Pulmonary Embolism Deep Venous Thrombosis BY Ragab Abdelsalam

Pulmonary Embolism & Deep Venous Thrombosis BY Ragab Abdelsalam (MD) Prof. of Cardiology

A. Risk Factors: 1. Venous stasis a) prolonged lower extremity immobility b) bed rest c) surgery d) right sided congestive heart failure

e) pregnancy (1) occurs in 1/1, 000 - 1/2, 000 pregnancies (2) DVT is considerably more likely in the left leg during pregnancy (3) risk of DVT is 5 X higher in pregnant women than controls

2. Endothelial injury a) previous DVT (1) risk of recurrent DVT is 17. 5% in 2 years (2) highest risk is in patients with malignancy and hypercoaguable states b) femoral intravenous cathethers

c) trauma & lower extremity surgery (eg. hip surgery) (1) calf vein thrombosis: (a) 40 -60% of patients with hip prothesis (b) 60 -70% of patients with knee prothesis (c) 58% of patients with major trauma

(2) proximal DVT (a) 20% in either hip or knee prothesis (b) 18% of patients with major trauma d) strenuous muscle activity ** primarily a risk for upper extremity DVT >> in patients with isolated upper extremity DVT, inherited hypercoaguability is rarely present

3. Hypercoagulability a) Primary (inherited) hypercoaguable states (1) Factor V Leiden mutation caused by a mutation in the factor V gene resulting in a resistance of factor V to activated protein C

NB: The risk of clotting depends on the number of abnormal genes: > Homozygous individuals are at extremely high risk of life-threatening thrombosis (approximately 80 -fold increased risk). > Heterozygous individuals are at about 5 -10 fold increased risk of thrombosis. Age > 44 y

(2) Hyperhomocysteinemia * High plasma homocysteine levels are a risk for DVT and can be caused by > genetic abnormalities (cystathionine Bsynthetase and 5, 10 methylenetetrahydrofolate reductase) > drugs (methotrexate, phenytoin, theophylline, and carbamazepine) > medical conditions (renal insufficiency, poor nutrition, hypothyroidism, cancer, and diets high in animal fat

- Diagnosis is by fasting serum homocysteine level. >> However, 40% of patients with hyperhomocysteinemia will be missed and require serum homocysteine levels before and after oral methionine loading -Treatment: folic acid 3 -5 mg/day, B 6 50 mg/day, and B 12 100 mg/day

3) Prothrombin G-A 20210 gene variant a) Genetic variant which results in increased levels of prothrombin and in hypercoaguability and accounts for approximately 14% of all patients with DVT/PE. b) Heterozytotes have increased risk of DVT by about 3 -fold and homozygotes have extremely high incidence of thrombosis

4) Protein C deficiency (a) Heterozygote prevalence is about 1: 200 - 1: 300. (b) Patients with thrombosis and protein C deficiency will have levels around 50% of normal. (c) Coumadin can affect protein C levels so laboratory tests should be performed once the patient is off of coumadin.

(5) Protein S deficiency (a) Heterozygous state incidence is about 1 -2% of the population. (b) Coumadin will also falsely lower protein S levels. (6) Antithrombin III deficiency ** patients with thrombosis and anti-thrombin III deficieny will have levels less than 70 or 80% of normal

(7) Miscellaneous inherited risks: levels of factor XI - hypoplasminogenemia, -dysplasminogenemia, tissue plasminogen activator release deficiency, - increased levels of plasminogen activator inhibitor, dysfibrinogenemia, -heparin cofactor II deficiency, fibrinolytic abnormalities, elevated levels of factor VIII, elevated levels of factor IX

b) Secondary hypercoaguable states: Anti-phospholipid antibody *This syndrome can occur as a primary condition, * However, many diseases can also cause anti-phospholipid antibodies including:

systemic lupus erythematosus, rheumatoid arthritis, Sjogren's syndrome, systemic sclerosis, ankylosing spondylitis, HIV, syphilis, and Lyme disease. * Additionally, a number of drugs can induce anti-phospholipid antibodies including: phenothiazines, procainamide, hydralazine, phenytoin, and oral contraceptives

* Malignancy : - will be diagnosed at the initial hospitalization of DVT/PE in 12% of patients. - The most common primary malignancies associated with DVT/PE pancreas, ovary, liver, and brain; -however, many malignancies can result in hypercoaguability.

