Thamer Bin Traiki

 The goal of prophylaxis is to prevent the mortality and morbidity of VTE.  In surgical patients, the risk of VTE is dependent upon the type of operation and the presence of one or more risk factors.  Without prophylaxis, patients undergoing surgery for intra-abdominal malignancy have a 25% incidence of DVT in the postoperative period.

 Patients at highest risk are ◦ elderly patients undergoing major surgery ◦ previous VTE, ◦ malignancy, ◦ or paralysis.

 Age > 60  Malignancy especially ◦ Prostatic Ca ◦ Pancreatic Ca ◦ Carcinomatosis  Hx of DVT, PE, VV  Prolonged bed rest or immobilization  Obesity  Cardiac dis. spe CHF  Major Surgery spe Pelvic  Pregnancy  Oral contraceptive  Hypercoagulability ◦ Congenital ◦ Acquired  Trauma

 Pharmacologic or mechanical modalities.  The methods of VTE prophylaxis include ◦ LDH, ◦ LMWH, ◦ Elastic Stockings (ES), ◦ Intermittent Pneumatic Compression (IPC), ◦ Warfarin.

MOA :  Binds to ATIII and inactivate factors IIa, Xa, IXa, & XIIa (Major mechanism for anticoagulant effect, produced by only one third of heparin molecules)  Binds to heparin cofactor II and catalyzes inactivation of factor IIa (this effect requires high concentrations of heparin).  Binds to factor IX and inhibits factor Xa activation which requires very high concentration of heparin, and is AT- and HCII-independent.

 Molecular Wt : ◦  Route of administration : ◦ Parenterally SQ / IV  T ½ : ◦ 90 min  Prophylactic dose : ◦ 5ooo IU SQ before the surgery & every 8 or 12 h after.

 Therapeutic dose : ◦ Weight-based UFH dosages have been shown to be more effective than standard fixed boluses in rapidly achieving therapeutic levels. ◦ Bolus of 80 IU/kg ( Total Body Weight)IV,to be rounded to the nearest 50 U ◦ Maintenance continuous infusion is started at 18 IU/kg / h IV also rounded to the nearest 5o U Ann Intern Med 119:874, 1993.

 Monitoring : ◦ aPTT Q 6 hours until aPTT levels reach a steady state. ◦ Thereafter, aPTT can be obtained daily. ◦ aPTT levels must be kept 1.5 – 2.5 times the control level for VTE treatment.

aPTT Dose  35 s 80 U/kg bolus, then 4 U/kg/h  35–49 s 40 U/kg bolus, then 2 U/kg/h  50 –70 s No change  71–90 s infusion rate by 2 U/kg/h  > 90 s Hold infusion 1 h, then infusion rate by 3 U/kg/h

 Complication : ◦ Hemorrhage is the primary complication of UFH therapy.  The rate of major hemorrhage (fatal, intracranial, retroperitoneal, or requiring transfusion of greater than two units of packed red blood cells) is approximately 5% in hospitalized patients (1% in medical patients and 8% in surgical patients).

 CBC Coag profile  The first step is discontinuation of heparin ◦ This may be sufficient if the operation can be delayed for several hours.  For more rapid reversal: ◦ Protamine Sulfate

 Origin : ◦ Was formerly isolated from the sperm of various fish, but is now produced through recombinant biotechnology.  Dose : ◦ 1 mg IV of protamine sulfate for every 100 units of heparin most recently administered is immediately effective. ◦ For each hour that has elapsed since the last heparin dose, the amount of protamine should be halved.  Should be administered with ◦ slow infusion ( i.e. < 50 mg / 10 min)  Monitoring of the adequacy of the reversal by ◦ aPTT or activated clotting time.

 Side Effect : ◦ Hypotension, ◦ Pulmonary edema, ◦ Anaphylaxis. ◦ The phenomenon of "heparin rebound“  Prolongation of the clotting time recurs after adequate postoperative antagonism of the heparin, which can contribute to postoperative bleeding.  May also be a result of the anticoagulant effect of protamine.  Any of these D/C protamine sulphate.

 Heparin-induced thrombocytopenia (HIT) ◦ Type I :  Mild thrombocytopenia (plt > )  Usually 2 – 10 days after starting heparin  Non immune mediated  Doesn’t require cessation of Heparin

 Severe immune mediated syndrome  Caused by heparin-dependent antiplatelet Abs directed against platelet factor 4.  Usually 4 – 15 days after 1 st exposure& within hours after reexposure.  10 – 50 % TE events including arterial thrombosis  Bleeding is rare.  It occurs in 1 to 5% of patients being treated with heparin. N Engl J Med 332:1330, 1995.

