Venous Thromboembolism

I. Risk Factors for Venous Thromboembolism is Hospitalized pts

SURGERY :
major surgery ( abdominal , gyn , urological , ortho , neuro , cancer related surgery

TRAUMA :
multisystem trauma , spinal cord trauma , spinal fracture , fracture of the hip and pelvis

MALIGNANCY :
any malignancy , overt or covert , local or metastatic , risk is high during chemo, radiotherapy

ACUTE MEDICAL ILLNESS :

stroke , MI , HF , neuromuscular weakness syndrome ( G-B )

PATIENT SPECIFIC FACTORS :

history of Thromboembolism , obesity , hypercoagulable states , age older than 40 y

ICU RELATED FACTORS :

prolonged mechanical vent , central venous catheters , sever sepsis , heparin induced thrombocytopenia

 The risk of VTE during general surgery is determined by 3 main factors

 The type of the procedure ( major or minor / cancer related surgery )

 The age of the patient
 Any possible patient specific risk factors .
 Major surgery : performed under general anesthesia and lasts for more than 30 mint
 Minor surgery : performed under local or spinal anesthesia and lasts for less than 30 mint
 II. Thromboprophylaxis for general surgery

Prophylaxis regimens:

 LDUH 1 : unfractionated heparin 5000 u sc / 12 h

 LDUH 2 : unfractionated heparin 5000 u sc / 8 h
 LMWH 1 : enoxaparine 40 mg sc once daily or deltaparin 2500 u sc once daily
 LMWH 2 : enoxaparine 30 mg sc / 12 h or deltaparine 5000 u sc once daily
 MECHANICAL AID : graded compression stockings or intermittent pneumatic compression

LOW RISK :
Minor surgery + age less than 40 y and no other risk Early mobilization
factors

Moderate risk :
Major surgery + age less than 40 y and no other risk LDUH 1 or LMWH1 : 1st dose 2 h before surgery
factors

High risk : LDUH 2 or LMWH2 : 1st dose 2 h before surgery

Major surgery + age more than 40 y or risk factors

Highest risk : LDUH2 or LMWH 2 : 1st dose 2 h before surgery +

Major surgery + age more than 40 y + risk factors mechanical aid

 There are some types of major surgery that have low risk of VTE and there is no need for Thromboprophylaxis
unless the patient has one or more risk factor as ( laparoscopy , vascular surgery , and closed urologic procedures
as transurethral prostatectomy )
 III. Thromboprophylaxis for hip and knee surgery

 During mainly elective hip and knee arthropalsty , hip fracture surgery

1- LMWH : enoxaparine 30 mg sc / 12 h or deltaparine 2500 u sc at 1st dose then 5000 u sc once daily
give the 1st dose 12 - 24 h before the surgery or 6 h after the surgery

2- Fondaparinux : 2.5 mg sc once daily … 1st dose 6 – 8 h after surgery ( may be the preferred regimen
for hip fracture surgery )

3- Adjusted dose warfarin to achieve INR or 2 - 3 … 1st dose the evening before the surgery

Duration
A: for elective hip and knee surgery the prophylaxis should continue for 10 days after the surgery
B: for hip fracture surgery , prophylaxis should continue for 28 – 35 days after surgery

IV. Thromboprophylaxis for special medical conditions

Clinical situation Recommended prophylaxis

1. Major trauma LMWH2 or leg compression ( IPC )

2. Spinal cord injury LMWH2 + leg compression ( IPC )

3. Intracranial surgery Leg compression ( IPC )

4. Gyn . operation

a. Benign disease LDUH1

b. Malignancy LDUH2 or LMWH2

5. Urologic surgery

a. closed procedures Early mobilization only

b. open procedures LDUH1 or leg compression ( IPC )

6. High risk medical illness LDUH1 or LMWH1

 Methods of Thromboprophylaxis
 1. External leg compression :
 these method can be used as an adjunct to anticoagulant prophylaxis or as a replacement for the
anticoagulant prophylaxis in pts who r bleeding or at high risk of bleeding

