This article is part of the Antiphospholipid Syndrome (APS) resource library that I’m building up on my site. In this post, we will focus on medications and Antiphospholipid Syndrome. In particular, warfarin is a key medication for the management of APS, especially if you’ve experienced blood clotting events in the past. We will also take a look at what DOACs (direct oral anticoagulants) are, how other medications such as NSAIDs (non steroidal anti-inflammatory drugs) can interact with warfarin, and exciting new drugs in the pipeline.
If there are specific terms or topics in this post that you were wondering about, such as injections, diet, bone health or something else, it will be covered in the complete resource guide coming soon, so keep an eye out for that!
Pin to Your Medications and Antiphospholipid Syndrome Boards:
*Disclaimer: This article is meant for educational purposes, and is based on my personal experiences as a patient. Whilst I have done my utmost to be meticulous in research, I am not a doctor, and nothing in this article should be substituted for medical advice. Please consult your own doctor before changing or adding any new treatment protocols. This post may also contain affiliate links. It will cost you nothing to click on them. I will get a small referral fee from purchases you make, which helps with the maintenance of this blog. Read our Privacy Policy page for more information. Thank you!
Table of Contents
A Brief Introduction to Vitamin K
Vitamin K is important to know all about as a patient with Antiphospholipid Syndrome, as it interacts with warfarin and is a key contributor to the blood clotting process. It is a fat-soluble vitamin that comes in the form of vitamin K1 (phylloquinone) and vitamin K2 (a series of menaquinones). There is also a synthetic form – Vitamin K3 (menadione), which is no longer used in dietary supplements as they have been found to damage hepatic cells (Office of Dietary Supplements, 29 March, 2021).
Vitamin K1 is the the main form of vitamin K in the human diet, and can mostly be found in green, leafy vegetables, certain fruits, and its absorption is increased in the presence of butter or oils. Vitamin K2 is mainly derived from fermented foods, dairy produce and animal-based sources.
According to Halder et al. (2019):
“VKDPs [vitamin K-dependent proteins] are categorized as hepatic and extra-hepatic VKDPs. Hepatic VKDPs include coagulation factors II, VII, IX, X, and anticoagulant protein C, protein S, and protein Z, all of which are involved in regulating blood coagulation. Extra-hepatic VKDPs include Matrix Gla protein (MGP), Osteocalcin, and Gla-rich protein (GRP). These VKDPs are primarily involved in maintaining bone homeostasis, as well as inhibiting ectopic calcification.”
In basic terms, what this means is that vitamin K, whether in K1 or K2 form, is an essential component of blood clotting processes, maintenance of bone health, and prevention of vessel mineralisation, depending on how and where they are metabolised. Whilst it’s important to be aware of vitamin K, I won’t deep dive into it in this post as I’d like to focus on medications and Antiphospholipid Syndrome. I’ve written about vitamin K more extensively on the blog elsewhere, and you can read the related posts below for more information.
Vitamin K Antagonists (VKAs)
Vitamin K antagonists (VKAs) are a class of medications used for the treatment and prevention of thrombosis. The most well-known and commonly used VKA is warfarin. For the sake of interest, other types of VKAs include: ethyl biscoumacetate, phenindione, anisindione, dicoumarol, phenprocoumon and diphenadione. There is a reason why warfarin is the most commonly used, as many of these other VKAs are erratic, highly toxic, or can cause other adverse side effects (Vardanyan and Hruby, 2006).
The administration of VKAs is convenient and practical, as they can be taken orally, and have a long half-life (warfarin has a half-life of 36 – 42 hours). Doctors are also able to adjust dosages for more precision in individual patients as needed, based on risk factors and medical history. VKAs work by antagonising the enzyme vitamin K epoxide reductase (VKOR) to prevent vitamin K from being recycled. This results in inhibition of the coagulation cascade, as many clotting factors rely on vitamin K to synthesise (Schein et al., 2016).
Coumarins
Vitamin K antagonists such as warfarin, acenocoumarol and phenprocoumon are derivatives of coumarin, which can be of natural or synthetic origin. In 1945, Karl Link experimented with 150 naturally occurring coumarin derivatives, before concluding that one compound was particularly active – warfarin. For a rare subset of patients with mutations in VKOR, VKAs are unfortunately low in efficacy or ineffective due to coumarin resistance (Kasperkiewicz et al., 2020).
Warfarin – THE Medication for Antiphospholipid Syndrome
Warfarin is a vitamin K antagonist, and is probably the most important drug for the management of Antiphospholipid Syndrome, and for the prevention of thrombosis. There are two brands of warfarin available – Coumadin and Marevan. It is important to stick to the same brand, as the formulation is not an exact match. What that means is that the anticoagulation effects can vary between each brand, and might mess your INR up. Do discuss with your doctor first, should you need to switch brands for any reason.
(Not so) fun fact: Warfarin also first started out as rat poison, but has declined in usage for such purposes due to an increase in resistance from these rodents, which is inheritable (Thijssen, 1995).
How Warfarin Works to Prevent Blood Clotting
Warfarin inhibits vitamin K dependent clotting factors II, VII, IX, and X, and also the anticoagulant proteins C and S (Crader et al., 1 May, 2023). This means that it inhibits multiple pathways in the blood clotting process, as compared to DOACs, which only disrupt a specific point. Specifically, prothrombin, FVII, FIX, protein C, and protein S are strictly related to blood coagulation processes (Girolami et al., 2018). Approximately 10% – 40% of factors II, VII, IX and X are inhibited by warfarin (Wadelius et al., 2004).
Vitamin K ‘activates’ these clotting factors via the enzyme, epoxide reductase, which is inhibited by warfarin. In rare cases, patients who are first taking warfarin may experience warfarin-induced skin necrosis. This is especially true for patients who are deficient in protein C, as it has the shortest half-life amongst them all. In such cases, patients are often co-administered heparin, as it has a quicker effect (Barmore et al., 24 February, 2023).
