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A. Vera-Arroyo and R. A. Zack-Guasp
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17. Garraud O, Tissot J-D. Transfusion, history and ethics: hun­dred years after WWI battleeld operations. Transfus Clin Biol [Internet]. 2019;26(1):1–2. Available from: https://doi.
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21. Chong MA, Krishnan R, Cheng D, Martin J. Should transfu­sion trigger thresholds differ for critical care versus perioperative patients? A meta-analysis of randomized trials. Crit Care Med. 2018;46(2):252–63.
22. Hovaguimian F, Myles PS. Restrictive versus liberal transfusion strategy in the perioperative and acute care settings. Anesthesiology. 2016;125(1):46–61.
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29. Karkouti K, Djaiani G, Borger MA, Beattie WS, Fedorko L, Wijeysundera D, et al. Low hematocrit during cardio­pulmonary bypass is associated with increased risk of perioperative stroke in cardiac surgery. Ann Thorac Surg. 2005;80(4):1381–7.
30. Hajjar LA, Vincent J-L, Galas FRBG, Nakamura RE, Silva CMP, Santos MH, et al. Transfusion requirements after car­diac surgery: The TRACS randomized controlled trial. JAMA. 2010;304(14):1559–67.
31. Mazer CD, Whitlock RP, Fergusson DA, Hall J, Belley-Cote E, Connolly K, etal. Restrictive or liberal red-cell transfusion for car­diac surgery. N Engl J Med. 2017;377(22):2133–44.
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34. Carson JL, Stanworth SJ, Alexander JH, Roubinian N, Fergusson DA, Triulzi DJ, etal. Clinical trials evaluating red blood cell trans­fusion thresholds: an updated systematic review and with additional focus on patients with cardiovascular disease. Am Heart J [Internet]. 2018;200:96–101. Available from:
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Substance Abuse andCoagulopathy
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MitchellC.Fuller, GeorgeM.Jeha, LuSun, AriunzayaAmgalan, IvanUrits, ElyseM.Cornett, andAlanDavidKaye
40
Introduction
Maintaining blood in a homeostatic liquid state is crucial for adequately supplying oxygen and nutrients to peripheral tis­sues. Conversely, when the body is exposed to vascular injury, it is a healthy physiologic adaptation for the blood to convert to a solid-state at the injurysite. This mechanism is called coagulation. Coagulation is a highly dynamic process largely determined by a balance of pro-coagulation factors, anticoagulants, and brinolysis [1]. The set of diseases that alter this intricate balance of bleeding and vessel thrombosis is called coagulopathies.
Coagulopathies are a highly concerning cause of morbid-
ity and mortality in hospitals that drive signicanteconomic
M. C. Fuller Froedtert Hospital, Medical College of Wisconsin, Milwaukee, WI, USA
G. M. Jeha LSU School of Medicine, Department of Anesthesiology, New Orleans, LA, USA
L. Sun · E. M. Cornett ( LSU Health Shreveport, Department of Anesthesiology, Shreveport, LA, USA e-mail: ecorne@lsuhsc.edu
A. Amgalan Georgetown University School of Medicine, Washington, DC, USA
I. Urits LSU Health Shreveport, Department of Anesthesiology, Shreveport, LA, USA
Beth Israel Deaconess Medical Center Harvard Medical School, Boston, MA, USA
A. D. Kaye Department of Anesthesiology and Pharmacology, Toxicology, and Neurosciences, Louisiana State University School of Medicine­Shreveport, Shreveport, LA, USA
LSU Health Shreveport School of Medicine, New Orleans, LA, USA
Tulane School of Medicine, New Orleans, LA, USA
*)
burden in our healthcare system. Common causes of coagu­lopathy are drug-related, drug-drug interactions, and nutra­ceutical agents. In this regard, nosebleeds, abnormal bruising, and GI bleeding are linked to oral anticoagulant use, while hemorrhoidal bleeding can be linked to drugs that cause con­stipation [2]. Additionally, several other factors contribute to drug-induced bleeding, including advancing age, polyphar­macy, drug-drug interactions, and coexisting medical condi­tions. As the chronic disease burden continues to rise, multiple medical regimen therapies are more commonplace than ever and can be directly related to abnormal bleeding states.
