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K. Gress et al.
transmission reaching 1, 4.3, and 2.5 infections per 1000units
of blood, respectively [7]. In high-income countries, these
rates are approximated to be 1in 2 million, 1in 100,000, and
1in 2.5 million, respectively [7]. Unfortunately, these infection rates likely underestimate true transmission of disease
since acquired viruses can be passed on via a wave of secondary infections [1]. As of 2016, antibody to HCV is not
part of routine blood screening in many parts of Africa, and
only a small proportion of blood banks use enzyme-linked
immunosorbent assay (ELISA) kits for HBsAg because testing is not considered cost-effective given the endemic nature
of the virus [1]. The delicate interplay between quantity and
quality of supply is exemplied by malaria, a leading cause
of anemia requiring transfusion in Africa that can also be
transmitted by transfusion [1]. Despite the morbidity and
mortality associated with malaria, excluding donors with
low-grade parasitemia in endemic areas has the potential to
signicantly reduce supply of available blood [1]. Of note, it
is equally important for DGCs to assure quality of blood
products by pairing donors and recipients using appropriate
blood groupings and crossmatching techniques [5]. Infection
by bacterial components secondary to blood bank contamination and breakdown of the cold chain, often due to frequent power cuts during transport, are factors that are
frequently overlooked yet have a signicant capacity to
decrease quality of available supply [1].
Looking Ahead: Solutions
andRecommendations
The approaches that are typically used to secure an adequate
supply of high-quality blood in high-income countries are
not necessarily appropriate, validated, or practical for implementation in DGCs [8]. In DGCs, realistic solutions must
encourage reliance on local resources, establish networks for
research and education, and promote use of guidelines and
audits for gradual improvement of clinical practice [1]. In
many countries where inadequate supply and lack of funding
are signicant obstacles, progress can be made by reorganizing existing systems [4]. First, transfusion medicine should
be integrated into the national health-care system [1, 4].
Second, a national blood policy must be created to dene the
organization(s) responsible for providing blood services,
means of funding these services, acceptable forms of donation, and regulations for conducting procurement and transfusion [4]. Unfortunately, in 2016 while nearly all African
states had established a national blood policy, more than half
were unable to implement their policies [1]. In many cases,
inability to carry out a national blood policy stems from a
system of organization that relies on the ability of hospitals
to run their own blood services without national control or
coordination [4]. The International Foundation of Patient
Blood Management (PBM) structures the development of a
successful PBM program around the idea of “giving the right
blood products in the right amount to the right patient at the
right time” [
transfusion guidelines, appropriate education and training
for clinical staff, and feedback mechanisms for evaluating
appropriateness of transfusion [9]. Using this framework,
countries like Uganda have been able to develop patient
blood management (PBM) programs featuring national oversight committees and standard operating procedures within
individual hospitals [9]. Currently, most sub- Saharan African
countries, including Uganda, are in the early stages of developing PBM programs [9].
9]. It provides formal recommendations for
Bolstering Supply
It is important to keep in mind that at present, approximately
80% of the world has access to only 20% of the world’s
blood products [10]. Unfortunately, the best way to bolster
supply is to encourage repeat donation by non-remunerated
voluntary donors who, in a study of 2880units of blood in
Egypt, have been demonstrated to have signicantly better
health proles than replacement or remunerated donors [11].
While it is difcult to motivate donors, entities like the
Federal Ministry of Health in Nigeria have seen success by
engaging the media and televising donations by public gures [1]. Nigeria has also implemented strategies such as
Club 25 to recognize donors under the age of 25years, while
Zimbabwe created the Pledge 25 Club, a program that uses
education incentives to attract students to give blood 25
times [1]. In India, issues in access resulting from a dispersed
population were addressed by the institution of a system of
“walking blood banks,” which consists of a pool of preapproved, healthy donors who can be recruited by rural hospitals to provide a reliable and timely supply of blood [12,
13]. Educational programs and materials created by the Red
Cross and the WHO have proven helpful in dispelling apprehensions and false beliefs about the process of blood donation, especially in rural areas [1, 5]. It is likely that the most
effective approaches for recruiting new donors and converting replacement donors to become repeat donors will involve
the combined efforts of local and international organizations.
Going hand in hand with augmentation of supply is reduction of waste. Some surgical procedures are associated with
an inherent risk of blood loss and typically require preemptive crossmatching of blood, but this blood is often
wasted at a cost of approximately $40 per unit [14]. Studies
out of Britain recommend that crossmatching be performed
only if audits suggest that there is a greater than 50% likelihood that the unit will be used. This practice, along with the
general practice of auditing usage of blood supply, is likely
to promote better stewardship of available products [14].
46 Blood Product Management inDeveloping Countries
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441
Decreasing Demand
A signicant proportion of the blood requirement in DGCs is
dedicated to the treatment of anemia, especially in children.
In South Africa, the prevalence of anemia is estimated to be
31% in females and 17% in males [15]. While many of these
cases of anemia require treatment, demand can be managed
by considering alternative interventions such as use of hematinics for the treatment of nutritional anemia and stimulation
of erythropoiesis prior to resorting to transfusion [5, 15].