How Warfarin is Metabolised
Warfarin is a potent anticogualant that is well absorbed by the body via the intestine with 90% bioavailability, and also offers high water solubility. It is then metabolised in the liver (hepatic), primarily through the CYP2C9 enzyme, with a half-life of approximately 20 – 60 hours. Other minor enzymatic pathways for metabolism include: CYP2C8, 2C18, 2C19, 1A2, and 3A4. How much of the drug gets metabolised is also dependent on each individual’s genetic variations (Patel et al., 24 March, 2023; Kasperkiewicz et al., 2020).
The warfarin molecule is further broken down into two forms – S- and R-warfarin, with S-warfarin 3 – 5 times more potent than R-warfarin. They are mainly broken down in the liver; metabolism of active S-warfarin is mainly via the CYP2C9 enzyme, and CYP enzymes CYP1A2 and CYP3A for R-warfarin.
Does Warfarin Interact with Other Medications?
The issue with warfarin is that it is also highly bound to serum albumin, which when combined with cytochrome P450 (CYP) metabolism, interacts with many drugs and foods. This results in warfarin either becoming more or less potent – thus increasing or decreasing its anticoagulatory effects, which can be risky either way for a patient with Antiphospholipid Syndrome (Tay et al., 2013).
Some drugs that interact with the CYP450 2C9 are cardiovascular medications such as amiodarone, and anti-infectives such as fluconazole. Some drugs that interact with CYP1A2 or CYP3A4 are quinolones and macrolides (bactericidal antibiotics). Inhibition of these enzymes can enhance the effects of warfarin, thus increasing the risk for bleeding further. Other drugs such as rifampicin (an antibiotic), carbamazepine (an anticonvulsant) and azathioprine (a DMARD) on the other hand, induces these enzymes and can decrease the potency of warfarin (Tay et al., 2013).
Highly Probable to Highly Improbable Interactions
In a systematic review by Holbrook et al. (2005), they categorise drugs that might potentially interact with warfarin from level 1 (highly probable) to level 4 (highly improbable). According to Holbrook et al. (2005):
“Of all 184 reviewed reports, 128 (70%) described a potentiation of warfarin’s effect, while inhibition and “no effect” reports each comprised 28 (15%). There were 34 reports of a major interaction—3 case reports of thrombosis associated with trazodone, sulfasalazine, and propofol and 31 case reports describing a major potentiation.”
Some drugs also yielded conflicting evidence for interaction with warfarin, i.e. terbinafine, ritonavir, and influenza vaccine. Linkins (2013) breaks down these medication categories by Holbrook et al. (2005) into a table according to type – antibiotics, antifungals, cardiovascular, cholesterol lowering agents, analgesics or antiinflammatory agents, and others. This is definitely not an exhaustive list of medications that interact with warfarin – there are way too many to be listed in one post, plus many others whose interactions are yet unknown.
What if I Have No Choice but to Take a Medication That Interacts with Warfarin?
Sometimes, taking medications that interact with warfarin is unavoidable, such as antibiotics for an infection, or an essential drug for another medical condition. For example, I was on carbamazepine and azathioprine for a period of time in the past, in a bid to control my epilepsy and Lupus (SLE) activity.
First, your rheumatologist (or doctor who manages your warfarin and Antiphospholipid Syndrome) should be consulted. They will then monitor and adjust your warfarin dose as needed, in combination with the other medications. As the medications I took were on a daily basis, that makes things easier as the main strategy to maintaining your target INR range is consistency in medication and food intake.
I eventually had to stop taking those medications not because they interacted with warfarin, but because they were ineffective or unsuitable for me for various reasons. Your doctor will also work with you to retitrate your warfarin dose when and if you need to stop taking these other medications. Remember that this applies to major dietary changes as well.
The main takeaway that I’d like to highlight is to always inform and work with your doctor when introducing a new medication that might potentially interfere with warfarin. Another important point is to always state that you’re on warfarin when you visit any new healthcare professional, including (especially) at the A&E/ER. In fact, you should have received a medical card that states that you are on warfarin – laminate this and keep it in with you at all times so that you can show it to them.
How to Check for Warfarin Interaction with Other Medications
Often, it can be a hassle and impractical to consult your doctor every time you need to take a new medication or food product. I personally use the MedScape app on my phone to do a quick check for medication interactions on the fly (I’ve seen doctors use it as well!). It tells you if there are minor or major contraindications, and why. It’s especially handy when I’m travelling. You can also tap into its comprehensive database to learn more about any other medication.
They also have a browser version here that you can use, plus other educational tools and resources on their website. Do note that it’s still important to cross-check with other verified sources and your doctor whenever possible, as not everything may be 100% accurate – that is impossible as research can sometimes be conflicting, and is also being constantly updated with new discoveries.
Screenshot Examples of the MedScape App:
How Much Warfarin Do I Need to Take with Antiphospholipid Syndrome?
The dose requirement of warfarin varies more than 10-fold amongst patients, due to genetic polymorphisms of CYP2C9, dietary differences, and other factors. According to Takahashi and Echizen (2003):
“Therapeutic targets measured by international normalized ratio (INR) of prothrombin time appear to differ between populations: INR of 2–3 for most indications in Caucasian patients1 and 1.5–2.5 for Asian patients.”
And according to Wadelius et al. (2004):
“CYP2C9 variants, age, weight, concurrent drug treatment and indication for treatment significantly influenced warfarin dosing in these patients, explaining 29% of the variation in dose. CYP3A5 did not affect warfarin dosing.”