 Dx by ELISA or radiolabeled serotonin release study.  It is NOT route, type or dose dependent.  Rx : ◦ Hold heparin & use direct thrombin inhibitor ◦ DONOT give Warfarin as it may cause venous limb gangrene ◦ Warfarin may be used after 5 – 7 days after thrombosis is controlled with direct thrombin inhibitor

 So because of HIT CBC should be done after 3 days of starting heparin.  Another complication of prolonged high-dose heparin therapy is osteopenia, which results from impairment of bone formation and enhancement of bone resorption by heparin.

 MOA : ◦ Predominantly anti active factor X  Molecular wt : ◦ One third of UFH 3000 – 7000  T ½ : ◦ 3 – 12 hours.  Origin : ◦ Porcine intestinal mucosa.

 The anticoagulant response of LMWHs is effective and predictable when given in a weight-based dose, thereby decreasing the need for routine laboratory monitoring.  LMWHs are eliminated through the kidneys and must be used with caution in patients with creatinine clearance less than 30 mL/min.  In most patients, monitoring of LMWH's anticoagulant effect is generally not necessary.

 When required, monitoring of LMWHs is performed by assessing anti-Xa levels  Monitoring in : ◦ less than 50 kg, ◦ obese patients greater than 120 kg receiving weight-adjusted doses, ◦ pregnant patients, ◦ and patients with renal failure

 HIT is seen in only 2 to 3% of patients receiving LMWHs.  Platelet counts should still be ascertained weekly in patients receiving LMWHs.  A decrease in the incidence of heparin- associated osteoporosis has not been conclusively demonstrated in humans.

 LMWH for VTE prophylaxis is contraindicated in patients with: ◦ intracranial bleeding, ◦ spinal hematoma, ◦ ongoing and uncontrolled hemorrhage, or ◦ uncorrected coagulopathy.

 Fondaparinux is the first chemically synthesized agent that contains the five-polysaccharide chain that binds and activates antithrombin, which then specifically inhibits factor Xa.  Fondaparinux does not contain any animal products.  It is also specific to antithrombin and does not bind to platelets and therefore minimizes the risk of HIT.

 Prophylactic doses : ◦ 2.5 mg  T ½ : ◦ 17 hrs  Route : ◦ SQ & 100 % bioavalability.  Therapeutic dose : ◦ mg  Monitoring : ◦ anti-factor Xa assay

 Large prospective randomized studies for both DVT and PE treatment have been conducted.  For DVT, the recurrent DVT/major hemorrhage rate for pentasaccharide was equivalent to LMWH.  For PE, recurrent PE/major hemorrhage rate for pentasaccharide was equivalent to standard UFH.

 Direct thrombin inhibitors that was first derived from the leech.  Hirudins form a tight complex with thrombin that inhibit thrombin from conversion of fibrinogen to fibrin as well as thrombin- induced platelet aggregation.  Hirudins do not bind to platelet factor 4. So can be used in HIT.

 IV with a loading dose of 0.4 mg/kg followed by a continuous infusion of 0.15 mg/kg /h.  The aPTT is used to monitor the effects of hirudins.  The dose of hirudin must be adjusted in patients with renal failure because it is metabolized in the kidneys.

 Synthetic direct thrombin inhibitor that reversibly binds to thrombin.  Approved for use as an anticoagulant for prophylaxis or treatment of thrombosis in patients with HIT.  Approved as an anticoagulant in patients with or at risk for HIT who are undergoing percutaneous coronary intervention.  T ½ :39 to 51 minutes and reaches a steady state with intravenous infusion at 1 to 3 hours.

