Lecture 19-22 Thromboembolism Flashcards
What is a “white clot”?
located in an artery
the flow in the vessel is high flow and pressure (atherosclerosis)
clot is composed of platelets, and is treated with antiplatelets
clinically presents as ACS or atherosclerotic stroke
What is a “red clot”?
located in a vein,, flow in the vessel is low flow and pressure (stasis)
clot is composed of RBCs trapped within fibrin, and is treated with anticoagulants
clinically presents as VTE or cardioembolic stroke
What is Virchow’s triad and what is involved in it?
describes factors and clinical conditions contributing to the risk of thrombosis
- ABNORMALITY OF THE BLOOD (HYPERCOAGULABLE STATE): causing ‘overactive’ clotting factors (hypercoagulable), increased estrogen (pregnancy supplementation), cancer
- ABNORMALITY OF BLOOD VESSEL (ENDOTHELIAL INJURY): disruption of atherosclerotic plaque (MI, cerebrovascular stroke), injury (trauma - fractures, surgery, prior VTE, indwelling catheter), change in ‘tissue’ (heart valve replacement, invasive tumors)
- ABNORMALITY OF BLOOD FLOW (CIRCULATORY STASIS, ‘sluggish flow’): venous blood flow relatively low pressure vs arterial ⇒ stasis may occur (prevent clearing of clotting factors), risks include: immobilization (bed rest, paralysis ⇒ VTE), disease states (HF, AF ⇒ embolic stroke)
What is venous thromboembolism (VTE)?
general term encompassing blood clot that forms in a vein and may/may not embolize
includes ⇒ deep vein thrombosis (DVT): thrombosis occurring in deep veins, most commonly in leg, may occur in other arms (arms, mesenteric, cerebral)
and pulmonary embolism (PE): blockage of lung artery by clot that travelled from somewhere else, most commonly from DVT of leg or pelvis
What is the epidemiology of VTE?
incidence increases with age, occurs in 1-2 per 1000 person years in gen pop
annual incidence of sx DVT around 145/100,000 and PE around 66/100,000, mortality from PE occurs early
What is proximal and distal DVT?
Proximal: anything above the knee/located in popliteal vein or above, larger veins so larger clots so increased likelihood of embolization to lungs,, 70-80% of DVTs ⇒ most commonly popliteal vein and superficial femoral vein
Distal: anything below the knee, smaller veins so smaller clots
20-30% of DVTs ⇒ isolated in veins of calf, anterior tibial, peroneal, and posterior tibial veins
likelihood of clot growth/extension into proximal is around 15%
What is superficial thrombophlebitis or superficial vein thrombosis (SVT)?
in the lower extremities, the greater saphenous vein (60-80%), small saphenous (10-20%)
similar risk fx as VTE, also varicose veins in 75-88%
risk fx for future VTE (4-6x), 25% concomitant VTE
presents with reddened, warmed, inflamed tender area overlying saphenous vein
assess with compression ultrasound (as per DVT)
What are S&S of DVT?
pain and tenderness in affected area, swelling (distal to clot), discoloration, joint pain and soreness, warmth in affected area, palpable cord, superficial venous dilation, presentation is relatively non-specific as these S&S aren’t unique to this, objective testing needed
What are S&S of PE?
SOB, hypoxemia, tachycardia, sudden unexplained cough, pleuritic chest pain (worsens with breathing, coughing, sneezing), dyspnea, fatigue, increase in pulmonary vascular resistance ⇒ right ventricular strain/enlargement/failure (cor pulmonale), syncope, confusion, coma/shock, hemodynamic instability
What is a D-dimer test and when do we use it?
it is a simple blood test, is elevated with acute VTE ⇒ it is sensitive but not specific to acute VTE, also elevated in: malignancy, DIC, pregnancy, infection, post-surgery/trauma, inflammatory conditions
if its (+) = not helpful, if its (-) = helpful as it rules out VTE
How is DVT diagnosed?
using compression ultrasonography: most common imaging to diagnose, non-invasive
highly sensitive for proximal ones, less so for distal
ultrasound of proximal leg only unless clinician requests whole leg
How is PE diagnosed?
