VENOUS THROMBOEMBOLISM (VTE)

Dr P. Saraswathidevi Prof and HOD

Dept of Anesthesia,Pain and Critical care Kidwai Memorial Institute Of oncology

Bangalore

INTRODUCTION : VTE is a serious preventable cause of morbidity & mortality in the world. Deep Vein Thrombosis (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 and under-used prophylaxis with high fatality has made DVT a significant medical problem. The immediate need of the hour is to have standard practical, acceptable and implementable guidelines for management of DVT. DVT FACTS : (1)

According to American heart association, DVT occurs in about 2 million Americans every year.

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 DVT received preventive treatment ; (according to U.S. multicentric study).(2)

Without prophylaxis 40-80% high risk patients develop DVTand Upto 60% patients who undergo total hip replacement surgery may develop DVT.(3)

Cancer patients undergoing surgical procedures have at least two times the risk of post operative DVT. and greater than three times risk of fatal PE than non cancer patients undergoing similar procedure.

In elderly, DVT is associated with 21% one-year mortality rate and PE is associated with 39% one-year mortality rate.

VTE. is not uncommon in patients in India.(4)

Evaluation and proper management is essential to decrease the burden of VTE

Remember that non-surgical medical patients are at an equal or at higher risk of developing VTE when compared to surgical patients (FRAMINGHAM HEART STUDY: out of 15.6% of deaths due to PE, only 18% were surgical patients while 82% were medical patients).

DEFINITION : A deep vein thrombus is a blood clot that develops in the deep veins usually in leg. Less commonly DVT. occurs in deep veins of arm or pelvis. MECHANISM : Based on Virchow’s triad, predisposition to development of DVT is primarily related to the stasis of blood flow, vessel wall damage, and activation of clotting system resulting in a hypercoagulable state. 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 that VTE. 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 DVT. - Oral contraceptives & Hormone replacement therapy ; oestrogen is

responsible for DVT* - Pregnancy : due to (i) Hormonal Changes

(ii) Pressure on veins by fetus - Highest incidence in puerperium especially just after childbirth - Dehydration : increases blood viscosity - Immobility/ Prolonged bed rest : Stasis of blood

- Long distance travel : due to (i) Inactivity (ii) Dehydration, especially if journey is > 3 Hrs. B. Surgical Conditions : (5)

- especially includes surgery under G.A for >3 hours duration - pelvic surgery and pneumoperitoneum, orthopedic surgery

to lower limb - Increased use of central venous line has caused more

involvement of upper limbs in DVT. - Polytrauma (esp spinal cord injury, pelvic and lower limb

fractures)

C. Medical Conditions : - M.I./ Heart failure causing poor cardiac output - Inflammatory bowel disease - Malignancy (esp abdominopelvic and metastatic) or its

treatment - Nephrotic syndrome - systemic infections - Behcets syndrome - Homocysteinemia - Paraplegia/Quadriplegia - Vasculitis

D. Hematological Disorders :

- Primary proliferative polycythemia - Essential thrombocythemia - Myelofibrosis / Myeloproliferative diseases inc Leukaemias - Paroxysmal nocturnal hemoglobinuria - Paraproteinaemias

E. Anticoagulant dysfunctions :

- Antithrombin III Deficiency: 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 deficiency - Prothrombin G20210 A mutation - Protein C&S deficiency

F. Increased Clotting factors :

- XI and VIII G. Antiphospholipid Antibodies :

- Lupus anticoagulant - Anti Cardiolipin antibodies

Risk factors are low, moderate and high Moderate and High risk factors ( odd ratio 2-9 & >10 ) are

Duration of surgery: >3 hrs especially under GA

THR,TKR and Surgeries to the abdomen and pelvis

Patient factors such as previous history of DVT,PE, thrombophilias( Protein C&S deficiency, Factor V Leiden, Lupus anticoagulant etc) , Pregnancy , puerperium , oestrogen therapy (OCP’s & HRT )*, age >40 yrs, obesity, immobility and varicose veins * Combined third generation OCP’s and HRT’s increase the incidence of

venous thromboembolism 3-4 times

They should be discontinued 4 wks prior to intermediate or major surgery and

restarted only after 2 wks following full mobilization ( patient on OCP’s should

be changed over to alternative contraception method)

Those who continue these medication in the periop period should receive s/c

LMWH and antiembolism stockings.

