In the name of God

Primary Therapy versus Secondary Prevention: Primary therapy consists of clot dissolution with thrombolysis or removal of PE by embolectomy. Anticoagulation with heparin and warfarin or placement of an inferior vena caval filter constitutes secondary prevention of recurrent PE rather than primary therapy.

 Anticoagulation with heparin and then warfarin.  Heparin should be started as soon as the diagnosis is suspected in the absence of specific contraindications  Heparin should be continued for 5 days after the start of warfarin even if INR is in therapeutic range. This is because warfarin not only inhibits vitamin K dependent clotting factors, it also reduces protein C levels. Thus a hypercoagulable state may exist during early stages of warfarin therapy, before the longer half-life factors (II, IX, X) are inhibited.  Low molecular weight heparin is as least as effective as unfractionated heparin in preventing recurrent venous thromboembolism and at least as safe with respect to major bleeding. Agent of choice for intermediate or low risk PE.  Unfractionated heparin indicated for patients with renal failure. There is a wide discrepancy in recommended unfractionated heparin dosage regimes. The American College of Chest Physicians recommend an initial bolus of 80 U/kg followed by 18 U/kg/h. Subsequent changes in infusion rate are based on APTT (2-3 times =60-80).Or U bolus followed by U/h.

Fondaparinux An anti-Xa pentasaccharide, is administered as a once- daily subcutaneous injection in a prefilled syringe to treat DVT and PE as a "bridge" to warfarin. No laboratory monitoring is required. Patients weighing 100 kg receive 10 mg. Fondaparinux does not cause heparin-induced thrombocytopenia. The dose must be adjusted downward for patients with renal dysfunction because the kidneys metabolize the drug.

 The most serious adverse effect of anticoagulation is hemorrhage. For life- threatening or intracranial hemorrhage due to heparin or LMWH, protamine sulfate can be administered. There is no specific antidote for bleeding caused by fondaparinux or direct thrombin inhibitors.  Major bleeding from warfarin is best managed with prothrombin complex concentrate. With non-life threatening bleeding in a patient who can tolerate large volume, fresh-frozen plasma can be used. Recombinant human coagulation factor VIIa (rFVIIa), FDA-approved for bleeding in hemophiliacs, is an off-label option to manage catastrophic bleeding from warfarin. For minor bleeding or to manage an excessively high INR in the absence of bleeding, oral vitamin K may be administered.  Heparin-induced thrombocytopenia (HIT) and osteopenia are far less common with LMWH than with UFH. Thrombosis due to HIT should be managed with a direct thrombin inhibitor: argatroban for patients with renal insufficiency and lepirudin for patients with hepatic failure. In the setting of percutaneous coronary intervention, one should administer bivalirudin.  During pregnancy, warfarin should be avoided if possible because of warfarin embryopathy, which is most common with exposure during the sixth through twelfth week of gestation. However, women can take warfarin postpartum and breast-feed safely. Warfarin can also be administered safely during the second trimester.

 Acute DVT patients with good family and social support, permanent residence, telephone service, and no hearing or language impairment often can be managed as outpatients. They, a family member, or a visiting nurse must administer a parenteral anticoagulant. Warfarin dosing can be titrated to the INR and adjusted on an outpatient basis.  Acute PE patients, who traditionally have required hospital stays of 5–7 days for intravenous heparin as a "bridge" to warfarin, can be considered for abbreviated hospitalization if they have a reliable support system at home and an excellent prognosis. Criteria include clinical stability, absence of chest pain or shortness of breath, normal RV size and function, and normal levels of cardiac biomarkers.

Thromboembolic disease and pregnancy :  warfarin should not be used before delivery  heparin continued until labour begins and is restarted in postpartum period when bleeding has stopped  streptokinase (and probably other thrombolytics) does not cross the placenta and has been used for pregnant patients at high risk of death from PE

Novel Anticoagulants: Novel oral anticoagulants are administered in a fixed dose, establish effective anticoagulation within hours of administration, require no laboratory coagulation monitoring, and have few of the drug-drug or drug-food interactions that make warfarin so difficult to dose. Rivaroxaban, a factor Xa inhibitor, and dabigatran, a direct thrombin inhibitor, are approved in Canada and Europe for prevention of VTE after total hip and total knee replacement.. Because of these drugs' rapid onset of action and relatively short half-life compared with warfarin, "bridging" with a parenteral anticoagulant is not required.

