504
Heparin-induced antibodies recognize and bind to heparin-platelet factor 4
complexes and subsequently activate platelets via the platelet Fc -receptor to medi-
ate HIT. A SNP commonly occurs in the platelet Fc -receptor gene, resulting in an
arginine or histidine at codon 131 (131Arg/His), and appears to affect platelet
aggregation.
Invasive procedures on patients receiving anticoagulation therapy require an
individualized assessment of the risk of bleeding versus the risk of thrombo-embolic
events. Besides SNPs, tailoring anticoagulation therapy according to the risk of
individual patients is the best way to optimize the benefi t/risk ratio, and is recom-
mended in treatment guidelines of fondaparinux (a heparin analog) as well as dabi-
gatran etexilate, the oral direct thrombin inhibitor (Rosencher and Albaladejo 2012 ).
Dose of fondaparinux should be reduced in renal impairment. Availability of two
approved doses of dabigatran etexilate for thromboprophylaxis following orthope-
dic surgery enables the dose to be tailored to the individual patient’s characteristics,
based on the age and renal function of the patient, as recommended by the European
Medicines Agency, in order to maintain effi cacy while decreasing bleeding risk.
A multicenter, randomized, controlled trial of warfarin involving patients with
atrial fi brillation or venous thromboembolism in whom genotyping for CYP2C92,
CYP2C93, and VKORC1 (−1639G → A) was performed with the use of a POC test
(Pirmohamed et al. 2013 ). Results showed that pharmacogenetic-based dosing was
associated with a higher percentage of time in the therapeutic INR range than was
standard dosing during the initiation of warfarin therapy. Acenocoumarol (Sintrom
or Sinthrome), a derivative of coumarin, is an anticoagulant that functions as a vita-
min K antagonist like warfarin. Three genetic polymorphisms involving the genes
VKORC1, CYP2C9 and CYP4F2 are considered to be useful for establishing the
correct dosage. However, two single-blind randomized clinical trials, comparing a
genotype-guided dosing algorithm based on clinical variables and genotyping for
CYP2C9 and VKORC1 with a dosing algorithm that included only clinical vari-
ables showed that genotype-guided dosing of acenocoumarol or phenprocoumon
did not improve the percentage of time in the therapeutic INR range during the 12
weeks after the initiation of therapy (Verhoef et al. 2013 ). An editorial comment on
pharmacogenomic guided anticoagulation commented that we should concentrate
on improvements in the infrastructure for INR testing, including better communica-
tion among the laboratory, the physician, and the patient; in the use of formal algo-
rithms for dosing, without concern for genotype; in patient adherence to therapy and
possibly more responsibility for dosing being assumed by the patient; and in
increased diligence by medical and paramedical personnel in testing, monitoring,
and dosing on the basis of the INR, given the high percentage of medical
mismanagement associated with these anticoagulant agents (Furie 2013 ).
Antiplatelet Therapy
Prasugrel, an approved antiplatelet drug for cardiovascular thrombotic disease, is a
prodrug with rapid and almost complete absorption after oral ingestion of a loading
dose. It is metabolized into its active form, which binds irreversibly to the adenosine
14 Personalized Management of Cardiovascular Disorders