SIGNS & SYMPTOMS (DVT) : DVT. 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 the distended 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 like vein may be palpable. DVT. of calf vein.:- It is difficult to notice because of only one of multiple veins involved allowing adequate venous return through the remaining patent 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 or modest swelling and rarely cord like vein. 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 PE. MOSES’ SIGN : Calf muscle tenderness demonstrated by squeezing the affected calf. However 95% of patients with symptoms suggestive of DVT. have another diagnosis and 50-80% of DVTs have no symptoms. DIAGNOSIS (DVT): (6) A. Clotting Properties of blood : (i) D-Dimer: degradation products of cross-linked fibrin by plasmin that are detected by diagnostic assays

level may be elevated in any medical condition where clots form. D-dimer level is elevated in trauma, recent surgery, cancer, and sepsis.(32). .These are associated with higher risk for DVT.

D-dimer levels remain elevated in DVT for about 7 days.

The D-dimer assay is a highly sensitive test, up to 97%; however, it is not specific, with rates as low as 35% and therefore should only be used to rule out DVT, not to confirm the diagnosis of DVT

D-dimer assays include ELISAs, VIDAS & SimpliRED

(ii) aPTT/PT/INR : Altered value suggests clotting defects

(iii) 125 I fibrinogen leg scanning : this indicates vascular insufficiency. B. Venography : - This is reference standard for diagnosis of DVT. - 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 DVT

- Limitations : a.) Difficult to perform b.) Require expertise for interpretation - Complications :a.) Foot/calf pain

b.) Superficial Phlebitis c.) DVT.

d.) Hypersensitivity to radio contrast media C. Impedence Plethysmography : (7) This measures changes in venous capacitance during physiological maneuvers Sensitivity 83% , Specificity 92% .Serial 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 for calf veins thrombosis D. Real time B-mode (or Duplex) USG : This is 2D imaging and pulse wane doppler interrogation 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 DVT 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 collaterals. Predictive value is more than impedence plethysmography but this also is less sensitive in identifing 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) New clot Propagation

(ii) Clot dislodgment & pulmonary embolism (iii Clot enlargement (iv) Post thrombotic syndrome

GENERAL PROPHYLACTIC AND THERAPEUTIC MEASURES : 1. LIMB ELEVATION : The affected extremity is elevated above the level of heart until edema or tenderness subside. Rest 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 / EARLY MOBILIZATION : Encourage the patient to perform gentle foot & leg exercises every hour. Pumping effect of muscles promotes venous return. Gentle exercise minimizes 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 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. GRADUATED COMPRESSION STOCKINGS /THROMBOEMBOLIC DETERENT (TED) STOCKINGS: enhanced protection against DVT when used in combination with s/c heparin. Below the knee stockings as effective as above the knee . advised for all undergoing laproscopic procedures. Avoid in patients with severe arterial disease ( monitor ankle systolic pressure).They are mainly used to relieve pain & swelling and to prevent post thrombotic syndrome. They are tighter at foot than higher up the leg. . They improve venous flow & may need to be worn for several months or more.

6. INTERMITTENT PNEUMATIC COMPRESSION DEVICES : They compress the leg by 35-40 mmHg for about 10 sec every minute. As effective as heparin in reducing DVT. Particularly useful in orthopaedics. Foot pumps similarly compress the venous plexus of the feet . (25) 7. LOCAL / REGIONAL ANESTHESIA : Local anaesthesia eliminates lower

limb immobility associated with GA. Central neuriaxial blockade is protective

against DVT to a certain extent in THR & TKR

GENERAL PRINCIPLES OF ENDOVASCULAR INTERVENTION Percutaneous transcatheter treatment of patients with DVT consists of thrombus removal with catheter-directed thrombolysis, mechanical thrombectomy, angioplasty, and/or stenting of venous obstructions. The goals include reducing the severity and duration of lower-extremity symptoms, preventing pulmonary embolism, diminishing the risk of recurrent venous thrombosis, and preventing postthrombotic syndrome. Catheter-directed thrombolysis results in a lower incidence of postthrombotic syndrome and improved iliofemoral patency in patients with a high proximal DVT and low risk of bleeding.

