Introduction

     
    Heparin is routinely used for the prevention of venous thromboembolism (VTE) and in the treatment of unstable angina (UA). Low molecular weight heparins (LMWH) are at least as effective as unfractionated heparin (UH) for the treatment and prevention of VTE (1). Recent studies indicate that unmonitored outpatient LMWH is as safe and as effective as intravenous UH and warfarin in reducing the risk of recurrent VTE (2).

   A comprehensive institutional policy of propylaxis in patients at risk of VTE is an effective way of reducing deaths from pulmonary embolism (PE). Primary prophylaxis is cost effective (3,4). In patients at high risk of VTE/PE, the prophylactic use of LMWH has been proven to reduce significantly the incidence of DVT and death from PE (2).

  A number of low molecular heparin fractions are available, but Dalteparin (Fragmin) and Enoxaparin (clexane/Lovenox) are the most widely used LMWH preparations in clinical practice. Both are included in Hamad Hospital Formulary.

Since the dose, frequency, and route of administration of LMWH are different from UH, guidelines for their use are needed. These guidelines apply only to adult patients.


Pharmacokinetics


   LMWH are derivatives of UH, produced by controlled enzymatic or chemical de-polymerization processes. Their molecular weight varies from 4000-6000 with a mean of 5000. Like UH, they exert their action by activating anti-thrombin (AT). This action is mediated by a unique pentasaccharide sequence that is randomly distributed along the heparin chain. When this pentasaccharide sequence binds to AT, it accelerates its interaction with thrombin (FIIa) and activated factor Xa by 1000 fold. LMWH and UH differ by their relative inhibitory activity against FXa and FIIa. Like UH, LMWH inactivates factor Xa, but they have a lesser effect on thrombin (2-3).

   LMWH have a number of advantages over UH. They have a longer half life, better bio-availability, and more predictable effect. UH binds to several plasma proteins, activated platelets, proteins, macrophages and endothelial cells. Binding of LMWH to plasma proteins, macrophages and endothelial cells is much less, accounting for better bio-availability. Hepatic clearance of LMWH is much less than UH, and renal clearance is slower than hepatic uptake.

   Since the action of LMWH is more predictable, laboratory monitoring is not needed, except in certain situations (2). In fact, there is little correlation between Xa activity and either bleeding or recurrent thrombosis.

   LMWH are not equal; they differ in their molecular weight, half life, and relative inhibition to factor Xa:IIa. Enoxaparin (clexane) tends to have a longer half-life and a better anti-Xa: anti-IIa ratio, theoretically offering a better therapeutic benefit and safety profile; hence, Enoxaparin is recommended by many institutions.


Monitoring


    • PTT is not useful for drug monitoring of LMWH.

   • Drug level can be monitored using an anti-Xa inhibition assay. Plasma levels are best done at peak level, 3-4 hours after subcutaneous (SC) enoxaparin. The therapeutic level for VTE is 0.5-1.1 anti-Xa units/ml. UH assay cannot be used for LMWH assays.

   • Drug level monitoring is only needed in:
           • Renal impairment
           • Pregnancy
           • Body weight < 60 kg or >90 kg.
           • In patients who are bleeding or continuing to clot while on LMWH.
           • Monitoring need not be frequent. Once a level is satisfactory, the patient is expected to have a consistent blood level, except in pregnancy, where monitoring should be done every few weeks.

• CBC (platelets & Hb) every 3-7 days should be done to anticipate any bleeding or HIT, although risk of HIT is far lower than with UH (which would need daily CBC).

 

Table 1. Surgical Indications of LMWH

Prophylactic Indications for LMWH


     Surgical


    Randomized clinical trials comparing LMWH with UH in general surgical patients have found that LMWH given once or twice daily are as effective or more effective in preventing thrombosis (1,5,6). LMWH is indicated in any surgery lasting more than 30 minutes, with general anesthesia, obese patients, patients with prior DVT, patients above 50 years of age, or patients with cancer. LMWH is also effective and superior to low dose heparin for patients who have suffered multiple trauma (7) and in patients who have had an acute spinal cord injury associated with paralysis (8).
Table 1 shows surgical indications and regimen for prophylactic use of LMWH.


    Medical


   No decrease in mortality has been demonstrated to result from prophylaxis against venous thromboembolism in general medical patients, although reductions in the incidence of DVT and PE have been noted (9). Medical patients are classified as low, moderate, or high risk for venous thromboembolism, depending upon their underlying medical condition and other comorbid fatctors.

    For patients with ischemic strokes and lower limb paralysis, low dose heparin or low molecular weight heparin is recommended (10).

    Heparin or warfarin is recommended for patients following myocardial infarction (11). There is a high incidence of deep venous thrombosis accompanying acute myocardial infarction (AMI), which rises with duration of bed rest, increasing age, and the presence of congestive heart failure (11). These patients are at high risk for embolism. Low dose heparin therapy following AMI has been shown to significantly reduce the incidence of venous thrombosis and embolism (11). LMWH has not been evaluated for preventing or treating left ventricular thrombi or systemic emboli.

     Table 2 summarizes the medical indications and recommendations for LMWH.


 

Table 2. Medical Indications for LMWH

Special Consideration


     Acute Coronary Syndromes


    Heparin is the mainstay of therapy in UA as its efficacy has been documented in several large, randomized trials.

