Warfarin and Superwarfarin Toxicity

Coumarins inhibit hepatic synthesis of the vitamin K ̶ dependent coagulation factors II, VII, IX, and X and the anticoagulant proteins C and S. Vitamin K is a cofactor in the synthesis of these clotting factors. The vitamin K ̶ dependent step involves carboxylation of glutamic acid residues and requires regeneration of the used vitamin K back to its reduced form.

Coumarins and related compounds inhibit vitamin K1 -2,3 epoxide reductase, preventing vitamin K from being reduced to its active form. The degree of effect on the vitamin K ̶ dependent proteins depends on the dose and duration of treatment with warfarin.

Since warfarin does not affect the activity of previously synthesized and circulating coagulation factors, depletion of these mature factors through normal catabolism must occur before the anticoagulant effects of the drug are observed. Each factor differs in its degradation half-life: factor II requires 60 hours, factor VII requires 4-6 hours, factor IX requires 24 hours, and factor X requires 48-72 hours. The half-lives of proteins C and S are approximately 8 and 30 hours, respectively. As a result, 3-4 days of therapy may be needed before complete clinical response to any one dosage is observed.

Because warfarin also reduces the activity of anticoagulant proteins C and S, a transient hypercoagulable state may occur shortly after treatment with warfarin is started. Rapid loss of protein C temporarily shifts the balance in favor of clotting until sufficient time has passed for warfarin to decrease the activity of coagulant factors.

The oral bioavailability of warfarin and the superwarfarins is nearly 100%. Warfarin is highly bound (approximately 97%) to plasma protein, mainly albumin. The high degree of protein binding is one of several mechanisms whereby other drugs interact with warfarin. Warfarin is distributed to the liver, lungs, spleen, and kidneys. It does not appear to be distributed to breast milk in significant amounts. It crosses the placenta and is a known teratogen.

The duration of anticoagulant effect after a single dose of warfarin is usually 5-7 days. However, superwarfarin products may continue to produce significant anticoagulation for weeks to months after a single ingestion. In one reported overdose case with measured serum levels, the half-life of brodifacoum was 56 days.[4]

Warfarin is metabolized by hepatic cytochrome P-450 (CYP) isoenzymes predominantly to inactive hydroxylated metabolites, which are excreted in the bile. It also is metabolized by reductases to reduced metabolites (warfarin alcohols), which are excreted in the kidneys. Warfarin metabolism may be altered in the presence of liver dysfunction or advanced age but is not affected by kidney impairment. Drug interactions are extensive and many known examples are enumerated below. Excessive anticoagulation may also occur because of unintentional or intentional overdose.

Lack of familiarity with the interactions between warfarin and other drugs may lead to clinically relevant and avoidable increases or decreases in prothrombin time (PT).

Drugs that prolong the prothrombin time

Note that the S-isomer is more potent than the R-isomer; thus, drugs that inhibit S-isomer metabolism have a greater effect on PT.

Drugs that inhibit warfarin metabolism include the following:

• Allopurinol
• Amiodarone
• Azole antifungals
• Capecitabine
• Cephalosporin antibiotics
• Chloramphenicol
• Chlorpropamide
• Cimetidine
• Cotrimoxazole
• Disulfiram
• Ethanol (acute ingestion)
• Flutamide
• Isoniazid (INH)
• Macrolide antibiotics
• Metronidazole
• Omeprazole
• Penicillin antibiotics
• Phenytoin
• Propafenone
• Propoxyphene
• Quinidine
• Quinolone antibiotics
• Statins (particularly lovastatin and pravastatin)
• Sulfinpyrazone
• Sulfonamides
• Tamoxifen
• Tolbutamide
• Zafirlukast
• Zileuton

Many antibiotics, especially parenteral cephalosporins, can inhibit vitamin K activity. A high penicillin dose also can inhibit the activity of vitamin K, possibly due to decreased gastrointestinal (GI) flora synthesis of vitamin K. Using data from the Medicare Part D prescription drug program, Baillargeon et al found that patients 65 years and older who were continuous warfarin users had a two-fold increased risk of bleeding requiring hospitalization within 15 days of exposure to an antibiotic (azole, cephalosporins, cotrimoxazole, macrolides, penicillin, quinolones).[5]