Indications for intervention include the relatively rare phlegmasia or symptomatic inferior vena cava thrombosis that responds poorly to anticoagulation alone, or symptomatic iliofemoral or femoropopliteal DVT in patients with a low risk of bleeding Absolute contraindications include active internal bleeding or disseminated intravascular coagulation, a cerebrovascular event, trauma, or neurosurgery within 3 months. Unfortunately, most patients with DVT have absolute contraindications to thrombolytic therapy. Currently, the ACCP consensus guidelines recommend thrombolytic therapy only for patients with massive ileofemoral vein thrombosis associated with limb ischemia or vascular compromise

Percutaneous mechanical thrombectomy devices are a popular adjunct to

catheter-directed thrombolysis. Although these devices may not completely

remove thrombus, they are effective for debulking and for minimizing the dose

and time required for infusing a thrombolytic. Percutaneous mechanical

thrombectomy has developed as an attempt to shorten treatment time and

avoid costly ICU stays during thrombolytic infusion. The most basic

mechanical method for thrombectomy is thromboaspiration, or the aspiration

of thrombus through a sheath. Mechanical disruption of venous thrombosis

has the potential disadvantage of damaging venous endothelium and valves, in

addition to thrombus fragmentation and possible pulmonary embolism

Surgical Thrombectomy Surgical thrombus removal has traditionally been used in patients with massive swelling and phlegmasia cerulea dolens. In many patients, fibrinolysis alone is highly effective, and it has become the primary treatment of choice for many forms of venous and arterial thrombosis. Unfortunately, when thrombosis is extensive, fibrinolysis alone may be inadequate to dissolve the volume of thrombus present. Even when the bulk of the thrombus is not excessive, many patients with thrombosis are poor candidates for fibrinolysis because of recent surgery or trauma involving the central nervous system or other noncompressible areas.

Precisely defining the location and extent of thrombosis before considering any surgical approach to the problem is important. Duplex ultrasonography may sometimes be sufficient for this purpose, but venography (including routine contralateral iliocavography) is a more reliable guide to the anatomy and the particular pathology that must be addressed.

The patient must be heparinized before the procedure. Traditional venous thrombectomy is performed by surgically exposing the common femoral vein and saphenofemoral junction through a longitudinal skin incision. A Fogarty catheter is passed through the clot, and the balloon is inflated and withdrawn, along with the clot. However, care must be taken to avoid dislodging the clot or breaking it into small fragments because pulmonary embolus will result.

A proximal balloon or a temporary caval filter may be used to reduce the likelihood of embolization. Venography is mandatory to confirm the clearance of the thrombus. Back bleeding does not indicate clot clearance because a patent valve can block flow, or flow can be present with patent tributaries.

Venous valves may sometimes prevent the passage of a catheter in a retrograde direction down the leg. When this happens, the leg may be wrapped tightly with an Esmarch bandage in an attempt to force clot extrusion. After the thrombus has been removed, construction of a small arteriovenous fistula may assist in maintaining patency by increasing the flow velocity through a thrombogenic iliofemoral venous segment and promoting collateral

development. The fistula is usually performed between the saphenous vein and the femoral vein. To reduce the likelihood of rethrombosis, heparin anticoagulation is usually initiated before surgery, continued during the procedure, and maintained for 6-12 months afterward. Leg compression devices are useful to maintain venous flow.

Outcomes from multiple studies have shown rethrombosis rates around 12% when a temporary arteriovenous fistula is used. Optimal results were found in thrombosis less than 7 days, clearance of thrombus from the external and internal iliac veins, intraoperative venography, early ambulation, and use of compression stockings.