Thus, there is no hard and fast rule as to how much warfarin one should take, as that needs to be titrated on an individual basis. Apart from the diverse genetic and dietary differences amongst patients, other factors need to be taken into account as well, such as comorbidities and the medications used to treat them, medical history, and other risk factors. If you’ve had had a thrombosis in the past, your INR target range might need to be higher as well, as that is an indication of an increased risk for blood clotting.
Pin to Your Warfarin, Medications and Antiphospholipid Syndrome Boards:
Tecarfarin – A Novel Vitamin K Antagonist in Phase III Trials
Tecarfarin is a novel VKA with a structural analog of warfarin, and can be measured via INR just like warfarin. It is being developed by Cardrenal Therapeutics for patients with implanted medical devices, end-stage renal disease (ESRD) and atrial fibrillation (AFib), although they are looking to expand its scope to include other patients who require anticoagulation too, such as in APS.
It has orphan drug with fast track designation from the FDA – meaning to say that it has governmental support for its development as a pharmaceutical agent for rare diseases. It is currently in Phase III clinical trials and in fact, since the time I drafted this section, it has already completed the ARIES-HM3 trial and presented its findings at the International Society for Heart & Lung Transplantation (ISHLT) 44th Annual Meeting & Scientific Sessions on June 3, 2024.
There are over hundreds of medications and foods that warfarin can interact with, due to the way it is metabolised by CYP2C9. Genetic variability in CYP2C9 gene can also affect the instability of INR. Tecarfarin on the other hand is metabolised by hCE-2, a pathway with no significant drug interactions, or genetic variability (Albrecht et al., 2017). It however, does not display any advantages over warfarin for people with VKORC1 polymorphisms.
In a multicentre study of 66 AFib patients for up to 12 weeks in a phase IIA trial, tecarfarin was shown to be well-tolerated without any adverse effects (Ellis et al., 2009). It was also shown to be well-tolerated in a small study of 40 Healthy Chinese volunteers in a phase I trial (Zhou et al., 2023).
This means that tecarfarin might be a potential warfarin alternative or even replacement in future, as research has shown thus far similar effects as warfarin, minus the many interactions with other foods and drugs. I guess only time will tell, after it jumps through all the hoops of the essential clinical trials!
Enoxaparin – Another Important Medication in the APS Treatment Arsenal
We’ve covered quite a bit on warfarin, because it is such an important medication in the APS management arsenal. Another important drug is enoxaparin (brand names: Lovenox and Clexane), which is also known as a “low molecular weight heparin” (LMWH). Two other FDA approved LMWHs in the USA are dalteparin (Fragmin) and tinzaparin (Innohep). Note that they should not be used interchangeably.
Enoxaparin is a medication that’s commonly substituted for warfarin, when APS patients need to pause their warfarin intake for whatever reason. It is often used as a bridge medication between surgical operations, where there is a higher chance of excessive bleeding.
This does not only include major surgeries, but also minor ones such as dental procedures, implantation of contraceptive devices, and procedures that require intramuscular injections such as the HPV vaccine. Enoxaparin has a quicker onset as compared to warfarin, and only has a half-life of about 4.5 – 7 hours (Cook, 2010). Hence, it is safer to be on enoxaparin during periods where excessive bleeding might be anticipated. You will need to do a warfarin reversal when switching to enoxaparin, which your doctor and gynaecologist will guide you through.
Whilst derived from heparin, the final formulation of enoxaparin is different. It has a bioavailability of 90% when given in the subcutaneous form (injection into the fat just under the skin), and is a more stable and predictable drug that can be self-administered by patients at home (Jupalli and Iqbal, 28 August, 2023). Pregnant women with APS generally need to substitute warfarin for enoxaparin/LMWH during the term of their pregnancy, as warfarin can be harmful to foetuses.
How Does Enoxaparin / LMWH Work?
“[LMWHs and fondaparinux] target anti–factor Xa activity rather than AT [antithrombin]. With LMWH and fondaparinux, there is a reduced risk of heparin-induced thrombocytopenia (HIT), and monitoring of the aPTT is also not required, because the aPTT is insensitive to alterations in factor Xa.”
This means that the anticoagulatory mechanisms of LMWH differs from that of vitamin K antagonists, and that patients do not need to measure their INR like they do when on warfarin. I actually prefer being on enoxaparin as compared to warfarin despite the hassle of injections, because it gives me a chance to indulge in all the foods I love (yes, like broccoli and tofu…), as it does not interact with foods in the same way as VKAs do. Sadly, enoxaparin is not a good long-term medication as it is known to impair bone health and bone healing (Li et al., 2022).
Having said that, that does not mean that there are no drug interactions with enoxaparin. Mayo Clinic has listed some medications that can interact with enoxaparin here, and also certain medical conditions that should be highlighted to your doctor if you have them.
Differences Between ‘Standard’ Heparin and Low Molecular Weight Heparin
It is easy to get confused between enoxaparin/LMWH and heparin, since technically enoxaparin is derived from heparin. Many patients and sometimes even doctors refer to enoxaparin as heparin in casual speech. However, whilst enoxaparin can be self-administered by the patient via subcutaneous injections, unfractionated heparin (UFH) is usually given intravenously within a hospital setting, as there is a risk of Heparin Induced Thrombocytopenia (HIT).
HIT is a life-threatening condition where massive activation of platelets take place, with multi-cellular release of micro particles that contribute to hypercoagulability (Gruel et al., 2020). Compared to LMWH, unfractionated heparin is a highly variable drug as well, where almost 75% of patients fail to achieve the intended aPTT. Hence, patients need to be closely monitored when on unfractionated heparin (Krishnaswamy et al., 2010).
