Anticoagulants, thrombocyte aggregation inhibitors, fibrinolytics and volume replacement agents

Pharmacology

Heparin is a chain-linked, sulfated glycosaminoglycan, that is found naturally in the body and is produced by basophils and mast cells. Heparins prevent thrombus formation and limit thrombus extension by binding to lysine sites on antithrombin III and producing a conformational change that accelerates the rate at which antithrombin III neutralizes the hemostatic enzymes, thrombin (factor IIa) and factor Xa. Decreased levels of antithrombin III lead to resistance to heparin. When heparin is administered in low doses for prophylaxis, it is mainly factor Xa that is neutralized; in higher therapeutic doses, thrombin will also be neutralized. Heparins can initiate plasminogen activator release by endothelial cells, and this accounts for their fibrinolytic activity. Unfractionated heparin (UFH) has a molecular weight ranging from 5,000–30,000 daltons (Da). It inhibits factors IIa and Xa equally well. Low molecular weight heparins (LMWH) are fragments of the native heparin molecule with molecular weights that range between 1,000–10,000 Da. They have a different anticoagulant profile and are less able to catalyze the inhibition of thrombin relative to factor Xa due to their shorter chain lengths, which range between 5–17 monosaccharides.

Heparin is the strongest organic acid which exists in the body. The strong negative charge of heparin is important for the inhibition of coagulation. The formation of chemical salts with organic cations, such as protamine ( Section 2.9.3 ), quickly overrides the actions of heparin.

UFH has a short half-life of 1–2 hours. Due to its strong negative charge and high molecular weight UFH is not absorbed in the gut. Consequently, heparin must be administered intravenously or subcutaneously. This is also true for LMWHs, such as certoparin , dalteparin , enoxaparin , nadroparin , reviparin and tinzaparin . LMWH are increasingly preferred to UFH for thromboprophylaxis as well as for the treatment of VTE and in the pregnant patient. Their advantage lies in a longer half-life requiring only one or two injections per day, better bioavailability (85%) and their association with a lower incidence of osteoporosis, allergy, and heparin-induced thrombocytopenia (HIT). analyzed all studies published to the end of 2003 for the use of LMWH during pregnancy. They extracted data on VTE recurrence and adverse side effects from almost 2,800 pregnancies and found that LMWH were both safe and effective when used to treat VTE during pregnancy. Bleeding events and allergic skin reactions occurred in almost 2% and osteoporotic bone fractures in 0.04% of the cases. The authors did not find a single case of HIT. In addition, 95% of the pregnancies resulted in a live-born infant.

The long-term therapy with UFH has been associated with an increased risk of heparin-induced bone loss and osteoporotic fracture. Depending on the dose and duration of use, LMWH may have less influence on bone metabolism than UFH and therefore cause less bone loss, although not all studies have confirmed this effect ( , ). The decrease in bone loss observed in some of the studies may be related to maternal supplementation with calcium during treatment. More studies are needed before the true incidence of heparin-induced osteoporosis in pregnant women can be determined. Long-term anticoagulant therapy is associated with an increased risk of bleeding; however, the risk associated with the use of heparin is relatively low, around 2% ( , , , ).

Prolonged anticoagulation therapy increases the risk for spinal hematoma formation, especially following neuraxial blockade ( ). Guidelines for neuraxial blockade and thromboembolic prophylaxis have been established in a number of countries ( , ). These guidelines specify the interval of time that the medications should be discontinued prior to puncture or removal of a catheter in order to avoid bleeding complications. Timing intervals vary among the different guidelines, but generally the interval of time that is recommended is two times the elimination half-life of the drug that is administered. Accordingly, prophylactic doses of UFH should be discontinued at least 4 hours prior to neuraxial blockade or catheter withdrawal and therapeutic doses of UFH should be discontinued at least 6 hours before blockade or catheter removal. Since LMWH have longer half-lives, prophylactic or therapeutic treatment with these drugs should be stopped 12 or 24 hours, respectively, before neuraxial blockade or catheter removal ( ). A study of 284 pregnant women who were treated with enoxaparin for an average of 251days found that the rate of hemorrhagic complications during delivery was not significantly increased when enoxaparin was discontinued at least 12 hours beforehand ( ).

Toxicology

Placental transfer of UFH or LMWH is expected to be minimal due to their high molecular weight and negative charge ( , , ). This has been confirmed by studies that have failed to find detectable levels of UFH or LMWH in samples from the umbilical cord vein after administration to pregnant women or in the fetal circulation following dual perfusion of an isolated placental lobule ( , ). The frequency of malformations or other adverse effects did not appear to be increased in more than 20 clinical studies of infants whose mothers were treated with either LMWH or UFH for various periods of time during pregnancy ( , , , , , , , , , , , , , , , , , ) On the other hand, major birth defects were reported in seven (11%) of 65 infants whose mothers had been given a prescription for heparin during the first trimester of pregnancy in a surveillance study of Michigan Medicaid recipients (Rosa, cited in ); the expected rate of birth defects was 5%. Four of the malformed infants had cardiovascular defects. The possible contribution of confounding factors in this study, such as maternal use of other drugs and underlying maternal disease, is not known. Congenital aplasia cutis has been reported in two infants whose mothers were given tinzaparin during pregnancy ( ). Whether the association observed in these two case reports is causal or coincidental is unknown.

To date, heparin-induced alteration of the fetal coagulation system has been demonstrated in a sheep model ( ), but not in humans; although subdural hemorrhages of prenatal onset were reported in one infant whose mother took dalteparin for deep vein thrombosis during pregnancy ( ). It is feasible, then, that transplacental passage of LMWH may occur on rare occasions, as in pregnancies complicated by preterm delivery and placental abnormalities. In one study of 693 newborns whose mothers had received enoxaparin during pregnancy, there were 10 (1.4%) children with hemorrhages; none were thought to be treatment related ( ).

Pharmacology and toxicology

Protamines are simple (alkaline) proteins found in the sperm of several species. Protamine-HCl and protamine sulfate are agents that are used intravenously to reverse the effects of heparin prior to surgical procedures or for the treatment of heparin overdose. They are basic polypeptides that neutralize the strongly negatively charged heparin by complexing with it to form a stable salt. Protamine-heparin complexes have no inhibitory effect on coagulation. The ability of protamines to neutralize heparin varies with heparin chain length. Short chain fragments cannot be neutralized with protamine, resulting in incomplete neutralization of anti-factor Xa activity. This explains why protamine has weaker effectiveness against LMWH than UFH. Protamines are also mixed with insulin formulations and administered subcutaneously to prolong the glucose-lowering activity of insulin. No data has been published regarding the embryo- or fetotoxic effects of protamine. However, in animal studies, protamines have been found to inhibit angiogenesis ( ) and, therefore, may pose a risk to the developing embryo. There are two case reports of neonatal bradycardia, hypotension and hypotonicity after maternal administration of protamine prior to delivery ( , ). These effects are similar to side effects that have been reported in adults following administration of protamine.