DEEP VEIN THROMBOSIS (DVT)

A brief review

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G. Vyas *, S.B. Gawarikar**, V. Garg**, V. Patidar***, Ashish Sharma*** Sapna Bhandari@

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INTRODUCTION :

Venous thromboembolism (VTE) is a serious preventable cause of morbidity & mortality in the world. DVT & pulmonary embolism (PE) are distinct but related aspects of VTE. Being silent (80% DVT) and difficult to diagnose it poses great challenges in establishing diagnosis. Higher incidence, underestimation of risk, low level of clinical suspicion, under-used prophylaxis with high fatality has made DVT a world wide cause for concern. The immediate need of the hour is to have standard guidelines for management of DVT. These guidelines have to be practical, acceptable and implementable in institution all over.

D.V.T. FACTS : (1)

• According to American heart association, DVT occurs in about 2 million Americans every year.
• More people suffer from DVT annually than heart attack or stroke.
• Upto 6,00,000 people are hospitalized in U.S. each year for D.V.T.
• Fatal P.E. may be the most common preventable cause of hospital deaths is U.S.
• Only 1/3 of the hospitalized patients with risk factors for blood clots received preventive treatment ; (according to U.S. multicentric study).(2)
• Without preventive treatment, Upto 60% patients who undergo total hip replacement surgery may develop D.V.T.(3)
• Cancer patients undergoing surgical procedures have at least two times the risk of post operative D.V.T. and greater than three times risk of fatal P.E. than non cancer patients undergoing similar procedure.
• In elderly, D.V.T. is associated with 21% one-year mortality rate and P.E. is associated with 39% one-year mortality rate.
• P.E. is the leading cause of maternal death associated with childbirths. A woman’s risk of developing DVT is six times greater when she is pregnant.
• V.T.E. is not uncommon in patients in India.(4)
• Evaluation and proper management is essential to decrease the burden of V.T.E.
• While surgical patients seem to draw attention of medical fraternity; it needs to be remembered that non-surgical medical patients are at an equal or at higher risk of developing V.T.E. when compared to surgical patients (FRAMINGHAM HEART STUDY: out of 15.6% of deaths due to P.E., only 18% were surgical patients while 82% were medical patients).

DEFINITION :

A deep vein thrombus is a blood clot or thrombus that develops in deep vein usually in leg, here they pass through the centre of leg, surrounded by muscles, less commonly D.V.T. occurs in deep veins of arm or pelvis.

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* Prof. & HOD, ** Assoc. Prof, *** Asst. Prof., @ PG Trainee (DNB)

Dept. of Medicine, R.D. Gardi Medical College, Ujjain (M.P.), INDIA

1

MECHANISM :

Based on Virchow’s triad; development of D.V.T. is primarily related to the stasis of blood flow, vascular wall damage, activation of clotting system and hypercoaguable state.

Blood passing through the deepest veins in calf or thighs flows relatively slowly than from a solid clot which becomes wedged in the veins.

INCIDENCE :(1)

U.S. 100/100000-500/100000 at 80 yr age

U.K. 1 in 2000

CHINA 17.1/100000 ; 81.1/100000> 66 yr age

SINGAPORE : 388 cases between 1996-97 broke the myth-V.T.E. rare in Asia, India & South Asian countries : 6-75%, not well Highlighted.

PREDISPOSING FACTORS :

A, Patient Factors :

• -Age> 40 risk increase exponentially with age
• Obesity (BMI > 30 kg/ m²⁾
• Varicose veins or venous thrombophlebitis
• Previous D.V.T.
• Oral contraceptives & Hormone replacement therapy ; oestrogen is responsible for D.V.T.
• Pregnancy : due to (i) Hormonal Changes

(ii) Pressure on veins by fetus

• Highest incidence in puerperium especially just after childbirth
• Dehydration : increase blood viscosity
• Immobility : Stasis of blood
• Long distance travel : due to (i) Inactivity

(ii) Dehydration

• due to these factors blood becomes more sticky specially if journey is for more than 5 hrs.

B. Surgical Conditions : (5)

- Specially includes surgery for more that half an hour duration

- Abdominal, pelvis, orthopedic surgery to lower limb

- Increased use of central venous line has caused more involvement of upper limbs in D.V.T.

C. Medical Conditions :

- M.I./ Heart failure

- Inflammatory bowel disease

- Malignancy or its treatment

- Nephrotic syndrome

- Behcets syndrome

- Homocysteinemia

- Major injuries/ paralysis

D. Hematological Disorders :

- Primary proliferative polycyathemia

- Essential thrombocythemia

- Myelofibrosis / Myeloproliferative diseases

- Paroxysmal nocturnal hemoglobinuria

2

E. Anti-Coagulants Deficiencies :

- Antithrombin III : such patients are also relatively resistant to heparin

Therapy.