According to Krishnaswamy et al. (2010):
“Unfractionated heparin (UFH) exerts its effect by binding and inducing a conformational change in antithrombin (AT), converting AT to a more efficient inhibitor of circulating thrombin (factor IIa), factor Xa, factor IXa, factor XIIa, and kallikrein. Contributing to its efficiency, heparin can dissociate from the thrombin: AT complex and catalyze the activity of other AT molecules.”
Referring back to Lawrence’s (2011) explanation of the mechanisms of LMWHs, in comparison unfractionated heparin readily binds to antithrombin as well. This makes unfractionated heparin a more potent anticoagulant as compared to LMWH – but also brings with it more complications and bleeding risks. It is still an important medication to combat acute cases and medical emergencies however, such as pulmonary embolisms and heart attacks.
Pin to Your Medications and Antiphospholipid Syndrome Boards:
DOACs & Antiphospholipid Syndrome
DOACs stands for ‘Direct Oral Anticoagulants’, and they can be categorised into these main classifications: oral direct factor Xa inhibitors (apixaban, rivaroxaban, edoxaban, and betrixaban), and direct thrombin inhibitors (i.e. dabigatran) (Nasiri et al., 2022).
You can actually skip this entire section with a main takeaway – warfarin is still the mainstay drug for patients with Antiphospholipid Syndrome, especially for those who are high risk, or who have had a thrombosis before. However knowing me, I went down the research rabbit hole and found a lot of interesting information about these anticoagulants. I’ve actually asked my own rheumatologist before why I can’t be on DOACs as opposed to warfarin, as their benefits seemed much better. Now I know clearly why. If you’re interested to learn how DOACs work as an anticoagulant and why they aren’t quite recommended for APS patients, then read on!
What are DOACs and How do They Work?
DOACs are anticoagulants like VKAs, but their mechanism differs. The main advantages are that patients who are on DOACs need not monitor their diet or INR, and they have a rapid onset and offset of action (Pastori et al., 2021). One interesting finding about DOACs is that beyond their anticoagulation properties, they may also have an anti-inflammatory, anti-fibrotic and anti-angiogenic properties (Signorelli et al., 2018).
That might sound great, but APS patients are advised to use VKAs such as warfarin instead, especially if you’ve had a history of arterial thrombosis, or are triple positive, or even maybe double positive for antiphospholipid antibodies (Girón-Ortega and Girón-González, 2023; also see Bejjani et al., 2024). I personally have had multiple DVTs and a PE before, so my target INR with warfarin needs to be higher than the average APS patient, as I am at a greater risk of clotting. That can be better achieved via VKAs as compared to DOACs.
VKAs also target all phases of thrombin generation, whereas DOACs target only the initiation and/or propagation process. Rivaroxaban and apixaban in particular were found to be significantly inferior to VKAs for the prevention of recurrent thrombosis in APS patients (Girón-Ortega and Girón-González, 2023). DOACs also showed an increased risk of stroke amongst APS patients, and they may also be at a higher risk of thrombotic events (Shah et al., 2023).
Another problem with DOACs is that not all of them have an antidote at present, and more studies are yet to be done as to their safety and efficacy in actual patients. There are also specific groups of individuals whom DOACs are not suitable for, such as those with poor renal function, who have a prosthetic heart valve, a disorder of haemostasis, amongst others (Tran al., 2014).
What is Thrombin?
A blood clot is also known as a thrombus, and thrombin plays an important role in the blood clotting process. Thrombin converts fibrinogen to fibrin, which is a tough protein that forms blood clots to seal wound sites. Thrombin is also the most potent platelet agonist (i.e. clots the blood). The more technical explanation, according to Posma et al. (2019):
“Activation of the blood coagulation cascade leads to fibrin deposition and platelet activation that are required for hemostasis. However, aberrant activation of coagulation can lead to thrombosis. Thrombi can cause tissue ischemia, and fibrin degradation products and activated platelets can enhance inflammation.”
DOACs: Direct Thrombin Inhibitors (DTIs)
According to Eriksson et al. (2011):
“DTIs directly neutralize thrombin by occupying the catalytic binding site, fibrinogen binding site, or both. DTIs also inhibit both fluid-phase and fibrin-bound thrombin.”
They do pretty much what their name states – inhibition of thrombin, which results in a reduction of blood clotting. A key advantage of DTIs is their ability to bind directly to thrombin, and they do not bind to other plasma proteins either (Lee and Ansell, 2011).
Dabigatran – The Only Approved DTI
The only approved DTI for use at present is dabigatran etexilate, which is a prodrug that metabolises into dabigatran in the body. Other DTIs such as ximelagatran have been withdrawn due to hepatotoxicity reports (Posma et al., 2019; van Ryn et al., 2013). Dabigatran is approved in over 70 countries, for the purpose of stroke prevention in patients with atrial fibrillation, and for the prevention of thrombosis after orthopaedic hip and knee surgery (van Ryn et al., 2013).
Whilst dabigatran seems to be a highly effective anticoagulant with a good safety profile thus far, it is important to note that it is primarily used in patients that don’t have Antiphospholipid Syndrome. International guidelines still indicate VKAs as the choice drug for patients with APS, especially if they have experienced a blood clotting event before, or are a high-risk patient, such as being triple positive (Pastori et al., 2021).
DOACs: Factor Xa Inhibitors
Factor Xa inhibitors on the other hand, reduces thrombin generation, and thus interferes with the process of fibrinogen to fibrin conversion. They also have no direct effect on platelet aggregation. It is theorised that this targeted action on factor Xa serves to limit the cascade of thrombin generation, and therefore less of the drug may be needed as compared to a DTI. Factor Xa also has minimal functions outside of coagulation, unlike thrombin, and side effects may be more contained (Cabral and Ansell, 2015).