Ventilation/Perfusion (V/Q) Scanning: ventilation - gaseous nucleotide inhaled, perfusion - IV injection of radioactive albumin
both phases imaged, identify mismatches
CT Angiography: main imaging modality if suspected, very sensitive, non-invasive using venous dye, risk of cancer attributable to radiation hence protocols for use should be optimized
What does evidence show for thrombolytic tx for PE?
lysis accelerates resolution of PE BUT increases risk of major bleeding to a point where harm outweighs benefit for the majority of patients
should be reserved for patients at greatest risk of dying from PE ⇒ with ‘massive’ PE or PE with cardiopulmonary compromise
What are examples of direct oral anticoagulants (DOACs)?
dabigatran etexilate (Pradaxa), apixaban (Eliquis), rivaroxaban (Xarelto), edoxaban (Lixiana)
Dabigatran for tx of VTE (MOA, bioavailability, t1/2 and time to peak, renal elimination %, metabolism, drug intx mech, dosing/duration, AE, reversal agent)
MOA: direct Factor II inhibitor
Bio: 6%,, T1/2 and Peak: peaks in 2 hours, with half life of 14-17 hours
Renal and other elimination: 80% renally eliminated, also conjugated
Drug Intx Mech: is a substrate of P-gp efflux so if P-gp is inhibited then it is affected
Dosing/Duration: after 5-10 days of parenteral anticoagulant tx ⇒ 150 mg BID, can be taken with/without food, is used for 3 months to lifelong tx
AE: dyspepsia, bleeding,, Reversal Agent: Idarucizumab
What is the monitoring regimen look like for DOACs?
no routine coagulation monitoring needed
just do an annual CBC, annual SCr (sooner if renal dysfxn)
What is idarucizumab (Praxbind)?
antidote specific for reversal of dabigatran,, binds non-competitively to dabigatran with 350x stronger affinity than thrombin
indicated for adult pt tx with dabigatran when rapid reversal of anticoagulant effect required - emergency surgery/procedures, life-threatening or uncontrolled bleeding,, Admin as IV bolus/infusion of two vials (each 2.5 mg = total 5 mg)
used in emergency rooms, is expensive and requires fridge
Rivaroxaban for tx of VTE (MOA, bioavailability, t1/2 and time to peak, renal elimination %, metabolism, drug intx mech, dosing/duration, AE, reversal agent)
MOA: direct Factor X inhibitor,, Bio: >80%,, T1/2 and Peak: peaks in 2-4 hours with half life 7-11 hours
Renal and other elimination: 33& renal, also 3A4 (18-50%), 2J2 and CYP independen
Drug Intx Mech: is substrate of P-gp and metabolised partially by 3A4, so interacts with effectors of 3A4 and P-gp,, Dosing/Duration: 15 mg BID F3W then 20 mg QD (can also be 10 mg QD after 6-12 months), is taken with food, tx lasts 3 months to lifetime
AE: bleeding,, Reversal Agent: Andexanet alfa
Apixaban for tx of VTE (MOA, bioavailability, t1/2 and time to peak, renal elimination %, metabolism, drug intx mech, dosing/duration, AE, reversal agent)
MOA: direct Factor X inhibitor
Bio: 66%,, T1/2 and Peak: peaks in 3 hours and half life of 8-15 hours,, Renal and other elimination: 27% renal, also 3A4 (20-25%), 1A2, 2J2, 2C8, 2C9, 2C19
Drug Intx Mech: is substrate of P-gp and metabolised partially by 3A4, so interacts with effectors of 3A4 and P-gp,, Dosing/Duration: 10 mg BID F7D then 5 mg BID (could also be 2.5 mg BID for tx after 6 months unless high risk), with/without food, tx lasts 3 months to lifetime
AE: bleeding,, Reversal Agent: Andexanet alfa
What is the DOAC that is taken with food?