COMPLICATIONS : (16) 1) Recurrence 2) Post thrombotic (Phlebitic) Syndrome : Recurrent DVT 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 ulcers on the leg. 3) Pulmonary Embolism: (17) 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. PULMONARY EMBOLISM : FACTS :

Pulmonary thromboembolism causes 10% of all hospital deaths

Thromboemboli most commonly arises from the deep venous system

Most PE’s arise from DVT’s in the proximal veins of the pelvis and lower

extremities

This is the most common serious complication that has made DVT. a major (18) cause for concern.

Incidence of PE is 25-30% of DVT population. (19)

fatal P.E. Untreated 1 in 10 die. 75% of patients who die of P.E. do so within 1 hr of onset of symptoms.

PE 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.

DEFINITION : Obstruction of pulmonary blood flow by Thrombus, Air, Fat or Amniotic fluid. MECHANISM : A piece of clot lodged in the deep venous conduits of the limb dislodges and embolises through the body to the lung where it becomes lodged again causing cardio-respiratory compromise

SIGNS & SYMPTOMS (PE): – These are nonspecific and include tachypnea,

tachycardia, dyspnoea, bronchospasm and fever. Other findings include

chestpain , haemoptysis, cyanosis, dysrhythmias, hypotension, raised JVP,

oliguria, hypoxemia and decreased etco2 and collapse with large embolisms .

DIAGNOSIS: Wells Prediction Rule for Diagnosing Pulmonary Embolism:

Clinical Evaluation Table for Predicting Pretest Probability of Pulmonary

Embolism*

Clinical Characteristic Score

Previous pulmonary embolism or deep vein thrombosis + 1.5

Heart rate >100 beats per minute + 1.5

Recent surgery or immobilization (within the last 30 d) + 1.5

Clinical signs of deep vein thrombosis + 3

Alternative diagnosis less likely than pulmonary embolism + 3

Hemoptysis + 1

Cancer (treated within the last 6 mo) + 1

Clinical Probability of Pulmonary Embolism Score

Low 0-1

Intermediate 2-6

High ≥7

*Reprinted from Am J Med, Vol. 113, Chagnon I, Bounameaux H, Aujesky D, et

al, Comparison of two clinical prediction rules and implicit assessment among

patients with suspected pulmonary embolism, pp 269-75, Copyright 2002.

Revised Geneva Scoring System

Risk Factors Points

Age older than 65 y 1

Previous DVT or pulmonary embolism 3

Surgery (under general anesthesia) or fracture (of the lower limbs)

within 1 mo

2

Active malignant condition (solid or hematologic, currently active

or considered cured < 1 y)

2

Symptoms

Unilateral lower limb pain 3

Hemoptysis 2

Clinical Signs

Heart rate 75-94 beats/min 3

Heart rate ≥95 beats/min 5

Pain on lower limb deep venous palpation and unilateral edema 4

Clinical Probability Score

Low 0-3 total

Intermediate 4-10 total

High ≥11 total

*Adapted from Prediction of pulmonary embolism in the emergency

department: the revised Geneva score. Le Gal G, Righini M, Roy PM, Sanchez

O, Aujesky D, Bounameaux H, Perrier A. Ann Intern Med. 2006 Feb

7;144(3):165-71.

The performance of this scoring system appears equivalent to that of the Wells score.

The Geneva criteria, which depend only on objective measures, lead to a stratification with a pulmonary embolism prevalence of 8% in the lowest-risk group (Geneva score of 0)—a prevalence too high to be neglected.

Lab investigations ECG : Normal in 50%, nonspecific tachycardia and in severe cases Right

ventricular strain pattern, Right axis deviation, RBBB, and anterior T wave

changes. S1Q3T3 has high specificity but poor sensitivity.

Chest X ray : unremarkable unless pulmonary infarction has occurred.

Oligaemic lung fields and prominent pul artery in severe cases

ABG : Hypocapnea and resp alkalosis progressing to hypoxaemia, hypercapnea

and met acidosis.

