DEEP VEIN THROMBOSIS

DR MOSES KAZEVU

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WARM UP: SINGLE BEST ANSWER

• Thrombotic event is seen in all of following
except
A. Paroxysmal nocturnal hemoglobinuria
B. Disseminated intravascular coagulation
C. Idiopathic thrombocytopenic purpura
D. Heparin induced thrombocytopenia
E. Thrombotic thrombocytopenic purpura
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THROMBOSIS
• Thrombi can occur in an artery or vein.
• Thrombosis occurring in the veins is commonly seen in the veins of the leg and the pelvis.
• Thrombosis is a pathologic formation of an intravascular blood clot.
• Most common locations are in the deep veins (DVT) of the leg below the knee.
• The thrombus is characterized by:
➢ Lines of Zahn: characterized by alternating layers of platelets/fibrin and RBCs
➢ Attachment to vessel wall
• Both features distinguish thrombus from postmortem clot.
• There are 3 major risk factors for thrombosis (Virchow’s triad):
➢ Disruption in blood flow (stasis)
➢ Endothelial cell damage
➢ Hypercoagulable state

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LINES OF ZAHN (ALTERNATING LAYERS

OF PLATELETS/FIBRIN AND RBCS)

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DISRUPTION IN BLOOD FLOW

• Stasis or turbulence of blood flow increases risk for
thrombosis.
• Examples:
➢ Immobilization- increased risk for DVT
➢ Cardiac wall dysfunction e.g. arrhythmia i.e. atrial
fibrillation or myocardial infarcation
➢ Aneurysm

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ENDOTHELIAL DAMAGE
• Endothelial damage disrupts the protective function of endothelial cells, increasing the risk for thrombosis.
• Endothelial cells prevent thrombosis by several mechanisms:
➢ Block exposure to subendothelial collagen and underlying tissue factor
➢ Production of prostacyclin (PGI2)- blocks platelet aggregation and NO- causes vasodilation
➢ Secretion of heparin-like molecules- augment antithrombin III (ATIII) which inactivates thrombin and coagulation
factors
➢ Secretion of Tissue plasminogen activator (tPA)- converts plasminogen to plasmin which
o Cleaves fibrin and serum fibrinogen
o Destroys coagulation factors
o Blocks platelet aggregation
➢ Secretion thrombomodulin- redirects thrombin to activate protein C, which inactivates factors V and VIII
• Causes of endothelial damage include atherosclerosis, vasculitis and high levels of homocysteine
➢ Vitamin B12 and folate deficiency result in mildly elevated homocysteine levels, increasing the risk for thrombosis.
o Recall: folic acid (tetrahydrofolate, THF) circulates as methyl-THF in the serum
o Methyl is transferred to cobalamin (vitamin B12) allowing THF to participate in the synthesis of DNA precursors
o Cobalamin transfers methyl to homocysteine resulting in methionine
o Lack of vitamin B12 or folate leads to decreased conversion of homocysteine to methionine resulting in buildup of
homocysteine
➢ Cystathionine beta synthase (CBS) deficiency results in high homocysteine levels with homocystinuria
o CBS converts homocysteine to cystathionine, enzyme deficiency leads to homocysteine buildup
o It is characterized by vessel thrombosis, mental retardation, lens dislocation and long slender fingers