rivaroxaban
Edoxaban for tx of VTE (MOA, bioavailability, t1/2 and time to peak, renal elimination %, metabolism, drug intx mech, dosing/duration, AE, reversal agent)
MOA: direct Factor X inhibitor
Bio: 62%,, T1/2 and Peak: peak in 1-2 hours and half life 10-14 hours
Renal and other elimination: 50% renal, also 3A4 (<4%)
Drug Intx Mech: is substrate of P-gp so affected by things interacting with P-gp (MAINLY INDUCERS)
Dosing/Duration: after 5-10 days tx with parenteral anticoagulant dosed as either 60 mg QD (if CrCl >50) OR 30 mg QD if any one of: CrCl 15-50, body weight </= 60 kg, concomitant P-gp inhibitor (excluding amiodarone or verapamil), with or without food, AE: bleeding
Reversal Agent: Andexanet alfa
What DOACs are administered after parenteral anticoagulation is done first?
dabigatran and edoxaban
What is andexanet alfa (Ondexxya)?
is an antidote for Factor Xa inhibitors like apixaban, rivaroxaban, and edoxaban,, is a factor Xa molecule that acts as a decoy to target and sequester both oral and injectable FXa inhibitors (competitive binding)
indicated for rapid reversal for anticoagulation (apixaban or rivaroxaban or edoxaban) due to life threatening or uncontrolled bleeding
not yet available in Canada
admin as either low dose - bolus 400 mg then 4 mg/min F2H, or high dose - bolus 800 mg then 8 mg/min F2H
What are drugs which cause inhibitory DDIs with DOACs and are contraindicated/cautioned with concomitant use, and their MOAs of DDI?
Ketoconazole, itraconazole, voriconazole, posiconazole: strong 3A4 inhibition and P-gp inhibition (not voriconazole)
ritonavir: strong 3A4 and P-gp inhibition
cobicistat: strong 3A4 and P-gp inhibition,, glecaprevier/pibrentsivir: strong P-gp inhibition
dronedarone: moderate 3A4 and P-gp inhibition
St. Johns Wort: 3A4 and P-gp inhibition
SSRIs/SNRIs: platelet mediated, ok to still use DOACs but use caution
Ritonavir COVID: hold DOAC start LMWH if high clot risk, if low clot risk hold DOAC and start ASA
What are drugs which cause inducing DDIs with DOACs and are contraindicated/cautioned with concomitant use, and their MOAs of DDI?
Rifampin: P-gp and 3A4 induction
Carbamazepine: strong 3A4 and P-gp inducer
Phenytoin: strong 3A4 and P-gp inducer
Phenobarbital: strong 3A4 and P-gp inducer
What is the MOA of warfarin?
competitively inhibits Vitamin K epoxide reductase complex subunit 1 (VKORC1) an enzyme that plays a part in activating available vitamin K ⇒ therefore it leads to inhibition of clotting factors II (prothrombin), VII, IX, and X
How is warfarin tx monitoring done?
prothrombin time (PT),, INR standardizes the PT to allow universal interpretation = patient PT/mean normal PT
INR crudely measures time it takes for blood clot to form
INR without warfarin = 1.0 (0.8-1.2) ⇒ with warfarin = 2.0-3.0, 2.5-3.5
the INR range for VTE is 2-3
How is warfarin used in the acute tx of VTE?
has a delayed effect ⇒ must cross-over using a rapid acting anticoagulant = a parenteral one (LMWH, fondaparinux, UFH)
overlap at least 5 days until the INR is at least 2.0 for 24 hours (= 2 consecutive days)
should be started on the day parenteral is used
for those at high risk of clot in 1st month and whose INR falls below 2 should have cross-coverage using rapid acting anticoagulant (ex. LMWH, fondaparinux, UFH)
How is warfarin dosed for VTE?
dose ranges from 0.5 mg QD - 38 mg QD, dose response is curvilinear
Phases: 1. Initiation: establishing INR target, hospitalized vs ambulatory, stability of dosing achieved
- Maintenance: ongoing achievement of INR
What does the initiation phase of warfarin dosing look like usually?