Definitive diagnosis requires Te/Xe lung scan, pulmonary angiogram or high

resolution spiral CT of the chest

ASSESSMENT OF SEVERITY

Minor (<30% pul obstruction, no RV dysfunction and normotensive)

Nonspecific symptoms, pleuritic chest pain, dyspnoea, fatigue

Specific treatment- anticoagulation ( heparin, then warfarin )

Moderate (30-50% pul obstruction, some RV dysfunction but normotensive)

Haemoptysis, tachypnoea, Raised JVP. Tachycardia

Specific treatment- Thrombolysis

Massive ( >50% obstruction, severe RV failure and haemodynamic collapse)

Severe dyspnoea, hypotension, hypoxia, chestpain, syncope, shock, arrest

Specific treatment- embolectomy

INTRAOPERATIVE TREATMENT:

This is mainly supportive and includes oxygenation with 100% O2, inotropic

support with Dobutamine and Milrinone and pulmonary vasodilators such as

Bosantan, PGI2 & NO.As Intraoperative heparin and thrombolytic therapy

isn’t an option due to risk of bleedingan IVC Filter may be placed .However

Severe refractory hypoxaemia or hypotension may require Cardiopulmonary

Bypass and pulmonary embolectomy with placement of an IVC filter

MECHANOPROPHYLAXIS FOR PE

I.V.C. FILTERS An inferior vena cava filter is a mechanical barrier to the flow of emboli larger than 4 mm. They 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 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 embolectomy. 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. ANAESTHETIC CONSIDERATIONS IN PULMONARY THROMBOEMBOLECTOMY

Procedure- removal of clot or tumour from pul artery

Time- 2-3 hrs

Pain- ++/+++

Position- supine

Blood loss- moderate to massive

Special t

echniques- CPB

Intraoperative monitoring

It should include continous arterial and CVP monitoring with pulmonary

artery pressure monitoring and/or TEE in addition to standard monitoring

Preoperative considerations

Patient is often collapsed , resuscitation may be in progress

A healthy heart requires 50-80% of the pul trunk to be obstructed before rt

ventricular failure ensuses

Pt may have recently received thrombolytic therapy

Urgent CPB is necessary to re-establish oxygenation.

Peri-operative considerations

Intubate and ventilate with 100% oxygen, maintain perfusion with inotropes

and institute CPB without any delays

Administer 300-500U/Kg heparin

Substantial airway Haemorrhage from pul infarction may make ventilation

difficult and ETT may require frequently suctioning. A double lumen ETT is

helpful in controlling bleeding, isolating the infracted side and thus aiding in

ventilation

Consider placing an IVC filter post embolectomy

Postbypass

Inotropic support is likely to be needed, keep the heart well filled, and reduce

SVR with vasodilators if tolerated

NO, Inhaled PGI2 or an inodilator ( milrinone, sidenafil ) may help reduce

pulmonary arterial pressure.

Delay heparinization for 24 hrs to reduce surgical bleeding.

Special considerations

Very high right sided pressures may open the foramen ovale, causing right to

left shunting and resulting in worsening of hypoxia and paradoxical embolism

with resultant CVA

Following embolectomy and successful re-establishment of pul circulation , the

capnogram which formerly detected little or no ETCO2 , now shows a

dramatic improvement.

PHARMACO-PROPHYLAXIS AND SPECIFIC MEDICAL THERAPY : (22,23) 1. ANTICOAGULANTS : (8) ARGATROBAN Ind- Treatment or prophylaxis of thrombosis in patients with or at risk of

heparin induced thrombocytopenia

Dosage-2mcg/kg/min iv infusion to a max of 10 mcg/kg/min adjusted to an

aPTT of 1.5-3.0 times the baseline value.

Action-direct highly selective thrombin inhibitor. Inhibits fibrin formation,

factors V,VIII,XIII and platelet aggregation

Clearence-Hepatic met with 65% biliary and 22% renal excretion with 16%

drug excreted unchanged.

