VTE

thrombus

stationary blood clot, remains at point of origin

embolus

blood clot (or other foreign material) which has traveled from its point of origin to another location which occludes a vessel

embolism

obstruction or occlusion of a vessel by an embolism

underlying arterial mechanism for thrombosis

often consequence of atherosclerotic disease

acute plaque rupture initiates clotting process

most common VTE

deep vein thrombosis (DVT), pulmonary embolism (PE)

Deep vein thrombosis (DVT) common areas

thrombus formation, usually in deep veins of the legs

can also have upper extremity DVT (UEDVT), less common

Superficial vein thrombosis (SVT) common areas

occurs in the superficial veins (either upper or lower extremity), low extremity SVT often related to varicose veins

distal DVT vs proximal DVT

distal- confined to veins below popliteal veins, most common location

proximal- involves the popliteal and/or a more proximal vein- bigger risk of embolism

pulmonary embolism

a clot (embolus) that lodges in the pulmonary artery (or one of its branches), causing complete or partial obstruction of pulmonary blood flow.

Virchow’s Triad

• age- risk doubles with each decade after age 50

• prior history of VTE (strong rf for DVT and PE)

hypercoagulability:

• drugs (estrogen, SERMs)

• malignancy

• pregnancy

• genetic abnormalities

stasis:

• major medical illness

• immobility (eg: bedrest for >/=3 days during hospital admission

• major surgery

vascular injury:

• major orthopedic surgery (eg: hip and knee replacements)

• major trauma

• indwelling venous catheters

signs and symptoms of DVT

calf/leg (or arm) pain and tenderness

calf or leg (or arm) swelling

erythema/warmth

cyanosis/discoloration

palpable cord

homan’s signs

clinical probability scoring tools DVT

Wells DVT risk score

D-dimer

diagnostic testing DVT

doppler ultrasound

PE signs and symptoms

dyspnea

tachypnea/tachycardia

pleuritic chest pain/palpitations

cough

diaphoresis

± hemoptysis

severe: syncope, shock

PE clinical probability scoring tools

Wells PE risk score

D dimer

diagnostic testing for PE

CTPA (computed tomography pulmonary angiogram)-main test used for PE diagnosis

V/Q scan (relies on mismatch between perfusion and ventilation (embolus obstructs perfusion (Q), but not ventilation (V) ; radionucleotide imaging)

what are D dimers

measure broken up fibrin (plasmin cleaves fibrin to D dimers)

when do you usually do D dimer in the diagnosis of VTE

if someone has suspected VTE, clinical pretest probability is low do D dimer (or if moderate depending on assay used)

if D dimer is normal it’s likely no overactive clotting and can exclude VTE

***but likely to do D dimer anyways bc determines how severe clotting was

initial/acute phase goals of therapy for VTE

prevent death

prevent thrombus recurrence or extension (need to have anticoagulation working as soon as possible)

for DVT: to prevent pulmonary embolism

long term goals of therapy for VTE

to prevent post thrombotic syndrome (DVT)

to prevent pulmonary hypertension (chronic thromboembolic pulmonary hypertension, CTEPH)

to prevent recurrent thromboembolism (may require longer term therapy from several months up to lifelong)

lab tests to review when treating VTE

activated partial thromboplastin time (aPTT)

• measures effect of intrinsic and common pathway

prothrombin time (PT)

• a measure of the integrity of the extrinsic and final common pathways

international normalized ratio (INR)

• ratio of a patient’s prothrombin time (PT) to a normal (control) sample, raised to the power of the ISI value for the analytical system used

anti-Xa levels (for LMWH)

• indirectly measures the amount of LMWH in the blood by measuring its inhibition of factor Xa activity

CBC

• hemoglobin and platelets

serum creatinine and creatinine clearance calculations

• assessment of dosing for several anticoagulants

UFH moa

potentiates the action of antithrombin III and thereby inactivates thrombin. heterogenous mixtures of molecules of varying lengths which results in variability of effect

onset of effect UFH

IV onset minutes

SC onset 1-2hr

baseline testing UFH

weight, CBC, INR, aPTT

how is UFH dosed

weight based dosing nomograms using TBW

dose adjustment of UFH in renal impairment

none

monitoring of UFH (efficacy + bleeding)

aPTT as per protocol

CBC/platelets every 2-3 days while on therapy

dose adjustments made based on aPTT (range for anticoagulation usually 1.5-2.5x control)

can UFH be used in pregnancy

yes

UFH adverse effects

thrombocytopenia: early: usually mild/transient, rarely <100, and rebound with continued therapy

late: heparin induced thrombocytopenia

• usually occurs in 7-14 days, may occur within 24 to 48hr if recent heparin use; immune mediated

• more severe, leads to thrombotic complications if not recognized + treated

• defined as platelets <100 or 30-50% reduction from baseline; remains low until heparin d/c

• higher risk with longer duration of therapy and IV route of administration

• cross reactive with LMWH

LMWH moa

inhibits primarily factor Xa (smaller effect on IIa) (versus UFH: factor IIa and X)

