Venous Thromboembolism (VTE)

Introduction
It is one of the most common cardiovascular disorders.
Is manifested as
DVT; i.e., thrombus causing obstruction of a deep vein
in the leg, pelvis, or abdomen and
PE; i.e., thrombus causing obstruction of a pulmonary
artery or one of its branches and resulting in pulmonary
infarction)
Most frequently seen in patients hospitalized for a
serious medical illness, trauma, or major surgery

2 04/18/2023
 EPIDEMIOLOGY AND ETIOLOGY
An estimated 2 million people in the US develop VTE
each year, of whom
600,000 are hospitalized and 60,000 die

30%–50% will develop a recurrent VTE event in the

following 5–10 years.
Around 30% develop postthrombotic syndrome

3 04/18/2023
 After a DVT event, 20% of patients die within the
following year.
After a PE event, 40% of patients die within the
following year.

The estimated annual direct medical costs are well

over $1 billion.
As the population ages, the total number of DVT and
PE cases continues to rise

4 04/18/2023
5 04/18/2023
 VTE risk factors can be categorized into one of the 3
elements of Virchow triad:
1. Stasis in blood flow,
2. Vascular endothelial injury, and
3. Inherited or acquired changes in blood constituents
resulting in hypercoagulable states
A prior history of venous thrombosis is perhaps the
strongest risk factor for recurrent VTE,
because of damage to venous valves and obstruction of
BF caused by the initial event

6 04/18/2023
7 04/18/2023
 PATHOPHYSIOLOGY
When a vessel is injured, a dynamic interplay between
thrombogenic (activating) and antithrombotic (inhibiting)
forces results in
the local formation of a hemostatic plug that seals the
vessel wall and prevents further blood loss.
A disruption of this delicate system of checks and
balances may lead to
inappropriate clot formation within the blood vessel
that can obstruct blood flow or embolize to a distant
vascular bed.

8 04/18/2023
 Primary hemostasis
Vascular injury exposes the subendothelium.
Platelets adhere to the subendothelium with their
glycoprotein (GP) Ib surface receptors and facilitated by
von Willebrand factor (vWF).
This causes platelets to become activated,
releasing a number of procoagulant substances that
stimulate circulating platelets to expose GP IIb and IIIa
surface receptors
o subsequently allowing platelets to adhere to one another,
o resulting in platelet aggregation

9 04/18/2023
 Secondary hemostasis
The damaged vascular tissue
releases tissue factor that activates the extrinsic pathway of
the coagulation cascade.
Once a clotting factor precursor is activated by specific
stimuli,
it activates the next clotting factor in the sequence
The final steps in the cascade are
the conversion of prothrombin (factor II) to thrombin (factor
IIa) and fibrinogen to fibrin.
Without effective self-regulation, the coagulation cascade
would proceed unabated until
all clotting factors and platelets are consumed.
10 04/18/2023
 Traditionally, the coagulation cascade has been
divided into three distinct parts:
the intrinsic,
the extrinsic, and
the common pathways

11 04/18/2023
12 Figure: Coagulation cascade 04/18/2023
 Clinical presentation and Diagnosis
Most patients with VTE never develop symptoms.
However, may suffer long-term consequences, such as
PTS and recurrent VTE
The symptoms of DVT or PE are nonspecific, and
it is extremely difficult to distinguish VTE from other
disorders on clinical symptoms alone.
Therefore, objective tests are required to confirm or
rule out the diagnosis

PTS produces chronic lower extremity swelling, pain,

and tenderness that lead to skin discoloration and
ulceration.
13 04/18/2023
14 04/18/2023
 Clinical Presentation of DVT and PE

15 04/18/2023
16 04/18/2023
Deep
17 vein thrombosis diagnostic algorithm. (CUS, compression ultrasound) 04/18/2023
 Pulmonary embolism
The Wells model can be used to determine the pretest
probability
Patients who have a low pretest probability, and who
have a negative D-dimer can have a
PE ruled out of their differential diagnosis.
Other patients should proceed to CT or other imaging
studies to confirm the diagnosis.