 MOA : ◦ Through inhibition of the vitamin K-dependent gamma- carboxylation of  coagulation factors II, VII, IX, and X  Proteins C and S Chest 2004; 126:204S Engl J Med 1986; 314:1298

 Anticoagulant effect due to the inhibition of procoagulants (factors II, VII, IX, and X)  Thrombogenic effect by impairing the synthesis of naturally occurring inhibitors of coagulation (proteins C and S)

 T ½ : ◦ 40 hours  Route : ◦ Orally.  Monitoring : ◦ INR.  The recommended INR for VTE therapy ◦ Between 2 and 3 in most cases

 The ultimate anticoagulant effect of warfarin is delayed until the normal clotting factors, especially prothrombin, are cleared from the circulation.  The peak effect does not occur until 36 to 72 hours after drug administration especially because the plasma half-life of factor II is approximately 3 days. Circulation 1968; 38:169.  In another study factor II takes more than 10 days. Clin-Pharmacokinet Apr; 30(4):

 During the first few days of therapy, prolongation of the prothrombin time mainly reflects its action on the extrinsic pathway, through the depression of factor VII, which has a t 1/2 of only five to seven hours.

 But the intrinsic coagulation pathway is still active.  So, the patient is not fully anticoagulated with warfarin until the components of the intrinsic coagulation pathway are also reduced.  Equilibrium levels of factors II, IX, and X, approximately 10 to 35 percent of normal at therapeutic INR levels, are reached about one week after the initiation of therapy. Blood Coagul Fibrinolysis 1997; 8:48.

 For this reason, warfarin started after full day of heparin.  Heparin and warfarin treatment should overlap by four to five days when warfarin is initiated in patients with thrombotic disease. OR  UFH is stopped 2 days after the patient's INR reaches 2 to 3 on warfarin therapy. Chest 119:176S, 2001

 The perioperative risk of thromboembolism after warfarin withdrawal may be increased by ◦ Rebound hypercoagulable state ◦ Prothrombotic effect of surgery

 Indicate a hypercoagulant condition occurring after warfarin withdrawal. Clin-Pharmacokinet Apr; 30(4):  The clinical effects of rebound hypercoagulability after stopping warfarin are unlikely to be significant, despite biochemical evidence for this phenomenon.

 In one study of 19 patients, for example, thrombin and fibrin formation increased after abrupt cessation of warfarin therapy but no patient had a thromboembolic event Br J Haematol 1996; 92:479.

 In another report, however, 32 patients were randomly assigned to receive abrupt or gradual withdrawal of warfarin.  Very high levels of thrombin activation were seen in a few patients treated with abrupt withdrawal, two of whom developed a thrombotic event. Thromb Haemost 1994; 72:222.

 Therapeutic INR <5 without bleeding : ◦ the next dose of warfarin should be omitted and/or ◦ the maintenance dose of warfarin reduced. ◦ There is no need to reduce the dose of warfarin if the INR is only minimally prolonged Chest 2004;126;

 INR 5 to 9 without bleeding ; ◦ The estimated risk of a major hemorrhage within the next 30 days is estimated to be approximately1%. ◦ Omit the next 1 to 2 doses of warfarin, monitor INR more frequently, and resume treatment at a lower dose when INR is in therapeutic range, or ◦ Omit a dose and administer 1 to 2.5 mg oral vitamin K1. This option is preferred in patients at increased risk for bleeding (eg, history of bleeding, stroke, renal insufficiency, anemia, hypertension). ◦ In a retrospective review, a history of an INR >6 was highly specific (94 %) for predicting a future hemorrhage. Chest 2004;126;

 INR > 9 without bleeding : ◦ Hold warfarin ◦ 5 to 10 mg oral vitamin K1. ◦ Monitor INR more frequently ◦ administer more vitamin K1 as needed, ◦ Resume warfarin at a lower dose when INR is in therapeutic range. Chest 2004;126;

 A meta-analysis of 10 randomized and 11 prospective trials was performed to determine the relative effectiveness of the various routes of vitamin K administration for improving the INR in patients overanticoagulated with warfarin to an INR of 4.0 to 10.0 without bleeding.  Placebo — 20 percent (95% CI 0-47)  Subcutaneous vitamin K — 31 percent (95% CI 7- 55)  Intravenous vitamin K — 77 percent (95% CI )  Oral vitamin K — 82 percent (95% CI 70-93)

 The authors concluded that the subcutaneous route for vitamin K was no better for this purpose than placebo, and should not be employed.  Since the oral and intravenous routes were equally effective, and there is a risk of anaphylaxis with the intravenous route, the oral route is to be preferred.

