinical suspicion of VTE, an
anticoagulant should be initiated while waiting for test
results
• Compression Ultrasonography
– Most common imaging to diagnose DVT, non-invasive
– Highly sensitive for proximal DVTs, less so for distal
– U/s of proximal leg only, unless clinician requests whole leg
Artery & Vein without gentle compression
Vein with gentlecompression, and compressibility
(no thrombus)
Vein with gentle compression, and no compressibility
(thrombus present)
PE Diagnosis
2 types of image
• Ventilation/Perfusion (V/Q) scanning
– Ventilation: Gaseous nucleotide inhaled
– Perfusion: IV injection of radioactive albumin
– Both phases imaged
– Identify mis-matches –probability:
• Low – intermediate = non-diagnostic
• High = diagnostic
• CT angiography – Main imaging modality if suspected PE – Very sensitive – Non-invasive, venous dye – Risk of Cancer attributable to radiation, hence protocols for use should be optimized
Following Diagnosis - Focus on
Community Management
• Guidelines have long suggested ambulatory management ofacute DVT
• Recent guidelines (2016) suggest those with low-risk PE with adequate home circumstances should be treated at home over hospitalization
• Locally (Edmonton Zone), the following are discharged home from the emergency department:
– > 40% with pulmonary embolism
– > 85% with deep vein thrombosis
• Implication: Community pharmacists will encounter these patients right after diagnosis & must ensure appropriate therapies given risk of death early on
VTE Phases of Care
Acute to Long-term (= Active Treatment) & Extended (= Secondary Prevention)
see sloode 32
Anticoagulant therapy is used for treatment of VTE to stabilize the clot, prevent growth, and prevent embolization
• DVT or PE are active clots that must receive treatment doses of a rapid acting anticoagulan
Initial (day 0-7-21) to Long –Term (out to 3-6 months
Initial – Long-Term Treatment Phase: Options
DVT & PE Rivaroxaban 15mg BID x 3 weeks, then
Rivaroxaban 20 mg daily
VTE Parenteral Anticoagulant for 5-10 days,
then Dabigatran 150mg BID†
VTE Apixaban 10 mg BID x 7 days, then
Apixaban 5mg BID
VTE Parenteral Anticoagulant for 5-10 days,
then Edoxaban 60mg daily‡
VTE Parenteral Anticoagulant (LMWH or
fondaparinux) + Warfarin to an INR of 2.0-
3.0, then warfarin (INR 2.0-3.0) alone
VTE + Cancer = CAT
LMWH or DOAC (avoid DOAC if high risk of bleeding, GI/GU cancer, DDI)
as long as underlying cancer is present
Treatment Options for Acute VTE
Must Act Quickly
Direct Acting Anticoagulants • Dabigatran (oral) • Rivaroxaban (oral) • Apixaban (oral) • Edoxaban (oral)
Indirect Acting Anticoagulants • Heparins – Low molecular weight heparin (LMWH) - subcutaneous – Unfractionated heparin (UFH) – intravenous or subcutaneous • Fondaparinux (subcutaneous) • Warfarin (oral)* *does not act quickly – was the only oral agent until 2012
Dabigatran Etexilate (Pradaxa™) MOA dosage form
• Oral, capsule
• Foil packaging, removal just prior
to taking dose (blisters)
*Swallow capsule whole
• Peaks in 2 hours (rapid absorption)
• 6% bioavailability – formulation of drug surrounded by tartaric acid
• T1/2 ~ 14-17 hours
• *Prodrug, converted to dabigatranvia esterase-catalysed hydrolysis in plasma / liver
Dabigatran Etexilate is a substrate
for efflux P-Glycoprotein (gp)
• *MOA: Competitive, reversible direct thrombin inhibitor (both free and fibrin bound thrombin)
• 80% renal elimination**
• Take with (or without) food – food delays absorption
Dabigatran Etexilate (Pradaxa™) AE, drug int antidote see slide 38-39
• Side Effects: – Bleeding – Dyspepsia • Drug Interactions: – P-glycoprotein inhibitors / inducers – primarily GI (administer dabi gatran 2 hours before) – Acid neutralizers – Increasing risk of bleeding • Antidote: Pradaxa Product Monograph, March 2020. – Idarucizumab (Praxbind™)
Dabigatran Dosing
Treatment of VTE After 5-10 days treatment
with a parenteral anticoagulant: 150mg BID†
As per VTE assessment, 3 months to lifelong
Not used much for acute VTE – approved by Health Canada, yet
manufacturer did not proceed to get any drug coverage for this indication
Idarucizumab (Praxbind™)
(Antidote specific for only Dabigatran)
MOA
indication
• Binds non-competitively to dabigatran with ~350 stronger affinity than thrombin
• Indicated for adult patients treated with dabigatran when rapid reversal of anticoagulant effect is required for:
– Emergency surgery / urgent procedures
– Life-threatening or uncontrolled bleeding
• IV bolus / infusion of two vials (each idarucizumab 2.5mg = 5g dose)
• Use in Emergency Departments / Operating Rooms
– Expensive, requires refrigerat
