The Lowdown On Drugs And Antiphospholipid Syndrome (Warfarin, Enoxaparin, DOACs, NSAIDs & Extra)

This text is a part of the Antiphospholipid Syndrome (APS) useful resource library that I’m build up on my website. On this submit, we’ll give attention to medicines and Antiphospholipid Syndrome. Specifically, warfarin is a key medicine for the administration of APS, particularly if you happen to’ve skilled blood clotting occasions previously. We can even check out what DOACs (direct oral anticoagulants) are, how different medicines resembling NSAIDs (non steroidal anti-inflammatory medication) can work together with warfarin, and thrilling new medication within the pipeline.

If there are particular phrases or matters on this submit that you just had been questioning about, resembling injections, weight loss plan, bone well being or one thing else, you may most likely discover in solutions within the discover the solutions within the full Antiphospholipid Syndrome A – Z information right here!

Pin to Your Drugs and Antiphospholipid Syndrome Boards:

*Disclaimer: This text is supposed for academic functions, and is predicated on my private experiences as a affected person. While I’ve achieved my utmost to be meticulous in analysis, I’m not a physician, and nothing on this article ought to be substituted for medical recommendation. Please seek the advice of your personal physician earlier than altering or including any new remedy protocols. This submit might also comprise affiliate hyperlinks. It can value you nothing to click on on them. I’ll get a small referral price from purchases you make, which helps with the upkeep of this weblog. Learn our Privateness Coverage web page for extra data. Thanks!

A Transient Introduction to Vitamin Okay

Vitamin Okay is essential to know all about as a affected person with Antiphospholipid Syndrome, because it interacts with warfarin and is a key contributor to the blood clotting course of. It’s a fat-soluble vitamin that comes within the type of vitamin K1 (phylloquinone) and vitamin K2 (a sequence of menaquinones). There may be additionally an artificial type – Vitamin K3 (menadione), which is not utilized in dietary dietary supplements as they’ve been discovered to break hepatic cells (Workplace of Dietary Dietary supplements, 29 March, 2021).

Vitamin K1 is the principle type of vitamin Okay within the human weight loss plan, and may principally be present in inexperienced, leafy greens, sure fruits, and its absorption is elevated within the presence of butter or oils. Vitamin K2 is especially derived from fermented meals, dairy produce and animal-based sources.

In keeping with Halder et al. (2019):

“VKDPs [vitamin K-dependent proteins] are categorized as hepatic and extra-hepatic VKDPs. Hepatic VKDPs embrace coagulation components II, VII, IX, X, and anticoagulant protein C, protein S, and protein Z, all of that are concerned in regulating blood coagulation. Additional-hepatic VKDPs embrace Matrix Gla protein (MGP), Osteocalcin, and Gla-rich protein (GRP). These VKDPs are primarily concerned in sustaining bone homeostasis, in addition to inhibiting ectopic calcification.”

In primary phrases, what this implies is that vitamin Okay, whether or not in K1 or K2 type, is an integral part of blood clotting processes, upkeep of bone well being, and prevention of vessel mineralisation, relying on how and the place they’re metabolised. While it’s essential to pay attention to vitamin Okay, I gained’t deep dive into it on this submit as I’d prefer to give attention to medicines and Antiphospholipid Syndrome.

Vitamin Okay Antagonists (VKAs)

Vitamin Okay antagonists (VKAs) are a category of medicines used for the remedy and prevention of thrombosis. Essentially the most well-known and generally used VKA is warfarin. For the sake of curiosity, different forms of VKAs embrace: ethyl biscoumacetate, phenindione, anisindione, dicoumarol, phenprocoumon and diphenadione. There’s a motive why warfarin is probably the most generally used, as many of those different VKAs are erratic, extremely poisonous, or could cause different antagonistic unintended effects (Vardanyan and Hruby, 2006).

The administration of VKAs is handy and sensible, as they are often taken orally, and have a protracted half-life (warfarin has a half-life of 36 – 42 hours). Docs are additionally in a position to modify dosages for extra precision in particular person sufferers as wanted, based mostly on threat components and medical historical past. VKAs work by antagonising the enzyme vitamin Okay epoxide reductase (VKOR) to stop vitamin Okay from being recycled. This ends in inhibition of the coagulation cascade, as many clotting components depend on vitamin Okay to synthesise (Schein et al., 2016).

Coumarins

Vitamin Okay antagonists resembling warfarin, acenocoumarol and phenprocoumon are derivatives of coumarin, which could be of synthetic or natural origin. In 1945, Karl Hyperlink experimented with 150 naturally occurring coumarin derivatives, earlier than concluding that one compound was significantly lively – warfarin. For a uncommon subset of sufferers with mutations in VKOR, VKAs are sadly low in efficacy or ineffective resulting from coumarin resistance (Kasperkiewicz et al., 2020). Learn extra about coumarins within the A to Z APS useful resource information right here.

Warfarin – THE Remedy for Antiphospholipid Syndrome

Warfarin is a vitamin Okay antagonist, and might be crucial drug for the administration of Antiphospholipid Syndrome, and for the prevention of thrombosis. There are two manufacturers of warfarin accessible – Coumadin and Marevan. You will need to keep on with the identical model, because the formulation is just not a precise match. What meaning is that the anticoagulation results can range between every model, and would possibly mess your INR up. Do focus on together with your physician first, ought to it’s essential swap manufacturers for any motive.

(Not so) enjoyable reality: Warfarin additionally first began out as rat poison, however has declined in utilization for such functions resulting from a rise in resistance from these rodents, which is inheritable (Thijssen, 1995).

How Warfarin Works to Forestall Blood Clotting

Warfarin inhibits vitamin Okay dependent clotting components II, VII, IX, and X, and likewise the anticoagulant proteins C and S (Crader et al., 1 Could, 2023). Because of this it inhibits a number of pathways within the blood clotting course of, as in comparison with DOACs, which solely disrupt a selected level. Particularly, prothrombin, FVII, FIX, protein C, and protein S are strictly associated to blood coagulation processes (Girolami et al., 2018). Roughly 10% – 40% of things II, VII, IX and X are inhibited by warfarin (Wadelius et al., 2004).

Vitamin Okay ‘prompts’ these clotting components by way of the enzyme, epoxide reductase, which is inhibited by warfarin. In uncommon circumstances, sufferers who’re first taking warfarin could expertise warfarin-induced pores and skin necrosis. That is very true for sufferers who’re poor in protein C, because it has the shortest half-life amongst all of them. In such circumstances, sufferers are sometimes co-administered heparin, because it has a faster impact (Barmore et al., 24 February, 2023).