More recent clinical literature has linked illicit and recre­ational drug use to coagulopathy with signicant clinical consequences. Literature shows that recreational alcohol consumption is on the rise [3]. The role of alcohol on coagu­lopathy has been controversial, but it is currently hypothe­sized that alcohol has a bidirectional effect on coagulopathy and brinolysis [4].
In the setting of complex medication regimens and risk­adverse recreational drug use, patient education offers a rationale model for optimizing patient safety in both the hos­pital and outpatient settings. In particular, as an increasingly large number of drugs are introduced every year, it becomes no longer practical for the pharmacist to take sole responsi­bility of patient education or the physician to rely on mem­ory to avoid drugs, which may induce bleeding [5].
Therefore, a multidisciplinary approach is necessary to develop pharmacotherapeutic regimens designed to mini­mize bleeding risk, downstream morbidity, and economic and clinical burden. Patients undergoing surgical operations and procedures require adequate anesthesia consultation to ascertain whether the drugs and medications they are taking can increase therisk of bleeding and consequently increase therisk of morbidity and/or mortality.
This chapter discusses the prevalence of substance abuse and coagulopathies and focuses on in-depth assess­ment of patients, anesthesia considerations, and treatment strategies.
© Springer Nature Switzerland AG 2021 C. S. Scher et al. (eds.), Essentials of Blood Product Management in Anesthesia Practice,
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States ofCoagulopathy
Patients with liver disease may have complex alterations in procoagulant and anticoagulant proles resulting in increased risk ofbleeding and thrombosis [6]. This is fur­ther complicated by the etiology of liver disease, which may independently inuence hemostasis. For example, in addition to its propensity to lead to chronic liver disease and cirrhosis, hepatitis C virus (HCV) infection causes changes in hemostasis by disrupting vascular endothelium, altering procoagulant and anticoagulant pathways, and inuencing platelet function [7]. Furthermore, positivity for HCV is present in approximately 21% of HIV-infected adults [8, 9]. In patients such as these, the concomitant presence of liver cirrhosis, chronic HCV infection, HIV infection, and the potential presence of alcohol abuse, hep­atitis B virus (HBV) infection, malnutrition, or other comorbid conditions further complicate the hematologic balance. This makes it difcult to fully elucidate the etiol­ogy of coagulopathy.
Chronic liver disease is a signicantcause of morbidity and mortality in the United States and in the world, account­ing for 44,000 deaths nationally and two million deaths worldwide each year [10–12]. Approximately 4.5 million people are living with diagnosed liver disease [13]. Infection with HBV and HCV is a known risk factor for the develop­ment of chronic liver cirrhosis and cancer. The prevalence of HBV in the United States is approximately 0.35%, and most HBV-related deaths are due to hepatocellular carcinoma and decompensated cirrhosis [12, 14, 15]. The prevalence of chronic HCV infection in the United States is 1% [12]. It is estimated that up to 68% of chronic hepatitis C infections remain undiagnosed [16].
HIV infection is associated with an increased risk for thromboembolic events. Although the precise mecha­nisms behind this effect are inadequately understood, it is thought that prolonged inammatory states, chronic immune activation, and alterations in coagulation factors are contributing factors [17–19]. Thrombocytopenia is commonly associated with HIV, putting infected patients at increased risk for major bleeding events [20, 21]. The prevalence of HIV-related thrombocytopenia has decreased with the introduction of antiretroviral therapy (ART). In the pre-ART era, thrombocytopenia may have been present in up to 40% of patients with HIV [22]. In today’s era of highly active antiretroviral therapy, this number is likely between 0.6% and 15% [21, 23, 24]. Comorbidities such as hepatitis C virus infection and cir­rhosis are risk factors for thrombocytopenia in HIV­infected patients [20].