In a study of patients taking antibiotics and warfarin, serious bleeding events occurred significantly more often with antibiotics considered to be high-risk for interactions with warfarin (trimethoprim/sulfamethoxazole, ciprofloxacin, levofloxacin, metronidazole, fluconazole, azithromycin, and clarithromycin) than with antibiotics considered low-risk (clindamycin and cephalexin). Of the 22,272 patients in the study, 14,078 received high-risk agents and 8194 received low-risk antibiotics. Bleeding events occurred in 93 patients in the high-risk group and 36 patients in the low-risk group. Increases in international normalized ratio (INR) values were common; for example,  9.7% of patients prescribed fluconazole had an INR greater than 6.[6]

An additive anticoagulant effect is produced by the following drugs:

• Aspirin
• Clopidogrel
• Heparin
• Low molecular weight heparin
• Direct thrombin inhibitors (eg, argatroban, lepirudin)

Drugs that interfere with protein binding

Drugs that interfere with protein binding—and thus enhance the anticoagulant effect of warfarin—include the following:

• Chloral hydrate
• Clofibrate
• Diazoxide
• Ethacrynic acid
• Miconazole (including intravaginal use)
• Nalidixic acid (displaces protein binding)
• Salicylates
• Sulfonamides
• Sulfonylureas

Drugs that can reduce PT by decreasing the warfarin effect

The following drugs cause inhibition of warfarin absorption:

• Cholestyramine
• Sucralfate
• Aluminum hydroxide
• Colestipol

The following drugs cause enhanced warfarin metabolism:

• Barbiturates
• Carbamazepine
• Ethanol
• Glutethimide
• Griseofulvin
• Phenytoin
• Rifampin

The following foods have a very high vitamin K content (> 200 mcg):

• Brussel sprouts
• Chickpeas
• Collard greens
• Coriander
• Endive
• Kale
• Liver
• Parsley
• Red leaf lettuce
• Spinach
• Swiss chard
• Black/green teas
• Turnip greens
• Watercress

The following foods have a high vitamin K content (100-200 mcg):

• Basil
• Broccoli
• Butterhead lettuce
• Canola oil
• Chives
• Coleslaw
• Cucumbers (with peel)
• Green onions
• Mustard greens
• Soybean oil

The following foods have a medium vitamin K content (50-100 mcg):

• Apples (green)
• Asparagus
• Cabbage
• Cauliflower
• Mayonnaise
• Nuts (pistachios)
• Summer squash

The following foods have a low vitamin K content (< 50 mcg):

• Apples (red)
• Avocados
• Beans
• Breads/grains
• Carrots
• Celery
• Cereal
• Coffee
• Corn
• Cucumbers (without the peel)
• Dairy products
• Eggs
• Fruits
• Iceberg lettuce
• Meats/fish/poultry
• Pastas
• Peanuts
• Peas
• Potatoes
• Rice
• Tomatoes

Occurrence in the United States

According to American Association of Poison Control Centers (AAPCC) data, 761 single exposures to pharmaceutical warfarin were reported in 2021. Children younger than 6 years accounted for 121 exposures, and persons older than 19 years accounted for 557. The majority of cases (655) were unintentional exposures. Major outcomes occurred in 9 cases and 3 deaths were reported.[7]

In addition, the AAPCC reported 103 single exposures to warfarin-type anticoagulant rodenticides, with 76 involving children younger than 6 years. Exposure was unintentional in 99 cases. No major outcomes or deaths were reported.[7]

Therapeutic anticoagulants represented the most frequent medication type seen for adverse effects in 60 US emergency departments (EDs) between 2017-2019. The estimated incidence was 4.5 per 1000 population.  Warfarin accounted for 7471 ED visits during this period.[8]

Age-related demographics

Complications from incorrect dosing of warfarin occur most often in adults. Unintentional ingestions of superwarfarins are far more common in children, with approximately 89% of reported exposures occurring in children younger than age 6 years. Pediatric exposures usually involve a single small ingestion and result in no symptoms or alteration in the PT.[9] Adults who intentionally ingest superwarfarin agents are more likely to ingest a toxic dose and to experience the anticoagulant effects of these products.

Hemorrhage

Bleeding is the primary adverse effect of warfarin and superwarfarin toxicity and is related to the intensity of anticoagulation, length of therapy, the patient's underlying clinical state, and use of other drugs that may affect hemostasis or interfere with warfarin metabolism.[10] Fatal or nonfatal hemorrhage may occur from any tissue or organ.