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HYPERCOAGULABLE STATE
• Due to excessive pro-coagulant proteins or defective anticoagulant proteins.
• It may be inherited or acquired.
• Classica presentation is recurrent DVTs or DVT at a young age. Usually occurs in the deep veins of the legs. Other sites include the hepatic and
cerebral vein
• Examples:
➢ Protein C and S deficiency (autosomal dominant) decreases negative feedback on the coagulation cascade
o Protein C and S normally inactivate factors V and VIII
o Increased risk for warfarin skin necrosis
▪ Warfarin blocks epoxide reductase in the liver that blocks the ability to activate vitamin K (factors II, VII, IX and X, protein C and S
cannot be synthesized effectively)
▪ Initial stage of warfarin therapy results in a temporary deficiency of proteins C and S (due to shorter half-life as protein C and S
degrade faster in comparison to the factors) relative to factors II, VII, IX and X
▪ In pre-existing C or S deficiency, a severe deficiency is seen at the onset of warfarin therapy increasing risk for thrombosis,
especially in the skin.
➢ Factor V leiden is a mutated form of factor V that lacks the cleavage site for deactivation by protein C and S. This is a common inherited
cause of hypercoagulable state.
➢ Prothrombin 20210A is an inherited point mutation in prothrombin that results in increased gene expression. Increased prothrombin results
in increased thrombin, promoting thrombus formation
➢ Antithrombin III deficiency:
o Decreases the protective effect of heparin-like molecules by the endothelium, increasing the risk for thrombus.
o Heparin-like molecules normally activate ATIII which inactivates thrombin and coagulation factors.
o In ATIII deficiency, PTT does not with standard heparin dosing.
o Pharmacologic heparin works by binding and activating ATIII
o High doses of heparin activate limited ATIII, Coumadin is then given to maintain an anticoagulated state.
➢ Oral contraceptives are associated with a hypercoagulable state: Estrogen induces increased production of coagulation factors, thereby
increasing the risk for thrombus
• Note: heparin therapy is monitored using the PTT and you would expect it to rise.

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SUPERFICIAL THROMBOPLEBITIS
• This commonly involves the saphenous veins and is often associated with varicosities.
• Occasionally the axillary vein is involved usually as a result of trauma. There is local
superficial inflammation of the vein wall, with secondary thrombosis.
• The clinical picture is of a painful, tender, cord-like structure with associated redness and
swelling.
• The condition usually responds to symptomatic treatment with rest, elevation of the limb
and analgesics (e.g. NSAIDs)
• Fondaparinux 2.5mg OD SC has been seen to significantly reduce the rate of
thromboembolic events (pulmonary embolism and deep vein thrombosis)

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DEEP VEIN THROMBOSIS

• This is formation of an intravascular thrombus (blood clot) in the deep veins.
• A thrombus forms in the vein and any inflammation of the vein wall is secondary to this.
• Thrombosis commonly occurs after periods of immobilization but it can occur in normal
individuals for no obvious reasons.
• A deep vein thrombosis in the legs occurs in 50% of patients after prostatectomy (without
prophylactic heparin) or following a cerebral vascular event or an obstetric operation.
• Thrombosis can occur in any vein of the leg or pelvis, but is particularly found in veins of
calf. Around 10% progress to the proximal leg and become (more) symptomatic.
• Axillary vein thrombosis occasionally occurs, sometimes related to trauma but usually for
no obvious reason.
• 50% of untreated proximal thrombi progress to pulmonary embolism (PE), the commonest
type of venous thromboembolism.
• Less commonly, PEs are caused by fat, fluid, or infective emboli.

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RISK FACTORS
• Non-modifiable
➢ Age >60years
➢ Personal history or first degree relative with a history of venous thromboembolism
• Modifiable
➢ Active cancer or cancer treatment: there is activation of thrombin. Prostate and ovarian
are particularly associated.
➢ Critical care admission (immobility), immobility leads to venous status
➢ Dehydration
➢ Known thrombophilia
➢ Obesity (BMI >30)
➢ Significant medical comorbidities e.g. heart disease, metabolic, endocrine or respiratory
pathologies, acute infectious diseases, inflammatory conditions, IBD, Nephrotic syndrome,
Polycythemia rubra vera.
➢ Use of hormone replacement therapy or estrogen containing contraceptive therapy:
estrogen increases fibrinogen, prothrombin and clotting factor levels.
➢ Varicose veins with phlebitis
➢ Pregnancy/childbirth