18 04/18/2023
 Wells Criteria Clinical Model for Evaluating the
Pretest Probability of PEa

19 04/18/2023
 PREVENTION
VTE is often clinically silent and potentially fatal
 Identify all patients at risk
 determine each patient’s level of risk, and
 select and implement regimens that provide sufficient
protection for the level of risk
Prophylaxis should be continued throughout the period
of risk.

20 04/18/2023
 Padua prediction score is recommended for assessment
of medical patients, and the
Caprini score is recommended for assessment of general
surgical patients.
Bleeding risk should also be assessed

21 04/18/2023
22 04/18/2023
23 04/18/2023
24 04/18/2023
 VTE Risk in Different Hospitalized Patient
Groups

25 04/18/2023
 Patients with moderate to high risk of VTE
should receive pharmacologic prophylaxis
If pharmacologic prophylaxis is contraindicated,
nonpharmacologic prophylaxis should be used

26 04/18/2023
27 04/18/2023
 For hospitalized general surgical and medical patients,
UFH 5000 units subcutaneously (SC) every 8 to 12 hours,
enoxaparin 40 mg SC daily,
dalteparin 2500 to 5000 units SC daily, or
fondaparinux 2.5 mg SC daily

28 04/18/2023
 For the prevention of VTE following major orthopedic
surgery,
UFH, LMWH, fondaparinux, adjusted dose warfarin,
aspirin, and DOACs (apixaban, dabigatran, edoxaban,
and rivaroxaban).
ASA produces a very modest reduction in VTE following
orthopedic surgeries of the lower extremities.
It use is controversial
LMWH or fondaparinux use preferentially over other
options

29 04/18/2023
 Dabigatran is only approved for use following hip
replacement surgery.
Dabigatran 110-mg dose, followed by 220 mg once
daily
However, not be used in CrCl <30 mL/min or
concomitantly with P-gp inhibitors.

30 04/18/2023
31 04/18/2023
32 04/18/2023
33 04/18/2023
 Duration of VTE Prophylaxis

34 04/18/2023
 TREATMENT
Desired Therapeutic Outcomes
The aim of initial therapy is
to prevent propagation or local extension of the clot,
embolization, hemodynamic collapse, and death.
The goal of long-term and extended therapy is
to prevent complications such as PTS, pulmonary
hypertension, and recurrent VTE.

35 04/18/2023
 General Treatment Principles
Anticoagulant drugs are the mainstay of therapy for
DVT and PE
Treatment can be divided into 3 phases:
acute (first 5–10 days),
long term (first 3 months), and
extended (beyond 3 months)
The acute treatment phase is typically accomplished
by administering
a fast-acting parenteral anticoagulant or a DOAC

36 04/18/2023
37 04/18/2023
38 04/18/2023
 Dosing of Injectable Anticoagulants for VTE

39 04/18/2023
 Table: Recommended initial dosing for UFH in VTE
treatment

40 04/18/2023
 Approaches to VTE Treatment

41 04/18/2023
 The long-term and extended phase treatments are usually
accomplished using
warfarin, or DOACs
In patients with cancer and pregnant,
LMWHs are the preferred agents due to better safety or
efficacy.
Patients with unprovoked or cancer-associated VTE
have a higher risk of recurrence
The etiology of VTE will guide the duration of therapy.

42 04/18/2023
 In the absence of contraindications, treatment should
initially include
a rapidly acting DOAC (eg, apixaban, rivaroxaban,
edoxaban) or
a rapid-acting injectable anticoagulant (eg, UFH, LMWH,
fondaparinux).
If warfarin is used, it should be
initiated on the same day as the parenteral anticoagulant, and
the parenteral agent should be overlapped for a
minimum of 5 days and until the INR is ≥ 2 for at
least 24 to 48 hours.
43 04/18/2023
 If dabigatran or edoxaban is used, they should be
initiated
after 5 to 10 days of initial treatment with a parenteral
anticoagulant.
Anticoagulation therapy should be continued for a
minimum of 3 months.
However, duration of anticoagulation therapy should
be based on
the patient’s risk of VTE recurrence and major bleeding

44 04/18/2023
45 04/18/2023
46 04/18/2023
© NICE 2020
47 04/18/2023
48 04/18/2023
49 04/18/2023
50 04/18/2023
51 04/18/2023
52 04/18/2023
 Guidelines
ASH 2020: For patients with DVT and/or PE,
suggests using DOACs over VKAs (conditional
recommendation based on moderate certainty in the
evidence of effects ⨁⨁⨁○).
CHEST 2021: In patients with VTE (DVT of the leg
or PE), recommend
apixaban, dabigatran, edoxaban, or rivaroxaban over
VKA as treatment-phase (first 3 months) anticoagulant
therapy (strong recommendation, moderate-certainty
evidence).