if pt is sufficiently healthy for outpatient tx ⇒ initial dose 10 mg x 1-2 days, with INR measure on day 2 or 3
if pt is elderly, debilitated, malnourished, CHF, liver disease, recent surgery, drug intx ⇒ initial dose </= 5 mg x 2 days, INR on day 3
<5 mg rarely administered on day 1 and 2 with INR on day 3
initiation phase usually goes for 3-4 weeks,, INRs should be assessed 2-3 x/week, take doses in context
What does the maintenance phase of warfarin dosing look like usually?
clotting factors are at Css, make small changes in response to INRs out of range unless changes that may impact warfarin are identified
full effect of a given dose may not be evident until 3-5 days after
should use weekly (even past 10 days) doses to guide future due to: delayed effect, response not linear
With INR Target of 2.5 (3.0): <1.5 (1.9) ⇒ reload 0-2x, increase weekly dose by 5-15%,, 1.5-1.9 (2-2.4) ⇒ reload 0-1x, increase weekly by 0-10%
2-3 (2.5-3.5) ⇒ no change,
3.1-3.5 (3.6-4) ⇒ hold 0-1x, decrease weekly by 0-10%,, 3.6-4.9 (4.1-4.9) ⇒ hold 0-2x, decrease weekly by 5-15%
5-9 ⇒ hold warfarin, use vitamin K 1-2.5 mg PO x 0-1,, >9 ⇒ hold warfarin, vitamin K 2-5 mg PO
What are drug interactions involved with warfarin?
A. Induction/inhibition of Cyt P450 ⇒ major 2C9, minor 3A4 and 1A2
B. Displacement of plasma binding proteins
C. alterations in Vitamin K status
D. contributing to bleeding/clotting risk
What are different things which can affect INR?
A. Changes to health ⇒ acute changes (fever, flu, diarrhea, etc), chronic changes - exacerbation of HF, alterations in thyroid fxn, etc
B. Changes to Meds
C. Changes to lifestyle ⇒ vitamin K intake, alcohol consumption, level of activity
What is considered critical in INR management and how may it be managed?
if an INR > 5,, check for S&S or bleeding, unusual bruising or something more concerning
clot vs bleed risk, factors contributing to the critical INR
Management/Recommendations: if INR 4.5-10 ⇒ omit 1-2 warfarin doses, consider vitamin K PO 1-2.5 mg and reassess IN
if INR > 10 ⇒ hold warfarin, vitamin K PO 2.5-5 mg and reassess INR
What are antidotes for warfarin usage?
Vitamin K ⇒ oral works within 16-24 hours, IV in 6-8 hours, SC and IM not recommended
Prothrombin Complex Concentrate (Factors II, VII, IX, X) ⇒ temporary reversal of INR within minutes, used for urgent bleeding cases
What are AEs of warfarin?
bleeding - major and minor
teratogenic - 6-12 weeks gestation, lower body weight, slower growth, intellectual disability, hypoplastic nose, stippled epiphyses, skeletal and ocular abnormalities,, Rare: skin necrosis, purple toe syndrome
What are the injectable anticoagulant drugs and their MOAs?
Drugs: LMWH (SC) - enoxaparin, dalteparin, tinzaparin,,, Fondaparinux (SC)
UFH (SC or IV)
they act quickly, indirectly act as cofactor to impact clotting factors in circulation
MOA: LMWH - anti Xa»_space; anti IIa, is smaller molecule so mainly inhibits Xa, pentasaccharide that binds to antithrombin = accelerated interaction with Xa
Fondaparinux - anti Xa, synthetic pentasaccharide sequence that binds to antithrombin
UFH - anti IIa»_space; anti Xa, larger molecule than LMWH so it can wrap around IIa, pentasaccharide that binds to antithrombin
they ALL require antithrombin = they aren’t direct acting unlike DOACs which don’t require cofactor
What is the onset and plasma t1/2, dosing basis, and antidote for injectable anticoagulants?