Drugs Associated withCoagulopathies
Synthetic Cannabinoids
The term “synthetic cannabinoids” describes a heterogeneous group of chemical compounds that functionally resemble Δ9­tetrahydrocannabinol (THC) [25]. The development of synthetic analogs of THC has been an area of interest ever since its dis­covery as the active ingredient in marijuana [26]. Given their ease of synthesis, low cost, high potency, and inability to be detected on routine drug screenings, synthetic cannabinoids have become attractive to the illicit drug market and, in recent years, have emerged as a popular alternative to marijuana. They are listed as Schedule I substances under the Controlled Substances Act, and due to lack of regulation, the composition of these substances is highly variable [27]. They have become commercially available in products sold on the Internet and in convenience stores and gas stations, often under the name of herbal blends, incense, and air fresheners with labels such as “not for human consumption.” [25, 28, 29]. Despite attempts to createlegislation controlling the production and distribution of these compounds, manufacturers commonly manipulate chemi­cal structures as necessary to evade legal ramications [29–33].
The lifetime prevalence of synthetic cannabinoid use is between 0.2% and 4% and peaks in the late teen years and early 20s [34]. These drugs tend to be popular among recre­ational cannabis users [35]. Among US, high school seniors, the annual prevalence of synthetic cannabinoid use is second only to cannabis [36]. Between 6% and 17% of US college students have used synthetic cannabinoids at least oncedur­ing their college years, and 1% of Europeans between the ages of 14 and 18have used synthetic cannabinoids at least once in their lifetime [37–39].
In the United States, there have been hundreds of cases of contamination of synthetic cannabinoids with long-acting anticoagulant rodenticides (LAARs) resulting in coagulopa­thy and bleeding complications. Synthetic cannabinoids received national attention in March and April of 2018 when the Illinois Department of Public Health reported an out­break of severe coagulopathies among patients with recent synthetic cannabinoid use [40]. Over 150 cases, including 5 deaths, were reported. Further investigation revealed that the coagulopathy was related not directly to the consumption of synthetic cannabinoids but rather to the contamination of the drugs with vitamin K antagonists such as brodifacoum, bro­madiolone, and/or difenacoum, agents used in commercially available rodenticides [25, 40–42]. In July of 2018, the US. Food and Drug Administration issued a press release warning of signicant health risks related to the use of syn­thetic cannabinoids contaminated with brodifacoum and
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other LAARs, stating that hundreds of patients have been hospitalized after consuming these products [29].
While the rationale for adulteration with LAARs is not clear, it isspeculated that the compounds either prolong or enhance the psychoactive effect of the drug [27, 43]. Among reported cases of coagulopathy associated with the use of synthetic cannabinoids contaminated with vitamin K antagonists, brodifacoum seems to be the most common contaminant [25].
To date, state health departments in Illinois, Maryland, Florida, Indiana, Kentucky, Missouri, Pennsylvania, Virginia, and Wisconsin have reported at a total of 202 cases of acci­dental brodifacoum poisoning [40, 42]. The exact prevalence of synthetic cannabinoid-associated coagulopathy is unknown. However, given the relative lack of awareness and the illicit nature of the topic, it is not unquestionable that the total number of cases remains underrepresented [41].
Alcohol
Alcohol is a commonly used substance. According to the 2017 National Survey on Drug Use and Health, in the United States, 86.3% of people report that they have used alcohol at some point in their lifetime, and 70.1% report using it in the past year. An estimated 14.1 million people aged 18 and older have alcohol use disorder [44, 45]. Alcohol is responsible for as many as 88,000 deaths annually, making it the third lead­ing cause of preventable death in the United States [46].
Alcohol is a known hepatotoxin that cancause hepatitis, steatosis, brosis, cirrhosis, and liver cancer [47, 48]. Additionally, alcohol consumption has been shown to affect the vascular endothelium, platelets, and the brinolytic sys­tem [49, 50]. Liver cirrhosis is associated with both increased bleeding risk due to abnormalities in procoagulant and anti­coagulant protein synthesis and a prothrombotic state due to the systemic inammation associated with liver dysfunction [51]. In a prospective study of over 48,000 men, alcohol con­sumption was associated with an increased risk of major gas­trointestinal bleeding [52]. The number of annual deaths due to alcoholic liver disease is approximately 14,000 [53].
Patient Assessment
The rst step in theclinical evaluation of a patient with sus­pected substance abuse is to perform an assessment – the next step is to treat, which will be covered later in this chap­ter. Depending on the clinical setting, there are two forms of initial substance abuse workup: assessment and screening.