53 04/18/2023
54 04/18/2023
 Figure: Cumulative Risk of Recurrent VTE or Related Death during 6 Months of
55 04/18/2023
Treatment
 Figure: Cumulative Risks of a First Event of Major Bleeding and of Any
Bleeding
56 04/18/2023
 Thrombolytics
In a select group of high-risk patients with
massive iliofemoral DVT who are at risk of venous
gangrene and limb loss.
In patients with acute PE, use of thrombolytics
provides
short term benefits such as restoring pulmonary artery
patency and hemodynamic stability.
But, does not reduce mortality and is associated with a
greater risk of major bleeding.

57 04/18/2023
 Candidates for thrombolytic therapy are patients with
acute massive embolism who are hemodynamically
unstable (SBP < 90 mm Hg) and at low risk for bleeding.
Current guidelines recommend
a short infusion time (2 hours) over a prolonged infusion
time (24 hours) and
administration through a peripheral vein over a
pulmonary artery catheter.

58 04/18/2023
59 04/18/2023
 Unfractionated Heparin
For the treatment of VTE,
UFH is generally given as a continuous IV infusion.
The half-life of UFH is dose dependent and ranges
from 30 to 90 minutes.
AT deficiency and elevated factor VIII levels are
common in pregnant patients.
AT deficiency has been linked to higher UFH dose
requirements.
The requirement of these higher UFH doses is termed
heparin resistance.

60 04/18/2023
 Weight-based dosing UFH should be used
to exceed the therapeutic threshold in the first 24 hours after
initiating treatment.
Achieving a therapeutic aPTT in the first 24 hours after
initiating UFH is critical
because it has been shown to lower the risk of recurrent
VTE.
For obese patients, use an adjusted body weight (ABW)
instead.

61 04/18/2023
 Due to significant interpatient variability and changes
in patient response over time,
UFH requires close monitoring and periodic dose
adjustment.
UFH dose is then adjusted based on the aPTT
measurement.
Therapeutic aPTT range is defined as 1.5 to 2.5 times the
control aPTT value (25 – 35 secs).
In patients with heparin resistance,
antifactor Xa concentrations may be a more accurate
method of monitoring the patient’s response.
62 04/18/2023
63 04/18/2023
64 04/18/2023
 If major bleeding occurs, UFH should be stopped
immediately.
1 mg protamine sulfate per 100 units of UFH,
up to a maximum of 50 mg, given as a slow IV
infusion over 10 minutes.
The effects of UFH are neutralized in 5 minutes, and
the effects of protamine persist for 2 hours.

65 04/18/2023
 Heparin-induced thrombocytopenia (HIT) is a very
serious adverse effect.
It results from an autoantibody directed against
endogenous platelet factor 4 (PF4) in complex with
heparin.
This antibody activates platelets and can cause
catastrophic arterial and venous thrombosis.
It should be suspected if
platelet count drops by >50% from baseline or to < 150 ×
103/mm3 (150 × 109/L).
thrombosis occurs despite UFH use

66 04/18/2023
 Immediate discontinuation of all heparin-containing
products including the use of LMWHs and heparin-
based flushes is required.
Alternative anticoagulation with parenteral DTIs
should be initiated.

67 04/18/2023
 Algorithm for evaluating

68 04/18/2023
69 04/18/2023
 For treatment of VTE in children,
the UFH 50 units/kg bolus followed by an infusion of
20,000 units/m2 per 24 hours.
Alternatively, a loading dose of 75 units/kg followed
by an infusion of
28 units/kg/hour if <12 months and
20 units/kg/hour if >1 year may be considered

70 04/18/2023
 Low-Molecular-Weight Heparins
They exhibit less binding to plasma and cellular
proteins,
resulting in a more predictable anticoagulant response.
Thus, routine monitoring of anticoagulation activity
and dose adjustments are not required in most patients.
Longer plasma half-lives, allowing once- or twice-
daily administration, improved SC bioavailability
(>90%), and dose-independent renal clearance.
A lower incidence of HIT, osteopenia, and
osteoporosis.

