Deep Vein Thrombosis/Pulmonary Embolism
Potential DRP’s
1) Drug interactions eg. NSAID’s and warfarin
2) Experiencing s/sx, requires treatment
3) Requires prophalactic treatment
4) Risk of recurrent due to lifestyle eg. smoking
Signs and Symptoms
DVT
- Calf pain and tenderness
- Calf or leg swelling
- Erythema
- Leg Warmth
- Dilation of Superficial Veins
- Palpable Cord – affected vein may feel like a rope deep
under the skin in the calf or thigh
- Homan’s sign – dorsiflexion of the foot may elicit pain
behind the knee
PE
- dyspnea, tachypnea
- chest pain, tachycardia, palpitations
- cough
- diaphoresis
- hemoptysis
- neck vein distension
- fever (low-grad)
- cyanosis, hypoxemia
- gallop rhythm
- hypotension, syncope
- oligria
- shock
Pathophysiology
VTE results from colt formation within the venous circulation. It
can manifest as either DVT or PE
- Venous thrombi are composed almost entirely of fibrin and
erythrocytes, platelets, wbc, this is a red clot.
- Arterial clot is just platelets so it is a white clot.
- Distal vs. Proximal : Distal is in the calf etc, proximal is
higher up. Proximal is more dangerous because the veins
are larger thus the clot would be larger.
- Virchow’s Triad: (1) Blood flow (2) Blood vessels (3)
circulating elements in the blood – if anything abnormal is
trial = clot formation.
- Most venous thrombi begin in the valve cusps of deep calf
veins. Then they can:
1. remain asymptomatic
2. lyse
3. obstruct the venous circulation
4. propagate to more proximal veins
5. emobolize
6. act in any combination of the above
- For PE:
1. Thrombus can go from site of origin to inferior
vena cava
2. Right ventricle pumps thrombus into
pulmonary arteries where thrombus lodges
3. Embolus obstructs pulmonary arteries and
causes increase in resistance to blood flow in
pulmonary vessels
4. May lead to severe pulmonary hypertension,
RV strain and cardiac heart failure
Urgency
DVT: Urgent – it can progress to PE very fast. Can be
asymptomatic DVT and go to symptomatic PE.
PE: URGENT – 30% mortality and 8% even if treated
Causes
1. VTE is uncommon in the absense of risk factors and the
effect of the risk factors is additive
D/Dx
Cellulitis
MI
Diagnosis
DVT
1.
venography
- gold standard
- high cost
- nephrotoxic contrast medium/ invasive procedure
- possible induction of VTE
2.
ultrasonography
- insensitivity for small thrombi and most distal DVTs
- noninvasive
Ultrasound imaging (Doppler) is now the first investigation of
choice for proximal (popliteal or femoral) vein thrombosis,
although venography retains a key role in cases of suspected
calf vein thrombosis (where ultrasound is relatively insensitive) or
recurrent disease
PE
1.
pulmonary angiography
gold standard
high cost
nephrotoxic contrast medium/ invasive procedure
possible induction of VTE
2.
ventilation/perfusion (VQ) scan
- less sensitive but less invasive
Risk Factors:
- Age
- Males
- Venous Stasis (Major Medical Illness (CHF, MI), major
surgery, immobility after surgery, paralysis, polycythemia
vera (high blood viscosity), obesity, varicose veins
- Vascular Injury (Major orthopedic surgery (knee/hip
replacement), trauma, in-dwelling venous catheter)
- Hypercoagulable state – malignancies, activated protein C
resistance/factor V Leiden, Prothrombin (20210A) gene
mutation, protein C deficiency, protein S deficiency,
Antithrombin deficiency, Factor VIII excess, Factor XI
excess, Antiphospholipid antibodies, disfibrinogemia,
hyperhomocysteinemia, plasminogen activator inhibitor
excess nephritic sydrome
- Pregnancy/post-partum
- Any of drugs listed below
Drugs Causing Similar S&S
- Estrogen-containing oral contraceptive pills
- Estrogen replacement therapy
- Selective estrogen receptor modulators (SERMs)
- estrogens increase serum clotting factor concentrations and
induce activated protein C resistance...thus the increased
risk of VTE observed during pregnancy and the immediate
postpartum period
- risk of DVT especially high if smoking on OTC and patient is
>30 yrs
- Heparin-induced thrombocytopenia (HIT)
Nonpharmacological Options
Elevate leg
Compression stockings
No standing or sitting for long periods of time
No crossing of legs
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No restrictive clothing
Pharmacological Options
1.
Unfractionated Heparin
- Along with LMWH, mainstay of acute treatment of VTEs
- Composed of glycosoaminoglycans of various lengths
- Onset: 1-2 hours (IV immediate onset)
- SEs: bleeding, local irritation, mild pain, erythemia, Heparin
Induced Thrombocytopenia,
- Contraindications: active bleeding, hemophilia, hemorrhagic
tendencies, severe liver disease
- DIs: Antithrombolytics and antiplatelets increase risk of
bleeding
- Low bioavailability, therefore have to give parenterally – IV
better b/c more predictable
- Drug itself is cheap but overall costs more than LMWH due
to monitoring needed
2.
LMWH (ardeparin, dalteparin, enoxaparin, nadroparin,
tinzaparin)
- Also mainstay of treatment
- Longer halflife (2-4 times longer than UFH), better
bioavailability
- Peak anticoagulation at 3-5 hours
- Similar SEs, Contraindications and DIs to UFH
- Less bleeding than UFH
- Accumulates in renal impairment
- Can be given SC q12-24h
- Relatively expensive
3.