- Factor II Leiden : Genetic polymorphism of P.T. gene

- Factor V Leiden : Mutation leading to APC resistance

- Heparin cofactor II

- Prothrombin G20210 A mutation

F. Increased Clotting factors :

- XI and VIII

G. Antiphospholipid Antibodies :

- Lupus anticoagulant

- Anti Cardiolipin antibodies

SIGNS & SYMPTOMS :

D.V.T. of iliac, femoral or popliteal vein –

U/L leg swelling, warmth, erythema, increased tissue turgor, distention of superficial veins and appearance of prominent venous collaterals. In some patients deoxyhemoglobin in straight veins gives it a cyanotic hue called as ‘Phlegmasia cerulea dolens’.

In markedly edematous legs, interstitial tissue pressure may exceed capillary perfusion pressure causing pallor – ‘phlegmesia alba dolens,.

Tenderness is present along individual vein and a cord may be palpable.

D.V.T. of calf vein.:-

It is difficult to notice because of only one of multiple veins involved allowing adequate venous return through the remaining patient Vessels . The most common complaint is of calf pain which is noticeable or worse when standing or walking. Examination shows posterior calf tenderness, warmth, increased tissue tigour or modest swelling and rarely cord. Sometimes mild fever may occur usually < 38⁰C.

HOMANS, SIGN :

Pain in calf on forcible dorsiflexion of the foot.

The sign is unreliable and may enhance risk of P.E.

However 95% of patients with symptoms suggestive of D.V.T. have another diagnosis and 50-80% of DVTs have no symptoms.

DIAGNOSIS : (6)

A. Clotting Properties of blood :

(i) D-Dimer : it is by-product of clotting material. Measurement gives an indication hypercoagubility.

(ii) apTT/PT/INR : Increased valve suggests clotting defects

(iii) ¹²⁵ I fibrinogen leg scanning : this indicates vascular insufficiency.

B. Venography :

- This is reference standard for diagnosis of D.V.T.

- Contrast medium is injected into superficial veins of foot and directed to words deep veins by

tourniquets. Presence of filling defects or absence of filling of deep veins indicates D.V.T.

- Limitations : a.) Difficult to perform

- b.) Require expertise for interpretation

3.

- Complications : a.) Foot/calf pain

b.) Superficial Phlebitis

c.) D.V.T.

d.) Hypersensitivity to radio contrast media

C. Impedence Plethysmography : (7)

This measures changes in vevouls capacitance during physiological maneuvers verous obstruction becount the normal changes in venous capalitance that ocular following inflation or deflation of thigh usf.

Sensitivity 83% , Specificult 92% Sereal plethysmography increase sensitivity.

False + : a. Tensing leg muscles

b. Compression by extravasculars mass

c. Increased central pressure obstructing venous outflow

d. Decreased arterial flow

It is not sensitive to calf veins thrombosis

D. Real time B-mode (or Duplex) USG :

This is 2D imaging and pulse wane doppler interrodation

Direct visualization of major vascular channels and Doppler signals provides an audible and graphical depiction of blood flow. Failure to collapse the Vascular lumen completely with gentle probe pressure & finding of intraluminal echogenic material resulting from clot confirms the diagnosis of thrombosis. Sensitivity for proximal D.V.T. 97% and specificity 99%

False +ve : d/t inability to compress femoral vein d/t pregnancy or pelvic tumor.

False –ve : missing small clots

Misinterpreting total occlusion of femoral vein because of dilated collatrals.

Predictive value is more than impedence plethysmography but this also is less sensitive in inentifing isolated calf vein thrombosis. sensitively 50-75% specificity 95%

DIFFERENTIAL DIAGNOSIS :

Includes all disorder causing U/L leg pain or swelling :

• Muscle rupture
• Trauma
• Hemorrhage
• Ruptured popliteal cyst
• Lymphaedema
• Post phlebitic syndrome
• Streptococcal skin infections
• Nerve compression
• Arthritis
• Tendonitis
• Fractures
• Arterial occlusive disorders
• simple muscle strains

TREATMENT :

Aims of Rx : To prevent (i) Clot becoming larger

(ii) Clot becoming loose & traveling to lungs

(iii) New clot formation

(iv) Post thrombotic syndrome

4.

General Therapeutic Measures :

1. BED REST : The affected extremity is elevated above the level of heart until edema or tenderness subside. Rest decrease oxygen requirement, Limits risk of thrombus dislodgement, promotes fibrinolytic breakdown and clot destruction. Elevation improves venous flow using gravity to reduce pressure gradient between the extremity and heart.

2. EXERCISE :

Encourage the patient to perform gentle foot & leg exercises every hour. Dumping effect of muscle action promotes various return. Gentle exercise minimize further thrombus formation but overtly vigourous ones may dislodge the clots.