Similarly, treatment with hydroxyurea can be used to
decrease transfusion requirements in sickle cell anemia, and
high-hematocrit placental blood can be useful for smallvolume emergency transfusion in cases of neonatal anemia
[1]. Novel strategies have also been developed to reduce
excessive rates of exchange transfusions in infantile hyperbilirubinemia [16, 17]. It is proposed that formally assessing
total serum bilirubin and clinical signs of encephalopathy
allows for better prediction of kernicterus risk, reducing
transfusion requirements and improving overall health outcomes [17]. In cases of trauma associated with signicant
blood loss, investigations like the Clinical Randomisation of
an Antibrinolytic in Signicant Haemorrhage (CRASH-2)
study demonstrated that tranexamic acid, an antibrinolytic,
reduces all- cause mortality by 10% when administrated
within 3hours of the initial trauma [1]. Per PBM recommendations, minimizing blood loss through anesthetic and surgical techniques as well as optimizing coagulation status
before and during procedures is essential to reducing blood
requirements in both emergency and scheduled operations
[15]. Educating transfusion prescribers about appropriate
protocols and available alternatives such as saline and colloids may also help decrease demand [5]. Given that strict
enforcement of a transfusion protocol in a Malawian hospital
reduced transfusion numbers by 75%, it is possible that
implementation of these innovative interventions in conjunction with strict transfusion guidelines may help signicantly
decrease demand for blood and blood products in DGCs
without negatively impacting mortality [1].
Improving Quality
There are two main strategies for improving quality of available blood and blood products: pre-donation testing and
post-donation pathogen reduction. Recommendations for
blood product monitoring include testing for direct antiglobulin and screening all donations for HIV, HBV, HCV, and
syphilis, as well as regional pathogens such as arboviruses,
Trypanosoma cruzi, and human T-lymphotropic virus [1, 5,
18]. Unfortunately, the specicity, sensitivity, ease of use,
and costs associated with anti-HIV, anti-HCV, and HBsAg
testing vary [1]. For instance, widespread use of nucleic acid
testing (NAT) is limited in most DGCs by cost [1, 11].
Fortunately, more cost-effective substitutes for NAT such as
the use of two anti-HIV ELISA tests performed in parallel
are being investigated [1]. Similarly, there are data out of
Egypt suggesting that core antigen testing is more effective
than RNA testing for determining the presence of HCV without sacricing specicity [18]. Rapid immunochemical tests,
such as that developed for the HIV antibody, are under development for other infectious agents [1]. The development of
these tests has the potential to cut costs by decreasing the
need for highly skilled staff and advanced processing equipment [1]. Alternatively, researchers are considering the
option of prophylactically treating recipients of red blood
cells (RBCs) in endemic regions with antimalarial agents
instead of excluding donors with low-grade parasitemia [1].
Pathogen reduction refers to a series of interventions that
involve using heat or alcohol fractionation to eliminate viral
components from plasma products. Pathogen reduction is
promising but cannot be used for whole blood or packed
RBCs and is associated with logistic concerns such as cost
and requirements for complex equipment and skilled personnel [19]. It is important to note that as long as the prevalence
of these viruses remains high, residual risk of transmission
will not decrease even in the setting of adequate testing given
the existence of the window period [1]. Thus, while it is
important to channel efforts into developing adequate screening protocols, it is equally if not more vital to address availability of antiretroviral therapy.
References
1. Roberts DJ, Field S, Delaney M, Bates I.Problems and approaches
for blood transfusion in the developing countries. Hematol Oncol
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2. Oladapo O, Adetoro O, Ekele B, Chama C, Etuk S, Aboyeji A, etal.
When getting there is not enough: a nationwide cross-sectional
study of 998 maternal deaths and 1451 near-misses in public tertiary
hospitals in a low-income country. BJOG. 2016;124(6):928–38.
3. WHO.Model list of essential medicines. 21st ed. 2019.
4. Koistlnen J.Organization of blood transfusion services in develop-
ing countries. Vox Sang. 1994;67:247–9.
5. Gibbs WN, Corcoran P.Blood safety in developing countries. Vox
Sang. 1994;67:377–81.
6. Abdel Jalil AA, Katzka DA, Castella DO.Approach to the patient
with dysphagia. Am J Med. 2015;18(10):1138–42.
7. Jayaraman S, Chalabi Z, Perel P, Guerriero C, Roberts I. The
risk of transfusion-transmitted infections in sub-Saharan Africa.
Transfusion. 2010;50(2):433–42.
8. Custer B, Zou S, Glynn SA, Makani J, Tayou Tagny C, El Ekiaby
M, et al. Addressing gaps in international blood availability and
transfusion safety in low- and middle-income countries: a NHLBI
workshop. Transfusion. NLM (Medline). 2018;58:1307–17.
9. Eichbaum Q, Murphy M, Liu Y, Kajja I, Hajjar LA, Sibinga CTS,
et al. Patient blood management: an international perspective.
Anesth Analg. 2016;123(6):1574–81.
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10. Gani F, Cerullo M, Ejaz A, Gupta PB, Demario VM, Johnston FM,
etal. Implementation of a blood management program at a tertiary
care hospital. Ann Surg. 2019;269(6):1073–9.
11. Abdelrazik AM, Ezzat Ahmed GM. Priority needs and wisdom
strategy for blood transfusion safety in developing low-resource
countries. Transfus Apher Sci. 2016;54(1):147–9.
12. Sood R, Raykar N, Till B, Shah H, Roy N.Walking Blood Banks:
An immediate solution to rural India’s blood drought. Indian J Med
Ethics. 2018;III(2):134–7.
13. Selvakumar S, Shahabudeen P, Paul RT. An analysis of recongured blood transfusion network of urban India to improve the
service level: a simulation approach. J Med Syst. 2019;43(2):28.
14. Faridi S, Ahmad A, Beg MA, Siddiqui F, Edhi MM, Khan
M.Arranging blood for elective thyroid surgeries: dilemma continues in the developing world. BMC Res Notes. 2017;10(1):1–2.