How Warfarin is Metabolised

Warfarin is a potent anticoagulant that’s properly absorbed by the physique by way of the gut with 90% bioavailability, and likewise affords excessive water solubility. It’s then metabolised within the liver (hepatic), primarily via the CYP2C9 enzyme, with a half-life of roughly 20 – 60 hours. Different minor enzymatic pathways for metabolism embrace: CYP2C8, 2C18, 2C19, 1A2, and 3A4. How a lot of the drug will get metabolised can be depending on every particular person’s genetic variations (Patel et al., 24 March, 2023; Kasperkiewicz et al., 2020).

The warfarin molecule is additional damaged down into two varieties – S- and R-warfarin, with S-warfarin 3 – 5 instances stronger than R-warfarin. They’re primarily damaged down within the liver; metabolism of lively S-warfarin is especially by way of the CYP2C9 enzyme, and CYP enzymes CYP1A2 and CYP3A for R-warfarin.

Does Warfarin Work together with Different Drugs?

The problem with warfarin is that it is usually extremely sure to serum albumin, which when mixed with cytochrome P450 (CYP) metabolism, interacts with many medication and meals. This ends in warfarin both changing into kind of potent – thus growing or reducing its anticoagulatory results, which could be dangerous both approach for a affected person with Antiphospholipid Syndrome (Tay et al., 2013).

Some medication that work together with the CYP450 2C9 are cardiovascular medicines resembling amiodarone, and anti-infectives resembling fluconazole. Some medication that work together with CYP1A2 or CYP3A4 are quinolones and macrolides (bactericidal antibiotics). Inhibition of those enzymes can improve the consequences of warfarin, thus growing the chance for bleeding additional. Different medication resembling rifampicin (an antibiotic), carbamazepine (an anticonvulsant) and azathioprine (a DMARD) then again, induces these enzymes and may lower the efficiency of warfarin (Tay et al., 2013).

Extremely Possible to Extremely Inconceivable Interactions

In a scientific evaluate by Holbrook et al. (2005), they categorise medication that may probably work together with warfarin from stage 1 (extremely possible) to stage 4 (extremely inconceivable). In keeping with Holbrook et al. (2005):

“Of all 184 reviewed studies, 128 (70%) described a potentiation of warfarin’s impact, whereas inhibition and “no impact” studies every comprised 28 (15%). There have been 34 studies of a serious interplay—3 case studies of thrombosis related to trazodone, sulfasalazine, and propofol and 31 case studies describing a serious potentiation.”

Some medication additionally yielded conflicting proof for interplay with warfarin, i.e. terbinafine, ritonavir, and influenza vaccine. Linkins (2013) breaks down these medicine classes by Holbrook et al. (2005) right into a desk in keeping with sort – antibiotics, antifungals, cardiovascular, ldl cholesterol decreasing brokers, analgesics or antiinflammatory brokers, and others. That is undoubtedly not an exhaustive listing of medicines that work together with warfarin – there are approach too many to be listed in a single submit, plus many others whose interactions are but unknown.

What if I Have No Alternative however to Take a Remedy That Interacts with Warfarin?

Generally, taking medicines that work together with warfarin is unavoidable, resembling antibiotics for an an infection, or an important drug for an additional medical situation. For instance, I used to be on carbamazepine and azathioprine for a time period previously, in a bid to regulate my epilepsy and Lupus (SLE) exercise.

First, your rheumatologist (or physician who manages your warfarin and Antiphospholipid Syndrome) ought to be consulted. They may then monitor and modify your warfarin dose as wanted, together with the opposite medicines. Because the medicines I took had been every day, that makes issues simpler as the principle technique to sustaining your goal INR vary is consistency in medicine and meals consumption.

I finally needed to cease taking these medicines not as a result of they interacted with warfarin, however as a result of they had been ineffective or unsuitable for me for varied causes. Your physician can even work with you to retitrate your warfarin dose when and if it’s essential cease taking these different medicines. Do not forget that this is applicable to main dietary modifications as properly.

The primary takeaway that I’d like to spotlight is to all the time inform and work together with your physician when introducing a brand new medicine that may probably intervene with warfarin. One other essential level is to all the time state that you just’re on warfarin if you go to any new healthcare skilled, together with (particularly) on the A&E/ER. The truth is, you must have obtained a medical card that states that you’re on warfarin – laminate this and maintain it with you always as a way to present it to them.

Tips on how to Examine for Warfarin Interplay with Different Drugs

Typically, it may be a problem and impractical to seek the advice of your physician each time it’s essential take a brand new medicine or meals product. I personally use the MedScape app on my telephone to do a fast verify for medicine interactions on the fly (I’ve seen medical doctors use it as properly!). It tells you if there are minor or main contraindications, and why. It’s particularly useful once I’m travelling. You too can faucet into its complete database to study extra about every other medicine.

Additionally they have a browser model right here that you should use, plus different academic instruments and sources on their web site. Do notice that it’s nonetheless essential to cross-check with different verified sources and your physician every time potential, as not the whole lot could also be 100% correct – that’s unattainable as analysis can generally be conflicting, and can be being always up to date with new discoveries. (You possibly can try the most recent analysis on Antiphospholipid Syndrome on this submit.)

Screenshot Examples of the MedScape App:

How A lot Warfarin Do I Have to Take with Antiphospholipid Syndrome?

The dose requirement of warfarin varies greater than 10-fold amongst sufferers, resulting from genetic polymorphisms of CYP2C9, dietary variations, and different components. In keeping with Takahashi and Echizen (2003):

“Therapeutic targets measured by worldwide normalized ratio (INR) of prothrombin time seem to vary between populations: INR of two–3 for many indications in Caucasian sufferers¹ and 1.5–2.5 for Asian sufferers.”

And in keeping with Wadelius et al. (2004):

“CYP2C9 variants, age, weight, concurrent drug remedy and indication for remedy considerably influenced warfarin dosing in these sufferers, explaining 29% of the variation in dose. CYP3A5 didn’t have an effect on warfarin dosing.”

Thus, there isn’t a exhausting and quick rule as to how a lot warfarin one ought to take, as that must be titrated on a person foundation. Aside from the varied genetic and dietary variations amongst sufferers, different components must be taken under consideration as properly, resembling comorbidities and the medicines used to deal with them, medical historical past, and different threat components. If you happen to’ve had had a thrombosis previously, your INR goal vary would possibly must be increased as properly, as that is a sign of an elevated threat for blood clotting.

Pin to Your Warfarin, Drugs and Antiphospholipid Syndrome Boards:

Tecarfarin – A Novel Vitamin Okay Antagonist in Part III Trials

Tecarfarin is a novel VKA with a structural analog of warfarin, and could be measured by way of INR similar to warfarin. It’s being developed by Cardrenal Therapeutics for sufferers with implanted medical gadgets, end-stage renal illness (ESRD) and atrial fibrillation (AFib), though they wish to broaden its scope to embrace different sufferers who require anticoagulation too, resembling in APS.