Apixaban (Eliquis) – A Highly Selective Factor Xa Inhibitor
Apixaban (brand name: Eliquis) is a DOAC originally approved for atrial fibrillation (Afib) patients to reduce the risk of strokes and blood clots. It was later approved to treat DVTs and PEs (pulmonary embolisms) as well. It is a highly selective factor Xa inhibitor that exerts no effect on platelet aggregation, and mainly binds to plasma protein (Agrawal et al., 22 February, 2024). Side effects of taking apixaban are similar to other anticoagulant drugs, and include: bleeding, red or black, tarry stools, red, pink or brown urine, trouble breathing, dizziness, coughing up blood or material that looks like coffee grounds, and more.
Rivaroxaban (Xarelto) – Another Factor Xa Inhibitor
Rivaroxaban (brand name: Xarelto) is another type of DOAC under the factor Xa class. Based on the data available to date, rivaroxaban is less effective than VKAs in the prevention of recurrent thrombosis, but more research needs to be done as to its efficacy (Girón-Ortega and Girón-González, 2023).
A study of 120 high risk APS patients was terminated early due to the higher incidence of thromboembolic events for those who were on rivaroxaban, whereas none occurred in the group on warfarin (Pengo et al., 2018).
Pin to Your Medications and Antiphospholipid Syndrome Boards:
Current Reversal Agents Available for Anticoagulant Drugs
Patients who are on anticoagulants ironically run the risk of excessive bleeding or a haemorrhage, and not all DOACs have an antidote; the antidotes that are available are also expensive. In cases of severe bleeding, patients need to undergo reversal of their anticoagulant medication via a haemostatic agent.
According to Tomaselli et al. (2020) and Kustos and Fasinu (2019), these are the current reversal agents used for anticoagulant drugs during emergencies:
- Vitamin K Antagonists (warfarin) – Intravenous or oral vitamin K1. In addition, prothrombin complex concentrate (PCC) is preferred for immediate reversal, as compared to fresh frozen plasma (FFP) (Tran et al., 2013). Compared to FFP, 4F-PCCs contain approximate 25 times the concentration of vitamin K-dependent factors, and thus can be given at a smaller volume with a faster infusion rate.
- Vitamin K Antagonists (heparin) – Protamine.
- Indirect Thrombin Inhibitors (LMWH) – Protamine.
- DTI (dabigatran) – Idarucizumab (Praxbind). If unavailable, PCC or aPCC (activated prothrombin complex concentrate).
- Factor Xa Inhibitors (apixaban & rivaroxaban) – Andexanet Alfa. If unavailable, PCC or aPCC.
- Factor Xa (betrixaban & edoxaban) – Off-label treatment with high dose Andexanet Alfa. If unavailable, PCC or aPCC.
- In addition for the DOACs, activated charcoal may be considered for known recent ingestion in the last 2 – 4 hours.
This is just a brief, general guideline, and many more considerations need to be taken into account on an individual basis during an emergency. Please work with your own doctors and emergency care team for the best outcome.
A Bit More About Andexanet Alfa as a Reversal Agent
Andexanet alfa is administered via intravenous infusion with an onset time of 2 minutes. Side effects are primarily hot flashes and antibody development; they may also induce blood clotting ironically and result in strokes, DVTs, PEs, cardiac failure and more (Kustos and Fasinu, 2019; also see Escal et al., 2024). It is currently only approved for use as an antidote for apixaban and rivaroxaban, whilst its safety and efficacy is still being evaluated in relation to edoxaban and betrixaban.
Ciraparantag & Other Non-Specific Pharmacokinetic Antidotes to DOACs
Ciraparantag is a reversal agent still undergoing clinical trials, but shows promise as a non-immunogenic antidote for a wide array of anticoagulants (all types of DOACs, heparins and fondaparinux) (Escal et al., 2024).
Non-specific pharmacokinetic antidotes are sometimes used in addition to reversal agents to increase coagulation effects. According to Escal et al. (2024), these include:
- Activated Charcoal – Activated charcoal has the ability absorb various substances in the body within the gastrointestinal tract. It may help to reduce blood concentrations of DOACs and thus its bioavailability. It also remains active for a long time and is low in cost.
- Haemodialysis – This is more for patients on DTIs (dabigatran), and especially if they have renal impairment. They are ineffective for Factor Xa inhibitors as they mainly bind to plasma proteins. It can be difficult to access during emergency situations however, as it requires trained healthcare professionals who know how to use specific equipment.
- Haemostatic Agents – These are useful when the type of DOAC the patient is on is unknown, or when standard reversal agents are unavailable. They include naPCC (non-activated prothrombin complex concentrates), FEIBA (factor eight inhibitor bypassing activity), rFVIIa (recombinant activated factor VII) and tranexamic acid. Note that these are second-line treatments and that more research still needs to be done to determine their exact effects and safety profile.
Pin to Your Medications and Antiphospholipid Syndrome Boards:
Proteases & Protease-Activated Receptor (PAR) Antagonists
Proteases are important regulators of cellular activity, and they communicate directly to cells via protease-activated receptors (PARs). There are four different PAR profiles, from PAR1 to PAR4, which are expressed widely in the body, from the brain to lungs, muscles, bones, bladder and more (Han et al., 2021). PAR1, PAR3 and PAR4 are activated by thrombin, whereas Factor Xa activates PAR2, although other proteases can also contribute to activation (Posma et al., 2019).
Cleavage of PARs
Inflammation is at the tail end of the blood coagulation cascade, as can be seen from a graphic in this paper by Posma et al. (2019).
According to Burzynski et al. (2019):
“The current principal link between coagulation and immunity is cleavage of PARs by thrombin, which produces cytokines and inflammation.”
This reveals a direct link between coagulation and the immune system, which is an exciting perspective. What this means is that future Antiphospholipid Syndrome treatments might shift to an immunological one, instead of merely targeting anticoagulation. Unfortunately, despite the implication of PARs in Antiphospholipid Syndrome, there are no ongoing trials for APS patients (Signorelli et al., 2018). Let’s keep our fingers crossed!
