Protein C or S Deficiency

The role of protein C and S deficiencies in blood clots and updates on hormonal contraceptives and acute coronary syndrome are presented.

Blood clots result from a number of physiologic causes and may require lengthy anticoagulant therapy.

Congenital C and S proteins are natural substances in the blood that help prevent blood clots. Protein C deficiency occurs in approximately 1 of every 200 to 500 people, whereas protein S deficiency occurs in approximately 1 of every 500 individuals^.1,2 Deficiency may be determined from a blood sample.

Protein C is a vitamin K—dependent glycoprotein synthesized in the liver. It circulates in the blood as an inactive enzyme precursor. Its activation into the serine protease–like enzyme, activated protein C, is catalyzed by thrombin when it is bound to the endothelial proteoglycan thrombomodulin.^1,2 Activated protein C exerts its anticoagulant activity primarily through inactivation of coagulation factors Va and VIIIa, which are required for factor X activation and thrombin generation.

The catalytic activity of activated protein C is greatly enhanced by the vitamin K—dependent cofactor protein S.³ The function of protein S is to inactivate factor Va and factor VIIIa. This function is carried out directly by protein C, and protein S serves as a cofactor. The half-lives of protein C and S are 8 and 30 hours, respectively.

A deficiency of activated protein C disturbs the delicate balance between procoagulant and anticoagulant proteins and engenders a prothrombotic environment.^1-4 The role of activated protein C and other anticoagulant proteins in this balance appears to be especially important in the slow-flowing venous circulation, in which there is prolonged exposure of procoagulant proteins and platelet phospholipids to the vessel wall. This may explain, in part, why protein C deficiency appears to be associated primarily with venous thrombosis.

With a documented protein C or protein S deficiency, it is advisable to not receive warfarin without receiving another anticoagulant at the same time. Warfarin inhibits the body’s own production of proteins C and S. Therefore, initial treatment with warfarin alone may temporarily make clotting worse or precipitate a new clot or a severe skin rash known as skin necrosis.

Hormonal Contraceptives

A recent study that examined the influence of oral hormonal contraception on arterial thrombosis, myocardial infarction, and stroke reported that most mo-dern low-dose products have an acceptable increased risk of these events, given their contraceptive and other benefits.⁵

“Newer, lower-dosed, combined oral contraceptive products (estrogen and progesterone) increase the risk of arterial thrombotis by 50% to 80%, which is less than the 2.5 fold increased risk seen with older-generation pills,” wrote the authors of a study published in the Journal of the American College of Cardiology. “So very low doses of ethinyl estradiol (<50 mcg)—whatever the progestin and whether delivered orally or by means of the patch or ring&mdash;are safe enough.”

The transdermal contraceptive patch and vaginal ring, however, each confer a risk of arterial thrombosis that is comparable with the high-dose products and are not very suitable for women older than 35 years. Progestogen-only pills, hormone intrauterine devices, and soft cutaneous implants don’t confer any increase in risk of thrombosis.

Updates to Acute Coronary Syndrome Guidelines

The American cardiology societies recently announced new recommendations to update the unstable angina/non-STEMI guidelines that include ticagrelor (Brilinta) as one of the options for antiplatelet therapy alongside prasugrel (Effient) and clopidogrel (Plavix), aligning closely with European guidance issued in September 2011.

The rationale for recommending ticagrelor and prasugrel in preference to clopidogrel is that they are faster acting and more potent.5 To comply with the FDA’s boxed warning on ticagrelor, it must only be administered with a dose of 81 mg of aspirin. The 2012 American College of Cardiology Foundation/ American Heart Association Focused Update⁶ emphasizes that all patients at medium/high risk should receive dual antiplatelet therapy on admission, with aspirin being the first-line indefinite therapy.

Another recommendation was to stop taking either ticagrelor or clopidogrel 5 days before planned cardiac surgery. Prasugrel should be stopped 7 days prior to surgery. Issues of concern include bleeding with prasugrel and compliance with a twice-daily dosing with ticagrelor.

Mr. Brown is professor emeritus of clinical pharmacy and a clinical pharmacist at Purdue University College of Pharmacy, Nursing, and Health Sciences, Department of Pharmacy Practice, in West Lafayette, Indiana. This column’s information is based on current studies and references, but it may be changed without notice with newer studies or with different patient populations.

References

1. Foy P, Moll S. Thrombophilia: 2009 update. Curr Treat Options Cardiovasc Med. 2009;11:114—128.

2. Middeldorp S, van Hylckama Vlieg A. Does thrombophilia testing help in the clinical management of patients? Br J Hematol. 2008;143:321—335.

3. Dahlback B. Advances in understanding pathogenic mechanisms of thrombophilic disorders. Blood. 2008;112(1):19-27.

4. Lipe B, Ornstein D. Cardiology Patient Page, Deficiencies of natural anticoagulants, protein C, protein S and antithrombin. Circulation. 2011;124:e365-e368.

5. Lidegaard A, LA kkegaard E, Jensen A, et al. Thrombolic stroke and myocardial infarction with hormonal contraception. N Engl J Med. 2012: 366:2257-66.

6. Jneid H, Anderson JL, Wright SR, et al. 2012 ACCF/AHA focused update on the guideline formanagement of patients with unstable angina/nonST elevation mycardial infraction (Updating the 2007 guideline and replacing the 2011 focused update). A report of the ACCF/AHA. Circulation. 2012