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CLINICAL FEATURES
• The individual may be asymptomatic, presenting with clinical features of pulmonary embolism.
➢ Sudden onset of unexplained dyspnea (this may be the only sign)
➢ Pleuritic chest pain and Hemoptysis are present only when infarction has occurred.
➢ Tachypnea, pleural rub, coarse crepitation, pericardial effusion, tachycardia, atrial fibrillation, pulsus paradoxus,
raised JVP, right ventricular heave, gallop rhythm, widely split second heart sound or signs of right ventricular
overload with a right ventricular heave and loud pulmonary second sound may be seen on examination
• A major presenting feature is pain in the calf, often with swelling, redness and engorged superficial veins.
• The affected calf is often warmer and there may be ankle edema.
• Homan’s sign (pain in the calf on dorsiflexion of the foot) is often present but is not diagnostic and occurs with all lesions of
the calf.
➢ The Moses’ sign (Bancroft’s sign) is also found in patients with DVT of the lower leg involving the posterior tibial veins.
The sign is positive if pain is elicited when the calf muscle is compressed forwards against the tibia but not when the
calf muscle is compressed from side to side. This sign is neither sensitive or specific for DVT.
➢ The Lowenberg’s sign is also a clinical sign found in patients with DVT of the lower leg. The sign is positive when pain is
elicited rapidly when a blood pressure cuff is placed around the calf and inflated to 80mmHg. This sign is neither
sensitive or specific for DVT.
➢ These signs should be carried out with caution as they run the risk of dislodging the thrombus complicating into
pulmonary embolism.
• Thrombosis in the illiofemoral region can present with severe pain but there are often few physical signs apart from
occasional swelling of the thigh and/or ankle edema.
• Complete occlusion particularly of a large vein can lead to a cyanotic discoloration of the limb and severe edema, which can
very rarely lead to venous gangrene.

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INVESTIGATIONS
• Clinical diagnosis is unreliable but combined with D-dimer level it has a sensitivity of 80%.
➢ D-dimer are products of thrombolysis and once seen are indicative of a lysis of a
thrombi
• Confirmation of an illofemoral thrombosis can usually be made with B mode venous
compression ultrasonography or Doppler ultrasound with a sensitivity and specificity over
90%.
• Below-knee thromboses can be detected reliably only by venography with non-invasive
techniques, ultrasound, fibrinogen scanning and impedance plethysmography have a
sensitivity of only 70%.
• A venogram is performed by injecting a vein in the foot with contrast which will detect
virtually all thrombi that are present.
• Chest X-ray in suspected PE: may show wedge-shaped infarct (rare) but more for ruling
out other conditions.

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• Other investigations:
➢ Baseline aPTT before heparin and baseline INR before warfarin.
➢ ECG in PE: most commonly sinus tachycardia (50%). Less commonly (20-30% each),
RV strain (T wave inversion in V1-V3), S1Q3T3 (Prominent S in lead I, and Q wave and
inverted T in lead III), right bundle branch block and right axis deviation.
➢ Unprovoked venous thromboembolism: consider thrombophilia screen. Look for
underlying cancer only if suggested by history, exam and basic bloods.
➢ Arterial blood gasses in PE: decreased oxygen and carbon dioxide partial pressure,
increased pH.

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MANAGEMENT
• The main aim of therapy is to prevent pulmonary embolism and all patients with thrombi
above knee must be anticoagulated.
• Anticoagulation of below-knee thrombi is now recommended for 6 weeks as 30% of
patients will have an extension of the clot proximally.
• Bed rest is advised until the patient is fully anticoagulated.
• The patient should then be mobilized with an elastic stocking giving graduated pressure
over the leg.
• Low molecular weight heparin e.g. Enoxaparin have replaced unfractionated heparin as
they are more effective, they do not require monitoring and there is less risk of bleeding.
➢ Enoxaparin 1.5mg/kg SC every 24 hours until INR> 2 for >24 hours.
➢ Alternatively, 1mg/kg SC every 12 hours
➢ It should be administered the same time each day.
• DVTs are being treated at home with LMW heparin.