It has orphan drug with quick monitor designation from the FDA – that means to say that it has governmental help for its growth as a pharmaceutical agent for uncommon ailments. It’s at the moment in Part III scientific trials and in reality, because the time I drafted this part, it has already accomplished the ARIES-HM3 trial and offered its findings on the Worldwide Society for Coronary heart & Lung Transplantation (ISHLT) forty fourth Annual Assembly & Scientific Periods on June 3, 2024.

There are over a whole lot of medicines and meals that warfarin can work together with, because of the approach it’s metabolised by CYP2C9. Genetic variability in CYP2C9 gene also can have an effect on the instability of INR. Tecarfarin then again is metabolised by hCE-2, a pathway with no vital drug interactions, or genetic variability (Albrecht et al., 2017). It nonetheless, doesn’t show any benefits over warfarin for folks with VKORC1 polymorphisms.

In a multicentre examine of 66 AFib sufferers for as much as 12 weeks in a section IIA trial, tecarfarin was proven to be well-tolerated with none antagonistic results (Ellis et al., 2009). It was additionally proven to be well-tolerated in a small examine of 40 wholesome Chinese language volunteers in a section I trial (Zhou et al., 2023).

Because of this tecarfarin could be a possible warfarin various and even substitute in future, as analysis has proven up to now related results as warfarin, minus the numerous interactions with different meals and medicines. I assume solely time will inform, after it jumps via all of the hoops of the important scientific trials! (You possibly can try the most recent analysis on this submit.)

Enoxaparin – One other Necessary Remedy within the APS Remedy Arsenal

We’ve lined fairly a bit on warfarin, as a result of it’s so essential with regards to medicines and Antiphospholipid Syndrome. One other essential drug is enoxaparin (model names: Lovenox and Clexane), which is also called a “low molecular weight heparin” (LMWH). Two different FDA authorized LMWHs within the USA are dalteparin (Fragmin) and tinzaparin (Innohep). Word that they shouldn’t be used interchangeably.

Enoxaparin is a drugs that’s generally substituted for warfarin, when APS sufferers have to pause their warfarin consumption for no matter motive. It’s usually used as a bridge medicine between surgical operations, the place there’s a increased probability of extreme bleeding.

This doesn’t solely embrace main surgical procedures, but in addition minor ones resembling dental procedures, implantation of contraceptive gadgets, and procedures that require intramuscular injections such because the HPV vaccine. Enoxaparin has a faster onset as in comparison with warfarin, and solely has a half-life of about 4.5 – 7 hours (Cook dinner, 2010). Therefore, it’s safer to be on enoxaparin in periods the place extreme bleeding could be anticipated. You will have to do a warfarin reversal when switching to enoxaparin, which your physician and gynaecologist will information you thru.

While derived from heparin, the ultimate formulation of enoxaparin is completely different. It has a bioavailability of 90% when given within the subcutaneous type (injection into the fats slightly below the pores and skin), and is a extra steady and predictable drug that may be self-administered by sufferers at house (Jupalli and Iqbal, 28 August, 2023). Pregnant ladies with APS usually have to substitute warfarin for enoxaparin/LMWH in the course of the time period of their being pregnant, as warfarin could be dangerous to foetuses. You possibly can learn extra about being pregnant with Antiphospholipid Syndrome right here.

How Does Enoxaparin / LMWH Work?

In keeping with Lawrence (2011):

“[LMWHs and fondaparinux] goal anti–issue Xa exercise quite than AT [antithrombin]. With LMWH and fondaparinux, there’s a diminished threat of heparin-induced thrombocytopenia (HIT), and monitoring of the aPTT can be not required, as a result of the aPTT is insensitive to alterations in issue Xa.”

Because of this the anticoagulatory mechanisms of LMWH differs from that of vitamin Okay antagonists, and that sufferers don’t have to measure their INR like they do when on warfarin. I truly favor being on enoxaparin as in comparison with warfarin regardless of the trouble of injections, as a result of it provides me an opportunity to take pleasure in all of the meals I really like (sure, like broccoli and tofu…), because it doesn’t work together with meals in the identical approach as VKAs do. Sadly, enoxaparin is just not a great long-term medicine as it’s recognized to impair bone well being and bone therapeutic (Li et al., 2022). You possibly can study extra about musculoskeletal manifestations in APS right here.

Having mentioned that, that doesn’t imply that there aren’t any drug interactions with enoxaparin. Mayo Clinic has listed some medicines that may work together with enoxaparin right here, and likewise sure medical situations that ought to be highlighted to your physician when you have them.

Variations Between ‘Normal’ Heparin and Low Molecular Weight Heparin

It’s simple to get confused between enoxaparin/LMWH and heparin, since technically enoxaparin is derived from heparin. Many sufferers and generally even medical doctors discuss with enoxaparin as heparin in informal speech. Nonetheless, while enoxaparin could be self-administered by the affected person by way of subcutaneous injections, unfractionated heparin (UFH) is normally given intravenously inside a hospital setting, as there’s a threat of Heparin Induced Thrombocytopenia (HIT).

HIT is a life-threatening situation the place huge activation of platelets happen, with multi-cellular launch of micro particles that contribute to hypercoagulability (Gruel et al., 2020). In comparison with LMWH, unfractionated heparin is a extremely variable drug as properly, the place nearly 75% of sufferers fail to attain the meant aPTT. Therefore, sufferers must be carefully monitored when on unfractionated heparin (Krishnaswamy et al., 2010).

In keeping with Krishnaswamy et al. (2010):

“Unfractionated heparin (UFH) exerts its impact by binding and inducing a conformational change in antithrombin (AT), changing AT to a extra environment friendly inhibitor of circulating thrombin (issue IIa), issue Xa, issue IXa, issue XIIa, and kallikrein. Contributing to its effectivity, heparin can dissociate from the thrombin: AT advanced and catalyze the exercise of different AT molecules.”

Referring again to Lawrence’s (2011) rationalization of the mechanisms of LMWHs, compared unfractionated heparin readily binds to antithrombin as properly. This makes unfractionated heparin a stronger anticoagulant as in comparison with LMWH – but in addition brings with it extra problems and bleeding dangers. It’s nonetheless an essential medicine to fight acute circumstances and medical emergencies nonetheless, resembling pulmonary embolisms and coronary heart assaults.

Be taught extra about pulmonary and cardiovascular manifestations in APS, and likewise extra about thrombocytopenia on this submit.

Pin to Your Drugs and Antiphospholipid Syndrome Boards:

DOACs & Antiphospholipid Syndrome

DOACs stands for ‘Direct Oral Anticoagulants’, and they are often categorised into these major classifications: oral direct issue Xa inhibitors (apixaban, rivaroxaban, edoxaban, and betrixaban), and direct thrombin inhibitors (i.e. dabigatran) (Nasiri et al., 2022).