Isometric : eg plantar flexion against foot board – recommended after surgery, they increase venous flow but at the same time raise B.P.

ISOTONIC : eg active passive foot leg flexion & extension and ankle rotation are preferred.

3. FLUIDS : Increase fluid intake upto 2 l/day unless contraindicated. This increase vascular volume and decrease viscosity of blood thus improving the blood flow.

4.AVOID DEEP PALPATION : Rubbing or deep palpation or pressure under knees by sitting cross legged or by pillow can cause the clot break free & embolise. Sudden increase in intrathoracic pressure like valsalva maneuver can dislodge the clot.

5. COMPRESSION STOCKING : To relieve pain & swelling and to prevent post thrombotic syndrome, intermittent pneumatic (or graduated) compression stocking or T.E.D. (Thromboembolic deterent stockings) which are tighter at foot than higher up the leg are used. They improve venous flow & may need to be worn for several months or more.

SPECIFIC MEDICINAL TREATMENT :

1. ANTICOAGULANTS : (8)

Heparin : It acts indirectly by activating plasma Antithrombin III . dose : i/v bolus 7500-10000 IU followed by continues infusion so that 1000-1500 IU/Hr is maintained.

Deep SIC injection of 10,000-20,000 U every 8-12 hrs can also be given. The dose is adjusted so that aPTT becomes twice control value. Heparin treatment should be maintained for at least 5-7 days. This may cause thrombocytopenia in <5% of patients. Infrequently these patients may develop arterial thrombosis & ischemia.

LMWH : They are as effective or even better than UFH. They also cause antithrombin III dependent inhibition of activated coagulation.

Dalteparins, Enoxapain, Nadoparin are used S/C in fixed OD/BD doses i.e. 40 mg OD S/C for 6-14 days. Lower incidence of thrombocytopenia seen (9)(10)(11)

WARFARIN : It is oral anticoagulant acts by indirectly interfeeling with the synthesis of vit k dependent clotting factors in liver, 2-10 mg is started during first week of haparin therapy as early as the first day if aPTT is in therapeutic range. Dose adjusted accordingly to P.T. INR should be maintained 2-3 times control. Heaprin can then be withdrawn.

- Obese patient undergoing surgery may require higher doses than non obese .

- Anticoagulation can stop new blood clots from forming and old ones from growing. However, they

cant’ dissolve the existing clots. The body does this itself over time.

- Duration of anticoagulation :

- Idiopathic thrombus : 6-12 mts.

- Past OP/Secondary thrombus : 3 hrs.

- Secondary episodes of thrombus : at least 1 yr.

5.

Indication :

For patient with proximal D.V.T.

Their use for isolated D.V.T. of calf is controversial but the patient with calf vein thrombosis should be strictly followed up because 20-30% of calf thrombosis propagate to the thigh thereby increasing risk of pulmonary embolism. Also it is identified as cause of embolic stroke via patent foramen ovale. At least 6 weeks of anticoagulation recommended.

2. THROMBOLYTICS : (12,13,14)

There is no evidence of superiority of thrombolytics over anticoagulants for D.V.T. However, early administration of such drugs may accelerate clot lysis, pressure, venous valves and decrease potential for developing post phlebitic syndrome.(13)(14)

When used heparin is discontinued till aPTT <_ 1.5 times control

Streptokinase : 250000 IU loading then 100000 IU / hr for 24 hrs. OR

Urokinase : 4400 IU/kg loading then 4400 IU/hr for 24 hrs. OR

rtPA : 100 mg in 2 hrs.

Heparin restarted when aPTT becomes 1.5 times control followed by warfarin in the usual manner.

3. INFERIOR VENACAVA (IVC) PLICATION : No more used.

Mechanical interruption of blood flow through IVC.

4. I.V.C. INTERRUPTION :

I.V.C. filters are effective in primary prophylaxis of thromboembolism in patients with increased risk of bleeding viz. extensive trauma, visceral, cancer, spinal cord injury etc. There is no benefit to insertion of a filter paper in patients with free floating thrombi. However there are some therapeutic indications :

(i) Contraindication or complications of anticoagulation.

(ii) Recurrent V.T.E. despite adequate anticoagulation.

(iii) Chronic recurrent embolism with pulmonary hypertension and pulmonary embolestomy.

The most commonly used device, Greenfield filter inserted into femoral or internal jugular vein and has 20 yr efficacy rate 95% and patency rate 96%.

Anticoagulant therapy is resumed if possible.

Complications :

(i) Thrombus at the site of insertion

(ii) Migration of filter

(iii) Improper filter deployment

(iv) Formation of clot proximal to filter with proximal propagation and embolization.

(v) Venous insufficiency.

(vi) I.V.C. obstruction.