Children rarely ingest enough product to develop clinical evidence of anticoagulation. A study of 595 children younger than age 6 years who had ingested superwarfarin rodenticides found only 2 with elevated PTs (international normalized ratio [INR] 1.5 and 1.8), and neither had symptoms.[9]

Over the 20-year period from 1985-2004, the AAPCC’s Toxic Exposure Surveillance System (TESS) database reported no deaths in children younger than age 6 years after ingestion of superwarfarins and only one adult death due to unintentional ingestion.[11] Virtually all cases of severe hemorrhage occurred after intentional self-poisoning.

Minor bleeding from mucous membranes, subconjunctival hemorrhage, hematuria, epistaxis, and ecchymoses may occur.

Major bleeding complications include GI hemorrhage, intracranial bleeding, and retroperitoneal bleeding. Massive hemorrhage usually involves the GI tract but may involve the spinal cord or cerebral, pericardial, pulmonary, adrenal, or hepatic sites. Although rare, massive intraocular hemorrhage has been reported in patients with preexisting disciform macular degeneration.

In a population-based retrospective cohort study of patients aged 65 years or older with atrial fibrillation (AF) who underwent dialysis, warfarin was found to be associated with a 44% higher risk of bleeding and did not reduce the risk of stroke.[12]

Skin necrosis

Skin necrosis, usually observed between the third and eighth days of therapy, is a relatively uncommon, adverse reaction to warfarin. When skin necrosis occurs, it can be extremely severe and disfiguring and may require treatment through debridement or amputation of the affected tissue, limb, breast, or penis.

It occurs more frequently in women and in patients with preexisting protein C deficiency and is found, less commonly, in men and in patients with protein S deficiency. Patients initially become hypercoagulable because warfarin depresses levels of the anticoagulant proteins C and S more quickly than it does coagulant proteins II, VII, IX, and X.

Extensive thrombosis of the venules and capillaries occurs within the subcutaneous fat. Women note an intense, painful burning in areas such as the thigh, buttocks, waist, and/or breast several days after beginning warfarin; skin necrosis and permanent scarring may follow.

Immediate withdrawal of warfarin therapy is indicated. Heparin can be substituted safely for warfarin; however, treatment of patients who require long-term anticoagulant therapy remains problematic.

Restarting warfarin therapy at a low dose (eg, 2 mg) while continuing heparin treatment for 2-3 days may be reasonable. The dosage of warfarin can be increased gradually over several weeks.

Warfarin and pregnancy

Warfarin crosses the placenta during pregnancy and has the potential to cause teratogenesis and bleeding in the fetus. Warfarin and other coumarin derivatives cause an embryopathy commonly termed fetal warfarin syndrome (FWS). No data are available on whether superwarfarin compounds cross the placenta or are excreted in breast milk.

During the first trimester, particularly during weeks 6-12 of gestation, embryopathy caused by exposure and characterized by nasal hypoplasia with or without stippled epiphyses (chondrodysplasia punctata) may occur.

Central nervous system (CNS) abnormalities, including dorsal midline dysplasia characterized by agenesis of the corpus callosum, Dandy-Walker malformation, and midline cerebellar atrophy have been reported.

Ventral midline dysplasia, characterized by optic atrophy and eye abnormalities, has been observed. Seizures, deafness, blindness, and mental retardation can occur in any trimester. Spontaneous fetal abortion and stillbirth are known to occur, and an increased risk of fetal mortality is associated with warfarin use.

Although rare, other teratogenic occurrences reported after in utero exposure to warfarin include the following:

• Urinary tract abnormalities (eg, single kidney)
• Asplenia
• Anencephaly
• Spina bifida
• Cranial nerve palsy
• Hydrocephalus
• Cardiac defects and congenital heart disease
• Polydactyly
• Deformities of toes
• Diaphragmatic hernia
• Corneal leukoma
• Cleft palate
• Cleft lip
• Schizencephaly
• Microcephaly

The effects of anticoagulation on the fetus are a particular concern during labor, when the combination of the trauma of delivery and anticoagulation may lead to bleeding in the neonate.