* Heparin-induced thrombocytopenia >> Caused by an antibody directed against the heparin-platelet factor 4 complex which binds to Fc receptors on platelet 5 - Estrogen therapy.

* Diagnosis: 1. Clinical: a) Very inaccurate (about 50%). Frequent historical findings include: pain, swelling, and erythema. b) Frequent physical findings include: - Homan's sign - Moss, s sign - a palpable cord c) Of note, many patients will have no symptoms and a normal physical exam.

2. Duplex ultrasonography: a) 91% sensitive; 99% specific considering all DVT; the sensitivity approaches 100% for femoral DVT. b) For outpatients with suspected DVT, it is safe to withhold anticoagulation if an initial duplex ultrasound a second duplex in 5 -7 days are both negative

c) A positive duplex scan justifies treatment and does not require confirmation with venography. NB: Duplex ultrasound should always be done in both legs with suspected DVT

3. Venography: ** Although it is generally considered to be the "gold standard" in clinical trials, it is rarely used clinically since the development of duplex ultrasound.

4. Helical leg CT: a) Leg CT can be performed as a primary test or combined with helical chest CT. b) It should not be done routinely in patients under age 40 or in pregnant women because of the risk of genital and fetal radiation.

* Treatment: > Large vessel lower extremenity DVT should be treated similarly to pulmonary embolism; > Calf Vein Thrombosis warrents special mention. 20% will propagate up the thigh to cause iliofemoral DVT and therefore recommendations are to treat with heparin/coumadin like other DVTs. > If anticoagulation risky, an alternative is to follow the patient with serial duplex scans.

> Superficial vein thrombosis does not require treatment with anticoagulants but duplex ultrasonography should be performed to exclude concurrent calf vein thrombosis. - Upper extremity DVTs should be treated with heparin and coumadin similarly to lower extremenity DVT

Pulmonary Embolism (PE)

* It is a clinical syndrome characterized by: - dyspnea (78%), - pleuritic chest pain (59%), -cough (43%), - tachycardia (30%), - tachypnea (73%), - rales (55%), - syncope (13%), - and hypoxia (80%).

- These symptoms and signs are relatively nonspecific for PE but can help to raise your level of suspicion. - Any sign or symptom may be missing in a patient and the absence of one or more symptoms or signs cannot be used to rule out PE.

Hemodynamically it is classified into : 1 - Sudden death : if the occlusion involves more than 85% of the pulm. Vascular bed. 2 -Acute massive pulmonary embolism : ( 65 -85%) 3 - Pulmonary infarction : if it involves less than 65% 4 -Acute recurrent dyspnea in a predisposed patient 5 -acute pneumonia: if emboli is infected 6 -Subacute or chronic core pulmonale: recurrent shawers of small emboli.

1. Clinical presentation: a) Many PEs are asymptomatic; up-to 40% of patients with DVT had asymptomatic PE. b) If symptomatic, most frequent symptoms are: chest pain (88%), dyspnea (84%), cough (53%), hemoptysis (30%)

c) The physical exam is also non- specific. > Tachypnea and tachycardia are most common with 92% of patients having a respiratory rate greater than 14. > Fever occurs in 18 -50%. > Jaundice > Cyanosis. > Pleural rub. ( pulm. Infarction)>>pleurisy > Signs of Right HF , if acute core pulmonale occurs

c) The probability of PE can be estimated by : Well's criteria which assigns points for different clinical findings. A- Less than 2 points indicates low probability, B-2 -6 points indicates intermediate probability, C-and greater than 6 points indicates high probability

3. 0 - Signs of DVT 1. 5 - HR greater than 100 1. 5 - Immobilization for more than 3 days or surgery in past 4 months 1. 5 - Previous PE 1. 0 - Hemoptysis 1. 0 - Malignancy 3. 0 - PE as or more likely than other diagnoses

2. Chest x-ray: A-The plain chest x-ray is often normal, especially in the acute phase. B- When abnormalities are seen the most common findings are:

1 -Cardiomegaly 2 - enlargement of main pulmonary artery (normal right PA = 16 mm in men and 15 mm in women), 3 - elevated hemidiaphragm, ( tintig ) 4 - pulmonary opacities,

5 - Hampton's hump (3 -5 cm opacity usually on right hemidiaphram), 6 - atelectasis (usually 1 -3 cm above diaphragm; 7 -horizontal, linear, and several cm long, 8 -cavitation (suggests pulmonary infarction or septic embolus), 9 - pleural effusions.

