Thrombotic disorders and
anticoagulation therapy
Dr. Mohammad Harith Al-Saaty
Introduction
the balance of multiple procoagulant anticoagulant
factors , including coagulation proteins , platelets ,
leucocytes , erythrocytes & component of vascular
wall , prevent thrombosis development .
Procoagulant activity necessary for hemostasis is
modulated by the natural anticoagulant system (
protein C , protein S & antithrombin) thrombosis
occur when this balance is disturbed .
- There is what is called ( virchow triad ) which
contribute to the pathophysiology of thrombosis
:
1. Stasis of blood
2. Blood hypercoagulability ( thrombophilia) .
3. Vascular wall abnormailties .
Aetiology
It is usually multifactorial :
1. Patient factors :
a. Age
b.Obesity
c. Varicose veins
d. Previous DVT
e. Family hx.
f. Pregnancy /puerperium
g.Contraceptive pills ( specially estrogen containing pills )
h. Immobility e.g. long travel
i. IV drug users ( specially femoral v.)
2. Surgical conditions:
a. Major surgery
b. Abdominal & pelvic surgery ( specially for CA )
c. Major lower limb orthopedic surgery .
3. Medical conditions :
a. MI /HF
b. Inflammatory bowel disease
c. Malignancy
d. Nephrotic syndrome
e. Stroke , Guillian -Barre syndrome ( immobility).
4. Blood diseases :
a. Polycythemia rubra vera
b. Essential thrombocythemia
c. Myelofibrosis
d. PNH
e. Inherited thrombophilia ( protein C & S
deficiency , antithrombin deficiency , favtor V
leiden ….).
5. Antiphospholipid syndrome :
( recurrent venous thrombosis , arterial
thromboembolism , recurrent abortion & fetal
death )
Usually associated with :
-lupus anticoagulant : more strongly associated
with thrombosis than anticardiolipin Ab .
- Anticardiolipin antibody .
Inherited thrombophilic conditions
Indications for thrombophilia testing :
1. Venous thrombosis below 45 years ( specially if
unprovoked)
2. Recurrent venous thrombosis .
3. Family hx. Of recurrent thrombosis / unprovoked
thrombosis .
4. Combined arterial & venous thrombosis .
5. Venous thrombosis at unusual sites ! :
( cerebral venous thrombosis, budd chiari syndrome
, mesenteric vein ..) .
Investigations of possible thrombophilia :
1. Antithrombin
2. Protein C
3.Protein S
4. Antiphospholipid Ab , lupus anticoagulant &
anticardiolipin .
5. Factor V leiden
6. JAK2 mutation
7. Prothrombin G20210A
8. Flow cytometry e.g in PNH there is deficiency of CD 55
& CD 59 .
Deep venous thrombosis
( DVT)
-lower limb DVT is far more common than upper
limb DVT .
- Aetiology : mentioned in the previous slide .
- Lower limb DVT usually start in the distal veins
, causing pain , swelling , increase in temprature
& dilatation of the superficial veins , it is
typically unilateral , but can be bilateral & the
clot may extend proximally into the inferior vena
cava .
- Bilateral DVT is more commonly seen with
underlying malignancy or anomalies of the IVC.
You should differentiate DVT from other causes of
unilateral swelling :
*cellulitis ( marked erythema, well demarkated area
, source of entry of infection , fever ….)
* Traumatic musle tear or hematoma
* Rupture baker cyst
* Lymphadema .
Proximal DVT ( above knee ) is more significant
than distal one because there is higher chance
of pulmonary embolism with the proximal DVT .
Always assess the patient for signs & symptoms
of Pulmonary embolism .
Wells score for DVT
Investigations
The approach to patient with suspected DVT
depend on the pretest probability ( according to
wells score , ≤ 1 means low probability , 1-2
moderate probability , ≥ 2 means high probability ) .
In patient with low probability : measuring D Dimer
should be done , if it is normal further investigation
of DVT is unnecessary ! ( bec. D-Dimer has high
negative predictive value in low pretest probability
patients .)
If the pretest probability is moderate to high ,
further tests should be done to confirm DVT .
Compression ultrasound or doppler us is the
imaging modality of choice .
Contrast venography is rarely used now .
Pelvic us is also useful when there is suspecion
of pelvic mass .
Other investigations for thrombophilia should be
sent when the condition is recurrent .