PK difference of LMWH vs UFH

LMWH longer plasma half life, peak effect 3-5hr, more predictable PK profile

LMWH examples

enoxaparin (lovenox), dalteparin, tinzaparin, nadroparin

baseline testing LMWH

weight, SCr, CBC, INR, aPTT

can LMWH be used in pregnancy

yes

LMWH dosing

TBW for initial dosing SC (enoxaparin bid or q24hr, dalteparin q 24hr)

obse patients- consider bid split dosing (>100kg)

dosage adjustment in decreased renal function for LMWH

<30mL/min once daily (enoxaparin)

nadroparin CI

no specific recommendations for tinzaparin or dalteparin

LMWH monitoring

resolution/no progression of original s/sx

CBC/platelets, SCr periodically (optimal duration not defined)- more frequent monitoring for pts in special situations (Decreased renal function, combordities. etc)

anti-Xa levels available; however not routinely done, may be used in selected situations (obesity, pregnancy, decreased renal function)

LMWH ae

similar to UFH: bleeding, HIT (less than UFH)

fondaparinux moa

synthetic indirect inhibitor of factor Xa; contains the five-saccharide sequence of UFH responsible for its activity

fondaparinux baseline testing

weight, CBC, INR, SCr, aPTT

can fondaparinux be used in pregnancy

yes

fondaparinux dosing

based on body weufht

in obese patients, avoid dose capping

renal function dose adjustment fondaparinux

caution in moderate renal insufficiency (30-50mL/min), and avoid in CrCl <30

fondaparinux monitoring

resolution/no progresssion of original s/sx (may take days-weeks)
Scr, CBC (optimal duration not defined)

fondaparinux ae

bleeding

others uncommon (like HIT)

warfarin moa

inhibits vitamin K dependant clotting factors in liver (factors II, VII, IX, X); also protein C and protein S

warfarin bioavailability

100%

warfarin metabolism

hepatic metabolism (racemic mixture)
S (Active)= CYP2C9

R= CYP1A2

warfarin onset

3-7 days - dependant on depletion of factors

warfarin baseline testing

CBC, INR (aPTT)

warfarin dosing

individualized, nomograms available as guidelines

INR guide further dosing

warfarin dose adjustment renal function

none

can you use warfarin in pregnancy

no

warfarin monitoring

resolution/no progression of original s/sx (days-weeks)

CBC periodically

INR- initially q 3 days until stable INR for 2-3 readings, then extend duration between tests (1 week, 2 weeks, 3 weeks), to usually minimum testing once per month

INR should be checked within 1-2 wks of any change in dose

any INR that falls below therapeutic range should be checked within 1-2 weeks whether or not the dose is adjusted

warfarin overlapping

overlap warfarin with short acting agent (UFH, LMWH, fondaparinux) for atleast 5 days and until 2 consecutive INRs in range

what is warfarin dose adjustment based on

total weekly dose

dose adjustment depends on how far INR is below or above recommended range

target INR

2-3

if pt is non bleeding and INR <2 what to do

increase dose by 10-15%, repeat INR within 1 week

INR 3.1-3.5 in non bleeding pt, what to do

decrease by 0-10%, repeat INR within 2wks

INR 3.6-4 in non bleeding pt, what to do

decrease by 10-15%, repeat INR in 2wks

INR 4.1-6 in non bleeding pt, what to do

hold 1 dose, decrease by 10-15%, repeat INR within 2-3 days

INR 6.1-9 in non bleeding pt, what to do

hold 2 doses, decrease by 10-15%, repeat INR within 2 days

INR >9 in non bleeding pt, what to do

hold 2 doses, decrease by 10-15%, repeat INR next day

rivaroxaban, apixiban, edoxaban moa

oral direct factor Xa inhibitor

dabagitron moa

direct thrombin inhibitor

onset of effect of DOAC

3-4hr

baseline testing DOAC

weight, cbc, scr, INR, aPTT

apixiban adjustment for decreased renal function

none if CrCl 25+

avoid <15

rivaroxaban adjustment for decreased renal function

none CrCl 30

avoid <15-30

dabigatran adjustment for decreased renal function

avoid <30

edoxaban dose adjustments

30mg daily (half dose) for CrCl 30-50, low body weight <60kg, concommitant use of pgp inhibitors (except amiodarone and verapamil)

not recommended CrCl <30

DOAC monitoring

resolution/no progression of original s/sx (may take days-weeks)

CBC, SCr (INR, aPTT) periodically - optimal duration not defined, suggest q3-6mo depending on baseline for pts on extended therapy or any time if health changes)