Vorapaxar – An FDA-Approved PAR Antagonist
Vorapaxar is a first-in-class PAR1 antagonist approved for use by the FDA, for patients with coronary artery disease. Unfortunately, it is contraindicated for patients who have had thrombotic or bleeding events in the past. Like all antiplatelet agents, vorapaxar increases the risk of bleeding, which can be fatal. It also has a long half-life and no antidote (Han et al., 2021; Signorelli et al., 2018).
Another PAR-1 antagonist is atopaxar, but research has been discontinued as clinical trials in phase II demonstrated a high risk for bleeding with the drug (Zhao et al., 2013).
NSAIDs & Antiphospholipid Syndrome
NSAIDs (Non-Steroidal Anti-Inflammatory Drugs) are a class of anti-inflammatories that people often take for generic pain relief. You’re probably familiar with these over-the-counter drugs that go by the names of: Ibuprofen, Naproxen and Aspirin. Brand names include Neurofen, Advil, Motrin, Aleve, Alka-Seltzer, Pepto-Bismol, and more.
To be honest, NSAIDS would probably work better for my Lupus and Sjögren’s pains because of their anti-inflammatory properties, but I can’t take them due to interactions with warfarin. As I’m also allergic to paracetamol (Panadol), I can only rely on opioid classes of painkillers for pain relief.
NSAIDs interfere with blood clotting by inhibiting platelet function. Platelets (also known as thrombocytes) are essential components in our blood that help with clotting. Hence, patients who are on blood thinning medications have a higher risk of bleeding with NSAIDs.
There is also an increased risk of gastrointestinal bleeding and peptic ulcers with NSAIDs due to the mechanisms of the medication (Drini, 2017), which is also the biggest concern my rheumatologist has with them. I only use NSAIDs when absolutely necessary, such as during a high fever, and inform my healthcare team when I do so. I also take extra measures to protect my stomach such as eating proper meals, and check my own INR regularly.
Pin to Your Medications and Antiphospholipid Syndrome Boards:
Conclusion to Medications and Antiphospholipid Syndrome
In this post, we have covered the main medications used in the management of Antiphospholipid Syndrome, and for the treatment of its related complications. We have also covered some of the important drugs that can interact with warfarin, as well as new medications that are undergoing clinical trials.
I hope that this post on medications and Antiphospholipid Syndrome has been insightful and useful to you whether as an APS patient, or someone who is caring for one. Should you have any questions, experiences to share, or corrections (I am not a doctor, after all!), feel free to leave a comment below. Don’t forget to check out the rest of the posts in the Antiphospholipid Syndrome series listed below as well. Wishing you all the best that life can still bring!
If you liked this article, sign up for our mailing list so you don’t miss out on our latest posts! You will also receive an e-book full of uplifting messages, quotes and illustrations, as a token of appreciation!
Pin to Your Medications and Antiphospholipid Syndrome Boards:
- 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/
- 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 K antagonist oral anticoagulant. Thrombosis and Haemostasis, 117(04), 706-717. https://doi.org/10.1160/TH16-08-0623
- Barmore, W., Bajwa, T., & Burns, B. (24 February, 2023). Biochemistry, Clotting Factors. In StatPearls. StatPearls Publishing. Retrieved from: http://www.ncbi.nlm.nih.gov/books/NBK507850/
- 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, K. 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 Should Not Be Standard Treatment. Journal of the American College of Cardiology, 83(3), 444–465. https://doi.org/10.1016/j.jacc.2023.10.038
- Burzynski, L. C., Humphry, M., Pyrillou, K., Wiggins, K. A., Chan, J. N. E., Figg, N., Kitt, L. L., Summers, C., Tatham, K. C., Martin, P. B., Bennett, M. R., & Clarke, M. C. H. (2019). The Coagulation and Immune Systems Are Directly Linked through the Activation of Interleukin-1α by Thrombin. Immunity, 50(4), 1033-1042.e6. https://doi.org/10.1016/j.immuni.2019.03.003
- Cabral, K. P., & Ansell, J. E. (2015). The role of factor Xa inhibitors in venous thromboembolism treatment. Vascular Health and Risk Management, 11, 117–123. https://doi.org/10.2147/VHRM.S39726
- Cadrenal Therapeutics, Inc. (3 June, 2024). Cadrenal Therapeutics Highlights Presentation Of New Trial Data at Ishlt Conference Demonstrating The Importance Of Anticoagulation Quality In LVAD Patients. Cadrenal Therapeutics, Inc. Retrieved from: https://www.cadrenal.com/investors/press-releases/detail/cadrenal-therapeutics-provides-third-quarter-2023-corporate-update
- Cadrenal Therapeutics, Inc. (9 November, 2023). Cadrenal Therapeutics Provides Third Quarter 2023 Corporate Update. U.S. Securities And Exchange Commission. Retrieved from: https://www.sec.gov/Archives/edgar/data/1937993/000121390023084969/ea187953ex99-1_cadrenal.htm