You possibly can truly skip this whole part with a major takeaway – warfarin remains to be the mainstay drug for sufferers with Antiphospholipid Syndrome, particularly for individuals who are excessive threat, or who’ve had a thrombosis earlier than. Nonetheless realizing me, I went down the analysis rabbit gap and located numerous fascinating details about these anticoagulants. I’ve truly requested my very own rheumatologist earlier than why I can’t be on DOACs versus warfarin, as their advantages appeared significantly better. Now I do know clearly why. If you happen to’re to learn the way DOACs work as an anticoagulant and why they aren’t fairly really helpful for APS sufferers, then learn on!

What are DOACs and How do They Work?

DOACs are anticoagulants like VKAs, however their mechanism differs. The major benefits are that sufferers who’re on DOACs needn’t monitor their weight loss plan or INR, and so they have a fast onset and offset of motion (Pastori et al., 2021). One fascinating discovering about DOACs is that past their anticoagulation properties, they could even have an anti-inflammatory, anti-fibrotic and anti-angiogenic properties (Signorelli et al., 2018).

That may sound nice, however APS sufferers are suggested to make use of VKAs resembling warfarin as an alternative, particularly if you happen to’ve had a historical past of arterial thrombosis, or are triple constructive, and even perhaps double constructive for antiphospholipid antibodies (Girón-Ortega and Girón-González, 2023; additionally see Bejjani et al., 2024). I personally have had a number of DVTs and a PE earlier than, so my goal INR with warfarin must be increased than the typical APS affected person, as I’m at a better threat of clotting. That may be higher achieved by way of VKAs as in comparison with DOACs.

VKAs additionally goal all phases of thrombin technology, whereas DOACs goal solely the initiation and/or propagation course of. Rivaroxaban and apixaban specifically had been discovered to be considerably inferior to VKAs for the prevention of recurrent thrombosis in APS sufferers (Girón-Ortega and Girón-González, 2023). DOACs additionally confirmed an elevated threat of stroke amongst APS sufferers, and so they might also be at the next threat of thrombotic occasions (Shah et al., 2023).

One other drawback with DOACs is that not all of them have an antidote at current, and extra research are but to be achieved as to their security and efficacy in precise sufferers. There are additionally particular teams of people whom DOACs should not appropriate for, resembling these with poor renal perform, who’ve a prosthetic coronary heart valve, a dysfunction of haemostasis, amongst others (Tran et al., 2014).

What’s Thrombin?

A blood clot is also called a thrombus, and thrombin performs an essential position within the blood clotting course of. Thrombin converts fibrinogen to fibrin, which is a troublesome protein that varieties blood clots to seal wound websites. Thrombin can be probably the most potent platelet agonist (i.e. clots the blood). The extra technical rationalization, in keeping with Posma et al. (2019):

“Activation of the blood coagulation cascade results in fibrin deposition and platelet activation which might be required for hemostasis. Nonetheless, aberrant activation of coagulation can result in thrombosis. Thrombi could cause tissue ischemia, and fibrin degradation merchandise and activated platelets can improve irritation.”

DOACs: Direct Thrombin Inhibitors (DTIs)

In keeping with Eriksson et al. (2011):

“DTIs instantly neutralize thrombin by occupying the catalytic binding website, fibrinogen binding website, or each. DTIs additionally inhibit each fluid-phase and fibrin-bound thrombin.”

They do just about what their title states – inhibition of thrombin, which ends up in a discount of blood clotting. A key benefit of DTIs is their potential to bind on to thrombin, and they don’t bind to different plasma proteins both (Lee and Ansell, 2011).

Dabigatran – The Solely Accepted DTI

The one authorized DTI to be used at current is dabigatran etexilate, which is a prodrug that metabolises into dabigatran within the physique. Different DTIs resembling ximelagatran have been withdrawn resulting from hepatotoxicity studies (Posma et al., 2019; van Ryn et al., 2013). Dabigatran is authorized in over 70 international locations, for the aim of stroke prevention in sufferers with atrial fibrillation, and for the prevention of thrombosis after orthopaedic hip and knee surgical procedure (van Ryn et al., 2013).

While dabigatran appears to be a extremely efficient anticoagulant with a great security profile up to now, you will need to notice that it’s primarily utilized in sufferers who don’t have Antiphospholipid Syndrome. Worldwide tips nonetheless point out VKAs as the selection drug for sufferers with APS, particularly if they’ve skilled a blood clotting occasion earlier than, or are a high-risk affected person, resembling being triple constructive (Pastori et al., 2021).

DOACs: Issue Xa Inhibitors

Issue Xa inhibitors then again, reduces thrombin technology, and thus interferes with the method of fibrinogen to fibrin conversion. Additionally they haven’t any direct impact on platelet aggregation. It’s theorised that this focused motion on issue Xa serves to restrict the cascade of thrombin technology, and due to this fact much less of the drug could also be wanted as in comparison with a DTI. Issue Xa additionally has minimal features outdoors of coagulation, in contrast to thrombin, and unintended effects could also be extra contained (Cabral and Ansell, 2015).

Apixaban (Eliquis) – A Extremely Selective Issue Xa Inhibitor

Apixaban (model title: Eliquis) is a DOAC initially authorized for atrial fibrillation (Afib) sufferers to cut back the chance of strokes and blood clots. It was later authorized to deal with DVTs and PEs (pulmonary embolisms) as properly. It’s a extremely selective issue Xa inhibitor that exerts no impact on platelet aggregation, and primarily binds to plasma protein (Agrawal et al., 22 February, 2024). Negative effects of taking apixaban are much like different anticoagulant medication, and embrace: bleeding, purple or black, tarry stools, purple, pink or brown urine, bother respiratory, dizziness, coughing up blood or materials that appears like espresso grounds, and extra.

Rivaroxaban (Xarelto) – One other Issue Xa Inhibitor

Rivaroxaban (model title: Xarelto) is one other sort of DOAC underneath the issue Xa class. Primarily based on the info accessible so far, rivaroxaban is much less efficient than VKAs within the prevention of recurrent thrombosis, however extra analysis must be achieved as to its efficacy (Girón-Ortega and Girón-González, 2023).

A examine of 120 excessive threat APS sufferers was terminated early because of the increased incidence of thromboembolic occasions for individuals who had been on rivaroxaban, whereas none occurred within the group on warfarin (Pengo et al., 2018).