A few small studies have looked at the use warfarin in pregnancy after the 12th week of gestation, but these studies are insufficient to recommend the use of warfarin in the pregnant patient. Thus, do not administer warfarin during pregnancy.

Additional complications

Other adverse reactions that occur infrequently with long-term warfarin therapy include the following:

• Agranulocytosis
• Alopecia
• Anaphylactoid reactions
• Anorexia
• Cold intolerance
• Diarrhea
• Dizziness
• Elevated hepatic enzyme levels
• Exfoliative dermatitis
• Headache
• Hepatitis
• Jaundice
• Leukopenia
• Nausea and/or vomiting
• Pruritus
• Urticaria

Rare events of tracheal or tracheobronchial calcification have been reported in association with long-term warfarin therapy. The clinical significance is not known. Priapism is associated with anticoagulant administration; however, a causal relationship with warfarin is not established.

Spontaneous intramural hematoma of the intestine may cause bowel obstruction and has been reported with an estimated prevalence of 1 in 2500 patients taking warfarin.[13]

Instruct regular users of warfarin in the proper use of their medication and in methods of avoiding accidental overdose (eg, employment of daily pillboxes). Generally, the primary care provider handles this.

After acute ingestions by children, instruct parents to remove possible sources of intoxication (eg, poisons on the floor, under the sink, in the garage).

For patient education information, see Poisoning and Poison Proofing Your Home.

Bleeding is the only expected significant clinical manifestation. Internal bleeding may present as any of a vast array of symptoms or be occult. Other possible signs and symptoms include[14] :

• Skin necrosis
• Vasculitis
• Calciphylaxis
• Diarrhea
• Renal acidosis

Obtain an accurate history of the amount of warfarin or superwarfarin ingested, when it was ingested, and over what period it was ingested. Additionally, inquire about the circumstances of the ingestion to determine the patient's disposition. If the ingestion was suicidal or surreptitious in nature, the history may be difficult to obtain or the patient or caregiver may give misleading information.

An accurate medication list is important because many drugs increase or decrease the metabolism of warfarin (see Overview/Etiology).

The toxic dose of warfarin is highly variable. Generally, a single ingestion of warfarin (10-20 mg) does not cause serious intoxication. In contrast, long-term or repeated ingestion of even small amounts of warfarin (2-5 mg/day) eventually can lead to significant anticoagulation, especially in the presence of interacting drugs. Patients with hepatic dysfunction, malnutrition, or a bleeding diathesis are at the greatest risk of toxicity from warfarin use.

Superwarfarins are extremely potent and can produce prolonged effects even after a small ingestion; as little as 1 mg in an adult can cause coagulopathy.

Do not expect to see physical evidence of bleeding after an acute ingestion for at least 24 hours. Life-threatening complications include massive gastrointestinal bleeding and intracranial hemorrhage. More common findings of excessive anticoagulation are ecchymoses, subconjunctival hemorrhage, epistaxis, vaginal bleeding, bleeding gums, or hematuria.

In all patients, if prolongation of the prothrombin time (PT) is observed after an acute ingestion, it may appear in as early as 8-12 hours; however, peak effects commonly are delayed until at least 1-2 days postingestion.

Skin necrosis is a rare but serious manifestation of toxicity and usually occurs within a few days of starting therapy but has been reported up to three years later.  Due to the increased subcutaneous fat, the most common sites of necrosis are breasts, abdomen, buttocks, calves and thighs.[15]

Blood levels of warfarin are neither readily available nor helpful. Specific levels of superwarfarin rodenticides (eg, brodifacoum) may be useful in cases in which the ingestion is denied or for purposes of estimating the necessary duration of vitamin K1 therapy. However, most reference laboratories do not perform this analysis. (National Medical Laboratory [NMS] in Willow Grove, Pa, offers qualitative tests for anticoagulant rodenticides and brodifacoum.)

The anticoagulant effect is best quantified by baseline and daily repeated measurement of the prothrombin time (PT) and the International Normalized Ratio (INR), which may not be elevated until 1-2 days postingestion.[11] A normal PT 48-72 hours after ingestion rules out significant ingestion.