ECG: 1 - May be normal 2 - Characteristic pattern: a) S 1. S 2, S 3 b) or S 1, Q 3, T 3 3 -Rigt nent. Strain ( inverted T-wave in V 1 -4) 4 - Incomplete or complete RBBB. 5 -Atrial fibrillation : in 5% of cases

4. Plasma D-dimer levels: a) a negative D-dimer was effective in excluding DVT/PE if the clinical suspicion was low b) D-dimers are primarily useful in outpatients and in ER patients. c) The D-dimer is useful as an adjunct to other diagnostic testing but is generally not a sufficient test to diagnose pulmonary embolism by itself.

5. Arterial blood gases a) A-a gradient increased in 95% of patients with proven PE. b) A-a gradient = [150 - (5/4 x p. CO 2)] - p. O 2. >> normal = 4 + (age ÷ 4).

6. Ventilation/perfusion scan A-Normal: perfusion is normal. B-Low probability: small V/Q mismatches, focal V/Q matches without x -ray abnormalities, or perfusion defects much smaller than x-ray abnormalities.

C-Intermediate probability (indeterminate): diffuse severe airway obstruction, matched V/Q and x-ray abnormalities, or single segmental V/Q mismatch. D-High probability: perfusion defects much larger than x-ray abnormalities or 2 or more segmental V/Q mismatches

NB: 1) Ventilation defects can accompany pulmonary arterial embolization for up to 48 hours. 2) Patients with COPD pose problems because of the increased chance of indeterminate scans (60% of patients) and they are less likely to have normal (5% of patients) or high probability (5% of patients) scans compared to patients without cardiopulmonary disease. ** However, a high probability V/Q scan or a normal V/Q scan has the same predictive value in patients with COPD as in those without COPD

** Predictive value: > A normal study excludes pulmonary embolism. > All other findings must be taken in the context of the clinical suspicion of pulmonary embolism. > patients underwent both V/Q scans as well as pulmonary angiograms and to determine how well V/Q scans correctly identified patients with pulmonary emboli.

(1) a normal V/Q scan effectively excludes clinically significant PE (2) a high probability V/Q scan plus high clinical suspicion justifies treatment without an angiogram (3) a low probability V/Q scan plus low clinical suspicion justifies no treatment without an angiogram

7. Duplex ultrasound of the legs - In patients suspected of having PE, only 29% of duplex ultrasounds will be abnormal at the time of presentation - It has been hypothesized that the clots in the deep veins of the legs have dislodged in patients with PE and thus are not present for identification by duplex ultrasound of the legs.

8. Helical CT >> The utility of the CTpulmonary angiogram is dependent on several factors: (1) The quality of the scanner

(2) T he expertise of the radiology technician performing the test (including patient instruction for breath-holding and timing of the IV contrast dye bolus). (3) The experience of the radiologist performing the study.

(4) The population of patient being studied. - The best quality studies come from studies of otherwise relatively healthy patients with relatively normal chest x-rays (such as emergency department patients); in these patient populations the sensitivity for detecting pulmonary embolus is good (70%) and specificity very good (19%).

- However, in critically ill patients, the sensitivity is only 55% although the specificity is still good at 90% - Obesity also reduces the sensitivity of CT pulmonary angiography.

(5) The location of the pulmonary embolus. CT is best for proximal, main pulmonary artery clot but less accurate for segmental and subsegmental clot where it can be difficult to distinguish clot from lymph nodes, atelectasis, and mucus plugs.