Screening is a process used in primary care to evaluate the possible presence of a substance abuse problem generating a simple “yes” or “no” answer (i.e., CAGE, AUDIT, and TCUDS II alcoholism questionnaires) [ assessment is a process for dening the nature of the prob­lem, determining the diagnosis, and developing treatment recommendations. An array of assessment tools are typically employed in anesthesia, intensive care, and emergent care settings to treat high-acuity patients and will be the subject of interest herein.
54]. Conversely,
Normal Blood Homeostasis andClinical Evaluation
A review of normal clot physiology will help make sense of the substance-induced disease states to follow in this review. There are two clotting pathways, the extrinsic pathway and theintrinsic pathway, that meet to form the common pathway. The extrinsic pathway is activated by endothelial secreted tis­sue factor (TF). In contrast,the intrinsic pathway is activated when vascular endothelium is damaged, exposing subendo­thelial type IV collagen, von Willebrand factor (vWF), and other negatively charged surfaces [55]. The extrinsic pathway involvesa waterfall-type coagulation cascade of plasma factor VII and the common pathway. The intrinsic pathway is the long pathway made up of a similar coagulation cascade of plasma factors XII, XI, IX, and VIII, and the common path­way. The elaboration of both the intrinsic and extrinsic path­ways is the common pathway summarized as a coagulation cascade of plasma factors X and V, thrombin (factor II), and insoluble brin clots (factor I) [56]. Alterations in brin clot homeostasis by exogenous substances (e.g., drugs) can induce clot formation and if left untreated, may progress to dissemi- nated intravascular coagulopathy (DIC). DIC characterizes a group of systemic processes, not a single disease entity repre­senting a pathologic balance between coagulation factor/plate­let consumption and production leading to organ damage [56]. It is clinically imperative to understand the mechanisms of substance- induced coagulopathies to perform thorough clini­cal assessments.
Clinicians utilize a host of clinical tools to assess blood homeostasis and coagulopathies. Relevant labs include a complete blood count, clotting time assays (aPTT, PT, TT), individual clot-based assays (plasma brinogen, factor V), chromogenic assays (factor VIII), and cross-linked brin assays (D-dimer). Prothrombin time (PT) measures the time it takes plasma to clot post-exposure to TF, otherwise known as the extrinsic and common pathways, and is an easy rst laboratory to measure, especially in patients who will be
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Table 40.1 Parameter changers in setting of acute disseminated intra-
vascular coagulopathy (e.g., substance-induced coagulopathy)
Parameter Acute DIC Platelet count Reduced Prothrombin time Prolonged Activated partial thromboplastin time (aPTT) Prolonged Thrombin time Prolonged Plasma brinogen Reduced Plasma factor V Reduced Plasma factor VIII Reduced Fibrin degradation products Elevated D-dimer Elevated
undergoing surgical procedures or interventional pain proce­dures with appropriate histories or taking known medica­tions that alter the coagulation cascade. INR is also a gold standard for monitoring warfarin and is simply the individu­al’s PT/control subjects PT.A normal PT is 11–13seconds. The activated partial thromboplastin time (aPTT) measures the time it takes plasma to clot when exposed to substances that activate contact factors known as the intrinsic and com­mon pathways. A normal aPTT is 25–35seconds. Thrombin time (TT) measures the nal step of coagulation, conversion of brinogen to brin, and is usually 14–19seconds. Clot­based assays assess a single clotting factor, like factor V or brinogen, by running a normal PT/aPTT assay with plasma decient for a single factor. Slightly different,the chromo­genic assay uses thecleavage activity of a colored/chromo­genic substrate against a calibration curve to determine thepercent activation of a particular clotting factor. Factor VIII chromogenic assays can be used to rule out haemophilia A (deciency of factor VIII). Finally, brin degradation products assays – such as d-dimer – are ordered as non­specic markers to evaluate for the presence of thrombi.
If a drug inhibits the normal coagulation cascades clotting time will increase resulting in prolonged clotting times (aPTT, PT, TT). Table 40.1 displays the changes in blood homeostatic lab values when exposed to a drug that progress to a state of DIC characterized by a consumption of coagula­tion factors.