ADE (other than bleeding)- dyspepsia, gastritis (Dabigatran>rivaroxaban)

can you use DOAC in pregnancy

not recommended

when to consider fibrinolytics in VTE

pts with life or limb threatening VTE + no bleeding CI

ex: young pts with massive ileofemoral vein thrombosis or pts with hemodynamically unstable PE

used infrequently in VTE

fibronolytics (Altepase) moa

converts plasminogen to the natural fibrinolytic agent plasmin

plasmin lyses clot by breaking down the fibrinogen and fibrin contained in a clot

dosing of fibrinolytics

single dose

main ae of anticoagulants

bleeding

major bleeding

1. fatal bleeding and/or symptomatic bleeding in a critical area or organ, such as intracranial, intraspinal, intraocular, retroperitoneal, intraarticular or pericardial or intramuscular with compartment syndrome and/or

2. bleeding causing a fall in HgB of 20g/L or more, or leading to transfusion of 2+ units of whole blood or red cells

clinically relavent non major bleeding

does not meet criteria for major bleeding- usually requires intervention

signs/sx of bleeding

blood in stool (Dark, tarry, bright red)

blood in urine (pink, rust, cola color)

vomiting blood (dark brown, coffee ground, bright red)

epistaxis

gingival bleeding

unusally heavy bleeding or oozing from cuts or wounds

excessive menstrual bleeding

petechiae

change or blurred vision

falls or head trauma

joint pain, stiffness, or swelling

continuing or severe headache with or without confusion, dizziness, nausea, vomiting, weakness, or parasthesis

bleeding risk factors

hepatic or renal failure

ethanol abuse

cancer/metastatic cancer

older age (>65yrs, >75yrs)

reduced platelet count or function

previous bleeding

uncontrolled htn

anemia

frequent falls

previous stroke

diabetes

antiplatelet anticoagulant tx

poor anticoagulant control

comorbidity and reduced functional capacity

bleeding management

supportive care

stop anticoagulant/antiplatelet (usually more relavent for major bleeding)

specific targeted agents: idarucizumab, protamine, vit k, prothrombin complex concentrate, andexanet alfa

reversal agent for dabigatran

idrucizumab

UFH/LMWH reversal agent

protamine

INR >10 and no active bleeding management

omit doses, administer vitamin K

serious or life threatening bleeding and increased INR management

hold warfarin therapy

vit k

supplemented with prothrombin complex concentrate

outpatient DVT/low risk PE treatment regimen

apixiban or rivaroxaban as single drug therapy for 3-6mo

LMWH as single drug tx

LMWH or UFH overlap with warfarin

LMWH for 5-10d then dabigatran (no overlap)

LMWH for 5-10d then edoxaban (no overlap)

after 3-6mo stop anticoagulation if reversible risk factor, if not continue

what factors favour oral agent DOAC (over LMWH to warfarin or LMWH alone)

adequate renal/liver function

expected good adherance to meds

VTE with active malignancy (edoxaban, apixiban, rivaroxaban)

unable/unwilling to undergo subq injections and/or INR testing

med insurance coverage for DOAC or WTP

weight 120-140/150kg (rivaroxaban, apixiban prefered)

what factors favour LMWH bridging to warfarin (over DOAC/just LMWH)

severe renal dysfunction (CrCl <30mL/min)

significant drug-drug interaction with DOAC

pts weight >140-150kg

unable to obtain DOAC

known antiphospholipid syndrome

no history of HIT

what factors favour lmwh alone

activa malignancy if DOAC not an option

pregnancy

high bleeding risk

AND

no history of HIT

how to choose VTE treatment duration

if unprovoked continue therapy as long as risk of VTE outweighs bleeding risk

if provoked transient risk factor d/c after 3-6mo

if provoked persistent risk factor usually continue therapy until RF no longer present as long as VTE risk outweighs bleeding risk

after initial 6mo treatment w/ apixiban/rivaroxaban can you lower dose

yes bc now preventing

what is post thrombotic syndrome

cluster of leg s/sx in pts with a previous DVT, including:

chronic postural dependant swelling and pain

ambulatory discomfort

skin pigmentation

itching,burning

most extreme manifestation: venous leg ulcer

prevention of post thrombotic syndrome

no strategy proven effective for decreasing occurence

elastic stockings/compression bandages- stockings to provide an ankle pressure gradient of 30-40mmHg if feasible-may help with edema or treatment of pts

what is post pe syndrome

defined by suboptimal cardiac function, pulmonary artery flow dynamics, or pulmonary gas exchange at rest or during exercise, in combination with dyspnea, exercise intolerance, or diminished functional status or quality of life, without an alternative explanation

chronic thromboembolic pulmonary hypertension (CTEPH)- the most severe manifestation of the post pe syndrome

gold standard treatment of chronic thromboembolic pulmonary hypertension (CTEPH)

pulmonary endarterectomy (PEA)no

non pharm VTE prevention

ambulation

intermittent pneumatic compression (IPC)

graduated compression stockings (GCS)

inferior vena cava (IVC) filters

pharmacologic options for VTE prevention

low dose UFH

low dose LMWH (enoxaparin)

fondaparinux

warfarin (Rare)

DOACs*

what are DOACs approved for in VTE prevention

prophylaxis post elective hip and knee replacement surgery