15. Althoff FC, Neb H, Herrmann E, Trentino KM, Vernich L,
Füllenbach C, etal. Multimodal patient blood management program
based on a three-pillar strategy. Ann Surg. 2019;269(5):794–804.
16. Chhapola V, Sharma AG, Kanwal SK, Kumar V, Patra B.Neonatal
exchange transfusions at a tertiary care centre in North India: an
investigation of historical trends using change-point analysis and
statistical process control. Int Health. 2018;10(6):451–6.
17. Olusanya BO, Iskander IF, Slusher TM, Wennberg RP.A decisionmaking tool for exchange transfusions in infants with severe
hyperbilirubinemia in resource-limited settings. J Perinatol.
2016;36(5):338–41.
18. Abdelrazik AM, Abozaid HE, Montasser KA.Role of Hepatitis C
Virus (HCV) core antigen in improving blood transfusion safety
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Transfus Apher Sci. 2018;57(4):566–8.
19. Ware AD, Jacquot C, Tobian AAR, Gehrie EA, Ness PM, Bloch
EM. Pathogen reduction and blood transfusion safety in Africa:
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Considerations and Guidelines for Use
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of Anticoagulants and Antithrombotics
in Patients Undergoing Interventional
Pain Management
Jordan S. Renschler, Amanda L. Granier, George M. Jeha,
John E. Scheinuk, Matthew E. Nungesser, Joshua M.
Etienne, Abigail P. Erwin, Chrissy Cherenfant, Uchenna
Umeh, Michael P. K. Webb, Erik M. Helander,
and Alan David Kaye
47
Introduction
Chronic pain is increasingly treated via interventional pain
management. This is an emerging specialty involving procedures used to both diagnose and to treat patients. In most
interventional pain management cases, the procedures are
performed percutaneously. Additionally, regional anesthesia
and perioperative analgesia are percutaneously administered,
all of which carry risks germane to bleeding [1]. Patients
themselves may also have genetic risks of bleeding, and both
inherent and the iatrogenic anticoagulated merit additional
consideration for interventional techniques.
Procedures involving interventional pain management
and regional anesthesia all can be signicantly complicated by altered hemostasis. To address the risk of bleeding and hematomas following regional and neuraxial
techniques, the American Society of Regional Anesthesia
published guidelines, with the most recently updated
guidelines from 2018 [2]. Importantly, several studies have
J. S. Renschler · A. L. Granier · G. M. Jeha · J. E. Scheinuk
M. E. Nungesser · J. M. Etienne · A. P. Erwin · E. M. Helander
Department of Anesthesiology, LSUHSC New Orleans,
New Orleans, LA, USA
e-mail: jrensc@lsuhsc.edu; gjeha@lsuhsc.edu; mnunge@lsuhsc.edu;
ehelan@lsuhsc.edu
C. Cherenfant
NYU Langone Health, NYU Langone Orthopedic Hospital,
Department of Anesthesiology, Perioperative Medicine, and Pain
Medicine, New York, NY, USA
U. Umeh
NYU Langone Orthopedic, Department of Anesthesiology,
Perioperative Care and Pain Medicine, New York, NY, USA
e-mail: Uchenna.umeh@nyulangone.org
© Springer Nature Switzerland AG 2021
A. D. Kaye, S. Leavitt (eds.), Essentials of Blood Product Management in Anesthesia Practice,
https://doi.org/10.1007/978-3-030-59295-0_47
offered conicting recommendations that the guidelines
seek to reconcile, especially in the setting of increasingly
potent antithrombotic medications.
Interventional pain management is outpatient-oriented
with a greater overall variety of procedures [3]. Although the
ASRA guidelines address numerous important risks, they
were not intended for interventional pain practitioners. In
response, a summary of the literature and bleeding risk
stratication was developed and updated for interventional
pain physicians [1]. As in all procedures, the procedure’s
therapeutic benet must outweigh the risk involved when
assessing for the risk of bleeding in patients. Ultimately, the
practitioner must make an informed decision about whether
to continue the procedure after evaluating and analyzing the
risks and benets involved. To do so, the practitioner must
understand coagulation physiology, pathophysiological
mechanisms of bleeding disorders, anticoagulation
pharmacology, and the technical risks associated with
individual procedures.
M. P. K. Webb
Middlemore Hospital, Department of Anaesthesia and Pain
Medicine, Auckland, New Zealand
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
e-mail: akaye@lsuhsc.edu
*)
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J. S. Renschler et al.
Coagulation Physiology
Normally, a balance exists between hemostasis and bleeding,
maintaining an equilibrium. To keep this equilibrium, there
are complex interactions between activators, cofactors, and
inhibitors. Three processes essentially comprise the overall
process of hemostasis: (1) primary hemostasis, (2) secondary
hemostasis, and (3) brinolysis.
Primary hemostasis results in a weak platelet plug, making platelets crucial to this step [4]. Needle trauma to the
vascular endothelium induces the creation of a friable platelet plug to arrest bleeding. When the underlying extracellular
matrix is exposed during endothelial injury, platelets change
in a series of phases: adhesion, activation, and aggregation.
This process resulting in platelet deposition is known as primary hemostasis.