- Cadrenal Therapeutics, Inc. (n.d.). Tecarfarin. A late-stage novel therapy with orphan drug and Fast Track designations. Cadrenal Therapeutics, Inc. Retrieved from: https://www.cadrenal.com/tecarfarin/
- Cleveland Clinic. (28 April, 2022). Platelets. Cleveland Clinic. Retrieved from: https://my.clevelandclinic.org/health/body/22879-platelets
- Cook, B. W. (2010). Anticoagulation Management. Seminars in Interventional Radiology, 27(4), 360–367. https://doi.org/10.1055/s-0030-1267849
- Crader, M. F., Johns, T., & Arnold, J. K. (1 May, 2023). Warfarin Drug Interactions. In StatPearls. StatPearls Publishing. Retrieved from: http://www.ncbi.nlm.nih.gov/books/NBK441964/
- Department of Health, Government of Western Australia. (n.d.). Warfarin. HealthyWA. Retrieved from: https://www.healthywa.gov.au/Articles/A-Z/Warfarin
- Drini, M. (2017). Peptic ulcer disease and non-steroidal anti-inflammatory drugs. Australian Prescriber, 40(3), 91–93. https://doi.org/10.18773/austprescr.2017.037
- Drugs .com. (n.d.). Enoxaparin (Ingredient). Drugs .com. Retrieved from: https://www.drugs.com/ingredient/enoxaparin.html
- Ellis, D. J., Usman, M. H., Milner, P. G., Canafax, D. M., & Ezekowitz, M. D. (2009). The First Evaluation of a Novel Vitamin K Antagonist, Tecarfarin (ATI-5923), in Patients With Atrial Fibrillation. Circulation, 120(12), 1029–1035. https://doi.org/10.1161/CIRCULATIONAHA.109.856120
- Eriksson, B. I., Quinlan, D. J., & Eikelboom, J. W. (2011). Novel Oral Factor Xa and Thrombin Inhibitors in the Management of Thromboembolism. Annual Review of Medicine, 62(Volume 62, 2011), 41–57. https://doi.org/10.1146/annurev-med-062209-095159
- Escal, J., Lanoiselée, J., Poenou, G., Zufferey, P., Laporte, S., Mismetti, P., & Delavenne, X. (2024). Latest advances in the reversal strategies for direct oral anticoagulants. Fundamental & Clinical Pharmacology. https://doi.org/10.1111/fcp.12992
- Girolami, A., Ferrari, S., Cosi, E., Santarossa, C., & Randi, M. L. (2018). Vitamin K-Dependent Coagulation Factors That May be Responsible for Both Bleeding and Thrombosis (FII, FVII, and FIX). Clinical and Applied Thrombosis/Hemostasis, 24(9 Suppl), 42S-47S. https://doi.org/10.1177/1076029618811109
- Girón-Ortega, J. A., & Girón-González, J. A. (2023). Direct-acting oral anticoagulants in antiphospholipid syndrome: A systematic review. Medicina Clínica (English Edition), 161(2), 65–77. https://doi.org/10.1016/j.medcle.2023.03.017
- 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). Diagnosis and management of heparin-induced thrombocytopenia. Anaesthesia Critical Care & Pain Medicine, 39(2), 291–310. https://doi.org/10.1016/j.accpm.2020.03.012
- Halder, M., Petsophonsakul, P., Akbulut, A. C., Pavlic, A., Bohan, F., Anderson, E., Maresz, K., Kramann, R., & Schurgers, L. (2019). Vitamin K: Double Bonds beyond Coagulation Insights into Differences between Vitamin K1 and K2 in Health and Disease. International Journal of Molecular Sciences, 20(4), Article 4. https://doi.org/10.3390/ijms20040896
- Han, X., Nieman, M. T., & Kerlin, B. A. (2020). Protease‐activated receptors: An illustrated review. Research and Practice in Thrombosis and Haemostasis, 5(1), 17–26. https://doi.org/10.1002/rth2.12454
- Harvard Medical School. (16 December, 2019). Bad mix: Blood thinners and NSAIDs. Harvard Health Publishing. Retrieved from: https://www.health.harvard.edu/diseases-and-conditions/bad-mix-blood-thinners-and-nsaids
- 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 Food Interactions. Archives of Internal Medicine, 165(10), 1095–1106. https://doi.org/10.1001/archinte.165.10.1095
- Jupalli, A., & Iqbal, A. M. (28 August, 2023). Enoxaparin. In StatPearls. StatPearls Publishing. Retrieved from: http://www.ncbi.nlm.nih.gov/books/NBK539865/
- Kasperkiewicz, K., Ponczek, M. B., Owczarek, J., Guga, P., & Budzisz, E. (2020). Antagonists of Vitamin K—Popular Coumarin Drugs and New Synthetic and Natural Coumarin Derivatives. Molecules, 25(6), 1465. https://doi.org/10.3390/molecules25061465
- Krishnaswamy, A., Lincoff, A. M., & Cannon, C. P. (2010). The Use and Limitations of Unfractionated Heparin. Critical Pathways in Cardiology, 9(1), 35. https://doi.org/10.1097/HPC.0b013e3181d29713
- Kustos, S. A., & Fasinu, P. S. (2019). Direct-Acting Oral Anticoagulants and Their Reversal Agents-An Update. Medicines (Basel, Switzerland), 6(4), 103. https://doi.org/10.3390/medicines6040103
- Lawrence, P. F. (2011). Chapter 78—Pharmacologic Adjuncts to Endovascular Procedures. In W. S. Moore & S. S. Ahn (Eds.), Endovascular Surgery (Fourth Edition) (pp. 807–813). W.B. Saunders. https://doi.org/10.1016/B978-1-4160-6208-0.10078-3
- Lee, C. J., & Ansell, J. E. (2011). Direct thrombin inhibitors. British Journal of Clinical Pharmacology, 72(4), 581–592. https://doi.org/10.1111/j.1365-2125.2011.03916.x
- Li, Y., Liu, L., Li, S., Sun, H., Zhang, Y., Duan, Z., & Wang, D. (2022). Impaired bone healing by enoxaparin via inhibiting the differentiation of bone marrow mesenchymal stem cells towards osteoblasts. Journal of Bone and Mineral Metabolism, 40(1), 9–19. https://doi.org/10.1007/s00774-021-01268-5