71 04/18/2023
 Dose of LMWHs is determined based on the patient’s
weight and
Is administered SC once or twice daily
Dalteparin: 200 units/kg SC once daily or100 units/kg SC
twice daily
Enoxaparin: 1.5 mg/kg SC once daily or1 mg/kg SC twice
daily; if CrCl < 30 mL/min (0.50 mL/s): 1 mg/kg SC once
daily
Predictable anticoagulant effect
routine monitoring is not necessary in most patients
In patients with cancer,
the rate of mortality was lower in patients treated with an
72 LMWH compared to UFH 04/18/2023
 Use LMWHs cautiously in patients with renal
impairment.
Most patients with an uncomplicated DVT and PE
can be managed safely at home.
normal vital signs,
low bleeding risk,
no other comorbid conditions requiring
hospitalization, and
who are stable.

73 04/18/2023
 Monitoring of antifactor Xa activity may be
considered in adult patients who are
morbidly obese (weight > 150 kg [330 lb] or body mass
index [BMI] > 50 kg/m2),
weigh less than 50 kg (110 lb), or
have significant renal impairment (CrCl < 30 mL/min
[0.50 mL/s]).
in children, pregnant women, and those on long-term
therapy.

74 04/18/2023
 Protamine sulfate will partially reverse the anticoagulant
effects of the LMWHs
Due to its limited binding to LMWH chains,
protamine only neutralizes 60% of their antithrombotic
activity.
If the LMWH was administered within the previous 8
hours, give
1 mg protamine sulfate per
 1 mg of enoxaparin or
 100 antifactor Xa units of dalteparin

Give smaller protamine doses if more than 8 hours have

lapsed since the last LMWH dose

75 04/18/2023
 In patients undergoing spinal and epidural
anesthesia or spinal puncture,
spinal and epidural hematomas have been linked to the
use of LMWHs.
In patients with indwelling epidural catheters,
concurrent use of LMWHs and all other agents that
impact hemostasis should be avoided.
Children <1 year require higher doses
(eg, enoxaparin 1.5 mg/kg SC every 12 hours).

76 04/18/2023
 Factor Xa Inhibitors
Fondaparinux (Parenteral)
It exerts inhibitory activity specifically against factor Xa and has no
effect on thrombin
It has a half-life of 17 to 21 hours, permitting once-daily
administration,
but its anticoagulant effects will persist for 2 to 4 days after stopping
the drug.
Fondaparinux does not routine coagulation monitoring or dose
adjustments.
It is contraindicated in patients with CrCl < 30 mL/min [0.50
mL/s].
As safe and effective as
IV UFH for the treatment of PE and SC LMWH for the treatment of
DVT.
77 04/18/2023
 In the event of major bleeding,
fresh-frozen plasma and factor concentrates should be
given.
Use of fondaparinux during pregnancy, and its use in
pediatric patients has not been studied.

78 04/18/2023
 Oral: Apixaban, rivaroxaban, edoxaban, and
betrixaban
Are direct inhibitors of factor Xa
Apixaban and rivaroxaban approved by the FDA for
the treatment of VTE (DVT and PE) and reduction in the
risk of recurrence of DVT and PE.
Edoxaban is also approved for VTE treatment.

79 04/18/2023
 Apixaban was
noninferior in preventing recurrent VTE or VTE related death
but resulted in lower major bleeding events when compared
to LMWH and warfarin therapy.
Rivaroxaban and apixaban can be used as
monotherapy without parenteral anticoagulation overlap,
allowing for a single oral regimen approach for treating and
preventing recurrent VTE.
Edoxaban was
noninferior to warfarin in recurrent VTE and
associated with less major or clinically relevant nonmajor
bleeding (CRNMB).
It is initiated after completing 5 to 10 days of initial
treatment with a parenteral anticoagulant.
80 04/18/2023
81 04/18/2023
 DAOCs have a more rapid onset and offset of action
and shorter half-lives compared to warfarin
DOACs are all eliminated renally to varying degrees
All DOACs are substrates of the P-gp transport
system, and the Xa inhibitors are also substrates of the
hepatic cytochrome P-450 (CYP) isoenzyme system.
Any inhibition or induction of these metabolic
systems will alter their absorption.