 Graded compression stockings: they are designed to create 18 mm/hg external compression at the
ankles and 8 mm/hg external compression at the thigh. The resulting pressure gradient 10mm/hg acts
as driving force for venous outflow from the leg. These stocking have shown to reduce the incidence of
VTE when used alone after abdominal or neuro-surgery. it is the least effective method in
Thromboprophylaxis and shouldn’t be used alone in pts with moderate or high risk of VTE

 Intermittent pneumatic compression (IPC) pumps: they are inflatable bladders that are wrapped
around the lower leg. When inflated they create 35 mm/hg external compression at the ankle and 20
mm/hg external compression at the thigh. They also produce a pumping action by inflating or deflating
at regular intervals and this acts to further augment the venous flow. Its more effective than graded
compression stockings and can be used alone for Thromboprophylaxis for selected patients who aren’t
suitable for anticoagulant prophylaxis cause of bleeding. it’s popular after neurosurgery and in trauma
victims who ar at risk of bleeding.

2. Low dose unfractionated heparin (LDUH)

 Rational for low dose heparin : heparin is indirect acting drug that should be bound first to a co
factor(AT III ) to produce its effect . the heparin –AT complex can inactivates several coagulation factors
( IIa , IXa , Xa , XIa, XIIa ) . the inactivation of factor IIa is a sensitive reaction and occurs at a dose so far
below the dose needed for the inactivation of other coagulation factors which means that small doses
of heparin can produce antithrombotic effect without producing full anticoagulation . this is the basis
for the effect of LDUH in preventing the VTE in high risk hospitalized patients

 The heparin –AT complex also binds to platelet factor 4 and in some patients this may develop a heparin
induced antibody that can cross react with platelet binding sites and produce platelet clumping and
then thrombocytopenia. This is the mechanism for the heparin induced thrombocytopenia that can
happen with LDUH as well as therapeutic dose .

 Dosing regimen : the used regimen is 5000 u sc / 8 or 12 h . pre surgical dosing is important as the
thrombosis can start during the procedure and giving time to the thrombus to grow will reduce the
efficacy of the heparin . post operative prophylaxis is necessary for 7-10 days or until the pt is full
ambulatory .

 Who benefits : LDUH provides effective Thromboprophylaxis for high risk medical conditions and most
orthopedic surgeries more than major trauma and hip and knee surgery who get benefit more from
LMWH.

3. low molecular weight heparin (LMWH )

 The variable sized heparin molecules in UFH can be enzymatically cleaved to produce smaller molecules
or more uniform in size with more potent anticoagulant activity (the resultant LMWH is more potent
anticoagulant than UFH.

 The LMWH has more adv over UFH ( less frequent dosing , lower risk of bleeding or heparin induced
thrombocytopenia so there is no need for routine anticoagulant monitoring . the disadvantage of
LMWH is the cost which is 10 times /day more than unfractionated heparin .

 Who benefits : LMW is better than UFH in orthopedic procedures including hip and knee surgery and
major trauma including spinal cord injury

 Low- dose regimen : there is a variety of LMWH preparations but only 2 are used for
Thromboprophylaxis ( enoxaparine , dalteparin )

 Timing : for non – orthopedic surgery the 1st dose of each drug ( 30mg enoxaparine , 2500 u for dalteparin )
should be given 2 h before the surgery , and for orthopedic surgery the dose should be given 12-24
before the surgery however postoperative intake can increase the risk of bleeding . so postoperative
prophylaxis can be abandoned in favor of starting the prophylaxis 6 h before the surgery .

 Spinal anesthesia : the use of LMWH is combination with spinal anesthesia for orthopedic surgery can
result in spinal hematoma and paralysis .for orthopedic surgery with spinal anesthesia the 1 st dose of
LMWH should be delayed 12-24 after the surgery or adjusted dose warfarin should be used .

 Renal failure :LMWH is excreted primarily by the kidney and for pts with renal failure the dose of
enoxaparine should be reduced from 30 mg bid to 40 mg once daily for high risk pts and no dose
adjustment is needed for dalteparin

4. Adjusted dose warfarin

 Systemic anticoagulation with warfarin is a popular method of prophylaxis for major orthopedic surgery.
there are 2 benefits of warfarin :

(1) The preoperative doesn’t create a bleeding tendency during surgery due to the delayed onset of
action.