* A major advantage of helical CT over ventilation-perfusion scanning is the ability to diagose other lung diseases, especially in patients with pre-existing cardiopulmonary disease

** personal recommendations for current use: (1) if you are at an institution where there is a recent generation multi-channel CT scan, where there are technicians who are experienced with the correct technique, and there are radiologists experienced in interpreting the scans, CT can be used as a first line test in lieu of V/Q scans

(2) if you are at an institution where there are EITHER there is an older generation CT scanner OR technicians who are not experienced in the proper technique OR radiologist lacking experience in interpreting the scans, V/Q is still the initial test of choice.

(3) if the clinical suspicion is high or intermediate, a negative helical CT does not exclude PE. >> In this situation, a second study (usually D-dimer and a duplex ultrasound of the legs) should be performed >> and if indeterminate, then a pulmonary angiogram should be performed as a follow up test since false negative helical CT studies are common in this population.

(4) if the clinical suspician is low, and the helical CT is positive, confirmation of PE with an alternative method (such as pulmonary angiogram) may be desirable since false positives studies can occur

5) if the helical CT is "indeterminate" >> usually becuase of improper dye injection timing or artifact >> then additional tests are required (usually a pulmonary angiogram)

(6) if the patient has significant underlying lung disease and a baseline abnormal chest x-ray, then helical CT is probably preferable to V/Q scans as an initial technique since there is a high likelihood that V/Q will be "indeterminate" and require the patient to undergo additional testing to diagnose or rule out PE

(7) if the patient is at risk of dye injury (IV contrast dye allergy or renal insufficiency), then V/Q may be a better first study to avoid the large bolus of dye associated with helical CT, especially if a pulmonary angiogram becomes subsequently necessary.

9 -Echocardiography : Maybe of value: • 1 - diagnosis of pulm. Hypertension 2 - Differential diagnosis 3 -Importantly TEE may be of value in identification of the thrombus

TEE before treatment

TEE after treatment

10. Magnetic resonance angiography ØMRI is currently considered experimental for pulmonary embolism but offers the promise of future use. Ø A significant advantage is the abililty to avoid iodinated contrast dye in patients wtih renal insufficieny and dye allergy. ØInitial studies indicate that the sensitivity and specificity are probably eqivilent to CT.

11. Angiography a) complication rate = 1. 6% (0. 3% mortality - mainly in critically ill patients). b) gold standard but increasingly less frequently performed due to the widespread availability of CT. c) false positives have been reported in: malignancy, sarcoid, Takayasu's arteritis, and angiosarcoma

Diagnostic Criteria for Clinically Suspected Pulmonary Embolism Absent Negative pulmonary angiogram Normal or near-normal lung scan D-dimer level <500 micrograms per liter (ELISA (assay Low-probability lung scan and low clinical probability assessment

Pulmonary Embolism Present - Positive pulmonary angiogram - High-probability lung scan - Low- or intermediate-probability lung scan and ultrasonogram evidence of deep-vein thrombosis

Treatment 1. Heparinization strategies a) heparin should be begun when diagnosis is suspected, not when diagnosis is proven b) heparin does not cross the placenta and is safe during pregnancy c) contraindicated in: intracranial bleeding, intracranial lesions prone to bleeding, active internal bleeding, heparin-induced thrombocytopenia

d) treatment regimens: (1) continuous intravenous infusion: (a) adjust dose to achieve PTT = 1. 5 - 2. 5 times control (b) check PTT Q 6 hr. until PTT is between 60 and 105 then check PTT QD; check PTT 6 hours after any dose change (c) heparin drip adjustment based on patient's weight; mix 25, 00 units heparin in 250 ml D 5 W

* initial dose: 80 units/kg then 16 units/kg/hour - PTT < 45: additional 80 units/kg rebolus then increase drip by 3 units/kg/hour - PTT 45 -59: additional 40 units/kg rebolus than increase drip by 1 units/kg/hour - PTT 60 -105: no change - PTT 106 -125: decrease drip by 2 units/kg/hour - PTT 126 -180: hold infusion for 1 hour, then decrease drip by 3 units/kg/hour - PTT >180: hold infusion until dosing reevaluated by physician