 Any INR with Serious or life-threatening Bleeding: ◦ Hold warfarin ◦ Administer 10 mg vitamin K1 by slow IV infusion; ◦ Supplement with prothrombin complex concentrate, fresh frozen plasma, or recombinant human factor VIIa, depending on clinical urgency. ◦ Monitor and repeat as needed. Chest 2004;126;

 Hemorrhage : ◦ FFP to replace depleted vitamin K–dependent factors or ◦ intravenous vitamin K.  Skin necrosis: ◦ Usually in the first days of therapy & associated with protein C or S deficiency and malignancy. ◦ Individuals with protein C or S after exposed to warfarin, the sudden decline in proteins C and S leads to thrombus formation in venules with extensive skin and subcutaneous fat necrosis.  Teratogenicity.

 LOW risk patient ◦ Age < 40 ◦ No risk factor Minor surgery EARLY mobilization  But if major surgery ◦ SQ Heparin ◦ LMWH ◦ IPC ◦ Elastic stocking

 MODERATE risk patient ◦ Major surgery & age < 40 but no risk factor ◦ Minor procedure with Risk factors ◦ Age between 40 – 60  Need prophylaxis of one of the following ◦ SQ Heparin q 12 h ◦ LMWH ◦ IPC ◦ ES

 HIGH risk patient ◦ Major procedure &  Age > 40 or  With risk factors ◦ Minor procedure with  age > 60  Risk factors  Prophylaxis of ◦ SQ heparin q 8 h or LMWH ◦ But if there is increased risk of hematoma or infection IPC can be used instead

 HIGHEST risk patient ◦ Age > 40, ◦ Multiple risk factors & ◦ Major procedure.  Prophylaxis of ◦ SQ heparin Q 8 or 12 H OR LMWH + IPC or ES

 In a large randomized, double-blind study comparing LDH (5000 U SC bid) and LMWH (enoxaparin 30 mg SC bid) in trauma patients without intracranial hemorrhage,  There was a 30% risk reduction (p = 0.01) of DVT in patients given LMWH.  There was an overall major bleeding complication rate of 2% with no statistical difference between the two groups.  LMWH appears to be more effective than LDH, with a similar risk of major bleeding. N Engl J Med 335:701, 1996.

 LMWH 40 mg Vs.SQ UFH 5000 IU SQ BD or TDS has equal effect in moderate risk patient in DVT prophylaxis.  LMWH more effective in patient undergoing orthopedic procedure or after trauma or spinal injury. Arch Int Med 2003;163:

 Early ambulation,  Elastic stockings,  Electrical calf muscle stimulation, and  External pneumatic compression, with either ◦ uniform-pressure stockings or ◦ graded-pressure stockings

 Has been found as effective as low-dose heparin therapy.  In addition to augmentation of venous return with these devices, local and systemic fibrinolysis appears to be stimulated, even in areas remote from the application of the compression.  The length of time that IPC should be used has not been adequately determined, but most data suggest that at least 5 days or longer in the face of prolonged immobilization may be optimal.

 Prophylactic insertion of IVC filters has been suggested for VTE prophylaxis in high-risk trauma patients and in some patients with malignancy who have contraindications for LMWH.  Trauma patients at a higher risk especially those with severe head injury, spinal cord injury, and severe fractures of the pelvis or long bones.

 A 5-year study of prophylactic IVC filter placement in 132 trauma patients at high risk of PE reported a 0% incidence of symptomatic PE in patients with a correctly positioned IVC filter.  Forty-seven patients with a malpositioned IVC filter had a 6.3% incidence of symptomatic PE with three deaths. DVT occurred at the insertion site in 3.1% of the patients. Arch Surg 133:406, 1998

 Long-term complications associated with permanent IVC filters include IVC thrombosis and DVT.  Currently, the ACCP recommends IVC filters be placed only if a proximal DVT is present and anticoagulation is contraindicated.  Although widely practiced, IVC filter insertion is not recommended for primary prophylaxis.

 In an attempt to avoid long-term complications associated with permanent IVC filters, retrievable IVC filters have been developed for use in patients with a temporarily increased risk of PE. J Vasc Intervent Radiol 12:1053,  May be removed up to 4 weeks post insertion, even longer in some cases, assuming that ◦ period of increased PE risk has passed and ◦ no significant emboli are contained by the filter.  If the device traps a significant embolus, it may be left in place as a permanent filter.

 Optimal patients for retrievable filter placement may include : ◦ young trauma patients with transient immobility, ◦ patients undergoing surgical procedures associated with a high risk of PE, ◦ patients with hypercoagulable states who cannot be anticoagulated for a short period of time.