Doppler us in DVT
Management
The mainstay treatment of DVT is anticoagulation
with heparin ( specially low molecular wt. heparin )
followed by warfarin or other oral anticoagulants
like ( rivaroxaban ) which is oral Xa inhibitor , has
rapid onset of action & can be used immediately
without the need for LMWH .!
Treatment with LMWH should be continued for at
least 5 days , in the 3rd day when warfarin
introduced , heparin should be continued until the
INR has been in the target range ( 2-3) .
The duration of anticoagulation varies from pt to
pt , DVT that occur after a temporary risk factor
& then this factor has been removed should be
treated for at least 3 months .
Unprovoked DVT should be treated for at least 6
months .
Recurrent DVT should be treated with
anticoagulation for life.
Other lines of treatment including
- Elevation of the leg
- Analgesics
- In limb threatening DVT , thrombolysis sould be
considered .
- Inferior vena cava filter ! : this is indicated in the
following conditions :
a. When there is strong contraindication to
anticoagulation .
b. Recurrent thrombosis despite adequate
anticoagulation .
DVT in pregnancy !
Dvt is common in pregnancy , because of the
hypercoagulability & the pressure of the gravid
uterus on the lower limbs .
Treatment of DVT in pregnancy should be done by
LMWH throughout the whole pregnancy ( because
warfarin is teratogenic , although there are studies
suggest that warfarin can be used in the 2nd
trimester ! ) .
After delivery the pt. can be given warfarin .
Pulmonary embolism
The majority of pulmonary emboli arise from
the propagation of lower limb DVT , other
causes include : septic emboli ( from
endocarditis affecting right sided valves ) , fat
embolism , amniotic fluid embolism ….
Causes : ( the same applied for other
thromboembolic diseases ).
Clinical features
Clinical presentation varies , depending on number , size
& distribution of emboli & on the underlying
cardiorespiratory reserve .
**Always ask about the possible risk factors ! Which may
be present in majority of cases .
** always exclude other causes .
* Acute pulmonary embolism :
Symptomes:
1. Dyspnoea
2. Pleuritic chest pain
3. Hemoptysis ( specially with pulmonary
infarction )
4. Palpitation
5. Faintness or collapse ( with massive PE) .
Signs:
1. Tachypnoea
2. Tachycardia
3. Evidence of DVT ( not necessarily present)
4.Signs of pleural effusion ( which could be bloody
in case of infarction )
5. Pleural rub
6. In massive PE : cyanosis , hypotension , confusion
, elevated JVP , arrythmia …
7. Sometimes normal chest examination !
Investigations :
1. ECG :
Important to exclude other causes of chest pain
a. Sinus tachycardia ( most common finding)
b. RBBB
C. T wave inversion
d. AF
e. S1Q3T3 ( not always present , usually with large
emboli) .
2. CXR :
* Useful in excluding other causes of acute dyspnoea like ,
pneumothorax , pneumonia …
* Could be normal , in fact normal CXR in acutely breathless &
hypoxemic pt. should rise the suspecion of PE.
* Other CXR findings in PE :
a. Oligemia of the lung field ( westermark sign )
b. Wedge shape infarction ( triangular shape with the apex toward the
hilum, Hampton hump sign)
c. Paranchymal opacity
d. Elevated hemidiaphragm
e. Pleural effusion
f. Enlarged pulmonary artery
3. Arterial blood gas analysis :
Typically show reduced pao2 with normal or low paco2 & respiratory alkalosis
.
In massive PE there is metabolic acidosis .
4. D-dimer:
has high negative predictive value in low risk pts. i.e normal Ddimer in the
setting of low risk PE can exclude PE.
Measuring Ddimer in moderate – high probability PE is of little significanse ,
bec. Even if it is normal the pt. still has to be evaluated ( in high risk pt.) .
D dimer is elevated in other conditions :
a. Myocardial infarction
b. Pneumonia
c. Sepsis
d. After surgery
5. CT pulmonary angiography
Is the first line diagnostic test , it has the advantage of
visualizing the extent & distribution of the emboli &
excluding other dx. , before sending the pt. to the test
RFT should be normal bec. The contrast is nephrotoxic ,&
ask about any previous allergy to the contrast .
6. Ventilation perfusion scanning: used when CT angio is
not available or there is contraindications to the contrast
.
