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5 Fibrinolysis, Antibrinolytic Agents, andPerioperative Considerations

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quently and increases mortality: a multicenter evaluation of 2,540 severely injured patients. J Am Coll Surg. 2016;222:347–55.

82. Moore EE, Moore HB, Gonzalez E, Sauaia A, Banerjee A, Silliman CC.Rationale for the selective administration of tranexamic acid to inhibit brinolysis in the severely injured patient: rationale for the selective administration of TXA.Transfusion. 2016;56:S110–4.

83. Yuan Q, Sun Y-R, Wu X, Yu J, Li Z-Q, Du Z-Y, etal. Coagulopathy in traumatic brain injury and its correlation with progressive hemorrhagic injury: a systematic review and meta-analysis. J Neurotrauma. 2016;33:1279–91.

84. Gall LS, Davenport RA.Fibrinolysis and antibrinolytic treatment in the trauma patient. Curr Opin Anaesthesiol. 2018;31:227–33.

85. Dewan Y, Komolafe EO, Mejía-Mantilla JH, Perel P, Roberts I, Shakur H, etal. CRASH-3- tranexamic acid for the treatment of signicant traumatic brain injury: study protocol for an international randomized, double-blind, placebo-controlled trial. Trials. 2012;13:87.

86. Alshryda S, Sarda P, Sukeik M, Nargol A, Blenkinsopp J, Mason JM. Tranexamic acid in total knee replacement: a systematic review and meta-analysis. J Bone Joint Surg Br. 2011;93:1577–85.

87. Gombotz H, Rehak PH, Shander A, Hofmann A. The second Austrian benchmark study for blood use in elective surgery: results and practice change. Transfusion. 2014;54:2646–57.

88. Wei Z, Liu M.The effectiveness and safety of tranexamic acid in total hip or knee arthroplasty: a meta-analysis of 2720 cases: the effectiveness and safety of tranexamic acid in total hip or knee arthroplasty. Transfus Med. 2015;25:151–62.

89. Yu X, Li W, Xu P, Liu J, Qiu Y, Zhu Y. Safety and efcacy of tranexamic acid in total knee arthroplasty. Med Sci Monit. 2015;21:3095–103.

90. Farrow LS, Smith TO, Ashcroft GP, Myint PK. A systematic review of tranexamic acid in hip fracture surgery: tranexamic acid in hip fracture surgery. Br J Clin Pharmacol. 2016;82:1458–70.

91. Xu S, Chen JY, Zheng Q, Lo NN, Chia S-L, Tay KJD, etal. The safest and most efcacious route of tranexamic acid administration in total joint arthroplasty: a systematic review and network meta-analysis. Thromb Res. 2019;176:61–6.

92. Cheriyan T, Maier SP, Bianco K, Slobodyanyuk K, Rattenni RN, Lafage V, etal. Efcacy of tranexamic acid on surgical bleeding in spine surgery: a meta-analysis. Spine J. 2015;15:752–61.

93. Zhang Y, Liu H, He F, Chen A, Yang H, Pi B. Does tranexamic acid improve bleeding, transfusion, and hemoglobin level in patients undergoing multilevel spine surgery? a systematic review and meta-analysis. World Neurosurg. 2019;127:289–301.

94. Karanicolas PJ, Lin Y, Tarshis J, Law CHL, Coburn NG, Hallet J, etal. Major liver resection, systemic brinolytic activity, and the impact of tranexamic acid. HPB. 2016;18:991–9.

95. Roullet S, Pillot J, Freyburger G, Biais M, Quinart A, Rault A, etal. Rotation thromboelastometry detects thrombocytopenia and

hypobrinogenaemia during orthotopic liver transplantation. Br J Anaesth. 2010;104:422–8.

96. Badenoch A, Sharma A, Gower S, Selzner M, Srinivas C, Wąsowicz M, etal. The effectiveness and safety of tranexamic acid in orthotopic liver transplantation clinical practice: a propensity score-matched cohort study. Transplantation. 2017;101:1658–65.

97. Wu C-C, Ho W-M, Cheng S-B, Yeh D-C, Wen M-C, Liu T-J, etal. Perioperative parenteral tranexamic acid in liver tumor resection: a prospective randomized trial toward a “blood transfusion”-free hepatectomy. Ann Surg. 2006;243:173–80.

98. World Health Organization. WHO recommendations for the prevention and treatment of postpartum haemorrhage. Geneva: World Health Organization; 2012.

99. Ker K, Shakur H, Roberts I.Does tranexamic acid prevent postpartum haemorrhage? A systematic review of randomised controlled trials. BJOG. 2016;123:1745–52.

100. Shakur H, Roberts I, Fawole B, Chaudhri R, El-Sheikh M, Akintan A, etal. Effect of early tranexamic acid administration on mortality, hysterectomy, and other morbidities in women with postpartum haemorrhage (WOMAN): an international, randomised, double-blind, placebo-controlled trial. Lancet. 2017;389:2105–16.

101. Fleming JB, Hoh BL, Simon SD, Welch BG, Mericle RA, Fargen KM, etal. Rebleeding risk after treatment of ruptured intracranial aneurysms. J Neurosurg. 2011;114:1778–84.

