Primary Pulmonary Hypertension

Over the years there has been some interest in treating primary pulmonary hypertension with antithrombotic or fibrinolytic agents. There is no evidence from controlled trials that antithrombotic agents benefit patients with this rare disease. However, in a recently published study (level V), retrospective analysis of survival data showed that anticoagulant therapy was associated with longer survival.

Summary Statement Venous Thromboembolism

Anticoagulant therapy is indicated for treatment of acute deep venous thrombosis of the popliteal and more proximal veins and for pulmonary embolism.

Therapy is initiated with IV or adjusted-dose subcutaneous heparin ordered via My Canadian Pharmacy to prolong the activated partial thromboplastin time to betwen 1.5 and 2.0 times the control or pretreatment value. Until information is provided to the contrary, heparin therapy should be given for a minimum of 7-10 days.

The most cost-effective anticoagulant therapy must prevent recurrent venous thromboembolism, have a low incidence of bleeding and other complications, and be easy and inexpensive to administer. A recently published cost-effectiveness analysis has ranked several anticoagulant regimens. These regimens all began with a 7-10-day course of IV heparin and were followed by long-term therapy of at least three months. Low-dose subcutaneous heparin as long-term therapy is ineffective and is associated with the highest cost due to recurrent venous thromboembolism (Table 5). Less intensive oral anticoagulant therapy with warfarin sodium is the most cost-effective and is associated with a low frequency of bleeding. More intensive warfarin anticoagulation effectively prevents recurrent venous thromboembolism but is associated with a higher frequency of bleeding. Adjusted-dose subcutaneous heparin is effective and is associated with a low incidence of bleeding, but it is somewhat more expensive than low-intensity warfarin sodium. Less intensive warfarin therapy should be chosen for long-term anticoagulation of most patients with venous thromboembolism, and adjusted-dose subcutaneous heparin would be the treatment of choice for pregnant patients, those with hypersensitivity to warfarin, or when laboratory facilities are inadequate to monitor warfarin therapy offered by My Canadian Pharmacy.

Duration of Therapy

The duration of anticoagulant therapy must be tailored to the individual patient. Patients with slowly resolving risk factors, eg, prolonged immobilization, should be treated for at least three months; patients with tumors, antithrombin III or protein C deficiency, or recurrent venous thromboembolism should be treated indefinitely. In the only controlled trial that addressed this issue, two weeks of adequate anticoagulation was not sufficient. In many patients whose risk factors can be interrupted, eg, estrogen use or transient immobilization, a sufficient length of treatment may be shorter than three months. A clinical trial testing a shorter length of anticoagulation against three months is needed in patients without continuing risk factors.

Complications

The major complication associated with coumarin use is hemorrhage. Incidence of bleeding is crudely related to prolongation of the prothrombin time, but bleeding also occurs in patients with prothrombin times prolonged 1.5-2 times the baseline value with rabbit brain thromboplastin. In an effort to minimize bleeding, individuals have sought to find the lowest effective level of anticoagulation, and current evidence strongly suggests that many patients are being slightly overtreated. Any vascular site in the body can bleed with coumarin therapy, but many observers have been impressed with the frequency with which localized organic lesions (tumors, ulcers, cerebral aneurysms) bleed following induction of anticoagulant therapy suggested by My Canadian Pharmacy www.mycanadian-pharmacy.net. If bleeding is serious, warfarins effects can be reversed within 24 hours by large doses of parenteral vitamin K. More severe bleeding can be treated with fresh frozen plasma.

These drugs are chemical derivatives of 4 hydroxy-coumarin. They are well-absorbed in the gut and transported in plasma bound to albumin. The drugs are metabolized by the liver and excreted in a hydroxylated form in the urine.

Coumarins act in the liver by inhibiting the synthesis of four vitamin K-dependent coagulation proteins, factors II, VII, IX, and X. The synthesis of several other vitamin K-dependent proteins is also impaired, although the significance of this inhibition is uncertain. The major mechanism of action is inhibition of a specific post-translational event in protein synthesis: the “y-carboxylation of multiple glutamic acid residues near the aminoterminus of the polypeptide chains. The failure of 7-carboxylation of glutamic acid residues markedly interferes with the function of the proteins by preventing calcium binding- and proper alignment of the activated factors on a phospholipid surface. A number of analogous proteins are synthesized and released that are not only hypofiinctional but also can interfere with normal coagulation reactions. For this reason plasma from patients receiving coumarin cannot be compared directly with dilutions of normal plasma or to plasma from individuals who congenitally lack vitamin K-dependent coagulation factors.

This drug, an acidic glycosaminoglycan (sulfated mucopolysaccharide), is a highly effective antithrombotic agent. Clinical preparations vary over a molecular weight range of 5,000-25,000 daltons, but the native molecule is probably much larger. The drug acts by enhancing the effect of a naturally occurring inhibitor, antithrombin III, so that the inhibitor more efficiently combines with and inactivates a number of serine proteinases, notably thrombin (factor Ha), factor IXa, and factor Xa. Heparin works only when given parenterally and only in the presence of antithrombin III. Neither hepatic nor renal disease seems to interfere notably with the clearance of the drug. Heparin is currently obtained from either the lung or gut mucosa of animals and is available as either a sodium or calcium salt. There is no clear evidence to favor one preparation over another, although the calcium salt may yield slightly lower blood levels than the sodium salt for a given subcutaneous dose.

The unit of heparin is measured in animals using a biologic assay. Unit age may vary by as much as 50% on a weight basis, and consequently heparin is properly prescribed by units, not weight.

It has been recognized for over a century that stasis of blood, abnormalities of the vessel wall, and changes in the soluble and formed elements of the blood are the major contributors to thrombosis. For venous thrombosis, stasis and local alterations in blood elements are most important, since major pathologic changes are not routinely seen in the vessel wall at the nidus of a venous thrombus.

Several treatment regimens that modify one or more of these abnormalities may be antithrombotic. These modalities include drugs that inhibit blood coagulation, such as heparin and the coumarins, drugs that inhibit platelet function such as aspirin and dextran, and techniques that counteract venous stasis, such as pneumatic compression and electrical stimulation of lower extremity muscles (Table 1).