Comments-bleeding is major SE. caution in pts with severe htn, recent lumbar

puncture or major sx. When switching to or fro heparin allow aPTT to

decrease. Avoid loading doses of warfarin . dose reduction in hepatic

dysfunction

LMWH:. Started at admission or evening before surgery. Daily doses are dalteparin 2500 units or enoxaparin 2000 units Risk of epidural hematoma minimized by giving LMWH on the evening of surgery 12 hrs or more before central neuraxial blockade (LMWH plasma t1/2 is 4 hrs) or starting prophylaxis postoperatively LMWH They also cause antithrombin III dependent inhibition of activated coagulation. Dalteparins, Enoxapain, are used S/C in fixed doses for 6-14 days. (9)(10)(11)

DALTEPARIN

Indication- treatment or prophylaxis of DVT

Dosage- 100units/kg sc qid in treatment or 2,500-5,000 units sc bid in

prophylaxis

Action- inhibits both factor Xa and IIa

Clearence- hepatic metabolism and renal clearance

Comments- equally effective and predictable dose response curve compared to

standard heparin. Risks of spinal and epidural hematomas with

centreneuraxial blockade esp indwelling epidural catheters. Rarely causes

thrombocytopenia

ENOXAPARIN

Indication- treatment or prophylaxis of DVT

Dosage- 1mg/kg sc bid in treatment or 30 mg sc bid in prophylaxis

Action- inhibits both factor Xa and IIa

Clearence- hepatic metabolism and renal clearance

Comments- equally effective and predictable dose response curve compared to

standard heparin. Risks of spinal and epidural hematomas with

centreneuraxial blockade esp indwelling epidural catheters. Rarely causes

thrombocytopenia.

. 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

HEPARIN-Unfractionated

Indication- treatment and prophylaxis of thromboembolism

Dosage- loading dose of 50-150 units/kg iv with maintainence of 15-

25units/kg/hr iv infusion for treatment and 5000-10,000 units s/c q12h started

2 hours preop or ( q8h started at admission in high risk patients ) for

prophylaxis maintained for at least 5-7 days . The dose is adjusted so that

aPTT becomes twice the control value.

Actions- It acts indirectly by potentiating the action of plasma Antithrombin

III, blocking the activation of factors II, VII, IX, X, XI

Clearence - primarily by reticuloendothelial uptake and hepatic

biotransformation

Comments- reduces the incidence of DVT and fatal PE by 2/3rds. Largely replaced by LMWH .side effect inc bleeding , thrombocytopenia, allergic reactions and diuresis (36-48 hr after a large dose). Half life increased in renal disease and decreased in thromboembolism and liver diseases. Doesn’t cross the placenta. Reversed by protamine. Risks of spinal and epidural hematomas with neuraxial blockade esp indwelling epidural catheters .may cause thrombocytopenia in <5% of patients. Infrequently these patients may develop arterial thrombosis & ischemia.

WARFARIN

Indications- oral anticoagulation for patient with proximal DVT

Their use for isolated DVT 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 is recommended.

Dosage- 5mg po for 2-5 days( fixed low dose) started during first week of heparin therapy as early as the first day if aPTT is in therapeutic range then 2-10 mg po (monitored dose) , Dose adjusted accordingly to PT (maintained at 2-3 times control.) /INR ( maintained at 2-3). Heparin can then be withdrawn. Action- indirectly interferes with utilization of vit k by the liver and inhibits

synthesis of factors II, VII, IX, X

Clearence- hepatic metabolism and renal elimination

Comments- potentiated by ethanol, antibiotics, dextran, thyroxine, glucagon, methyldopa, MAO Inhibitors, phenytoin, CCF, Hyperthermia, liver disease, malabsorption. Antagonized by barbiturates, haloperidol, ocp’s hypothyroidism. Crosses the placenta - Obese patient undergoing surgery may require higher doses than non obese . - Anticoagulation can stop new thrombi from forming and old ones from propagating However, they can’t dissolve the thrombi. The body does this itself over time. - Duration of anticoagulation : Idiopathic thrombus : 6-12 mts. Secondary episodes of thrombus : 1-3yrs. 2. THROMBOLYTICS : (12,13,14) There is no evidence of superiority of thrombolytics over anticoagulants for DVT. However, early administration of such drugs may accelerate clot lysis, prevent venous valves damage and decrease potential for developing post phlebitic syndrome.(13)(14) When used ,heparin is discontinued till aPTT < 1.5 times control Heparin restarted when aPTT becomes 1.5 times control followed by warfarin in the usual manner.