(2) The warfarin can be continued after the discharge if prolonged prophylaxis is needed.

 The disadvantage of the warfarin is includes a multiple of drug interaction , the need for laboratory
monitoring of coagulation , the difficulty in adjusting dose to the desired effect because of the delayed
onset of action.

 Dose regimen: the initial dose of warfarin is 10 mg orally given the evening before surgery this is
followed by a daily dose of 2.5 mg starting the evening after surgery. the dose is then adjusted to
achieve INR ratio of 2 to 3 this isn’t usually reached until at least the 3 rd postoperative day
 Who benefits: adjusted dose warfarin is one of 3 effective regimens for major orthopedic procedures
involving the hip and kneed. Despite the LMWH is more effective warfarin may be preferred in pts who
require prolonged prophylaxis after discharge because of the convenience of oral dosing.

5. Fondaparinux : is a synthetic anticoagulant that selectively inhibits coagulation factor Xa like

heparin it must bind to antithrombin III to exert its anticoagulant effect but unlike heparin it only
inhibits the activity of factor Xa . the benefits of Fondaparinux are predictable anticoagulant effect
which obviates the need for laboratory monitoring and the absence of a heparin like –immune
mediated thrombocytopenia

 Dosing regimen : the prophylactic dose is 2.5 mg given once daily as a SC when used for surgical
prophylaxis the 1st dose should be given 6 – 8 h after surgery ( the earlier the dose the more the risk of
the bleeding tendency ) the drug is cleared by the kidney and when creatinin clearance is less than 30
ml/min the drug accumulates and the bleeding occur and therefore the drug is contraindicated in pts
with sever renal impairment and also in pts less than 50kg due to marked increase in bleeding
tendency .

 Who benefits: it effective as LMWH for thromboprophylaxis after major orthopedic surgery involving
the hip and knee. the only advantage of Fondaparinux over LMWH is the absence of heparin induced
thrombocytopenia

 Duration of prophylaxis : following major orthopedics procedures (hip and knee ) there is an increase
in symptomatic VTE after prophylaxis in terminated when the pt is discharged which is the most
common cause of readmission after hip replacement surgery . this findings gives an important
recommendations as follows :

1- The prophylaxis should be continued for at least 10 days following major orthopedic surgery even if
the pt is discharged before this time

2- Following hip surgery pts with high risk factors for VTE should receive prophylaxis for a total of 28-
35 day

 Post discharge prophylaxis can be achieved with usual prophylactic doses of warfarin , LMWH or
Fondaparinux ( the latter 2 agents are administered by SC which may be unsuitable for some pts ).
 Diagnostic approach to thromboembolism
 Thrombosis is deep leg veins is often silent and become evident only when a pulmonary embolus occur

 the clinical evaluation : the clinical presentation of acute pulmonary embolism is non-specific and there is
no clinically or laboratory findings that will confirm or exclude the presence of acute pulmonary embolism

Findings + ve predictive value -ve predictive value

Dyspnea 37% 75%

Tachycardia 47% 86%

Tachypnea 48% 75%

Pleuritic chest pain 39% 71%

Hemoptysis 32% 67%

Hypoxemia 34% 70%

Elevated plasma D-dimer 27% 92%

Increase dead space ventilation 36% 92%

 Plasma D-dimer levels: it’s a product of clot lysis and expected to be elevated in the setting of active
thrombosis. it has little value in evaluation of thromboembolism in ICU as there is many condition that
can elevate plasma D-dimer test (sepsis , malignancy , pregnancy , RF , HF ) .

 its more valuable in excluding the thromboembolism in ICU pts as the –ve predictive of is 92% which
means that when the plasma D- dimer level is within normal 92% of pts won’t have VTE however a little
number of ICU pts have normal plasma D-dimer test the value of this test is limited .

 Alveolar dead space: the cardiopulmonary consequences of pulmonary embolus include a decrease in
the pulmonary blood flow leading to increase in the alveolar dead space ventilation. In ER pts with
suspected pulmonary embolism a normal dead space (< 15%) has a high predictive value to exclude the
pulmonary embolism.

