CARDIOVASCULAR JOURNAL OF AFRICA • Volume 33, No 6, November/December 2022 324 AFRICA effects are uncommon with LMWH. HIT is a clinicopathological syndrome that occurs when heparin Ig G antibodies bind to the heparin/platelet 4 complexes, activating platelets and producing a hypercoagulable state. The immunological response also causes a consumptive coagulopathy, with the resultant thrombocytopenia. Treatment entails the use of an alternate anticoagulant class such as fondupurinax, a synthetic anti-Xa inhibitor. The most common VKA used in South Africa is Coumarin, trade name warfarin (Fig. 2) Warfarin competitively inhibits the vitamin K epoxide reductase complex 1 (VKORC1). This results in a reduction of the vitamin K reserves needed for the hepatic synthesis of the vitamin K-dependent clotting factors II, VII, IX and X, as well as coagulation regulatory protein C and protein S, natural anticoagulants.3 Warfarin may be pro-thrombotic when first initiated.26 Hence the drug is generally bridged with either LMWH or UFH. Absorption is rapid and complete, with an onset of action in 24 to 72 hours, peak plasma concentration after four hours and peak therapeutic effect seen on day five or seven after initiation. The drug is highly protein bound, metabolised by the liver and excreted by the kidneys. The probability of bleeding increases with certain polymorphic variants of the cytochrome P450 enzyme,27 as well as genomic variants in VKORC that reduce warfarin clearance.28,29 Warfarin is associated with bleeding that can be mild, such as skin bruising, epistaxis and bleeding gums, to severe intracranial or gastrointestinal bleeding. Rare cases of purple-toe syndrome and skin necrosis can occur due to the acquired protein C deficiency. This may be exacerbated in individuals with an inherent protein C deficiency.26 Calciphylaxis or calcium uraemic arteriolopathy is another rare adverse event that can occur with end-stage renal disease. Regimens: one size does not fit all, why? A delicate balance between maternal benefit and risk versus foetal benefit and risk should be considered. Current evidence recognises inherent risks and benefits to each regimen for both mother and foetus, with VKA having greater maternal benefit and the heparins favouring the foetus. Common regimens used include: • VKA throughout pregnancy (ideally low-dose < 5 mg/day). • Sequential therapy with switching to IV UFH heparin or dose-adjusted LMWH in the first trimester and transitioning back to warfarin in the second (from 13 weeks) and early third trimester, followed by bridging to UFH at 36 weeks in preparation for planned delivery. • Switching to dose-adjusted LMWH in the first trimester, continuing LMWH (with strict anti-Xa monitoring) in the second and third trimester, with bridging to IV UFH at 36 hours prior to planned delivery. • UFH throughout pregnancy (rarely used). Role of low-dose warfarin The meta-analysis by Steinberg et al. showed more live births and fewer foetal anomalies with low-dose VKA < 5 mg versus VKA > 5 mg.1 Their results support the recommendation by the ACC/AHA for the use of low-dose warfarin < 5 mg in the background of optimal INR levels over sequential therapy with either UFH or LMWH in the first trimester.11 This was supported by a meta-analysis by Xu et al. in 2015 as well as the ESC guidelines that recommend that women on low-dose warfarin can be counselled on continuing warfarin in the first trimester if the dosage is < 5 mg.9,30 They do however clarify that the mother should be aware that the risk of embryopathy and foetopathy still exists and they should therefore be given all options, shared decision making should be offered, with full informed consent if low-dose warfarin is to be continued in the first trimester.9 Similarly, D’Souza et al. found a twice as high rate of live births and a five times lower rate of adverse events with warfarin doses < 5 mg.31 However, they felt this data should be interpreted with caution based on the very small numbers; 10 studies (312 pregnancies) on < 5 mg and five studies (121 pregnancies) on > 5 mg. Both UFH and LMWH have a penta-saccharide molecular structure, the only difference is the length of the glycosaminoglycan (GAG) When UFH or LMWH binds to ATIII, it causes a conformational change allowing for the binding of ATIII to factor X and thrombin. The longer length of the GAG causes UFH to inhibit thrombin and factor Xa. LMWH only inhibits the activity of factor X due to its shorter GAG. ATIII ATIII ATIII ATIII UFH LMWH Thrombin Xa ATII: anti-thrombin III; GAG: glycosaminoglycan; Xa: activated factor X GAG GAG Fig. 1. Difference in mode of action of UFH and LMWH. Warfarin inhibits VKORC = less reserves for hepatic synthesis of vitamin K-dependant proteins Warfarin initially inhibits protein C and S, hence increases factors V and VIII >> increasing clotting Protein C and its co-factor protein S are natural anticoagulants that inhibit factor V and VIII Factor V and VIII are important co-factors within the coagulation cascade for clot formation VKORC: vitamin K epoxide reductase complex. Vitamin K hydroquinone Gamma carboxylase Vitamin K quinone Vitamin K epoxide Carboxylation of factors II, VII, IX, X, protein c and S makes them functional to be activated within the coagulation cascade Fig. 2. Mode of action of warfarin.
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