Pin to Your Drugs and Antiphospholipid Syndrome Boards:

Present Reversal Brokers Out there for Anticoagulant Medicine

Sufferers who’re on anticoagulants sarcastically run the chance of extreme bleeding or a haemorrhage, and never all DOACs have an antidote; the antidotes which might be accessible are additionally costly. In circumstances of extreme bleeding, sufferers have to endure reversal of their anticoagulant medicine by way of a haemostatic agent.

In keeping with Tomaselli et al. (2020) and Kustos and Fasinu (2019), these are the present reversal brokers used for anticoagulant medication throughout emergencies:

1. Vitamin Okay Antagonists (warfarin) – Intravenous or oral vitamin K1. As well as, prothrombin advanced focus (PCC) is most well-liked for instant reversal, as in comparison with recent frozen plasma (FFP) (Tran et al., 2013). In comparison with FFP, 4F-PCCs comprise roughly 25 instances the focus of vitamin Okay-dependent components, and thus could be given at a smaller quantity with a quicker infusion charge.
2. Vitamin Okay Antagonists (heparin) – Protamine.
3. Oblique Thrombin Inhibitors (LMWH) – Protamine.
4. DTI (dabigatran) – Idarucizumab (Praxbind). If unavailable, PCC or aPCC (activated prothrombin advanced focus).
5. Issue Xa Inhibitors (apixaban & rivaroxaban) – Andexanet Alfa. If unavailable, PCC or aPCC.
6. Issue Xa (betrixaban & edoxaban) – Off-label remedy with excessive dose Andexanet Alfa. If unavailable, PCC or aPCC.
7. As well as for the DOACs, activated charcoal could also be thought of for recognized current ingestion within the final 2 – 4 hours.

That is only a transient, normal guideline, and plenty of extra issues must be taken under consideration on a person foundation throughout an emergency. Please work with your personal medical doctors and emergency care crew for one of the best final result.

A Bit Extra About Andexanet Alfa as a Reversal Agent

Andexanet alfa is run by way of intravenous infusion with an onset time of two minutes. Negative effects are primarily sizzling flashes and antibody growth; they could additionally induce blood clotting sarcastically and lead to strokes, DVTs, PEs, cardiac failure and extra (Kustos and Fasinu, 2019; additionally see Escal et al., 2024). It’s at the moment solely authorized to be used as an antidote for apixaban and rivaroxaban, while its security and efficacy remains to be being evaluated in relation to edoxaban and betrixaban.

Be taught extra about how APS impacts main organs such because the lungs, mind and coronary heart on this submit.

Ciraparantag & Different Non-Particular Pharmacokinetic Antidotes to DOACs

Ciraparantag is a reversal agent nonetheless present process scientific trials, however reveals promise as a non-immunogenic antidote for a big selection of anticoagulants (all forms of DOACs, heparins and fondaparinux) (Escal et al., 2024).

Non-specific pharmacokinetic antidotes are generally used along with reversal brokers to extend coagulation results. In keeping with Escal et al. (2024), these embrace:

• Activated Charcoal – Activated charcoal has the flexibility to soak up varied substances within the physique inside the gastrointestinal tract. It could assist to cut back blood concentrations of DOACs and thus its bioavailability. It additionally stays lively for a very long time and is low in value.
• Haemodialysis – That is extra for sufferers on DTIs (dabigatran), and particularly if they’ve renal impairment. They’re ineffective for Issue Xa inhibitors as they primarily bind to plasma proteins. It may be tough to entry throughout emergency conditions nonetheless, because it requires educated healthcare professionals who know the right way to use particular tools.
• Haemostatic Brokers – These are helpful when the kind of DOAC the affected person is on is unknown, or when normal reversal brokers are unavailable. They embrace naPCC (non-activated prothrombin advanced concentrates), FEIBA (issue eight inhibitor bypassing exercise), rFVIIa (recombinant activated issue VII) and tranexamic acid. Word that these are second-line therapies and that extra analysis nonetheless must be achieved to find out their precise results and security profile.

Pin to Your Drugs and Antiphospholipid Syndrome Boards:

Proteases & Protease-Activated Receptor (PAR) Antagonists

Proteases are essential regulators of mobile exercise, and so they talk on to cells by way of protease-activated receptors (PARs). There are 4 completely different PAR profiles, from PAR1 to PAR4, that are expressed extensively within the physique, from the mind to lungs, muscle mass, bones, bladder and extra (Han et al., 2021). PAR1, PAR3 and PAR4 are activated by thrombin, whereas Issue Xa prompts PAR2, though different proteases also can contribute to activation (Posma et al., 2019).

Cleavage of PARs

Irritation is on the tail finish of the blood coagulation cascade, as could be seen from a graphic on this paper by Posma et al. (2019).

In keeping with Burzynski et al. (2019):

“The present principal hyperlink between coagulation and immunity is cleavage of PARs by thrombin, which produces cytokines and irritation.”

This reveals a direct hyperlink between coagulation and the immune system, which is an thrilling perspective. What this implies is that future Antiphospholipid Syndrome therapies would possibly shift to an immunological one, as an alternative of merely focusing on anticoagulation. Sadly, regardless of the implication of PARs in Antiphospholipid Syndrome, there are no ongoing trials for APS sufferers (Signorelli et al., 2018). Let’s maintain our fingers crossed! (Learn this submit for the most recent analysis on APS.)

Vorapaxar – An FDA-Accepted PAR Antagonist

Vorapaxar is a first-in-class PAR1 antagonist authorized to be used by the FDA, for sufferers with coronary artery illness. Sadly, it’s contraindicated for sufferers who’ve had thrombotic or bleeding occasions previously. Like all antiplatelet brokers, vorapaxar will increase the chance of bleeding, which could be deadly. It additionally has a protracted half-life and no antidote (Han et al., 2021; Signorelli et al., 2018).

One other PAR-1 antagonist is atopaxar, however analysis has been discontinued as scientific trials in section II demonstrated a excessive threat for bleeding with the drug (Zhao et al., 2013).

NSAIDs & Antiphospholipid Syndrome

NSAIDs (Non-Steroidal Anti-Inflammatory Medicine) are a category of anti-inflammatories that individuals usually take for generic ache reduction. You’re most likely accustomed to these over-the-counter medication that go by the names of: Ibuprofen, Naproxen and Aspirin. Model names embrace Neurofen, Advil, Motrin, Aleve, Alka-Seltzer, Pepto-Bismol, and extra.

To be trustworthy, NSAIDS would most likely work higher for my Lupus and Sjögren’s pains due to their anti-inflammatory properties, however I can’t take them resulting from interactions with warfarin. As I’m additionally allergic to paracetamol (Panadol), I can solely depend on opioid lessons of painkillers for ache reduction.

NSAIDs intervene with blood clotting by inhibiting platelet perform. Platelets (also called thrombocytes) are important elements in our blood that assist with clotting. Therefore, sufferers who’re on blood thinning medicines have the next threat of bleeding with NSAIDs.