STREPTOKINASE

Indication- in management of massive deep vein thrombosis and pulmonary

embolism

Dosage- 250,000 units iv over 30 mins , then 100,000 units/hr for 24-72h .

Action- thrombolytic agent

Clearence- eliminated by circulating antibodies and via the reticuloendothelial

system.

Comments- clinically useful if used within 6-12 hrs of thrombotic event.

Administer aspirin 325 mg at the start and heparin 800-1000 units/hr at the

end of the streptokinase infusion.avoid vascular punctures at non

compressible sites. C/I with recent administration of streptokinase ( Ab to

streptokinase remain for 3-6 months after the initial dose) , recent

streptococcus infection, active internal bleeding, CVA within 2 months,

intracranial or intraspinal surgery, major surgery within the last 10 days, GI

bleed, major trauma and severe hypertension. Fibrinolytic effect lasts for few

hours while anticoagulant effect persists for 12-24 hours.

rt-PA

Indication- in management of massive pulmonary embolism

Dosage- 100mg iv continous infusion over 2 hrs

Action- tissue plasminogen activator

Clearence- rapid hepatic clearance

Comments- doses above 150mg have been associated with an increased

incidence of intracranial heamorrhage. C/I with active internal bleeding, CVA

within 2 months, intracranial neoplasm or aneurysm, intracranial or

intraspinal surgery, major surgery within the last 10 days, GI bleed, major

trauma and severe hypertension. Used with caution in patients who have

received chest compressions , recent lumbar puncture and those who are

currently receiving other anticoagulants.

UROKINASE

Indication- deep vein thrombosis and severe or massive pulmonary embolism

Dosage-Bolus: 4000 units/kg iv over 10 mins followed by maintainence of

4400-6000 units/kg/hr iv infusion for 12-72 hrs

Action: thrombolytic agent

Clearence: hepatic with a small amount excreted unchanged in urine and bile

Comments: avoid vascular punctures at non compressible sites. C/I with

recent streptococcus infection, active internal bleeding, CVA within 2 months,

intracranial or intraspinal surgery, major surgery within the last 10 days, GI

bleed, major trauma and severe hypertension .

3. INHIBITORS OF PROPOGATION OF COAGULATION: These are newer agents : (15) (i) Fondaparinux : Action: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. Dosage:2.5-5 mg s/c once daily have predictable anticoagulant response. Comments: 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. Contraindicated in renal failure. (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 VTE & 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.

Other drugs occasionally used are DEXTRAN(70/40)

Indications – inhibition of platelet aggregation and improvement of blood flow

in low flow states Dosage- 30-50 ml iv over 30 mins as loading dose and 15-30

ml/hr iv as maintainence infusion of a 10% solution .

Actions- immediate short duration plasma expansion , decreases RBC

adhesiveness , blood viscosity and pletalet aggregation.

Comments: as effective as sc heparin. Fluid overload and anaphylaxis are

probable complications. May produce a bleeding tendency in large doses and

interference with cross matching.

CLOPIDOGREL

Indications- antiplatelet agent

Dosage- 300 mg po loading dose with 75 mg bid maintainence therapy

Action- ADP receptor blocker. Prevents fibrinogen binding reducing platelet

adhesion and aggregation

Clearence- hepatic metabolism and renal clearance

Comments- major side effect is bleeding esp with concurrent aspirin and

heparin use.

GI Intolerence in > 20% . dose reduction in hepatic insufficiency

Aspirin may provide some protection but less effective than others and is not much useful when used alone (24)

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). REFERENCES :

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