(d) check platelet count between day 3 & 5 and again betwen day 7 & 10 of heparin therapy and stop heparin if the platelet count falls below 100, 000 (e) continue heparin for minimum of 5 days (NEJM 1990; 322: 1260 -4) and the INR is therapeutic

(2) low molecular weight heparin >> low molecular weight heparin offers longer half life, less hemorrhagic complications, greater ease of administration (once or twice per day subcutaneously), and perhaps less tendency toward anti-heparin antibody formation than standard heparin preparations

1) enoxaparin 1 mg/kg SQ BID) given at home was equally effective as standard heparin given IV in the hospital for management of acute DVT -enoxaparin 1. 5 mg/kg SQ QD was equally effective as enoxaparin 1. 0 mg/kg SQ BID or unfractionated heparin IV

(b) current FDA-approved indications: 1) for inpatient treatment of DVT or PE - enoxaparin 1 mg/kg SQ BID - enoxaparin 1. 5 mg/kg SQ QD - tinzaparin 175 u/kg SQ QD 2) for outpatient treatment of DVT - enoxaparin 1 mg/kg SQ BID - tinzaparin 175 u/kg SQ QD

2. Coumadin strategies: a) contraindications: as per heparin; additionally, coumadin contraindicated during pregnancy since in the first trimester, coumadin causes congenital abnormalities b) begin same day heparin is begun

c) start with 10 mg/day for days #1 & #2, then administer at estimated daily dose (1) check INR QD until stable and adjust to achieve INR of 2. 0 - 3. 0 (2) the INR must be checked frequently (every 1 -2 weeks) while patients are receiving coumadin

(3) need minimum of 4 - 5 days overlap with heparin d) patients must be cautioned about common foods and drugs which can alter coumadin's effect (often dramatically!) e) the duration of anti-coagulation is dependent on the patient population (1) First DVT/PE and reversible causes of clotting: 3 months (2) First DVT/PE and idiopathic: 6 -12 months and consider indefinite anticoagulation

3) DVT/PE and 1 cause of hypercoagulability: 6 -12 months and consider indefinite anticoagulation (4) DVT/PE and anti-phospholipid antibody syndrome OR 2 combined causes of hypercoaguability: 12 months and consider indefinite therapy (5) DVT/PE and cancer: low molecular weight heparin for 3 -6 months and then coumadin until the cancer resoloves

3. Treatment of heparin-induced thrombocytopenia (a) lepirudin (Refludan) - inhibits free and clot bound thrombin - 0. 4 mg/kg (up to a maximum of 110 kg) IV over 20 seconds - 0. 15 mg/kg/hr (up to a maximum of 110 kg) x 2 -10 days - keep PTT 1. 5 -2. 5 normal - adjust dose for renal failure

(b) Argatroban - thrombin inhibitor - 2 ug/kg/min continuous infusion - keep PTT 1. 5 - 3. 0 times normal - adjust dose for hepatic failure (no dosage necessary for renal impairment)

4. Ximelagatran - A direct thrombin inhibitor, it is an orally available alternative to coumadin and requires no laboratory monitoring. In 2004, the FDA did not approve Ximelagatran for release because of hepatic toxicity and it is unlikely to reach the market.

Thrombolysis is indicated if 1 - PE is confirmed with angiogram (or high-probability V/Q in some opinions) 2 - and there is evidence of right heart failure (hypotension, JVD, EKG showing right heart strain) 3 - unresponsive to standard therapy. >> Thrombolysis may be considered in the setting of respiratory failure from PE, but the benefits are less well established.

Regimens approved by FDA include the following: - Streptokinase 250, 000 IU over 30 minutes followed by 100, 000 IU/hr for 24 to 72 hours. - TPA 100 mg as continuous infusion over 2 hours. - Catheter-directed thrombolysis has the same rate of systemic bleeding as IV thrombolysis and is rarely used.

** Patients still require heparin anticoagulation after thrombolysis. >> LMW heparin, although not approved for this indication, may be more effective than unfractionated heparin. . >> Menstruation is not a contraindication to the use of thrombolytics or heparin if they are needed to treat PE.