Platelets are derived from fragments of bone marrow
megakaryocytes and are surrounded by a coat of glycoproteins critical to the process of adhesion to the vascular endothelium. Upon endothelial injury, a subendothelial protein
called von Willebrand factor (vWF) is exposed. Platelets
express a glycoprotein Ib receptor that binds to the exposed
vWF, which facilitates platelet adhesion to damaged endothelium. After glycoprotein Ib binds to vWF, the platelet activates, degranulating and changing shape. Upon activation,
platelets express glycoprotein IIb/IIIa receptors, which initiate the platelet aggregation phase. Fibrinogen binds the glycoprotein IIb/IIIa receptors on the platelet surface, allowing
other platelets to aggregate and form bridges between IIb/
IIIa receptors via brinogen. This process is under tight regulation, with the surrounding intact endothelium, local anticoagulants, and humoral inhibiting factors preventing
inappropriate platelet adhesion outside the area of vascular
injury.
The coagulation cascade is the driving mechanism behind
secondary hemostasis, which follows primary hemostasis to
stabilize the weak platelet plug formed during primary hemostasis [4]. Inactive clotting factors constantly circulate until
activation through exposure to tissue factor or damaged endothelium. All clotting factors are synthesized in the liver in
zymogen form, except for von Willebrand factor (formed from
platelet alpha granules and endothelial cells) and factor VIII
(formed in endothelial cells). Activation of clotting factors
involves proteolysis into the active enzyme. Cleavage of clotting factors occurs in a stepwise fashion with each clotting
factor resulting in the cleavage and activation of a subsequent
clotting factor. The nal step is the activation of brinogen to
brin by thrombin. Fibrin is water-insoluble, while brinogen
is soluble before activation. Fibrin is the predominant factor
that results in stabilization of the platelet plug formed in primary hemostasis. Cross-linking of brin then strengthens the
already stabilized platelet plug, forming a clot.
Multiple theories exist about the precise mechanisms of
secondary hemostasis. The leading theory for much of the
time is founded on an intrinsic and an extrinsic coagulation
pathway. More recent research suggests an alternate mechanism, that of a “cell-based” pathway.
The extrinsic and intrinsic pathways of secondary hemostasis merge into a common pathway leading to a stable
hemostatic plug. The extrinsic pathway is activated only in
the presence of endothelial trauma, exposing tissue factor.
The exposure of tissue factor leads to factor VII activation to
factor VIIa, initiating the clotting cascade pathway [5]. The
intrinsic pathway does not require additional activation components, ki activating only with intrinsic components of
blood upon contact with articial surfaces [5]. Both intrinsic
and extrinsic pathways lead to the common pathway with the
activation of factor X to factor Xa with cofactor Va. Factor
Xa then cleaves factor II (prothrombin) to factor IIa (thrombin), which cleaves factor I (brinogen) to factor Ia (brin).
The cell-based theory of coagulation espouses three distinct phases in clot formation: initiation, amplication, and
the propagation phase. The central entity (i.e., the cell) in this
pathway is the platelet, and it is thought to provide a substrate to and physical locale for the reaction. Tissue factor
(TF) is the other key constituent. In initiation, TF-laden cells
complex with factor VII and activate it. This complex then
activates factors X and IX, which in turn activates factors V
and II. In normal circulation this small amount of IIa is kept
quiescent by local and humoral inhibitors, but in altered circulation, an amplication phase occurs. Platelets activated in
primary hemostasis have an enlarged, procoagulant surface,
and the small amount of thrombin (IIa) in turn activates IXa.
IX and VIIIa form a stable complex. In the propagation
phase, this IX + VIII complex readily activates X to Xa and
is called the “Xase.” The stable “Xase” then hydrolyzes multiple profactors into their active forms, primarily creating
more Va and IIa. This is known as the thrombin burst [6].
Coagulation is under strict regulation as to only occur
in areas of injury to prevent bleeding; dysregulation would
have severe consequences manifest as arterial and venous
thrombotic events. Three inhibitory pathways preside
over-regulation: (1) antithrombin III, (2) thrombomodulin,
and (3) tissue factor inhibitor. Antithrombin III inhibits
factors IIa, IXa, XIa, and especially Xa. Thrombomodulin
activates anticoagulant proteins C and S by binding thrombin, leading to proteolysis of factors Va and VIIIa. Tissue
factor pathway inhibitor utilizes a negative feedback loop
to prevent factor X activation. The brinolytic system also
regulates coagulation through plasmin, the activated form
of plasminogen. Plasminogen is cleaved to activated plasmin by tissue-type plasminogen activator (TPA). Plasmin
is a proteolytic enzyme capable of degrading brin, brinogen, factor V, factor VIII, prothrombin, and factor XII.
47 Considerations and Guidelines for Use of Anticoagulants and Antithrombotics in Patients Undergoing Interventional Pa…
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Because TPA binds the clot to activate plasminogen, proteolysis is limited to a localized clot.
Coagulation Pathophysiology
Pathological disturbance of the coagulation cascade manifests as either a hemorrhagic or thrombotic disorder.