Clinical Management ofDrugs Associated withCoagulopathies
Synthetic Cannabinoids
The clinical management of toxicities associated with syn­thetic cannabinoids is a challenge [57]. Current guidelines for reversal of LAAR-associated bleeding include adminis­teringblood products if necessary and vitamin K1 (phyllo­quinone/phytonadione) and adjusting doses based on close monitoring of coagulation assay values, clinical presenta­tion, and serum LAAR concentrations [27, 57–65]. For acute
severe bleeding with elevated INR, the recommendation is to give fresh frozen plasma or four-factor prothrombin complex plus intravenous vitamin K, check INR every couple hours, and repeat or adjust dose if INR remains elevated [
58, 62– 66]. Lowering vitamin K dose should be considered when
INR returns to normal and serum levels of brodifacoum become non-detectable, keeping in mind that coagulopathy may persist even at this point [57, 62–64]. Most recently, in 2019, the Johns Hopkins Health System published a protocol for the acute treatment of LAAR toxicity; the protocol effec­tively reducedINR below twowithin 24 hours in 75% of patients in their study [27]. A few case reports indicated use of recombinant activated factor VII as an alternative for acute treatment of LAAR-associated coagulopathy, but it has a relatively short duration of action (around 3hours), and there is limited data available on the effectiveness of this therapy [67, 68]. Given the long half- lives of LAARs and the possi­bility of persistent or recurrent coagulopathy, acute care needs to be followed with long-
term maintenance therapy with vitamin K [62–64]. The management of LAAR coagu­lopathy is similar to management of warfarin overdose, but since LAARs are more potent than warfarin, patients with LAAR toxicity require higher doses of vitamin K [27]. Exogenous administration of vitamin K, with doses ranging from 20 to 600mg/day, is required to treat LAAR-induced coagulopathy, but determining the exact dosing and duration of treatment is difcult due to the potency and long-half lives of LAARs [27, 62–64]. Depending on the degree of toxicity and LAAR serum levels, long-term daily administration of vitamin K may be required for weeks to over 1year [57]. In addition to the typical treatment regimen for LAAR coagu­lopathy reversal, case reports have used phenobarbital, a cytochrome P450 inducer, to accelerate brodifacoum clear­ance, but the interactions of phenobarbital with vitamin K and safety data have not been established [69, 70]. For this reason, a 2019 review advises against the use of cytochrome P450 inducers for now until there is more research available to suggest otherwise [70]. An important complication to con­siderwith cases of LAAR- induced hemorrhage is paradoxi­cal thrombosis, which has been described in case reports [71–74]. Paradoxical thrombosis may be the result of early depletion of anticoagulant proteins C and S caused by LAAR or a complication of blood product transfusion therapy [71–
74]. Effective management of patients with suspected LAAR
toxicity requires careful examination of risk-benet, factor levels, coagulation assays, and clinical presentation.
Nutraceuticals
There has been an explosion of over-the-counter products over the past two decades that are affordable and accessible and have not gone through the rigors required to achieve drug
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status. Many of these agents are marketed as wonder agents that can restore vitality and aid in complex medical condi­tions with limited therapies. In a study performed by Kaye etal. 70% of patients did not disclose that they were taking herbal products during routine anesthesia preoperative assess­ment. Furthermore,the prevalence of taking one or more of these herbal products was roughly one-third of the population scheduled to undergo surgery or a pain procedure [75]. In this regard, the kava plant, aloe vera, black cohosh, cascara, chap­arral, comfrey, ephedra, and many other herbal products com­monly sold worldwide over the counter have been linked to liver damage. Acetaminophen, aspirin, ibuprofen, and naproxen are examples of common over-the-counter analge­sic that are linked to liver damage in a dose- dependent manner.