6. Inferior venal caval interruption (Greenfield & birdnest filters) (a) Indications: anticoagulants contraindicated, PE despite anticoagulants, complications arising from anticoagulants

(b) Complications: migration, occlusion, caval perforation, development of collateral venous flow (thus permitting recurrent PE). (c) A new type of removable filter now exists. >> These filters can be placed temporarily but must be either repositioned or removed at 10 days. >>These devices can give protection during a period of time when anticoagulation is temporarily contraindicated.

5. emergency surgical embolectomy and angiographic catheter ( fragmentation/extraction) : * Both of these techniques should be reserved for: 1 - angiographically-proven massive PE with hemodynamic compromise, 2 - availability of experienced thoracic surgical team, 3 - failure of or contraindication to pharmacologic thrombolysis. * Both techniques pose additional risk and are associated with high mortality rates.

Prophylaxis: a) general surgery patients: (1) low risk, minor general surgery patients < 40 years: none (2) moderate risk general surgery patients and those 40 -60 years: SQ heparin 5, 000 units BID or low molecular weight heparin (3) high risk general surgery patients and those over age 60: SQ heparin 5, 000 units TID or low molecular weight heparin (intermittent pneumatic compression if patient is prone to wound hematoma formation with low dose heparin)

(4) very high risk general surgery patients: low dose SQ heparin (or low molecular weight heparin) + intermittent pneumatic compression or graduated compression stockings (5) very high risk surgery patients such as those undergoing cancer surgery should be considered for post-hospital low molecular weight heparin

b) gynecologic surgery patients: (1) brief procedures for benign disease early ambulation only (2) laparoscopic procedures plus other clotting risks: low dose unfractionated heparin, low molecular weight heparin, intermittent pneumatic compression or graduated compression stockings

(3) major procedures for benign disease: SQ heparin 5, 000 units BID (4) extensive procedures for malignancy: SQ heparin 5, 000 units TID or low molecular weight heparin (5) extensive procedures for malignancy in patients over 60 years old - continue prophylaxis for 2 -4 weeks after discharge

c) urologic surgery: (1) TURP and other low risk procedures: early ambulation only (2) major open procedures: SQ heparin 5, 000 units BID or TID; elastic stockings, intermittant pneumatic compression, or low molecular weight heparin are acceptable alternatives (3) highest risk patients: elastic stockings and/or intermittant pneuatic compression plus either low dose SQ heparin or low molecular weight heparin

d) orthopedic surgery: (1) total hip replacement: low molecular weight heparin, fondaparinux, or coumadin (dosed to keep the INR 2. 0 - 3. 0) (2) hip fracture patients: low molecular weight heparin, fondaparinux, or coumadin (dosed to keep the INR 2. 0 - 3. 0) (3) total knee replacement surgery: low molecular weight heparin, fondaparinux, or coumadin (dosed to keep the INR 2. 0 - 3. 0)

e) multiple trauma patients: (a) low molecular weight heparin (b) intermittant pneumatic compression devices if low molecular weight heparin is contraindicated (c) screening duplex ultrasound if inadequate prophylaxis given; IVC filter only if duplex ultrasound is positive

f) intracranial neurosurgical patients: > intermittent pneumatic compression with or without elastic stockings (low molecular weight heparin or low dose SQ heparin are alternatives) g) acute spinal cord injury with paralysis patients: low molecular weight heparin

h) medical patients: (a) congestive heart failure, severe respiratory disease, or confined to bed with one or more risk factors: low dose SQ heparin or IV heparin (b) critical care: low dose SQ heparin or IV heparin (graduated compression stockings or intermittant pneumatic compression devices if high risk of bleeding exists)

i) long distance travel: (a) for most travellers: avoid tight fitting clothing, avoid dehydration, stretch calf muscles frequently b) for high risk travellers, graduated ) compression stockings or a single dose of low molecular

drug dosing: (1) SQ heparin: 5, 000 u BID or TID (2) enoxaparin: 30 mg BID or 40 mg QD (3) dalteparin: 2, 500 to 5, 000 u QD (4) tinzaparin: 75 u/kg QD (5) nadroparin: 2, 850 u QD

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