There may be additionally an elevated threat of gastrointestinal bleeding and peptic ulcers with NSAIDs because of the mechanisms of the medicine (Drini, 2017), which can be the largest concern my rheumatologist has with them. I solely use NSAIDs when completely vital, resembling throughout a excessive fever, and inform my healthcare crew once I accomplish that. I additionally take additional measures to guard my abdomen resembling consuming correct meals, and verify my very own INR frequently.

Pin to Your Drugs and Antiphospholipid Syndrome Boards:

Conclusion to Drugs and Antiphospholipid Syndrome

On this submit, we’ve got lined medicines and Antiphospholipid Syndrome, in addition to among the essential medication that may work together with warfarin, and new medicines which might be present process scientific trials.

I hope that this submit on medicines and Antiphospholipid Syndrome has been insightful and helpful to you whether or not as an APS affected person, or somebody who’s caring for one. Ought to you have got any questions, experiences to share, or corrections (I’m not a physician, in any case!), be at liberty to go away a remark beneath. Don’t neglect to take a look at the remainder of the posts within the Antiphospholipid Syndrome sequence listed beneath as properly. Wishing you all one of the best that life can nonetheless convey!

P.s. If you happen to’d prefer to help the work I do, you may maintain me fueled with espresso utilizing the button beneath. You too can join our mailing listing so that you don’t miss out on our newest posts. You’ll obtain an e-book stuffed with uplifting messages, quotes and illustrations, as a token of appreciation!

Feed Sheryl Espresso Right here

Pin to Your Drugs and Antiphospholipid Syndrome Boards:

References:

1. Agrawal, A., Kerndt, C. C., & Manna, B. (22 February, 2024). Apixaban. In StatPearls. StatPearls Publishing. Retrieved from: http://www.ncbi.nlm.nih.gov/books/NBK507910/
2. Albrecht, D., Ellis, D., Canafax, D. M., Combs, D., Druzgala, P., Milner, P. G., & Midei, M. G. (2017). Pharmacokinetics and pharmacodynamics of tecarfarin, a novel vitamin Okay antagonist oral anticoagulant. Thrombosis and Haemostasis, 117(04), 706-717. https://doi.org/10.1160/TH16-08-0623
3. Barmore, W., Bajwa, T., & Burns, B. (24 February, 2023). Biochemistry, Clotting Elements. In StatPearls. StatPearls Publishing. Retrieved from: http://www.ncbi.nlm.nih.gov/books/NBK507850/
4. Bejjani, A., Khairani, C. D., Assi, A., Piazza, G., Sadeghipour, P., Talasaz, A. H., Fanikos, J., Connors, J. M., Siegal, D. M., Barnes, G. D., Martin, Okay. A., Angiolillo, D. J., Kleindorfer, D., Monreal, M., Jimenez, D., Middeldorp, S., Elkind, M. S. V., Ruff, C. T., Goldhaber, S. Z., … Bikdeli, B. (2024). When Direct Oral Anticoagulants Ought to Not Be Normal Remedy. Journal of the American Faculty of Cardiology, 83(3), 444–465. https://doi.org/10.1016/j.jacc.2023.10.038
5. Burzynski, L. C., Humphry, M., Pyrillou, Okay., Wiggins, Okay. A., Chan, J. N. E., Figg, N., Kitt, L. L., Summers, C., Tatham, Okay. C., Martin, P. B., Bennett, M. R., & Clarke, M. C. H. (2019). The Coagulation and Immune Programs Are Immediately Linked via the Activation of Interleukin-1α by Thrombin. Immunity, 50(4), 1033-1042.e6. https://doi.org/10.1016/j.immuni.2019.03.003
6. Cabral, Okay. P., & Ansell, J. E. (2015). The position of issue Xa inhibitors in venous thromboembolism remedy. Vascular Well being and Danger Administration, 11, 117–123. https://doi.org/10.2147/VHRM.S39726
7. Cadrenal Therapeutics, Inc. (3 June, 2024). Cadrenal Therapeutics Highlights Presentation Of New Trial Knowledge at Ishlt Convention Demonstrating The Significance Of Anticoagulation High quality In LVAD Sufferers. Cadrenal Therapeutics, Inc. Retrieved from: https://www.cadrenal.com/traders/press-releases/element/cadrenal-therapeutics-provides-third-quarter-2023-corporate-update
8. Cadrenal Therapeutics, Inc. (9 November, 2023). Cadrenal Therapeutics Gives Third Quarter 2023 Company Replace. U.S. Securities And Trade Fee. Retrieved from: https://www.sec.gov/Archives/edgar/information/1937993/000121390023084969/ea187953ex99-1_cadrenal.htm
9. Cadrenal Therapeutics, Inc. (n.d.). Tecarfarin. A late-stage novel remedy with orphan drug and Quick Observe designations. Cadrenal Therapeutics, Inc. Retrieved from: https://www.cadrenal.com/tecarfarin/
10. Cleveland Clinic. (28 April, 2022). Platelets. Cleveland Clinic. Retrieved from: https://my.clevelandclinic.org/well being/physique/22879-platelets
11. Cook dinner, B. W. (2010). Anticoagulation Administration. Seminars in Interventional Radiology, 27(4), 360–367. https://doi.org/10.1055/s-0030-1267849
12. Crader, M. F., Johns, T., & Arnold, J. Okay. (1 Could, 2023). Warfarin Drug Interactions. In StatPearls. StatPearls Publishing. Retrieved from: http://www.ncbi.nlm.nih.gov/books/NBK441964/
13. Division of Well being, Authorities of Western Australia. (n.d.). Warfarin. HealthyWA. Retrieved from: https://www.healthywa.gov.au/Articles/A-Z/Warfarin
14. Drini, M. (2017). Peptic ulcer illness and non-steroidal anti-inflammatory medication. Australian Prescriber, 40(3), 91–93. https://doi.org/10.18773/austprescr.2017.037
15. Medicine .com. (n.d.). Enoxaparin (Ingredient). Medicine .com. Retrieved from: https://www.medication.com/ingredient/enoxaparin.html
16. Ellis, D. J., Usman, M. H., Milner, P. G., Canafax, D. M., & Ezekowitz, M. D. (2009). The First Analysis of a Novel Vitamin Okay Antagonist, Tecarfarin (ATI-5923), in Sufferers With Atrial Fibrillation. Circulation, 120(12), 1029–1035. https://doi.org/10.1161/CIRCULATIONAHA.109.856120
17. Eriksson, B. I., Quinlan, D. J., & Eikelboom, J. W. (2011). Novel Oral Issue Xa and Thrombin Inhibitors within the Administration of Thromboembolism. Annual Evaluation of Medication, 62(Quantity 62, 2011), 41–57. https://doi.org/10.1146/annurev-med-062209-095159
18. Escal, J., Lanoiselée, J., Poenou, G., Zufferey, P., Laporte, S., Mismetti, P., & Delavenne, X. (2024). Newest advances within the reversal methods for direct oral anticoagulants. Elementary & Scientific Pharmacology. https://doi.org/10.1111/fcp.12992
19. Girolami, A., Ferrari, S., Cosi, E., Santarossa, C., & Randi, M. L. (2018). Vitamin Okay-Dependent Coagulation Elements That Could also be Liable for Each Bleeding and Thrombosis (FII, FVII, and FIX). Scientific and Utilized Thrombosis/Hemostasis, 24(9 Suppl), 42S-47S. https://doi.org/10.1177/1076029618811109
20. Girón-Ortega, J. A., & Girón-González, J. A. (2023). Direct-acting oral anticoagulants in antiphospholipid syndrome: A scientific evaluate. Medicina Clínica (English Version), 161(2), 65–77. https://doi.org/10.1016/j.medcle.2023.03.017
21. Gruel, Y., De Maistre, E., Pouplard, C., Mullier, F., Susen, S., Roullet, S., Blais, N., Le Gal, G., Vincentelli, A., Lasne, D., Lecompte, T., Albaladejo, P., Godier, A., Albaladejo, P., Belisle, S., Blais, N., Bonhomme, F., Borel-Derlon, A., Borg, J. Y., … Zufferey, P. (2020). Prognosis and administration of heparin-induced thrombocytopenia. Anaesthesia Essential Care & Ache Medication, 39(2), 291–310. https://doi.org/10.1016/j.accpm.2020.03.012
22. Halder, M., Petsophonsakul, P., Akbulut, A. C., Pavlic, A., Bohan, F., Anderson, E., Maresz, Okay., Kramann, R., & Schurgers, L. (2019). Vitamin Okay: Double Bonds past Coagulation Insights into Variations between Vitamin K1 and K2 in Well being and Illness. Worldwide Journal of Molecular Sciences, 20(4), Article 4. https://doi.org/10.3390/ijms20040896
23. Han, X., Nieman, M. T., & Kerlin, B. A. (2020). Protease‐activated receptors: An illustrated evaluate. Analysis and Follow in Thrombosis and Haemostasis, 5(1), 17–26. https://doi.org/10.1002/rth2.12454
24. Harvard Medical Faculty. (16 December, 2019). Dangerous combine: Blood thinners and NSAIDs. Harvard Well being Publishing. Retrieved from: https://www.well being.harvard.edu/diseases-and-conditions/bad-mix-blood-thinners-and-nsaids
25. Holbrook, A. M., Pereira, J. A., Labiris, R., McDonald, H., Douketis, J. D., Crowther, M., & Wells, P. S. (2005). Systematic Overview of Warfarin and Its Drug and Meals Interactions. Archives of Inner Medication, 165(10), 1095–1106. https://doi.org/10.1001/archinte.165.10.1095
26. Jupalli, A., & Iqbal, A. M. (28 August, 2023). Enoxaparin. In StatPearls. StatPearls Publishing. Retrieved from: http://www.ncbi.nlm.nih.gov/books/NBK539865/
27. Kasperkiewicz, Okay., Ponczek, M. B., Owczarek, J., Guga, P., & Budzisz, E. (2020). Antagonists of Vitamin Okay—Widespread Coumarin Medicine and New Artificial and Pure Coumarin Derivatives. Molecules, 25(6), 1465. https://doi.org/10.3390/molecules25061465
28. Krishnaswamy, A., Lincoff, A. M., & Cannon, C. P. (2010). The Use and Limitations of Unfractionated Heparin. Essential Pathways in Cardiology, 9(1), 35. https://doi.org/10.1097/HPC.0b013e3181d29713
29. Kustos, S. A., & Fasinu, P. S. (2019). Direct-Performing Oral Anticoagulants and Their Reversal Brokers-An Replace. Medicines (Basel, Switzerland), 6(4), 103. https://doi.org/10.3390/medicines6040103