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MANAGEMENT
• Warfarin is started after 1 or 2 days of heparin therapy and the heparin stopped when the INR is in the target range.
➢ Warfarin should not be started alone because it is pro-coagulant in the first days, it inhibits the synthesis of factors II,
VII, IX and X as well as Protein C and protein S. The half-lives of already synthesized Protein C are shorter than the
clotting factors so there is increased risk for coagulation.
➢ Warfarin should be started within 72 hours of starting Enoxaparin.
➢ Continue enoxaparin and warfarin for a minimum of 5 days and until therapeutic oral anticoagulation effect has been
achieved (INR 2.0-3.0, Target INR should be 2.5)
➢ Average administration is up to 7 days. Stop heparin after and continue with Warfarin.
➢ Anticoagulants do not lyse the thrombus that is already present
➢ Unfractionated heparin should only be used if LMWH is unavailable
o Loading dose 5000 units SC followed by 15 000 units every 12 hours with Lab monitoring preferably on a daily
basis and dose adjusted accordingly.
o Alternatively loading dose 75units/kg IV injection, followed by continuous intravenous infusion 18 units/kg/hour,
with Lab monitoring preferably on a daily basis and dose adjusted accordingly
• Warfarin dosage:
➢ Initial dose (induction dose): 2-5mg PO every day for 2 days or 10mg PO for 2 days in healthy individuals
➢ Maintenance dose 2-10 mg PO per day
• The duration of warfarin treatment is debatable-3 months is the period usually recommended but 4 weeks is long enough if a
definite risk factor (e.g. bed rest) has been present.
• Recurrent DVTs need permanent anticoagulants.
• Thrombolytic therapy is occasionally used for patients with a large illiofemoral thrombosis.

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ANTICOAGULANTS
• Blood coagulates by transformation of soluble fibrinogen into
insoluble fibrin.
• Circulating protein interact in a “cascade” where clotting factors
undergo limited proteolysis to become active serine proteases.
• Anticoagulants decrease the formation of fibrin clots
• Oral anticoagulants inhibit the hepatic synthesis of clotting factors
II, VII, IX and X in the liver
• The endogenous anticoagulants protein C and protein S cause
proteolysis of factors Va and VIIIa.

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ANTICOAGULANTS

• Heparin blocks the clotting factors of the intrinsic

pathway as such PTT is used to monitor the
intrinsic cascade and it increases the PTT
• Warfarin works on the liver not the factors already
synthesized. It blocks synthesis of vitamin K
dependent clotting factors

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Feature Heparin Warfarin (Coumadins)
Chemical nature Large polysaccharide, water soluble Small molecule lipid soluble derivatives of INTERNAL
vitamin K MEDICINE
Kinetics • Given parenterally (IV, SC), • Given orally
• Hepatic and reticuloendothelial elimination • 98% protein bound
• Half-life=2h (short) • When given orally it is metabolized by the liver
• No placental access • Half-life- 30+ hours
• Placental access (can cause teratogenicity and bleeding in the infant)

Mechanism Heparin catalyzes the binding of antithrombin III (a serine protease inhibitor) to Decreases hepatic synthesis of vitamin K dependent clotting factors (II, VII, IX and X).
factors IIa, IXa, X, XIa and XIIa resulting in their rapid inactivation Coumarins prevent gamma-carboxylation by inhibiting vitamin K epoxide reductase.
Works in vivo and in vitro It has no effect on factors already present. In vivo effects only

Monitoring Partial thromboplastin time (PTT) Prothrombin Time (PT), INR (international normalization ratio=
𝑃𝑇 𝑜𝑑 𝑡ℎ𝑒 𝑝𝑎𝑡𝑖𝑒𝑛𝑡
) INR
𝑃𝑇 𝑜𝑓 𝑡ℎ𝑒 𝑐𝑜𝑛𝑡𝑟𝑜𝑙
should be around 1.5-2.5
Antagonist Protamine sulfate- chemical antagonism, fast onset Vitamin K (displaces warfarin from epoxide reductase)- increases cofactor synthesis,
slow onset, fresh frozen plasma (fast)
Uses • Rapid anticoagulation (intensive) for thromboses • Longer-term anticoagulation (controlled) for thromboses
• Emboli • Emboli
• Unstable angina • Post-MI
• DIC • Heart valve damage
• Open heart surgery • Atrial arrhythmias etc.
Toxicity • Bleeding • Bleeding
• Osteoporosis • Skin necrosis (if low protein C deficiency)
• Heparin-induced thrombocytopenia (hypersensitivity type II response, • Drug interaction (high plasma protein bound, other drugs that are highly
heparin binds to platelet factor 4 leading to opsonization and destruction protein bound could potential displace warfarin and cause bleeding e.g.
by the platelets). LMW heparin (Enoxaparin) are less likely to cause heparin sulphonamides, sulfonylureas, NSAIDs other drugs deal with absorption as a
induced thrombocytopenia Vitamin K analogue it requires to be emulsified by bile so cholestyramine and
• Hypersensitivity cholestipole reduce absorption as they decrease bile)
• Teratogenic (bone dysmorphogenesis)
• Warfarin is contraindicated in pregnancy.