UFH onset is immediate with t1/2 of 1-2 hours, LMWH peaks at 2-4 hours and t1/2 of 4-6 hours, while fondaparinux peaks at 3 hours with t1/2 of 17-21 hours
they are all dosed based on weight, but if CrCl < 30 then LMWH and fondaparinux are not recommended
the antidote for UFH is protamine, as well as for LMWH but it’s not as effective, fondaparinux doesn’t have one
Where is UFH used in initial VTE tx?
situations wherein reversal of anticoagulant effect may be anticipated (extensive clot, circulatory compromise = massive PE) ⇒ IV drip typically used
renal dysfunction (CrCl <20)
is monitored using PTT
Where is LMWH used in VTE tx, and how is it monitored?
since it’s primarily renally eliminated (enoxaparin»_space; dalteparin > tinzaparin): CrCl <20 = use UFH, if 20-30 = tinzaparin, >30 = any three
for obese patients its recommended to dose based on total body weight (TBW), with no dose capping and admin Q12H
pretty much exclusively uses pre-filled syringes
Monitoring: recommends against routine anti Xa level monitoring, may be used to assess if potentially unsure of dosing (ex. weight extremes, renal dysfunction, failure of tx)
What are AEs of heparin?
bleeding - less with LMWH vs UFH, hematoma at injection site
osteoporosis - increases with tx duration, lower risk with LMWH,, alopecia
Heparin-induced thrombocytopenia (HIT) - Type I: non-immune mediated, transient, mild, early onset <4 days and reversible
Type II: immunologic rxn, severe, more common with UFH vs LMWH, delayed 5-14 days, can be with 1 day if exposure in last 100 days
= thrombotic disorder in 20-50%, limb amputation in 10%, fatal in 8-20%
How is heparin-induced thrombocytopenia monitored, what indicates it happened, and how is it treated?
Monitoring: Low risk (<0.1%) - pt with medical and obstetrical getting LMWH, or LMWH after minor surgery or trauma = no monitoring
intermediate (0.1-1%) - medical and obstetrical with UFH, LMWH after major surgery or trauma = platelet count Q2-3D for 4-14 days until heparin stopped
High (>1%) - surgical and trauma pt getting UFH = platelet counts at least Q2D for 4-14 days or until heparin stopped
Indication: platelet count typically falls below 150 x 10^9/L, however decrease from baseline of 40-50% is hallmark, S&S - clot, skin necrosis/lesions at injection site, systemic rxn after bolus
Tx: stop UFH/LMWH immediately, reverse warfarin with Vitamin K if bridging, initiate tx doses of an alternative non-heparin anticoagulant ⇒ Direct thrombin inhibitor: lepirudin, argatroban, bivalirudin (all short acting IV), danaparoid (heparanoid), fondaparinux, DOACs
What does the duration of anticoagulant therapy look like for DVT and PE, and what are some indications for whether or not treatment should be extended?
recommended for a 3-month treatment phase, and on completion of the 3 months all patients should be assessed for extended phase therapy,, in practice we often see a 6 month treatment phase,,,, if VTE provoked by major transient risk factor - surgery with general anesthesia > 30 min, hospital bed confinement, >/= 3 days with acute illness, caesarean section ⇒ recommended AGAINST EXTENSION
if VTE provoked by minor transient risk factor - surgery with general anesthesia < 30 min, hospitalized < 3 days with acute illness, estrogen tx, pregnancy or puerperium, confinement to bed out of hospital for at least 3 days with acute illness, leg injury associated with reduced mobility for at least 3 days ⇒ favours SUGGESTION AGAINST EXTENSION
if absence of transient provocation - unprovoked VTE or persistent risk fx ⇒ recommended FOR EXTENSION
What are some dose reduction options for DOACs if extended (secondary prevention) treatment is initiated?
apixaban 5 mg BID ⇒ 2.5 mg BID (AMPLIFY EXTENSION) - similar efficacy to 5 mg
rivaroxaban 20 mg QD ⇒ 10 mg QD (EINSTEIN CHOICE) - similar efficacy with less bleeding
What does therapy in the extended phase look like for VTE?