Hemorrhagic disorders can be either acquired or inherited
conditions. The three most common inherited disorders of
hemostasis are von Willebrand disease, hemophilia A, and
hemophilia B [7, 8].
von Willebrand disease affects approximately 1 in 1000
people, making it the most prevalent inherited bleeding disorder [8]. It is caused by either a quantitative or qualitative
defect in von Willebrand factor (vWF) [7]. As mentioned
above, vWF functions in primary hemostasis by binding subendothelial components and circulating platelets, causing
platelet adhesion by forming a bridge between the platelet
and subendothelial tissue. Additionally, vWF has a role in
stabilizing factor VIII by acting as a carrier protein for factor
VIII and increasing the half-life of factor VIII. In patients
with von Willebrand disease, both of these functions of von
Willebrand factor are impaired; platelet adhesion is degraded,
and factor VIII levels are reduced. Hereditary von Willebrand
disease is passed as an autosomal dominant disorder. Primary
symptoms include bruising and mucosal bleeding, especially
epistaxis and menorrhagia. In surgical procedures, prolonged
oozing at the surgical site may also manifest. Bleeding time
is not useful in diagnosing von Willebrand disease; instead,
evaluation of closure time by platelet function analyzer
(PFA-100) has better diagnostic value [7]. Treatment includes
desmopressin and factor VIII replacement. Clarifying the
specic type of vWD is important before treatment as “gain
of function” mutations exist, whereby pharmacological treatment can result in disastrous thrombotic complications.
Hemophilia A is a bleeding disorder that results from a
defect in factor VIII, preventing activation of factor X,
therefore, interrupting the intrinsic coagulation cascade.
The disease is X-linked and therefore primarily affects
males. Plasma concentrations of vWF are unchanged in
hemophilia A, but the risks associated with hemophilia A
are high. Bleeding events can be life-threatening, particularly intracranial bleeding, which is associated with a 30%
mortality rate. The activated partial thromboplastin time
(aPTT), a measure of the intrinsic coagulation cascade,
will be prolonged to diagnose hemophilia A. The prothrombin time as well as bleeding time will remain normal
in hemophilia A. The severity of the disease depends on
the plasma concentration of factor VIII; thus factor replacement is an essential component of therapy for hemophilia
A [8]. While factor VIII replacement is an option, a more
universal treatment in the setting of surgical or traumatic
bleeding is recombinant activated factor VII, which is
thought to ensure hemostasis by interacting with tissue
factor and the platelet surface [8]. Hemophilia B is clinically indistinguishable from hemophilia A, but the deciency is in factor IX. Treatment is similar to hemophilia
A, except recombinant or plasma-derived factor IX is
replaced, rather than factor VIII.
Vitamin K is crucial to the function of several coagulation factors; thus, a vitamin K deciency can cause a defect
of coagulation. Vitamin K deciency can be caused by malnutrition, fat malabsorption, antibiotic use, and liver disease [4]. The liver enzyme microsomal carboxylase is
necessary to convert factors II, VII, IX, and X into their
gamma-carboxylated, active forms. Microsomal carboxylase is dependent on vitamin K; thus a vitamin K deciency
reduces functionality of all four coagulation factors.
Vitamin K-decient patients may develop melena, hematuria, ecchymosis, and hematomas as a result of the impaired
coagulation [4]. In anticipation of a procedure, vitamin K
can be supplemented to prevent bleeding complications.
Normal liver function is crucial to production of circulating coagulation factors. Grossly impaired hepatic synthetic
function may impair coagulation in multiple ways. Liver
dysfunction deranged hemostasis can occur via thrombocytopenia, platelet dysfunction, reduced production of clotting
factors, increased clotting factor consumption, and increased
brinolysis. Hemostatic dysfunction increases sequentially
with the stage of liver disease, but at all stages, a risk of
bleeding exists [8]. Screening for liver disease before a procedure may reduce the risks of unexpected bleeding events.
By analyzing hemoglobin, PT, aPTT, platelet count, platelet
function analysis, brinogen level, and bilirubin levels risk
stratication can be performed. In patients identied with
liver disease at risk of a bleeding complication, therapies
include vitamin K supplementation, fresh frozen plasma,
platelets, and cryoprecipitate. In patients with biliary tract
disorders, vitamin K supplementation alone may sufce [9].
Impaired renal function may also lead to defective hemostasis [10]. Renal impairment may lead to qualitative defects
in platelets, subendothelial metabolism, and platelet-vessel
interactions. The effects of antiplatelet drugs and low molecular weight heparins are also enhanced by impaired renal
function, primarily via reduced excretion of the drugs. In a
renal failure patient, a complete coagulation study is critical
to patient safety. Bleeding time may indicate platelet dysfunction due to renal disease, while elevated PT or aPTT
may be indicative of coagulation factor deciency. To restore
homeostatic coagulation treatment of renally impaired
patients may include dialysis, anemia correction, desmopressin, cryoprecipitate, estrogens, and avoiding antiplatelet
drugs [10].
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Hemostasis Pharmacology: Clinical
Relevance to the Interventionalist
COX Inhibitors
Direct cyclooxygenase (COX) inhibitors work by directly
inhibiting the COX-2 and/or COX-1 prostaglandin pathway,
which results in numerous physiological changes ranging
from decits in homeostasis of coagulation to decreased
bodily inammatory responses [11]. Administration of nonspecic COX inhibitors results in reduced levels of thromboxane A2. This substance triggers platelet aggregation,
vasospasm, and eventually serotonin release from the platelets themselves [12]. Aspirin is a COX-inhibiting drug that
disrupts thromboxane A2 by irreversibly inhibiting the
COX-1 pathway via enzyme acetylation. Related to this
mechanism of action, it has been shown to be benecial in
decreasing thrombus formation and clotting by boosting the
prostacyclin/thromboxane A2 ratio, which leads to reduced
platelet aggregation [13]. This decrease in clot formation
also puts patients at a theoretical risk for increased bleeding;
however, this eventuality is uncommon. Aspirin at low doses
can trigger an antiplatelet effect that lasts 7–10 days until
the bone marrow can replace the current platelets [14].
In high doses ASA inhibits prostacyclin (PGI2) through
COX-2, which can counteract the antiplatelet mechanism.