7. Doppler us of the legs ( to exclude DVT)
8. Echocardiography :is useful in the differential dx. ,
there may be acute dilatation of the right heart in
massive embolism , & thrombus may be visible .
Differential Diagnosis of pulmonary embolism :
1. Myocardial infarction
2. Pneumonia
3. Pericardial tamponade
4. Aortic dissection
5. Pneumothorax
6. Acute pulmonary odema
7. In case of COPD : acute exacerbation of COPD .
Management of PE
1. General measures :
Oxygen should be given to all hypoxemic pts.to
maintain oxygen saturation above 90%.
Circulatory shock should be treated with iv fluid or
plasma expanders . Pain relieve is also important .
2. Anticoagulation :
Should be started immediately in pt. with
intermediate to high probability PE , the treatment
is started with heparin which reduce the
propagation of the clot & reduce the risk of further
emboli .
LMWH like enoxaparin can be given subcutaneously in a
dose of 1mg /kg every 12 hours
Or using unfractionated heparin ( iv ) first as bolus dose
80 u /kg direct iv , then continuous iv infusion 18 u /kg
/hour .
Treatment should be continued for at least 5 days ,
warfarin should be introduced within 48 -72 hr.
Heparin should not be stopped untill the INR at least 2 ,
then after at least 5 days & the INR reached 2-3 , heparin
can be stopped & warfarin continued .
Duartion of therapy ( as for DVT ) .
3. Thrombolytic therapy & surgery :
Thrombolysis is indicated in massive PE accompanied by
cardiogenic shock & hemodynamic instability ,
contraindications to thrombolytics should be identified
before starting therapy bec. There is risk of bleeding
specially intracranial bleeding .
Surgical embolectomy may be considered in resistant
cases .
4. Caval filter :
indicated in cases of strong C/I to anticoagulation , or pt.
develop hemorrhage on anticoagulations & in recurrent
thrombosis despite adequate treatment .
Anticoagulation therapy
HEPARIN :
Unfractionated heparin :Act by activating anti thrombin III
LMWH : act by inhibition of factor Xa.
*Indication for heparin:
1.Prevention & treatment of VTE.
2. Acute coronary syndrome.
3. PCI ( percutaneous coronary intervention)
4.Acute peripheral arterial occlusion
5. Cardiopulmonary bypass
6. Hemodialysis
LMWH has several advantages over UFH :
1.Nearly 100% bioavailable & therefore produce reliable dose
dependent anticoagulation .
2.Generally do not require monitoring of its anticoagulant effect.
3. Longer half life than UFH , allowing once or twice daily dose sc.
Rather than continuous iv route .
4. Incidence of heparin induced thrombocytopenia ( HIT) &
osteoporosis is less with LMWH .
Disadvantage of LMWH :
1. Difficult to be antagonize when there is bleeding due its half life.
( therefore , when there is conditions of high risk of bleeding , UFH is
preferred) .
2. Not preferred when there is renal impairement .
Heparin induced thrombocytopenia
(HIT)
Is a rare complication of heparin therapy ,
caused by induction of anti heparin / PF4
antibody which bind & inactivate platelets.
This result in platelet activation &
prothrombotic state with paradoxical
thrombocytopenia .
It is more common with unfractionated heparin
& in high doses.
Features: usually start in about 5-14 days after starting
heparin therapy , with a fall in platelet count with more
than 30 % from baseline . The pt. may develop venous or
arterial thrombosis with skin necrosis .
Other causes of thrombocytopenia should be excluded .
Treatment: once HIT is suspected , heparin should be
stopped immediately .
But alternative anticoagulant should be used such as
direct thrombin inhibitors like argotraban , lepirudin &
danaparoid .
New oral anticoagulants
New oral anticoagulants are now available as
alternatives to warfarin. These include dabigatran,
which targets thrombin, and rivaroxaban,
apixaban, and edoxaban, which target factor Xa. All
of these drugs have a rapid onset and offset of
action and have half-lives that permit once- or
twice-daily administration
The new oral anticoagulants have been compared
with warfarin for stroke prevention in patients with
nonvalvular atrial fibrillation.
- They usually do not need monitoring .
- Less intracranial bleeding than warfarin , but
increased risk of GIT bleeding ( specially
dabigatran) .
Antiphospholipid syndrome
Livido reticularis