82 04/18/2023
 There are currently
no universally available standardized laboratory
assays to measure the anticoagulant effect of DOACs.
In the event of a major life-threatening bleed,
Fresh-frozen plasma, factor concentrates, or
recombinant factor VIIa may be given
There are no adequate studies in pregnant women
and pediatrics
Routine anticoagulation monitoring is not required
Tests such as the PT, aPTT, and INR are
not recommended to assess the anticoagulant effects
of apixaban.
83 04/18/2023
84 04/18/2023
85 04/18/2023
86 04/18/2023
87 04/18/2023
 Direct Thrombin Inhibitors
Parenteral DTIs: lepirudin, bivalirudin, argatroban, and
desirudin.
drugs of choice for the treatment of VTE in patients with a
diagnosis or history of HIT.
Only lepirudin and argatroban are FDA approved
One agent, dabigatran is as effective and safe as warfarin in
the treatment and prevention of recurrent VTE.
Patients should be anticoagulated with UFH or LMWH for
the initial 5 to 10 days of therapy and
then transitioned to dabigatran for VTE treatment.
Dabigatran is converted to its active form dabigatran
etexilate by serum esterases that are independent of CYP
pathways.
88 04/18/2023
 Warfarin
In US, its use has decreased in favor of DOACs.
Has a narrow therapeutic index, requiring frequent
dose adjustments and careful patient monitoring.
Inhibit production of the vitamin K–dependent
coagulation factors II (prothrombin), VII, IX, and X,
as well as the anticoagulant proteins C and S
its therapeutic antithrombotic activity is delayed for 5
to 7 days (potentially longer in slower metabolizers).
This delay is related to half-lives of the clotting factors

89 04/18/2023
 Figure. Pharmacologic activity and metabolism of warfarin and its downstream effects
on the vitamin K cycle and clotting factor production.
90 04/18/2023
 Reductions in the concentration of natural
anticoagulants before the clotting factors are depleted
can lead to a paradoxical hypercoagulable state during
the first few days of warfarin therapy
The reason for patients with acute thrombosis receive
a fast-acting anticoagulant (heparin, LMWH, or
fondaparinux) while transitioning to warfarin therapy.
Use of DOACs as bridging agents has not been well
evaluated or approved.

91 04/18/2023
 Warfarin displays nonlinear kinetics.
Small-dose adjustments can lead to large changes in
anticoagulant response.
Warfarin dose must be determined by frequent
clinical and laboratory monitoring.
The dose of warfarin is determined by each
patient’s individual response to therapy and
the desired intensity of anticoagulation.
In addition to hepatic metabolism and genotype,
warfarin dose requirements are influenced by
diet, drug–drug interactions, and health status.

92 04/18/2023
 Optimal warfarin induction regimen
most patients can start with 5 mg daily, and subsequent
doses are determined based on INR response
A more conservative “initiation” dose (e.g., ≤ 4 mg)
should be given to patients
older than 75 years,
with heart failure, liver disease, or
poor nutritional status, and
who are taking interacting medications or are at high risk
of bleeding.

93 04/18/2023
94 04/18/2023
 Pharmacogenomic-based warfarin dosing
Some guidelines recommend against routine ordering of
preemptive genetic testing.

95 04/18/2023
 The full antithrombotic effect of warfarin
will not be reached until 5 to 7 days or even longer after
initiating warfarin therapy [overlapping!).
Typical maintenance dose of warfarin for most
patients will be
between 25 and 55 mg per week
Adjustments in maintenance dose should be
determined based on the total weekly dose and
by reducing or increasing the weekly dose by
increments of 5% to 25%.

96 04/18/2023
 When adjusting the maintenance dose,
wait at least 7 days to ensure a steady state has been
attained on the new dose before checking the INR again.
Checking the INR too soon can lead to
inappropriate dose adjustments and
unstable anticoagulation status
Due to wide variation in reagent sensitivity, different
thromboplastins will result in different PT results,
potentially leading to inappropriate dosing decisions.
To standardize result reporting, WHO recommended the
INR to monitor warfarin therapy.