in pt indicated - suggest use of reduced-dose apixaban 2.5 mg BID OR rivaroxaban 10 mg QD over full dose of either agent
can also recommend reduced dose DOAC over aspirin or no tx, and suggest rivaroxaban over aspirin
in pt with unprovoked proximal DVT or PE and stopping anticoagulants and no contra to ASA then can use ASA to prevent recurrent VTE
What are inferior vena cava filters and when can they be used?
useful in pt with acute proximal DVT with contra to therapeutic anticoagulation due to high bleeding risk
reduces risk of fatal PE in short-term and increases risk of DVT in long-term
presence of permanent one may require long-term anticoagulation
if it is a retrievable filter the removal rates are poor (20%)
What is post-thrombotic syndrome?
occurs in nearly 1/3 of pt within 5 years after unprovoked DVT
characterized by: pain - not as bad as DVT pain, usually worse after being on feet
edema - usually will decrease after feet are elevated unlike DVT, and it gets worse as leg is used, whereas with DVT its bad all the time
hyperpigmentation, eczema, varicose collateral veins, venous ulceration
severe cases can lead to intractable painful venous leg ulcers requiring ongoing nursing and medical care
Why is leg elevation and compression stockings used for DVT, when can they be used, and when shouldn’t they be used?
can be used to reduce acute sx of DVT or chronic sx in those with PTS
worn during waking hours, may start wearing within 1 month, designed to fit tight on leg to assist in moving blood from leg veins to circulation
Contra: arterial insufficiency, intermittent claudication, uncontrolled HF, infection in area covered by stocking
What is chronic thromboembolic pulmonary hypertension (CTEPH)?
serious complication of PE,, up to 5% of pt with PE are reported to develop this
thromboembolism may fail to resolve and organize into fibrotic deposits = permanent occluding of pulmonary arteries
initial phase of disease often asymptomatic and followed by progressive dyspnea and hypoxemia
right HF can frequently occur
progressive condition associated with mortality rates of 4-20%
How is superficial thrombophlebitis or superficial vein thrombosis (SVT) treated?
prophylactic anticoagulation with rivaroxaban 10 mg QD OR fondaparinux 2.5 mg QD if: this > 5 cm long that is 3 cm away from SFJ or SPJ, if severe sx or risk extension
therapeutic anticoagulation (x 3 months) if: concomitant VTE, this within 3 cm SFJ or SPJ
PRN use of topical NSAIDs, compresses (warm and cool), compression stockings
What are common diagnoses for heart valve replacement?
Stenosis - mechanical obstruction to blood flow, net result of reduced valve orifice area (mitral, aortic)
Regurgitation - backward flow of blood, leaky valve, may be called ‘insufficiency’ (mitral, aortic)
Prolapse - fall or slip down (mitral)
What are types of replacement heart valves?
Bioprosthetic (Tissue): heterograph (porcine), less durable with up to 30% failure rate at 10-15 years, less thrombogenic
Prosthetic (Mechanical): 3 gens - ball cage, single leaflet, double leaflet
more durable, more thrombogenic
What does risk of thromboembolism look like for heart valve replacement, and what tx are used?
Mechanical Valves: uses anticoagulant +/- antiplatelet (usually warfarin + ASA 50-100 mg/day)
for aortic goes from 12% chance to 0.5%, for mitral goes from 23% to 0.9% (MITRAL HAS HIGHER RISK THAN AORTIC)
Bioprosthetic: highest risk of thrombosis < 3 months post-surgery, long term risk at 0.2-0.6% per year, up to 30% failure at 10-15 years
anticoagulant for some and antiplatelet long-term (ex. antiplatelet alone, or warfarin for 3 months then antiplatelet (more likely with mitral to use warfarin))
DO NOT USE DOACs for PATIENT WITH MECHANICAL HEART VALVES
How does warfarin tx change if a person has an upcoming procedure?
must hold warfarin for 5 days prior to procedure ⇒ then will take it >/= 4 days after procedure to achieve therapeutic anticoagulation, can take at 1.5 x maintenance dose for 3 days then assess INR,,, if clotting risk is high may need to bridge with LMWH