Blood levels of vitamin K–dependent clotting factors (II, VII, IX, and X) are decreased if measured, but these are rarely available in a timely fashion and usually do not aid in clinical management. However, depressed levels may provide supporting evidence for suspected poisoning by warfarin or superwarfarins.[17]

Note that a "mixing study" using an aliquot of normal serum mixed with the patient's serum will restore an abnormal PT to normal. This may be useful when trying to distinguish anticoagulation caused by warfarin or a superwarfarin from that caused by a factor inhibitor (eg, lupus anticoagulant) or antifactor antibodies.[18]

Other laboratory tests that may be indicated include a blood count for baseline hemoglobin and/or hematocrit to assess for anemia if the ingestion is more remote. A blood type and crossmatch or antibody screening is indicated if substantial blood loss is suggested.  An absolute neutrophil count (ANC) of fewer than 100 neutrophils per microliter of blood is diagnostic for agranulocytosis.[14]  

In addition, other laboratory tests (eg, acetaminophen level) or toxicology screening may be indicated to rule out co-ingestions. If intracranial bleeding is suspected, obtain a noncontrast computed tomography (CT) scan of the head.

All patients with signs of active bleeding or at significant risk of life-threatening hemorrhage require admission to the hospital. Suicidal ingestions require psychiatric evaluation, as well as 48-72 hours of observation to monitor for anticoagulation. Significant superwarfarin poisoning may require many weeks of vitamin K1 therapy.[19]

With regard to prehospital emergency care, initiate usual supportive measures, including intravenous (IV) access if any suggestion of remote or active bleeding is evident. After an acute intentional ingestion, activated charcoal should be considered for clinically significant ingestions if it can be administered within an hour or two of the ingestion. Infuse crystalloid solution if signs of significant blood loss are present.

Initiate usual advanced supportive measures. Evaluate for current or remote bleeding with a thorough physical examination, including a rectal examination as indicated to check for occult gastrointestinal (GI) bleeding. If significant bleeding has occurred and the patient is unstable, be prepared to treat the patient with transfusions of packed red blood cells (RBCs), fresh frozen plasma (FFP), and intravenous (IV)/oral vitamin K1 as first-line therapy.[20] Further evaluation varies according to the situation.

Warfarin and superwarfarin ingestions may be acute or chronic. In either situation, determine whether the ingestion was unintentional or intentional and whether the patient requires long-term anticoagulation (eg, mechanical heart valve, chronic atrial fibrillation).

Acute ingestion

For acute ingestions, generally no evidence of bleeding is present on the initial clinical examination, unless the ingestion occurred more than 12-24 hours before emergency department (ED) presentation.

Obtain a baseline prothrombin time and international normalized ratio (PT/INR) and make arrangements for a repeat measurement in 24-48 hours. Administer activated charcoal for recent (within the last 1 - 2 hours) clinically significant ingestions. Gastric lavage is unnecessary if rapid administration of activated charcoal is feasible. Do not induce emesis.

Treat any co-ingestions, evaluate the patient for suicidal intention, and refer appropriately. Avoid drugs that may enhance bleeding or decrease metabolism of the anticoagulant.

Do not administer vitamin K1 prophylactically because (1) it is not needed in most patients, and (2) its presence masks the onset of anticoagulant effects in the few patients who do require prolonged treatment and follow-up care.

If the PT is elevated, treatment with vitamin K1 is appropriate; 10 mg orally is a reasonable daily dose. Since the pharmacologic effects of warfarin wear off within days, otherwise healthy patients with acute warfarin ingestions do not need supplemental vitamin K1 for more than several days. In the setting of superwarfarin-induced coagulopathies, 50-200 mg daily is recommended, and the duration of therapy may be many weeks.

Note that if a patient has a critical need for ongoing anticoagulation (eg, mechanical heart valve), heparin can be given as a temporary measure while the effects of warfarin are fully reversed.

Chronic intoxication

Chronic intoxication resulting from the therapeutic use of warfarin can be evaluated with a careful physical examination and a measurement of the PT and INR.

Chronic ingestions of rodenticide superwarfarin may also be intentional (eg, Munchhausen syndrome) or can occur in the setting of child abuse (Munchhausen by proxy).[21] These patients should be admitted for psychiatric or protective services evaluation.

If the INR is higher than therapeutic levels but less than 5 and the patient is not bleeding, the dose of warfarin may be lowered or the next dose may be omitted. If the patient requires more rapid reversal (eg, elective surgery), administer 1-2.5 mg of vitamin K1 orally with the expectation that the INR will begin to fall within 8 hours, with a maximal effect in about 24 hours.