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Medications Pros Cons Test used to monitor
Unfractionated heparin Short half-life, can turn off quickly if the patient Requires continuous IV Need to monitor PTT and platelet count at
bleeds. infusion least daily (for heparin induced
Although falling out of favor, still appropriate for thrombocytopenia)
acute coronary syndromes, cardiopulmonary Long-term use is associated
bypass, acute thrombotic events, mechanical heart with osteoporosis Reversible with protamine sulfate.
valves and anticoagulation in renal failure
Carries a risk of heparin
induced thrombocytopenia

LMWH No need to monitor PTT as dosing is weight based. Excretion is impaired in renal Will not prolong PTT, if monitoring is required,
failure (Creatinine clearance measure- Factor Xa activity
should be greater than
30ml/min)
Not reversible with protamine.
Requires injection.

Warfarin Oral Slow to reach therapeutic Monitor with INR, appropriate INR and
effect, requires the addition of duration vary by clinical situation
heparin with starting for an
acute clot. Reversible with FFP or vitamin K
Teratogenic, many drug
interactions.
Warfarin skin necrosis (Rare)

Direct thrombin Used for anticoagulation in patients with heparin Irreversible thrombin Monitor with PTT
inhibitors (Leepirudin or induced thrombocytopenia inhibitors, require continuous
argatroban) IV infusion

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COMPLICATIONS
• Cellulitis/ thrombophlebitis: can resemble, cause or follow
DVT.
• Post-thrombotic syndrome: varicose vein-like symptoms
(itch, swelling, dull pain), venous ulcers. It can occur up to
12 months post DVT. Prevention: compression stockings
on the affected leg for 2 years after DVT, though the
evidence is weak.

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PROPHYLAXIS
• Patients at risk for venous thromboembolism
➢ Medical patients with reduced mobility for more than 3 days or if their mobility is
reduced and they have more than 1 risk factor for venous thromboembolism
➢ Surgical and trauma patients are at risk:
o If they undergo surgical procedure with a combined anesthetic and surgery of
>90min (60 min if surgery on pelvis or lower limb)
o If they are admitted with an acute inflammatory or intra-abdominal condition
o If they have significantly reduced mobility
o If they have more than 1 risk factor for venous thromboembolism.

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PROPHYLAXIS
• Patients at risk should be considered for pharmacological prophylaxis (fondaparinux or LMW heparin or
unfractionated heparin if renal impairment) unless they have a risk factor for bleeding that outweighs the
benefits of venous thromboembolism prophylaxis.
• Risk factors for bleeding:
➢ Active bleeding
➢ Acquired bleeding disorders (e.g. acute liver failure)
➢ Concurrent use of anticoagulants (such as warfarin with INR >2)
➢ Lumbar puncture/epidural/spinal anesthesia within the previous 4 hours or expected within 12 hours
➢ Acute stroke
➢ Thrombocytopenia (Platelets <75 x 109/L)
➢ Uncontrolled systolic hypertension (>230/120 mmHg)
➢ Untreated inherited bleeding disorders (hemophilia and von Willebrand’s disease)
• Patients should also be encouraged to mobilize where possible and mechanical venous thromboembolism
(anti-embolism stockings (thigh or knee length), foot impulse devices, intermittent pneumatic compression
devices (thigh or knee length) may be appropriate in certain patients.
• On discharge patients should be provided with advice on the signs and symptoms of venous
thromboembolism and if prescribed pharmacological or mechanical prophylaxis advice on their usage.

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WARM UP: SINGLE BEST ANSWER

• Thrombotic event is seen in all of following
except
A. Paroxysmal nocturnal hemoglobinuria
B. Disseminated intravascular coagulation
C. Idiopathic thrombocytopenic purpura
D. Heparin induced thrombocytopenia
E. Thrombotic thrombocytopenic purpura
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