- 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
- MedlinePlus. (15 April, 2023). Rivaroxaban. Bethesda (MD): National Library of Medicine (US). Retrieved from: https://medlineplus.gov/druginfo/meds/a611049.html
- MedlinePlus. (15 November, 2023). Apixaban. Bethesda (MD): National Library of Medicine (US). Retrieved from: https://medlineplus.gov/druginfo/meds/a613032.html
- Nasiri, A., AlQahtani, A., Rayes, N. H., AlQahtani, R., Alkharras, R., & Alghethber, H. (2022). Direct oral anticoagulant: Review article. Journal of Family Medicine and Primary Care, 11(8), 4180–4183. https://doi.org/10.4103/jfmpc.jfmpc_2253_21
- Office of Dietary Supplements. (29 March, 2021). Vitamin K Fact Sheet for Health Professionals. National Institutes of Health. Retrieved from: https://ods.od.nih.gov/factsheets/VitaminK-HealthProfessional/
- Pastori, D., Menichelli, D., Cammisotto, V., & Pignatelli, P. (2021). Use of Direct Oral Anticoagulants in Patients With Antiphospholipid Syndrome: A Systematic Review and Comparison of the International Guidelines. Frontiers in Cardiovascular Medicine, 8. https://doi.org/10.3389/fcvm.2021.715878
- 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 patients with antiphospholipid syndrome. Blood, 132(13), 1365–1371. https://doi.org/10.1182/blood-2018-04-848333
- 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/
- 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 Models of Inflammatory Diseases. Arteriosclerosis, Thrombosis, and Vascular Biology, 39(1), 13–24. https://doi.org/10.1161/ATVBAHA.118.311655
- Ruff, C. T. (17 May, 2022). Direct Oral Anticoagulants (DOACs) vs. Warfarin: Key Differences. North American Thrombosis Forum [NATF]. Retrieved from: https://thrombosis.org/2020/11/doacs-vs-warfarin/
- Schein, J. R., White, C. M., Nelson, W. W., Kluger, J., Mearns, E. S., & Coleman, C. I. (2016). Vitamin K antagonist use: Evidence of the difficulty of achieving and maintaining target INR range and subsequent consequences. Thrombosis Journal, 14(1), 14. https://doi.org/10.1186/s12959-016-0088-y
- Shah, B. B., Shankar, A., Kumar, V., Kumar, S., Malik, U. A., Majeed, A., … & Ahmed, S. (2023). Direct oral anticoagulants vs. vitamin K antagonists in patients with antiphospholipid syndrome: a systematic review and meta-analysis. Annals of Medicine and Surgery, 85(7), 3574-3582. https://doi.org/10.1097/MS9.0000000000000903
- Signorelli, F., Balbi, G. G. M., Domingues, V., & Levy, R. A. (2018). New and upcoming treatments in antiphospholipid syndrome: A comprehensive review. Pharmacological Research, 133, 108–120. https://doi.org/10.1016/j.phrs.2018.04.012
- 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
- Tay, K. 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
- Thijssen, H. H. W. (1995). Warfarin-based rodenticides: Mode of action and mechanism of resistance. Pesticide Science, 43(1), 73–78. https://doi.org/10.1002/ps.2780430112
- Tomaselli, G. F., Mahaffey, K. 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 Expert Consensus Decision Pathway on Management of Bleeding in Patients on Oral Anticoagulants. Journal of the American College of Cardiology, 76(5), 594–622. https://doi.org/10.1016/j.jacc.2020.04.053
- Tran, H., Joseph, J., Young, L., McRae, S., Curnow, J., Nandurkar, H., Wood, P., & McLintock, C. (2014). New oral anticoagulants: A practical guide on prescription, laboratory testing and peri-procedural/bleeding management. Internal Medicine Journal, 44(6), 525–536. https://doi.org/10.1111/imj.12448
- Tran, H. A., Chunilal, S. D., Harper, P. L., Tran, H., Wood, E. M., & Gallus, A. S. (2013). An update of consensus guidelines for warfarin reversal. Medical Journal of Australia, 198(4), 198–199. https://doi.org/10.5694/mja12.10614
- U.S. Food & Drug Administration. (2 June, 2018). Generic Enoxaparin Questions and Answers. FDA. Retrieved from: https://www.fda.gov/drugs/postmarket-drug-safety-information-patients-and-providers/generic-enoxaparin-questions-and-answers
- 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
- Vardanyan, R. S., & Hruby, V. J. (2006). 24—Anticoagulants, Antiaggregants, Thrombolytics, and Hemostatics. In R. S. Vardanyan & V. J. Hruby (Eds.), Synthesis of Essential Drugs (pp. 323–335). Elsevier. https://doi.org/10.1016/B978-044452166-8/50024-8
- Wadelius, M., Sörlin, K., Wallerman, O., Karlsson, J., Yue, Q.-Y., Magnusson, P. K. E., Wadelius, C., & Melhus, H. (2004). Warfarin sensitivity related to CYP2C9, CYP3A5, ABCB1 (MDR1) and other factors. The Pharmacogenomics Journal, 4(1), 40–48. https://doi.org/10.1038/sj.tpj.6500220
- Zhao, H.-P., Jiang, H.-M., & Xiang, B.-R. (2013). Discontinued drugs in 2012: Cardiovascular drugs. Expert Opinion on Investigational Drugs, 22(11), 1437–1451. https://doi.org/10.1517/13543784.2013.832198
- Zhou, Q., Wang, Z., Wang, H., Chen, Z., Li, X., Dai, X., Zhang, Y., Yu, X., Zhou, R., & Hu, W. (2023). Safety and Tolerability of Tecarfarin (ATI-5923) in Healthy Chinese Volunteers: Multiple Oral Dose-Escalation Phase I Trial. American Journal of Cardiovascular Drugs, 23(1), 101–112. https://doi.org/10.1007/s40256-022-00562-5