Alcohol
Alcohol use disorder is associated withtrauma, liver cir­rhosis, and end-stage liver damage (ESLD), which leads to massive reduction of pro- and anticoagulant factors. Additionally, previous studies showeda direct association between alcohol and coagulopathy in thetrauma patients [76]. Therefore, proactive treatment of alcohol use disor­der is anecessary prophylaxis to a subset of coagulopa­thies. Examples of prophylaxis include medication, psychosocial treatment, or both, depending on the sever­ity of alcohol use disorder. For amild disorder, the effec­tiveness of medication is unclear; thereby appropriate psychosocial treatments are recommended, includ­ingmotivational interview, brief intervention, cognitive­behavioral therapy, residential treatment, mutual help group, and contingency management [77–79]. For moder­ate-to-severe disorders acombination of medication and proper psychosocial treatment areefcacious. Naltrexone and acamprosate are two commonly used medications to treat alcohol use disorder. Meta-analysis studies have shown no difference in efcacy between them [80, 81]. However, naltrexone may be a preferred choice for newly diagnosed patientsbecause patients can initiate the admin­istration while still drinking. Also, patients may be more compliant with naltrexone than acamprosate because they take one pill daily for naltrexone but two pills three times a day for acamprosate. On the other hand, in patients who are comorbid with liver damage (e.g., acute hepatitis and liver cirrhosis) due tochronic alcohol use disorder, acam­prosate is the favored treatment because it is excreted mostly through the kidney rather than metabolized by the liver. In patients with liver cirrhosis, baclofen is consid­eredsafe andis associated witha higher abstinence rate. However, there is a lackof evidence regardingthe efcacy of baclofen [82].
When surgical operations become necessary, patients with alcohol use disorder and cirrhosis are at higher risk in perioperative settings. Examples include aspiratory pneumo­nia, difculty in thetitration of oxygen, thespecial require­ment of uid and electrolytes, hypotension caused by dehydration, and wound infection due to immunosuppres­sion [
83]. Alife-threatening postoperative complication is
delirium tremens, which manifests as hallucinations, disori­entations, tachycardia, hypertension, hyperthermia, agita­tion, and diaphoresis [84]. The rst-line treatment is intravenous long-lasting benzodiazepines (e.g., diazepam and chlordiazepoxide) combined with supportive care. However, lorazepam and oxazepam are favored to treatpatients with acute hepatitis or liver cirrhosis sincetheir short-acting mechanism prevents oversedation.
When liver cirrhosis and the consequent liver failure develop due tochronic alcohol use disorder, balance between pro- and anticoagulant factors is disrupted, which may lead to coagulopathy and high bleeding risk. It is classically assessed by standard coagulation laboratory test in which prothrombin time (PT) is longer than 18seconds, the acti­vated partial thromboplastin time (aPTT) is longer than 60 seconds, the international normalized ratio (INR) is higher than 1.5, or any of these values is higher than 1.5 times of the laboratory reference value [ them, the prolongation of the aPTT is more specic for diag­nosis. Point-of-care techniques, including thromboelastogra­phy (TEG) and rotational thrombelastometry (RoTEM), measure the integrated viscoelastic properties of clot forma­tion [76]. Vitamin K deciency is often seen in decompen­sated liver cirrhosis. Injection of 10 mg vitamin K forthreedays is considered anadequate supplement to cor­rect vitamin K deciency-induced coagulopathy [87].
In trauma patients with massive hemorrhage, volume resuscitation with crystalloid and colloid is the rst step to stabilize systemic circulation, although large-volume infu­sion may further dilute the concentrations of erythrocytes (RBC), coagulant factors, and platelets. Therefore, fresh fro­zen plasma (FFP) is often co-administered with packed RBC and platelet with a ratio of 1:1:1 [88, 89]. FFP contains pro­and anticoagulant factors, antibrinolytic factors, albumin, and immunoglobin. FFP infusion offers fast compensation of coagulant factors, but associated risks such as acute lung injury, viral infection, exposure to immunoglobulin, and vol­ume overload should be noted [90]; especially in patients with liver cirrhosis and ESLD, since potential volume over­load may exacerbate the portal venous pressure [91].
Prothrombin complex concentrate (PCC) contains highly concentrated factors II, VII, IX, and X and small amounts of protein C and S, heparin, and antithrombin. It has been usedto treat hereditary deciency of coagulant factors men­tioned above and rapidly reverse the effects of vitamin K antagonism (warfarin) [92]. PCC does not easily cause vol-
85, 86]. Among
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ume overload like FFP, and it has also been suggested to be superior to FFP in thrombin generation, which facilitates brin production [93]. Additionally, PCC is suggested to be not associated with the increased risk of thrombosis [94]. Therefore, PCC may be a good candidate in treating coagulopathy in patients with ESLD who are already at higher risk of venous thrombosis.