   The FRISC (12) and ESSENCE (13), trials evaluated the efficacy and safety of low molecular weight heparin in patients with UA. These studies indicate that in patients with UA, the addition of LMWH to a standard medical regimen, which includes aspirin, reduces complications (death, myocardial infarction, recurrent angina) and the frequency of the need for revascularization. The enhanced benefits were particularly striking in patients with evidence of myocardial necrosis based upon elevated troponin T levels.

   In the randomized ESSENCE trial, the incidence of death, myocardial infarction, or recurrent angina was 17% lower in patients given LMWH than those given UH, P <O.02 (13). The same trial found that compared to UH, the use of LMWH is associated with a lower incidence of thrombocytopenia, less need for monitoring as well a being cost effective (14).


Precautions


    General measures


    • LMWH is contraindicated in patients with Heparin-induced Thrombocytopenia (HIT). Patients on UH or LMWH can bleed or develop HIT. CBC monitoring is recommended daily in case of IV UH, and every 3-7 days in case of LMWH.

   • For patients who experience bleeding, Protamine sulfate can reduce clinical bleeding. Protamine sulfate neutralizes anti-IIa activity, but only half of anti-Xa activity, thus decreasing its ability to reverse LMWH effect. It can still be given as 1 mg for each 100 anti-Xa units, if patient received LMWH in the last 3-4 hours (Enoxaparin: 1 mg of Protamine sulfate for each 1 mg Enoxaparin, if received in the last 3-4 hours).


In Spinal Anesthesia or Lumbar Puncture


    • Spinal hematoma has been described mainly in elderly women who received concomitant NSAID with LMWH.
    • Increased risk if blood is returned in the epidural catheter or traumatic tap.
    • To reduce incidence:
    • Avoid inserting an epidural catheter less than 2 hours before or 24 hours after LMWH.
    • Avoid removing a catheter less than 2 hours before or 24 hours after LMWH.



Acknowledgment:

The authors wish to thank Dr. Rachel Hajar for comments and suggestions on the manuscript.


REFERENCES:


1. Nurmohamed, MT, Rosendaal, FR, Buller, HR, et al. Low molecular eight heparain in the prophylaxix of venous thrombosis: A meta-analysis. Lancet 1992; 340:152 - 156.

2. Weitz Jl: Low molecular weight heparin. N. Engl. J. Med. 1997;337:688-698

3. Hirsh J and Hoak J. Management of DVT and PE: A statement for
health care professionals. Circulation 1966; 93: 2212 - 2245..

4. Salzman EW, Davies GC: Prophylaxis of venous thromboembolism: Analysis of cost effectiveness. Ann. Surg. 1980; 191:207 - 218.

5. Leisorovicz A, Picolet H, Peyrieu, JC, et al. Prevention of perioperative deep vein thrombosis in general surgery: A multicenter double-blind study comparing two doses of logiparin and standard heparin. Br Surg 1991; 78:412 - 416.

6. Kakkar VV, Cohen AT, Edmonson RA, et al. Low molecular weight versus standard heparin for prevention of venous thromboembolism after major abdominal surgery. Lancet 1993; 341:259 - 265.

7. Geerts WH, Jay RM, Code KI, et al. A comparison of low dose heparin with low-molecular-weight heaprin as prophylaxis against venous thromboembolism after major trauma. N Engl J Med 1996; 335:701 - 707.

8. Clagett GP, Anderson FA, Geerts W, et al. Prevention of venous thromboembolism. Chest 1998; 114:531- 560S.

9. Lederle, FA. Heparin prophylaxis of medical patients? [editorial] Ann Intern Med 1998;128:768 – 770.

10. Sherman DG, Dyken ML, Gent M, et al. Antithrombotic therapy for cerebrovascular disorders. Chest 1995; 108:444 - 456S.

11. Cairns, JA, Theroux, P, Lewis, HD, et al. Antithrombotic agents in coronary artery disease. Chest 1998; 114:611 - 633S.

12. Fragmin during instability in Coronary Artery Disease (FRISC) study group. Low-molecular-weight heparin during instability in coronary artery disease. Lancet 1996; 347:561 - 568.

13. Cohen M, Demers C, Gurfinkel EP, et al, for the Efficacy and Safety of Subcutaneous Enoxaparin in Non-Q Wave Coronary Events
Study Group. A comparison of low molecular weight heparin with unfractionated heparin for unstable coronary artery disease. N Engl J Med 1997; 337:447 - 452.

14. Mark DB, Cowper PA, Berkowitz SD, et al. Economic assessment of low molecular weight (enoxparin) versus unfractionated heparin in acute syndrome patients: Results from the ESSENCE randomized trial. Circulation 1998; 97:1702 - 1707.

   

 

                                                                            TUBERCULOSIS

                                                             A Distinctly Preventable Disease
 

Tuberculosis continues to occur in all parts of the world. In developing countries, most transmission of infectionprobably happens at night when all members of a family sleep in a single, poorly ventilated room. In North America and Europe,custodial institutions, homeless shelters, and other closed environments are often the loci of outbreaks.     Despitegreat technological advances, tuberculosis remains a problem, hence, the need for both vigilance and common sense in combating its further spread.