If the INR is higher than 5 but less than 9 and the patient is not actively bleeding, withhold warfarin for the next 1 or 2 doses, monitor the INR more frequently, and resume therapy at a lower dose when the INR is at the therapeutic level.

Another therapeutic approach would be to withhold 1 dose of warfarin and orally administer vitamin K1, 1-2.5 mg, particularly if the patient is at increased risk of bleeding. For more rapid reversal (eg, urgent surgery), administer vitamin K1, 2.5-5 mg, orally (expected reduction of the INR should occur in about 24 h).

If the INR is higher than 9 and the patient is not bleeding, oral vitamin K1 (2.5 - 5 mg) may be administered with the expectation of a subtstantial reduction in the INR in 24 - 48 hours. In the setting of superwarfarin-induced coagulopathies, daily doses of vitamin K1 in the range of 50-200 mg is recommended.

Treatment of serious hemorrhage

Active, serious hemorrhage should be treated with four-factor prothrombin complex concentrate (PCC), if available.[16] While costly, an essential advantage PCC confers to emergency care is that, in contrast to FFP, it results in a more rapid reversal of coagulopathy and does not require thawing or blood group typing. Additionally,it has a reduced risk of volume overload, transfusion-related acute lung injury, transfusion reactions, and infectious disease transmission. Despite these advantages, no mortality benefit has been proven for PCC compared with FFP.

Alternatively, recombinant factor VIIa (rFVIIa) has been reported to be effective in rapidly lowering INR due to warfarin toxicity and may be considered if PCC is not available. FFP is effective at lowering the INR and was historically first-line therapy for warfarin toxicity with serious or life-threatening bleeding, although it has now been superceded by PCC, which lowers the INR more rapidly. If PCC or rFVIIa are not available, 4 units of FFP may be administered instead. 

Administer vitamin K1, 10 mg, by slow IV infusion. Using IV vitamin K1 is rarely associated with an anaphylactoid reaction. If that occurs, the infusion should be stopped for 15 minutes, diphenhydramine administered, and vitamin K1 then restarted at a lower infusion rate. 

Since most warfarin and superwarfarin exposures result in minor or no significant effects, regional poison control centers can aid in decreasing the referral of patients to health care facilities and in reducing the performance of unnecessary laboratory tests in minor, unintentional exposures. The poison centers and clinical toxicologists may be helpful in evaluating a large anticoagulant overdose and can assist with long-term follow-up care after ingestion of a superwarfarin.

Obtaining a psychiatric referral is appropriate for intentional ingestions. Contact child welfare or protective services if child abuse is suspected.

The patient's primary care provider or the local coagulation clinic is an appropriate referral if an unintentional overdose occurs and the patient is considered to be at low risk for bleeding complications.

Consulting a neurosurgeon is appropriate for intracranial hemorrhage. Consulting a gastroenterologist is appropriate for gastrointestinal hemorrhage.

If the patient has any type of hemorrhage that the current facility is not capable of managing appropriately, transfer to a higher level of care is indicated.

Patients who are already on warfarin, who have had an unintentional overdose, and who are hemodynamically stable with no evidence of active bleeding can follow up with their regular source of anticoagulation care. The frequency of routine INR monitoring for patients on stable warfarin dosing may be able to be extended further than every 4 weeks, depending on future studies.[22]

With acute warfarin ingestions, discharge instructions must address the risk of rebound coagulopathy, which may occur as long as 3 days afterward. Patients need to understand the importance of completing a full course of vitamin K1.[23]

Children with acute unintentional ingestions can be discharged home with follow-up care by their pediatrician in the office or by telephone at 48 hours. Most authorities no longer recommend routine follow-up PT measurement, because the incidence of significant anticoagulation in children after accidental exposure is extremely low.[9, 24, 25]

The American Society of Hematology (ASH) 2018 guidelines for management of venous thromboembolism include the following suggestions for management of excessive anticoagulation in patients taking warfarin[26] :

• For patients with an international normalized ratio (INR) of > 4.5 but < 10 and without clinically relevant bleeding, temporarily stop warfarin  without adding vitamin K.
• For patients with life-threatening bleeding and an elevated INR, discontinue warfarin and administer intravenous vitamin K plus 4-factor prothrombin complex concentrate (PCC) rather than fresh-frozen plasma (FFP).