Recombinant FVII (rFVII) is commonly used, but its ef­cacy has become controversial. It isbenecial forobstetric hemorrhage and blunt trauma, where rFVII helped reduce massive transfusion without increased thromboembolic complications [90]. However, other studies suggested that rFVII may increase thromboembolic risk [54]. Given the inconsistent results from different studies, rFVII may be rec­ommended only when other therapies fail.
The hyperbrinolytic state that worsens bleeding has been discovered in patients with trauma and liver cirrhosis, probably due to the altered level of plasminogen activator inhibitor-1 [95]. Thus, antibrinolytics are potentially bene­cial in the situations of active bleeding and hemodilution. Currently available antibrinolytics include lysine analogs, e-aminocaproic acid, and tranexamic acid. They strengthen the weak brin clots that are otherwise susceptible to plas­min. Lysine analogues have been reported to reduce blood loss and the need for RBC transfusion in cardiac, orthopedic, and hepatic surgery [96]. Randomized placebo-controlled trials have demonstrated the efcacy of tranexamic acid in thereduction of patient mortality [90].
Venous thrombosis is another primaryconcern in patients with liver cirrhosis and ESLD, due to the imbalance of the pro- and anticoagulation processes. Prevention of deep venous thrombosis and pulmonary embolism can be per­formed both mechanically and pharmacologically. Compression stockings and pneumatic compression exem­plify the former. Commonly used pharmacological anti­thromboembolic prophylaxis includes enoxaparin, low-weight-molecular heparin, warfarin, and direct oral anti­coagulants [54].
tributors to drug-induced coagulopathies. There have been hundreds of cases of contamination of synthetic cannabinoids with long-acting anticoagulant rodenticides (LAARs), in the United States alone, resulting in coagulopathy and bleeding complications. Alcohol is a known hepatotoxin; however, alcohol consumption has been shown to affect the vascular endothelium, platelets, and the brinolytic system. Additionally, patients with liver disease may have complex alterations in procoagulant and anticoagulant proles result­ing in an increased riskof bleeding and thrombosis.
The rst step in theclinical evaluation of a patient with suspected substance abuse is to perform an assessment. Screening is a process used in primary care to evaluate the possible presence of a substance abuse problem. Clinicians utilize a host of clinical tools to assess blood homeostasis and coagulopathies. Relevant labs include a complete blood count, clotting time assays (aPTT, PT, TT), individual clot­based assays (plasma brinogen, factor V), chromogenic assays (factor VIII), and cross-linked brin assays (D-dimer). Concerning treatment, proactive treatment of alcohol use disorder is a necessary prophylaxis to a subset of coagulopa­thy. This can be achieved by medication, psychosocial treat­ment, or a combination of both, depending on the severity of alcohol use disorder. When surgical operations become nec­essary, patients with alcohol use disorder and cirrhosis are at a higher risk for perioperative complications. The clinical management of toxicities associated with synthetic cannabi­noids is a challenge. Current guidelines for reversal of LAAR-associated bleeding include administering blood products if necessary and vitamin K1 (phylloquinone/phyto­nadione) and adjusting doses based on close monitoring of coagulation assay values, clinical presentation, and serum LAAR concentrations. Ultimately, however, patient educa­tion about substance abuse and the potential for exacerbated existing coagulopathies or the development of coagulopathy is the most criticaltool healthcare providers can utilize.
Summary andConclusion
Coagulation is a dynamic process primarilydetermined by a balance of pro-coagulation factors, anticoagulants, and bri­nolysis. One particular cause of coagulopathy – drug induced bleeding – has gained attention because of increasing drug use, drug-drug interactions, and natural medicines. Drug­induced bleeding is commonly thought of as gastrointestinal bleeding after NSAID use. Still several other factors contribute to drug-induced bleeding including advancing age, nutraceuticals, polypharmacy, drug-drug interactions, and coexisting medical conditions. Recent clinical literature sug­gests that alcohol and synthetic cannabinoids are large con-
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