NSAIDs also work in decreasing prostaglandin production
to limit the inammatory response that results in analgesic
effects [15].
toring [
18]. Warfarin effect is monitored by prothrombin time
(PT) and international normalized ration (INR). PT measures
the extrinsic and common pathways of coagulation to determine the amount of time a patient’s plasma takes to clot via
brinogen and factors V, VII, and X. INR helps to monitor PT
and relate it to other patient labs to better control the dosage
of anticoagulants [19].
Glycoprotein Receptor Antagonists
The platelet aggregation pathway has a nal common receptor known as the glycoprotein IIb/IIIa receptor, which, if
blocked or inhibited, will cause reversible blocking of aggregation [20]. This mechanism still allows for the early stages
of the coagulation pathway and initial binding of platelets to
damaged vascular surfaces to occur [21]. Inhibitors of the
GPIIb/IIIa receptor include abciximab (ReoPro), eptibatide
(Integrilin), and tiroban hydrochloride (Aggrastat).
Abciximab is the Fab fragment of a humanized monoclonal
antibody that works as an antagonist to the Glycoprotein IIb
(GPIIb) receptor. It can inhibit close to 80% of platelet
aggregation when administered intravenously. Eptibatide
blocks the brinogen binding site on GPIIb, causing a
50–80% drop in platelet aggregation. Tiroban is a nonpeptide tyrosine derivative designed to mimic the natural ligand
of the IIB/IIIa receptor [21].
Thienopyridine Inhibitors
Warfarin
Vitamin K is needed for synthesis of the G1a protein family
that includes four coagulation factors (II, VII, IX, X) needed
for blood clotting in a normal individual [16]. These coagulation factors are important for homeostasis, and a deciency
can lead to life-threatening bleeding. Warfarin directly inhibits the gamma-carboxylation of glutamate residues in prothrombin and factors VII, IX, and X, preventing the vitamin K
epoxide from adopting its active form. This inhibition is not
immediate, but rather only becoming apparent when such
time has passed that the active factors have been consumed or
reabsorbed. The net effect on homeostasis caused by warfarin
is reliant on the half-life of each coagulation factor it impacts,
which ranges from 6–8 hours (VII) to 50+ hours (II) [17].
Warfarin, therefore, produces its maximal anticoagulant
effect 3–5 days after administration. Paradoxically, owing to
inhibition of proteins C and S, warfarin has a short procoagulant effect after initiation. Warfarin’s efcacy is extremely
dependent on the individual (age, gender, medical conditions,
genetics, diet), and initiation of therapy requires close moni-
These inhibitors work primarily by binding to P2Y12 receptor, which irreversibly modies and signicantly inhibits
ADP-dependent platelet aggregation after 2 hours of administration with peak effect at 6 hours [22]. Platelets treated
with this class are affected for their life (7–10 days); however, only 60–70% of the ADP receptors have been shown to
be sensitive to thienopyridines. Due to their consideration as
selective platelet-receptor inhibitors, thienopyridine inhibitors are considered relatively safe antiplatelet drugs. Drugs
included in this category are clopidogrel (Plavix), prasugrel
(Efent), and ticlopidine (Ticlid). Clopidogrel is used for the
prevention of ischemic stroke, myocardial infarction, and
vascular death in patients with a history of atherosclerosis or
vascular disease [6].
Heparin
Heparin is one of the oldest biological medications used for
the prevention and/or treatment of thrombosis [23]. Heparins
work by increasing antithrombin III activity to inhibit clot-
47 Considerations and Guidelines for Use of Anticoagulants and Antithrombotics in Patients Undergoing Interventional Pa…
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Table 47.1 Comparison of commonly used anticoagulants
Drug class Drugs MOA Effect Monitored Adverse effects
COX inhibitors
(COX-1 and
COX-2)
Warfarin Inhibits gamma-
Glycoprotein
receptor
antagonists
Thienopyridine
inhibitors
Heparin HMWH Increasing antithrombin
LWMH Binding antithrombin Increases inhibition of
NSAIDs
Aspirin
Abciximab
(ReoPro)
Eptibatide
(Integrilin)
Tiroban
Hydrochloride
(Aggrastat)
Clopidogrel
(Plavix)
Prasugrel (Efent)
Ticlopidine
(Ticlid)
Block cyclooxygenase-1
and -2
carboxylation of
prothrombin, factors VII,
IX, and X
Antagonist to
glycoprotein IIb receptor
Binds P2Y12 leading to
decreased ADPdependent platelet
aggregation
III activity
Inhibit TXA2 (blood
thinner) and inammation
(prostaglandins)
Decreased coagulation Prothrombin time
Decreased platelet
aggregation
Decreased clotting ability Increased bleeding
Leads to inhibition of
thrombin, IXa, and Xa,
which decreases clotting
thrombin and factor Xa,
leading to decreased
clotting
(PT) +
international
normalized ratio
(INR)
Partial
thromboplastin
time (PTT)
Partial
thromboplastin
time (PTT)
Increased bleeding
(COX-1)
Inhibited immune and
inammation response
(COX-2)
Increased probability of
bleeding and/or
hemorrhage
Bruising
Nausea and vomiting
Increased bleeding
Thrombocytopenia
Nausea and vomiting
Thrombotic
thrombocytopenic
purpura
Increased bleeding
Heparin-induced
thrombocytopenia (HIT)
Osteoporosis
Injection site reactions
Increased bleeding
Injection site reactions
HIT (less commonly
than unfractionated
heparin)
447
ting factors thrombin, IXa, and Xa. This activity is increased
due to the conformational change that ATIII undergoes to
reveal its active site. High molecular weight heparin
(HMWH) is known for its higher molecular weight ranging
anywhere from 5000 to 40,000 Da, making it unable to be
absorbed from the GI tract. It is administered intravenously
or subcutaneously and has limited utility in the outpatient
setting due to its short 1-hour half-life. Heparin is commonly
used in inpatient settings to prevent venous thrombosis.