 The value of dead space measurement in ICU isn’t reliable as most of ICU pts have elevated dead space
due to cardiopulmonary diseases. Monitoring for the changes in dead space ventilation which is easy in
ventilator dependent pts is more useful to evaluate pts who develop respiratory distress in the ICU.

 Venous ultrasound :
  As we mentioned before the clinical and laboratory tests aren’t reliable in confirming or excluding the
pulmonary embolism so specialized tests are required.

 Since most of pulmonary emboli originates from thrombosis is proximal leg veins, the evaluation of
suspected pulmonary embolism often begins with and ultrasound evaluation of the femoral vein by 2
main techniques

1) Compression ultrasound: this method shows both femoral artery and vein . external
compression is applied to with the probe which will compress the underlying vein and
obliterates its lumen . when a vein is filled with blood clots external compression doesn’t
compress the vein .

2) Doppler ultrasound: it detects the velocity of blood flow which can be detected audibly as the
faster the flow the higher the frequency of Doppler signal or by color changes as faster flow
cause shifts from blue to the red spectrum of light. its valuable in distinguishing arteries from
veins and can also detect sluggish flow in veins the combination of compression and doppler
ultrasound is called duplex ultrasound

 Accuracy: the duplex ultrasound is very sensitive and accurate in detecting proximal DVT in the legs as it
has +ve predictive value of 97% and –ve predictive value of 98% but duplex ultrasound doesn’t perform
well in detection of calf DVT with a sensitivity of 33 % -- 70% which means that 2/3 of the cases of DVT
below the knee can be missed by ultrasonography. if calf DVT is suspected with symptoms
( swelling ,pain ) we can do serial ultrasound examination and the other is contrast venography

 Despite the fact that most cases of pulmonary emboli originates from proximal DVT as many as 30% of
cases shows no evidence of DVT in the legs .when pulmonary embolism is suspected and the search for
leg vein thrombosis is unrevealing we should move to the next step (spiral computed tomography /
radionuclide lung scan ).

 Radionuclide lung scan :

 Ventilation perfusion lung scan is widely used to evaluate pts with suspected pulmonary embolism but
they secure in only 25-30% of cases. the problem is in the presence of lung disease especially infiltrative
there will be abnormal scan in 90% .

 Normal lung scan : excludes the presence of clinically important pulmonary embolus while high
probability lung scan carries a risk of 90% of pulmonary embolus

 Low probability lung scan : lung scan doesn’t reliably exclude the presence of pulmonary embolus but if
combined with –ve ultrasound evaluation of the leg it will be a good reason to stop the diagnostic
workup and observe the pt.

 Intermediate probability : it has no value in confirming or excluding the pulmonary embolus in this
situation we move to spiral CT angiography or conventional pulmonary angiography

 Spiral CT angiography
  in this technique the detector is rotated around the pt to produce a volumetric 2 dimensional view of
the lung . there must be no lung motion for 30 sec which means that the pt should be able to hold his
breath for 30 sec . This excludes pts who are ventilator dependent ( can be done using CPAP with heavy
sedation to inhibit the chest wall movements ) or who are unable to follow commands

 when its combined with peripheral injection of contrast agent . the central pulmonary arteries can be
visualized and the embolus appears as filling defect . with sensitivity and specificity of 93% and 97% but
unfortunately in about 70% of cases the emboli are located in small and subsegmental vessels and can
be missed

 pulmonary angiography
 its considered the most accurate method to detect pulmonary emboli

1. Proximal leg vein

ultrasonography

-ve +ve Anticoagulation

Mechanical ventilation?
No Yes go to 2

Lung disease YES

NO

2. Spiral CT angiogram
3. Radionuclide lung scan
-ve +ve

1- Normal stop Observe Anticoagulation

2- Low probability observe

3. Intermediate (with ventilator we do pulmonary angiogram / without ventilator we go back to 3)

4- High probability Anticoagulation.