Heparanoid (Danaparoid)
- Inhibits thrombin generation by an effect on Xa
- Peak Effect in 5 hours but 4-5 days before steady state
- SEs: Bleeding, bruising
- Can be used in pregnancy but only if UFH or LMWH is
contraindicated
- Accumulates in renal impairment
- More expensive than LMWH
4.
Anti-factor Xa inhibitor (Fondaparinux-indirect inhibitor)
- Bind Xa
- Fondaparinux approved in prevention of VTE following lower
extremity orthopedic procedures (2.5 mg SC q12h)
5.
Hidrudin and Direct Thrombin Inhibitors (Agratroban,
Lepirudin, Ximelagatran)
- Inhibit thrombin activity directly (both circulating and clot
bound thrombin)
- Used in prevention of VTE and in HIT
- Onset: Immediate
- SEs: Hemorhage, minor bleeding, small decrease in RBC
count, fever, N/V, allergic rxn
- DIs: Increased risk of bleeding with other antithrombolytics
and antiplatelets
- lepirudin and argatroban should be used cautiously in
women of child-bearing age b/c experience is limited
6.
Warfarin
- Approved for prevention and treatment of VTEs
- Inhibits the enzyme responsible for cyclic conversion of vit K
(inhibits synthesis of factors II, VII, IX, X)
- S isomer 2-5 times more potent but is racemic mixture
- Full effect not seen until 8-16 days after therapy initiated
(due to long half-lives of some of the factors)
- SEs: bleeding especially GI bleeding, purple toe syndrome,
skin necrosis (rare)
- LOTS OF DIs: b/c metabolized by CYP 450 including 1A2,
2C9, 3A4
- CI: active bleeding, hemorrhagic tendencies, PREGNANCY,
history of warfarin-induced skin necrosis
- Dosing is about 30-40 mg/week (divided into daily doses)
but lower dose in patients >65 years, elevated INRs, poor
nutritional status, liver disease
- CHEAP
THROMBOLYTIC THERAPY
7.
Streptokinase
- Activates plasminogen, dissolves fibrin, degrades fibrinogen
- For treatment of SEVERE or life-threatening VTEs
- Onset: Immediate
- Contraindicated: active bleeding, recent surgery, stroke or
severe trauma, recent streptococcal infection or
hypersensitivity
- Given IV, Expensive
8.
Urokinase
- Same effect as Streptokinase
- Immediate onset
- CIs: active bleeding, recent surgery, any hemorrhagic
disease
- Given IV
9.
Alteplase (Tissue Plasminogen Activator), Reteplase
- Activates plasminogen bound to fibrin, dissolves fibrin
- Treatment of severe or life-threatening VTEs
- Immediate onset
- CIs same as Urokinase
- Given IV
- Expensive
MANAGEMENT
1.
Start on LMWH
- LMWH (compared to UFH) has more predictable kinetics
and doesn’t require monitoring, less risk of major bleeding,
can be used on an outpatient basis, longer duration of
activity, doesn’t need daily INR (could be started on day 3)
BUT expensive (5 days of therapy ~$80),
- No major clinical differences among the types of LMWH –
pt’s standpoint would want once daily dosing – FRAGMIN
(daltaparene) – used more than others
2.
Start also on warfarin – initially as well – start with 10
mg/daily, monitor INR
- Warfarin dose requirements – dose DECREASES with age
- <30 – may need up to 10 mg
- >80 – average is 3 mg/day
- No good evidence that loading doses work – b/c no
difference in factor II decline (longest half-life) BUT they are
still used with the rationale that INRs normalize quickly and
can get them off Fragmin sooner
3.
Want INR between 2-3 and then d/c daltaparene
4.
Get INR around day 3 – b/c INR can decrease fast with
decrease in factor 7 (even though factor 2 may still be high)
therefore should wait few days for INR
5.
Counseling on warfarin:
- Internal bleeding
- Bad headache – may be CNS intracranial bleed
- If worst headache – go to ER
- If pain – ie. ab – perineal, go to ER
- BUT make sure not to alarm pt and say risk is < 1%
- Have blood monitored regularly – INRs
- Poor compliance is in younger pts – need to emphasize to
them
- No ASA or NSAIDs (unless already on it before adding
warfarin)
- Echinecea and Gingko – cause blood thinning – if they really
want to take it, take INR shortly (wait 5 days before next
INR) – but definitely start by discouraging use – if they do
use it, make sure they keep it consistent (same with diet –
keep it steady)
Clinical Outcomes
Eliminate the DVT
Prevent progression to PE
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Prevent recurrent DVT
Pharmacotherapeutic Outcome
The patient receives the anticoagulation medication in the right
dose, duration, frequency, route, with no intolerable side
effects or clinically significant drug interactions
P.T. Endpoints
Pain
Swelling
Clot
Improve/Eliminate
“
Eliminate
1-2 days/2-3 days
“
1 day
TPE Postiive
No recurrent DVT while on treatment (eg. Swelling or any
other s/sx
Warfarin target level INR in the 2.5-3 range
Negative
No abnormal bleeding anytime during treatment
No decrease in platelets
No skin reactions. (very rare s/e)
MONITORING
- INR should be done every 2-3 days after initiation of therapy
until target levels reached and gradually decrease
- Also monitor for headaches, excessive bleeding
- When to go the ER: SOB, chest pain, coughing bld, black
tarry stools, severe HA of sudden onset, slurred speech –
could be DVT/PE or cerebral hemorrhage (stroke)
SEE WEBSITE FOR COUNSELLING INFO FOR WARFARIN
AND POTENTIAL DRUG INTERACTIONS
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