Heparin effectiveness is measured by partial thromboplastin
time (PTT); however, close monitoring of heparin therapy is
not required, unlike warfarin therapy.
Low Molecular Weight Heparin
Low molecular weight heparins (LMWH) are fractionated
like their HMWH counterparts, but this process limits them
to lower molecular weights (most molecules under 8000
Da). LMWH works by binding to antithrombin, causing a
conformational change and increasing the propensity for
inhibition of thrombin and factor Xa [24]. Compared to the
high molecular weight fractions, LMWH have a higher bioavailability, longer half-life, and potential for once-daily
dosing. The drug is given primarily subcutaneously [23]
(Table 47.1).
Direct Thrombin Inhibitors
While heparins and vitamin K antagonists are the most commonly used agents in anticoagulation, direct thrombin inhibitors (DTIs) also play an expanding and key role in
anticoagulation. DTIs work by inactivating free thrombin and
thrombin already bound to brin. This inactivation is caused
by binding the active site and/or the exosites of thrombin. The
role of DTIs in the management of acute coronary syndromes
was reviewed by the Direct Thrombin Inhibitor Trialists’
Collaborative Group in a meta-analysis of data on individual
patients. As compared with heparin, DTIs reduced the incidence of the composite outcome of death and myocardial
infarction both at the end of treatment and at 30 days [25].
DTIs can be univalent or bivalent inhibitors. Univalent
inhibitors, such as argatroban and dabigatran, work by
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binding to the active sites of thrombin. Bivalent inhibitors,
such as hirudin derivatives desirudin, lepirudin, and bivalirudin, work by binding to the active site on thrombin with one
of its exosites.
Argatroban reversibly binds to the active site on thrombin
and inhibits thrombin’s ability to activate several clotting
factors. Importantly, argatroban has played a major role in
heparin-induced thrombocytopenia (HIT), being used as an
alternate form of anticoagulation when heparins are contraindicated. This can include systemic anticoagulation for cardiac bypass circuit initiation. Argatroban anticoagulation,
compared with historical control subjects, improves clinical
outcomes in patients who have HIT, without increasing
bleeding risk [26]. Dabigatran is the other univalent DTI that
is being used as a substitute for warfarin in acute venous
thromboembolism and prevention of stroke in patients with
atrial brillation. As with all anticoagulation, there is an
increased risk of bleeding. Dabigatran’s utility for atrial
brillation had been questioned on these grounds, particularly before the advent of a widely available reversal agent
(idarucizumab). Dabigatran administered at a dose of 150
mg, as compared with warfarin, was associated with lower
rates of stroke and systemic embolism but similar rates of
major hemorrhage [27]. Recombinant hirudin derivatives
such as desirudin, lepirudin, and bivalirudin are all alternatives for heparin. Compared with historical controls, lepirudin treatment of HIT complicated by thrombosis was
associated with reduced thrombotic events (relative risk
reduction [RRR], 0.63–0.78) [28] (Table 47.2).
Factor Xa Inhibitors
Direct factor Xa drugs are a modern class of drugs that
inhibit the clotting cascade. They have become popular in the
treatment of patients with pulmonary embolism, deep vein
thrombosis, and embolic stroke from atrial brillation. These
drugs are used in clinical care because they can be administered in xed doses without routine coagulation monitoring.
Factor Xa inhibitor therapy is well tolerated, and the most
common adverse event reported with the agents is bleeding.
Factor Xa inhibitors have black box warnings for increased
risk of stroke upon discontinuance of therapy and increased
risk for developing epidural or spinal hematomas. There is
no specic reversal agent for the factor Xa inhibitors, but a
new drug, andexanet, is promising. Andexanet is biologically
recombinant factor Xa, which acts as a decoy receptor, and
reversed the anticoagulant activity of apixaban and rivaroxaban in older healthy participants within minutes after administration and for the duration of infusion, without evidence of
clinical toxic effects [29].
Bleeding Complications and Risks in
Regional Anesthesia
Neuraxial procedures carry risks that are rare but can be
potentially devastating for patients, and bleeding complications are of particular concern [30]. This is especially true for
patients who present with bleeding disorders and/or those
taking antithrombic medication as this can increase the
potential risk of bleeding. Physicians must weigh the risks
and benets for this subset of patients before the start of a
procedure to reduce the chance of morbidity and mortality.
Some neuraxial procedure risk factors involve location of
the target structure, size of needle, and the number of needle
insertion attempts. A traumatic needle insertion can have
minor consequences, such as post-dural puncture headache,
or major consequences, such as spinal hematoma [31]. A
traumatic needle insertion increases the likelihood of spinal
hematoma by 11-fold [32]. The risk of needle insertion complications is inuenced by age, gender, BMI, and spinal cord
defects. For instance, patients without a spinal deformity
have a 2.6 greater chance of rst-pass success than those
with spinal deformities [33]. Preoperative assessment of a
patient’s risk associated with a successful needle insertion
can aid in reducing complications associated with multiple
needle insertion attempts.