For prothrombin complex concentrate (PCC), as a general guideline, a dosage of 50-100 units/kg IV at 12-hour intervals is recommended. The lower range is recommended for joint or mucous membrane bleeding. For soft tissue bleeding, 100 units/kg every 12 hours is recommended. For severe hemorrhage (eg, central nervous system [CNS] bleeding), 100 units/kg every 12 hours is recommended, although a more frequent dosing interval (ie, 6 h) may be indicated until clear clinical improvement is achieved.

Recombinant factor VIIa (rFVIIa; NovoSeven) has been shown to correct the international normalized ratio (INR) within hours.[27, 28, 29] Intravenous bolus doses in clinical trials for rFVIIa anticoagulation reversal have varied widely, from 5-320 mcg/kg. Mean doses ranged from 16.3-87.35 mcg/kg.

The potential benefits of rFVIIa or PCC over fresh frozen plasma (FFP) include faster administration (because rFVIIa and PCC do not have to be thawed), smaller infusion volumes, and decreased risk of transfusion-associated adverse reactions. However, no mortality benefit has yet been demonstrated for rFVIIa or PCC over FFP; studies have shown improvement only of secondary endpoints, such as intracranial hematoma size, total volume of blood products, and time to operative intervention.[28, 29, 30, 31]

FFP may be administered instead of PCC or rFVIIa if those therapies are unavailable. An FFP volume of 15 mL/kg (approximately 4 units in a 70-kg adult) is typically sufficient to reverse coagulopathy. Packed red blood cells may be transfused as needed for blood loss. 

Vitamin K1 is the only effective antidote for long-term management, but it takes several hours to reverse anticoagulation. Oral vitamin K1 has excellent bioavailability, is rapidly absorbed, and is recommended in the absence of serious or life-threatening hemorrhage.[32] Intramuscular or subcutaneous administration may cause hematoma in anticoagulated patients and offers no benefits over oral administration. Intravenous vitamin K1 has been reported to cause an anaphylactoid reaction but is the preferred route of administration for serious or life-threatening hemorrhage. 

Class Summary

Activated charcoal is empirically used to minimize systemic absorption of the toxin.

Vitamin K1 is used in the management of poisoning and overdose, in the prevention of toxic effects, and in metabolic disorders in which toxic substances accrue.

Activated charcoal (Actidose-Aqua, Char-Caps, Kerr Insta-Char)

Activated charcoal is the emergency treatment used for poisoning caused by drugs and chemicals. A network of pores present in activated charcoal adsorbs 100-1000 mg of drug per gram of charcoal. Activated charcoal does not dissolve in water.

Administer activated charcoal to patients who present 1-2 hours postingestion or to patients in whom co-ingestants may delay gastric emptying or gut motility; minimal benefit is expected if more than 4 hours have passed since the ingestion.

Phytonadione (MEPHYTON)

Phytonadione (Vitamin K1) can overcome competitive block produced by warfarin and other, related anticoagulants. (Note that vitamin K3 [menadione] is not effective for this purpose.) The clinical effect is delayed for several hours while liver synthesis of clotting factors is initiated and plasma levels of clotting factors II, VII, IX, and X are gradually restored.

Vitamin K1 is not to be administered prophylactically; use only if evidence of anticoagulation exists. The required dose varies with the clinical situation, including the amount of anticoagulant ingested and whether it is a short-acting or long-acting anticoagulant.

Class Summary

Fresh frozen plasma (FFP) has been the mainstay for urgent anticoagulation reversal in patients taking vitamin K antagonists (eg, warfarin). FFP requires blood group typing and thawing before use. Unlike plasma, human prothrombin complex concentrate does not require blood group typing or thawing and is administered in a significantly lower volume than plasma. Prothrombin does have a slightly higher risk for thromboembolic (TE) events compared with plasma, particularly in patients with a history of TE events.

Fresh frozen plasma

Each unit provides all plasma proteins and clotting factors to support adequate hemostasis to treat bleeding.

Prothrombin complex concentrate, human (Kcentra)

Contains Factors II, VII, IX, X, Protein C and S. It is indicated for urgent reversal of acquired coagulation factor deficiency induced by vitamin K antagonist therapy in adults with acute major bleeding.