97 04/18/2023
 After initiating warfarin therapy,
INR should be monitored at least every 2 to 3 days during
the first week of therapy.
Incidence of warfarin-related bleeding appears to be
highest during the first few weeks of therapy.
Vitamin K
can be given by IV or oral route;
SC route is not recommended as vitamin K is erratically
absorbed and frequently ineffective.
The IV route is reserved for cases requiring urgent
reversal and when patients have life-threatening
bleeding.
98 04/18/2023
 The dose of vitamin K should be based on
the degree of INR elevation and
whether bleeding is present
 A dose of 2.5 mg orally
 when INR is > 10 and no active bleeding
 Higher dose of 10 mg given via slow IV
 when life threatening bleeding is present
In cases of life-threatening bleeding,
fresh-frozen plasma or clotting factor concentrates
should also be administered, in addition to IV vitamin K

99 04/18/2023
 INR is <10, and there is no active bleeding or
imminent risk of bleeding,
simply withholding warfarin until INR decreases to
within therapeutic range and
reducing the weekly dose with frequent monitoring
Warfarin-induced skin necrosis (incidence <
0.1%) or a maculopapular rash that can progress
to necrotic gangrene thought to be
due to imbalances between procoagulant and
anticoagulant proteins early in the course of
warfarin therapy.

100 04/18/2023
 Warfarin-induced purple toe syndrome
a purplish discoloration of their toes
Warfarin therapy should be discontinued immediately, and
an alternative anticoagulant should be started
Warfarin is teratogenic and should be avoided during
pregnancy.
Women of childbearing potential should be instructed to
use an effective form of contraception.
Patients should be instructed to maintain
a consistent diet and avoid large fluctuations in vitamin K
intake rather than strictly avoiding vitamin K–rich foods.

101 04/18/2023
102 04/18/2023
103 04/18/2023
 Nonpharmacologic Therapy
Thrombectomy
Removal of the occluding thrombus by surgical
intervention.
Can be considered in patients with
massive iliofemoral DVT when there is a risk of limb
gangrene due to venous occlusion.
In patients who present with massive PE,
pulmonary embolectomy can be performed in patients with
contraindications to thrombolytic therapy,
when thrombolysis has failed clinically, or
when thrombolysis will not have sufficient time to take
effect.
104 04/18/2023
 Inferior Vena Cava Filters
Indicated in patients with newly diagnosed proximal
DVT or PE who have a contraindication to
anticoagulation therapy
IVC interruption: by insertion via internal jugular
vein or femora vein access and advancing the filter
into the IVC using ultrasound or fluoroscopic
guidance.

105 04/18/2023
 Summary
LMWH or fondaparinux are preferred over UFH for
acute VTE treatment; however,
with CrCl less than 30 mL/min (0.50 mL/s), UFH is the
preferred treatment approach
For the long-term and extended treatment phases,
DOACs are recommended over warfarin to prevent
recurrent thrombosis.
In patients with cancer-associated thrombosis,
LMWHs are an alternative option for the acute, long-
term, and extended phases of treatment due to efficacy
in preventing recurrence.

106 04/18/2023
 Anticoagulation therapy is continued for a minimum
of 3 months
but should be given longer depending on the
underlying etiology of the VTE,
thrombus location, and
the patient’s risk factors

107 04/18/2023
 Patients with provoked VTE by transient risk
factors (e.g., surgery, trauma) or an isolated distally
located DVT
require therapy for 3 months
Patients with unprovoked VTE have a recurrence
risk, thus most such patients
require extended if not indefinite anticoagulation,
particularly in those with
 PE or proximally located DVT and PE, and
 if the patient carries low-to-moderate bleeding risk.

108 04/18/2023
 OUTCOME EVALUATION
Preventing the occurrence of VTE in patients who are at
risk
Administering effective treatments in a timely manner to
patients who develop VTE,
Preventing treatment-related complications, and
Reducing the likelihood of long-term complications
including recurrent events.
Periodically evaluate patients who are receiving VTE
prophylaxis for signs and symptoms of DVT and PE.
Closely monitor patients receiving anticoagulant therapy
for signs and symptoms of bleeding

109 04/18/2023
 Thank you!!

110 04/18/2023