Spinal hematomas can result in permanent loss of neurologic function, and the incidence of hematomas is signicantly greater for those on anticoagulant medications. For
patients on anticoagulants, the approximated frequency of
epidural hematoma is 33 in 100,000 patients for epidural
anesthetics and 1 in 100,000 patients for spinal anesthetics.
This is greater than the estimated number of 1 in 150,000 and
1 in 220,000 patients not on anticoagulation for epidural and
spinal anesthetics, respectively [34].
Table 47.2 Direct thrombin inhibitors
Parameter Lepirudin Argatroban Dabigatran
Class Bivalent Univalent Univalent
Indication Anticoagulation in HIT Anticoagulation in HIT Stroke prevention
Administration Parenteral Parenteral Oral
Time to peak concentration 2.0 to 3.0 hours 2.0 to 4.0 hours 1.5 to 2 hours
Clearance Kidneys Liver Kidneys
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449
Anticoagulation medication such as heparin and warfarin
must be timed appropriately for the administration of neuraxial anesthesia and removal of an epidural catheter. Analysis
of drug-related factors in the development of spinal hematomas in neuraxial procedures showed that out of the 160
reported cases of spinal hematomas, 31% of the cases
involved use of low molecular weight heparin, 24% involved
unfractionated heparin, and 11% of the cases involved warfarin [35]. The FDA also highlighted 30 reports of patients
who were on low molecular weight heparin and developed
epidural or spinal hematomas [36]. There have been two
cases reported through MedWatch system since 1998 that
involved preoperative warfarin and the development of spinal hematomas when preforming a neuraxial block [37].
Physicians should also be aware of the increased risk of
bleeding during neuraxial procedures in patients with medical disease. Hepatic failure may cause thrombocytopenia and
other alterations in normal coagulation physiology [38]. In a
report of 166 cases of spinal hematomas, 4 cases were associated with liver disease, and 10 cases were associated with
renal insufciency [35].
Antithrombic medications work to decrease thrombosis
by interfering with the blood coagulation cascade. This
results in increased bleeding, and as such, physicians may
discontinue the use of this medication to decrease the risk of
bleeding before performing pain management procedures.
However, physicians must consider potential thrombosis
complications posed by the removal of antithrombic medications, particularly for those with a history of coronary artery
disease or cerebrovascular disease [35]. An online survey of
interventional pain physicians reported withdrawal of antithrombic medication before pain management techniques in
a substantial number of cases. According to the survey, “97%
discontinued clopidogrel; 96% ticlopidine; 95% Aggrastat
(tiroban); 93% cilostazol, 85% dipyridamole, 60% aspirin
350 mg; 39% aspirin 81 mg; and 39% other non-steroidal
anti-inammatory drugs (NSAIDs) before performing interventional pain management techniques.” An assessment performed indicated that complications due to thrombosis
formation were more severe and three times more likely to
occur than bleeding complications during pain management
procedures [1]. This information should give practitioners
pause for thought and the merits of ceasing medically indicated anticoagulation be carefully weighed. Knowing the
reason why patients are on anticoagulants can help facilitate
safe practices, and it may also be prudent to consult with the
patient’s prescribing physician regarding discontinuation of
their anticoagulants.
Physicians must consider the risks associated with altering antithrombotic medication before, during, and after pain
management procedures to ensure patient safety. For
instance, NSAIDs, including aspirin, do not appear to pose
risk of spinal hematomas during neuraxial procedures [32,
39]. Hence, discontinuing the use of low-dose aspirin may
increase risk of thrombosis while having no impact on risk of
bleeding. This is true only when aspirin is taken alone; aspirin taken with other antithrombic medications, SSRIs, and/or
supplement such as sh oil increases the risk of hematomas
[30]. For example, aspirin combined with the anticoagulation medication heparin increases risk of development of spinal hematoma during neuraxial procedures by a magnitude
of 26 [32].
Recommendations and Safety
In patients undergoing interventional techniques, the management of antithrombotic therapy requires consideration of
several factors, primarily the balance between the bleeding
risk associated with continuation of antithrombotic therapy,
the medical indication for anticoagulation, and the thromboembolic risk associated with its discontinuation or interruption [40–42]. While interruption is often required to minimize
risk of bleeding after surgery, discontinuation, continuation,
and recommencing of anti-clotting therapy in the perioperative setting come with associated risks [40–42]. In clinical
practice, patients receiving antithrombotic therapy are routinely discontinued on their medication before undergoing
interventional techniques despite a paucity of evidence of
signicant bleeding risk during these procedures and limited
evidence to guide clinical practice [40, 43–46]. In fact, there
is considerable risk with the traditional attitude of discontinuing medication 10 days before intervention and the indiscriminate use of bridging therapy [40, 46]. When managing
anti-clotting medication in these patients, recent studies suggest that it is benecial to stratify the anticipated surgical
intervention into a low-risk (<4% per annum), moderate-risk
(4–10%), and high-risk (>10%) category and adjust according to patient-specic risk factors [40, 46]. Additional considerations should include assessment for the need of
bridging therapy, patient co morbidities, and the individual
properties of the specic anti-clotting agent being utilized
[41, 46, 47].
Estimation of Thromboembolic Risk
The three most common indications for anticoagulation
therapy are atrial brillation, recent history of thromboembolism, and presence of prosthetic heart valves [41, 46–49].
The CHA2DS2-VASc score, a risk-stratication system
used to predict future risk of stroke and thromboembolism
in patients with nonvalvular atrial brillation (although not
prospectively validated in the perioperative setting), may
be useful in estimating relative thromboembolic risk in
patients undergoing surgical procedures and assessing the
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