Patients with PE after surgery, trauma, or estrogen exposure (from oral contraceptives, pregnancy, or postmenopausal therapy) ordinarily have a low rate of recurrence after 3–6 months of anticoagulation. For DVT isolated to an upper extremity or calf that has been provoked by surgery, trauma, estrogen, or an indwelling central venous catheter or pacemaker, 3 months of anticoagulation suffices. For provoked proximal leg DVT or PE, 3 to 6 months of anticoagulation is sufficient. For patients with cancer and VTE, the consensus is to prescribe 3–6 months of LMWH as monotherapy without warfarin and to continue anticoagulation indefinitely unless the patient is rendered cancer-free. However, there is uncertainty whether subsequent anticoagulation should continue with LMWH or whether the patient should be placed on warfarin.

 American College of Chest Physicians (ACCP) guidelines recommend considering anticoagulation for an indefinite duration with a target INR between 2 and 3 for patients with idiopathic VTE. An alternative approach after the first 6 months of anticoagulation is to reduce the intensity of anticoagulation and to lower the target INR range to between 1.5 and 2.  Counterintuitively, the presence of genetic mutations such as heterozygous factor V Leiden and prothrombin gene mutation do not appear to increase the risk of recurrent VTE. However, patients with moderate or high levels of anticardiolipin antibodies probably warrant indefinite-duration anticoagulation even if the initial VTE was provoked by trauma or surgery.

The two principal indications for insertion of an IVC filter are : (1) active bleeding that precludes anticoagulation (2) recurrent venous thrombosis despite intensive anticoagulation. Prevention of recurrent PE in patients with right heart failure who are not candidates for fibrinolysis and prophylaxis of extremely high-risk patients are "softer" indications for filter placement.

Paradoxically, by providing a nidus for clot formation, filters double the DVT rate over the ensuing 2 years after placement. Retrievable filters can now be placed for patients with an anticipated temporary bleeding disorder or for patients at temporary high risk of PE, such as individuals undergoing bariatric surgery who have a prior history of perioperative PE. The filters can be retrieved up to several months after insertion unless thrombus forms and is trapped within the filter.

 The preferred fibrinolytic regimen is 100 mg of recombinant tissue plasminogen activator (tPA) administered as a continuous peripheral intravenous infusion over 2 hours. Patients appear to respond to fibrinolysis for up to 14 days after the PE has  streptokinase: 1.5 million IU over 2h  urokinase: 3 million IU over 2h  rtPA: 100 mg over 2 h  check APTT after infusion of thrombolytic is complete. Start heparin without loading dose when APTT <2 times upper limit of normal. If APTT is above this level repeat measurement every 4 h until safe to start heparin

The only FDA-approved indication for PE fibrinolysis is massive PE. For patients with preserved systolic blood pressure and submassive PE with moderate or severe RV dysfunction, ACCP guidelines for fibrinolysis recommend individual patient risk assessment of the thrombotic burden versus the bleeding risk

Contraindications: Clear contraindications to the use of fibrinolytic agents include : 1) history of cerebrovascular hemorrhage at any time 2)nonhemorrhagic stroke or other cerebrovascular event within the past year 3)marked hypertension (a reliably determined systolic arterial pressure >180 mmHg and/or a diastolic pressure >110 mmHg) at any time during the acute presentation 4)suspicion of aortic dissection 5)active internal bleeding (excluding menses) 6)recent surgery 7)trauma.

Relative contraindications to fibrinolytic therapy, which require assessment of the risk/benefit ratio, include: 1)current use of anticoagulants (international normalized ratio >2) 2)a recent (<2 weeks) invasive or surgical procedure 3)prolonged (>10 min) cardiopulmonary resuscitation 4)known bleeding diathesis 5) Pregnancy 6) a hemorrhagic ophthalmic condition (e.g., hemorrhagic diabetic retinopathy) 7) active peptic ulcer disease 8)a history of severe hypertension that is currently adequately controlled. 9)Because of the risk of an allergic reaction, patients should not receive streptokinase if that agent had been received within the preceding five days to two years.

 The overall major bleeding rate is about 10%, including a 1–3% risk of intracranial hemorrhage

Prevention of Postphlebitic Syndrome: Daily use of below-knee 30- to 40-mmHg vascular compression stockings will halve the rate of developing postphlebitic syndrome. These stockings should be prescribed as soon as DVT is diagnosed and should be fitted carefully to maximize their benefit. When patients are in bed, the stockings need not be worn

1/determine patient at risk  Low risk (<40 years old, ambulating, minor surgery)  Moderate risk (>40 years old, abdominal, pelvic or thoracic surgery)  High risk (>60years old, prior DVTor PE malignancy, orthopedic surgery hypercoagulability state).

2/prohylaxis of choice  Encourage all patients to ambulate as soon as possible  Low risk patient don't need prophylaxis.  Moderate risk pneumatic compression boot or low dose heparin prophylaxis.  High risk combination of pneumatic compression boot and low dose heparin. Ophthalmologic surjury are NOT candidates for prophylaxis.

 Thank you for your attention