 Antithrombotic therapy
 Anticoagulation :
 Initial treatment of thromboembolism that isn’t life threatening is anticoagulation with heparin

 Unfractionated heparin:
- the standard TTT of both DVT and acute pulmonary embolism is UFH given by continuous IV infusion
using weigh-based dosing for pts less than 130 kg but for pts more than 130 kg this regimen can cause
excessive anticoagulation

 Weight based heparin dosing regimen

1- Prepare heparin infusion by adding 20.000 IU heparin to 500 ml diluent ( 40 IU / ml )

2- Give initial bolus dose of 80 IU/kg and follow with continuous infusion of 18 IU /kg / hr ( use actual body
weight )

3- Check PTT 6 h after start of infusion and adjust heparin dose as indicated below

PTT ( sec ) PTT ratio Bolus dose Continuous infusion

< 35 < 1.2 80 IU / kg Increase by 4 iu /kg /h

35 – 45 1.2 – 1.5 40 IU / kg Increase by 2iu / kg / h

46 – 70 1.5 – 2.3 -------------- ---------

71 – 90 2.3 – 3 -------------- Decrease by 2 iu /kg/h

> 90 >3 -------------- Stop infusion for 1 hr then decrease by 3 iu /kg/h

4- Check PTT 6 hr after each dose adjustment. when in the desired range ( 46 --- 70 sec) monitor everyday

 LMWH
 It’s an effective alternative for UFH the standard therapeutic dose is
 Enoxaparin, 1mg / kg / 12 h SC

 as mentioned before the LMWH is eliminated by the kidney and dose adjustment is necessary in pts with
renal impairment so UFH is recommended over LMWH in pts with renal failure however the LMWH is
preferred over UFH as ( simple dosing , no need to monitor the anticoagulant activity , the ability to treat the
outpatients )

 monitoring anticoagulation
- the anticoagulation effect produced by the UFH can vary at first due to the variable size of the molecules in
UFH which needs a laboratory monitoring to determine the response to UHF . aPTT can be used for this
purpose because it’s a reflection of coagulation factor IIa activity which is inhibited by UFH ( antithrombin
effect )

- the aPTT isn’t used to monitor anticoagulation effect of LMWH as it acts primarily to inhibit factor Xa and if
there is a need to monitor the anticoagulation response to LMWH it can be done be measuring factor Xa
activity .

 warfarin anticoagulation
- for pts with reversible cause of VTE ( major surgery ) oral anticoagulation with warfarin ( Coumadin ) can be
started on the 1st day of heparin therapy when the PT reaches an INR of 2—3 the heparin can be discontinued .
oral anticoagulation with warfarin is continued for at least 3 months which can be increased in pts who are
cancer related or wit recurrent VTE.

 Thrombolytic therapy
- It’s usually reserved for life threatening cases of pulmonary embolism that are hemodynamically unstable
and sometimes recommended in hemodynamically stable pts with RT. VENT. Dysfunction .

- The major problem with lytic therapy is the bleeding reaches to 12% incidence of major hemorrhage and
1% of intracranial hemorrhage. the presence of risk factors is a contraindication to the lytic therapy but
sometimes in the life threatening conditions the risk of not choosing the lytic therapy ( death ) should be
weighed against the risk of bleeding . the 2 main regimens used are :

Alteplase: 0.6 mg/kg over 15 mints

Reteplase: 10 u by bolus injection repeated in 30 mints

- The usual dose of Alteplase is 100 mg infused over 2h but the previously mentioned regimen achieves the
same lytic effect in shorter period.

 Inferior vena cava filters

- Mesh like devices placed in the IVC to trap thrombi that break from the leg and prevent it from reaching the
lungs

- Indications :

A. Pts with proximal DVT with :

- contraindication to anticoagulation

- Pulmonary embolization during full anticoagulation

- free floating thrombus

- Poor cardiopulmonary reserve and unlikely to tolerate a pulmonary embolus .

B. pts with no proximal DVT with :

- requires long term prophylaxis of pulmonary embolism

- pts with high risk of thromboembolism and high risk of hemorrhage from anticoagulant drugs ( trauma
victim )

 the most common used filters is the Greenfield filter . The major advantage in it is in its shape which is
elongated and conical allowing the basket to fill with thrombi up to 75% of its capacity with
compromising the cross sectional shape of the IVC

 insertion : IVC filters are inserted percutaneously usually through the internal jugular or femoral veins
and placed below the renal veins if possible . supernal placement in needed if the thrombus extends to
the level of renal veins and it doesn’t impair the venous drainage of the kidney