30. Lawrence, P. F. (2011). Chapter 78—Pharmacologic Adjuncts to Endovascular Procedures. In W. S. Moore & S. S. Ahn (Eds.), Endovascular Surgical procedure (Fourth Version) (pp. 807–813). W.B. Saunders. https://doi.org/10.1016/B978-1-4160-6208-0.10078-3
31. Lee, C. J., & Ansell, J. E. (2011). Direct thrombin inhibitors. British Journal of Scientific Pharmacology, 72(4), 581–592. https://doi.org/10.1111/j.1365-2125.2011.03916.x
32. Li, Y., Liu, L., Li, S., Solar, H., Zhang, Y., Duan, Z., & Wang, D. (2022). Impaired bone therapeutic by enoxaparin by way of inhibiting the differentiation of bone marrow mesenchymal stem cells in the direction of osteoblasts. Journal of Bone and Mineral Metabolism, 40(1), 9–19. https://doi.org/10.1007/s00774-021-01268-5
33. Mayo Clinic. (1 February, 2024). Enoxaparin (Intravenous Route, Subcutaneous Route, Injection Route). Mayo Clinic. Retrieved from: https://www.mayoclinic.org/drugs-supplements/enoxaparin-intravenous-route-subcutaneous-route-injection-route/side-effects/drg-20063670?p=1
34. MedlinePlus. (15 April, 2023). Rivaroxaban. Bethesda (MD): Nationwide Library of Medication (US). Retrieved from: https://medlineplus.gov/druginfo/meds/a611049.html
35. MedlinePlus. (15 November, 2023). Apixaban. Bethesda (MD): Nationwide Library of Medication (US). Retrieved from: https://medlineplus.gov/druginfo/meds/a613032.html
36. Nasiri, A., AlQahtani, A., Rayes, N. H., AlQahtani, R., Alkharras, R., & Alghethber, H. (2022). Direct oral anticoagulant: Evaluation article. Journal of Household Medication and Main Care, 11(8), 4180–4183. https://doi.org/10.4103/jfmpc.jfmpc_2253_21
37. Workplace of Dietary Dietary supplements. (29 March, 2021). Vitamin Okay Truth Sheet for Well being Professionals. Nationwide Institutes of Well being. Retrieved from: https://ods.od.nih.gov/factsheets/VitaminK-HealthProfessional/
38. Pastori, D., Menichelli, D., Cammisotto, V., & Pignatelli, P. (2021). Use of Direct Oral Anticoagulants in Sufferers With Antiphospholipid Syndrome: A Systematic Evaluation and Comparability of the Worldwide Tips. Frontiers in Cardiovascular Medication, 8. https://doi.org/10.3389/fcvm.2021.715878
39. Pengo, V., Denas, G., Zoppellaro, G., Jose, S. P., Hoxha, A., Ruffatti, A., Andreoli, L., Tincani, A., Cenci, C., Prisco, D., Fierro, T., Gresele, P., Cafolla, A., De Micheli, V., Ghirarduzzi, A., Tosetto, A., Falanga, A., Martinelli, I., Testa, S., … Banzato, A. (2018). Rivaroxaban vs warfarin in high-risk sufferers with antiphospholipid syndrome. Blood, 132(13), 1365–1371. https://doi.org/10.1182/blood-2018-04-848333
40. Patel, S., Singh, R., Preuss, C. V., & Patel, N. (24 March, 2023). Warfarin. In StatPearls. StatPearls Publishing. Retrieved from: http://www.ncbi.nlm.nih.gov/books/NBK470313/
41. Posma, J. J., Grover, S. P., Hisada, Y., Owens, A. P., Antoniak, S., Spronk, H. M., & Mackman, N. (2019). Roles of Coagulation Proteases and PARs (Protease-Activated Receptors) in Mouse Fashions of Inflammatory Ailments. Arteriosclerosis, Thrombosis, and Vascular Biology, 39(1), 13–24. https://doi.org/10.1161/ATVBAHA.118.311655
42. Ruff, C. T. (17 Could, 2022). Direct Oral Anticoagulants (DOACs) vs. Warfarin: Key Variations. North American Thrombosis Discussion board [NATF]. Retrieved from: https://thrombosis.org/2020/11/doacs-vs-warfarin/
43. Schein, J. R., White, C. M., Nelson, W. W., Kluger, J., Mearns, E. S., & Coleman, C. I. (2016). Vitamin Okay antagonist use: Proof of the problem of attaining and sustaining goal INR vary and subsequent penalties. Thrombosis Journal, 14(1), 14. https://doi.org/10.1186/s12959-016-0088-y
44. Shah, B. B., Shankar, A., Kumar, V., Kumar, S., Malik, U. A., Majeed, A., … & Ahmed, S. (2023). Direct oral anticoagulants vs. vitamin Okay antagonists in sufferers with antiphospholipid syndrome: a scientific evaluate and meta-analysis. Annals of Medication and Surgical procedure, 85(7), 3574-3582. https://doi.org/10.1097/MS9.0000000000000903
45. Signorelli, F., Balbi, G. G. M., Domingues, V., & Levy, R. A. (2018). New and upcoming therapies in antiphospholipid syndrome: A complete evaluate. Pharmacological Analysis, 133, 108–120. https://doi.org/10.1016/j.phrs.2018.04.012
46. Takahashi, H., & Echizen, H. (2003). Pharmacogenetics of CYP2C9 and interindividual variability in anticoagulant response to warfarin. The Pharmacogenomics Journal, 3(4), 202–214. https://doi.org/10.1038/sj.tpj.6500182
47. Tay, Okay. H., Shantsila, E., & Lip, G. Y. H. (2013). The Coagulation Pathway and Approaches to Anticoagulation. In G. Y. Lip & E. Shantsila (Eds.), Handbook of Oral Anticoagulation (pp. 1–5). Springer Healthcare Ltd. https://doi.org/10.1007/978-1-908517-96-8_1
48. Thijssen, H. H. W. (1995). Warfarin-based rodenticides: Mode of motion and mechanism of resistance. Pesticide Science, 43(1), 73–78. https://doi.org/10.1002/ps.2780430112
49. Tomaselli, G. F., Mahaffey, Okay. W., Cuker, A., Dobesh, P. P., Doherty, J. U., Eikelboom, J. W., Florido, R., Gluckman, T. J., Hucker, W. J., Mehran, R., Mess, é S. R., Perino, A. C., Rodriguez, F., Sarode, R., Siegal, D. M., & Wiggins, B. S. (2020). 2020 ACC Professional Consensus Choice Pathway on Administration of Bleeding in Sufferers on Oral Anticoagulants. Journal of the American Faculty of Cardiology, 76(5), 594–622. https://doi.org/10.1016/j.jacc.2020.04.053
50. Tran, H., Joseph, J., Younger, L., McRae, S., Curnow, J., Nandurkar, H., Wooden, P., & McLintock, C. (2014). New oral anticoagulants: A sensible information on prescription, laboratory testing and peri-procedural/bleeding administration. Inner Medication Journal, 44(6), 525–536. https://doi.org/10.1111/imj.12448
51. Tran, H. A., Chunilal, S. D., Harper, P. L., Tran, H., Wooden, E. M., & Gallus, A. S. (2013). An replace of consensus tips for warfarin reversal. Medical Journal of Australia, 198(4), 198–199. https://doi.org/10.5694/mja12.10614
52. U.S. Meals & Drug Administration. (2 June, 2018). Generic Enoxaparin Questions and Solutions. FDA. Retrieved from: https://www.fda.gov/medication/postmarket-drug-safety-information-patients-and-providers/generic-enoxaparin-questions-and-answers
53. van Ryn, J., Goss, A., Hauel, N., Wienen, W., Priepke, H., Nar, H., & Clemens, A. (2013). The Discovery of Dabigatran Etexilate. Frontiers in Pharmacology, 4, 12. https://doi.org/10.3389/fphar.2013.00012
54. Vardanyan, R. S., & Hruby, V. J. (2006). 24—Anticoagulants, Antiaggregants, Thrombolytics, and Hemostatics. In R. S. Vardanyan & V. J. Hruby (Eds.), Synthesis of Important Medicine (pp. 323–335). Elsevier. https://doi.org/10.1016/B978-044452166-8/50024-8
55. Wadelius, M., Sörlin, Okay., Wallerman, O., Karlsson, J., Yue, Q.-Y., Magnusson, P. Okay. E., Wadelius, C., & Melhus, H. (2004). Warfarin sensitivity associated to CYP2C9, CYP3A5, ABCB1 (MDR1) and different components. The Pharmacogenomics Journal, 4(1), 40–48. https://doi.org/10.1038/sj.tpj.6500220
56. Zhao, H.-P., Jiang, H.-M., & Xiang, B.-R. (2013). Discontinued medication in 2012: Cardiovascular medication. Professional Opinion on Investigational Medicine, 22(11), 1437–1451. https://doi.org/10.1517/13543784.2013.832198
57. Zhou, Q., Wang, Z., Wang, H., Chen, Z., Li, X., Dai, X., Zhang, Y., Yu, X., Zhou, R., & Hu, W. (2023). Security and Tolerability of Tecarfarin (ATI-5923) in Wholesome Chinese language Volunteers: A number of Oral Dose-Escalation Part I Trial. American Journal of Cardiovascular Medicine, 23(1), 101–112. https://doi.org/10.1007/s40256-022-00562-5