(vii) Rarely cause M.I., Vessel perforation, pericardial temponade and arrhythmias.

5. INHIBITORS OF PROPOGATION OF COAGULATION :

These are newer agents : (15)

FONDAPARINUX :

It binds to Antithrombin with highs affinity. Once bound, it evokes conformational changes in the reactive centre loop of Antithrombin that enhance its reactivity with factor X a.

Fondaparinux is a catalytic inhibitor i.e. after promotion of factor Xa it dissociates from Antithrombin and is available to activate additional antithrombin molecules.

Adm s/c once daily have predictable anticoagulant response. Routine monitoring is not required. It is found effective in prevention of VTE after hip fracture surgery and elective major surgery. It is also effective in initial treatment of PE. 6.

Contraindicated in renal failure.

IDRAPARNUX :

It is seemed generation drug with higher affinity than that of fendaparinux . Once weekly S/C closing is required owing to its long half-life.

(ii) Ximelagatran :- It is a prodrug of melagatran. It is the first oral direct thrombin inhibitor. After absorption from small intestine, inhibition found to be effective in secondary prevention of V.T.E. & prevention of VTE after total knee replacement surgery. Coagulation monitoring is usually not required as it produced predictable anticoagulant response and prolongation of apTT and INR are not dose dependent.

COMPLICATIONS : (16)

1) Recurrence

2) Post thrombotic (Phlebitic) Syndrome :

Recurrent D.V.T. can cause chronic venous insufficiency from venous valular destruction resulting in pooling of blood in lower leg. This can result in pain, swelling, discoloration and sores on leg.

3) P.E. : (17)This is the most common serious complication. It is this complication that has made D.V.T. a major (18) cause for concern. This occurs between on in three to one in four cases of D.V.T.A piece of clot lodged in leg vein breaks off & travels through the body to the lung where it becomes lodged again causing severe breathing difficulties accompanied by hypotension or shock, severe hypoxemic respiratory failure, acute r-sided heart dysfunction or obstruction of pulmonary vasculature that exceeds 50% (19)(Demonstrated by angiogram or V/Q scan) . This is termed as fatal P.E. Untreated 1 in 10 die 75% of patients who die of P.E. do so with in 1 hr of onset of symptoms.

4) Chronic thromboembolic pulmonary hypertension : (20)(21)

This is associated with progressive dyspnea & progressive heart failure & could be highly fatal.

5) Stroke :

rarely the clot can dislodge in other organs including the brain.

PROPHYLAXIS : (22,23)

1. ASPIRIN : Alone is not much useful (24)

2. MECHANICAL COMPRESSION DEVICES : Inermittent compression pumps is a mechanical device that automatically squeezes the feet and lower legs. This helps circulation of blood from legs in first few days after surgery. (25)

3. LMWH : Advantage Over UFH :(26) (27)

(i) Increased binding to plasma proteins or endothelium in turn leading to

a. Increased bioavailability b. Predictable anticoagulant response.

(ii) Affinity for macrophages resulting in increase half life.

(iii) Affinity for platelets and platelet factor 4 binding to osteoblasts

(iv) No monitoring required

(v) No hospitalization required

(vi) Convenient O.D. doses

(vii) Decreased incidence of thrombocytopenia

(viii) Osteopenia Unknown

7.

GENERAL PREVENTIVE ADVICE : FOR PERSONS AT RISK (15)

• Exercise legs regularly – 30 min. brisk walk daily
• Maintain B.M.I.
• Avoid sitting or lying in bed for long periods of time without moving legs
• Females > 35yrs should consider risks and benefits of OCPs & HRT.

FOR TRAVELERS : (28)

• Although added risk of developing D.V.T. caused by traveling appears to be low, it can be decreased even further by :
• Exercise legs once/hr during long distance travel special foot cushions can be used.
• Avoid sleeping pills – to prevent immobility.
• Wear loose fitting clothing.
• Keep legs uncrossed.
• Keep hydrated (urine should not be darker than pale yellow).avoid alcohol to prevent dehydration.
• Wear TEDs esp. travelers with high risk for D.V.T.
• Some recommend aspirin before travel.
• Anyone who develops swelling or pain in leg or breathing problems after travel should seek immediate medical advice.

CONCLUSION :

(29) Despite the availability of effective, prophylactic, therapeutic options ; venous (16) thromboembolism continues to be under diagnosed and under treated. Awareness levels are low particularly of medically ill patients to this potentially life treating killer disease. Though medical (non surgical) patients are at significant risk of developing (30) DVT in India/other asian countries is comparable to that in western countries serious challenges for our country in this regard are to find out prevalence of disease, maintaining standard protocols for its management and having high suspicion rate to decrease morbidity and mortality from the burden of this potentially fatal but preventable disease (deep vein thrombosis).

8.

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