102. Roos Y, Rinkel G, Vermeulen M, Algra A, van Gijn J.Antibrinolytic therapy for aneurysmal subarachnoid hemorrhage: a major update of a cochrane review. Stroke. 2003;34:2308–9.

103. Baharoglu MI, Germans MR, Rinkel GJ, Algra A, Vermeulen M, van Gijn J, etal. Antibrinolytic therapy for aneurysmal subarachnoid haemorrhage. Cochrane Stroke Group, editor. Cochrane Database Syst Rev [Internet]. 2013 [cited 2019 Jul 27]; Available

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104. Anker-Møller T, Troldborg A, Sunde N, Hvas A-M. Evidence for the use of tranexamic acid in subarachnoid and subdural hemorrhage: a systematic review. Semin Thromb Hemost. 2017;43:750–8.

105. Germans MR, Post R, Coert BA, Rinkel GJE, Vandertop WP, Verbaan D.Ultra-early tranexamic acid after subarachnoid hemorrhage (ULTRA): study protocol for a randomized controlled trial. Trials. 2013;14:143.

106. Goobie SM, Faraoni D. Tranexamic acid and perioperative bleeding in children: what do we still need to know? Curr Opin Anaesthesiol. 2019;32:343–52.

107. Montroy J, Hutton B, Moodley P, Fergusson NA, Cheng W, Tinmouth A, etal. The efcacy and safety of topical tranexamic acid: a systematic review and meta-analysis. Transfus Med Rev. 2018;32:165–78.

108. Ker K, Beecher D, Roberts I.Topical application of tranexamic acid for the reduction of bleeding. Cochrane Database Syst Rev. 2013;(7):CD010562.

Hypercoagulation andThrombotic

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Disorders

SaurinJ.Shah, JayanthDasika, andDavidC.McEnerney

Introduction

Hypercoagulable states, sometimes referred to as thrombophilias or thrombotic disorders, are clinical conditions whereby individuals are predisposed to arterial and/or venous thromboembolisms [1]. Clinical manifestations of thrombotic disorders can range from the asymptomatic to lethal; the causes of these manifestations may be complicated and multifactorial. Research over the last several decades has aided in identifying many of the risk factors associated with hypercoagulable states and has helped streamline chronic management of predisposed individuals. Acute management of these individuals, such as during surgery, poses a unique set of challenges for the anesthesia care team.

Individuals with hypercoagulable states are considered high risk for thromboembolic phenomenon in the perioperative setting [2]. The occurrence of venous thromboembolism (VTE) in the non-surgical population is 1–2 out of 1000; this frequency increases anywhere from 10 to 25 out of 1000 depending on the surgical procedure [3]. In addition, the administration of blood products, which may occur more frequently during surgery, may increase VTE occurrence two fold to threefold when compared to bloodless surgery [4]. Special consideration and management need to be given to surgical patients that may receive blood products in the setting of preexisting risk factor(s) for thrombotic disease.

primary (congenital) and secondary (acquired); there are some conditions of mixed etiology that may fall into both categories or are of unknown etiology.

Primary (Congenital) Hypercoagulable States

Primary hypercoagulable states are due to either (1) a defect/ deciency of an antithrombotic protein or (2) an abnormally increased level of a prothrombotic clotting factor. The most common conditions are listed in Table6.1.

Antithrombin Deciency

Antithrombin is a natural anticoagulant that inhibits thrombin (factor IIa), factor Xa, and other serine proteases in the coagulation cascade. Inherited antithrombin deciency is estimated to occur in 1in 2000–3000 individuals. It is an autosomal dominant disease with variable penetrance; laboratory evidence does not necessarily lead to the development of VTE or require maintenance anticoagulant therapy. Type I Deciency is the most severe and usually is the result of a quantitative decit of Antithrombin; Type IIb deciency is less severe and usually the result of a qualitative defect

Hypercoagulable States

Hypercoagulable states have been described since 1856 when Rudolph Virchow described a triad of conditions that promoted coagulation in the circulatory system [1]. The majority of these states can be classied into two groups:

S. J. Shah (*) · J. Dasika · D. C. McEnerney University of Florida– Jacksonville, Department of Anesthesiology, Jacksonville, FL, USA e-mail: saurin.shah@jax.u.edu

https://doi.org/10.1007/978-3-030-59295-0_6

Table 6.1 Primary hypercoagulable states (thrombophilias)

1. Decreased antithrombotic proteins (a) Antithrombin deciency (b) Protein C deciency (c) Protein S deciency

2. Increased prothrombotic proteins (a) Factor V Leiden (activated protein C resistance) (b) Prothrombin gene mutation G20210A (c) Increased levels of factors VII, XI, IX, VIII, von Willebrand

factor

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S. J. Shah et al.

within the structure of the Antithrombin protein. Other disease states may indirectly lower the concentration of antithrombin; however, this is usually associated with abnormalities in other factors, thus making it more difcult to evaluate and manage these acquired deciencies [1, 5].

Perioperative management of these patients can vary based on the complexity of the procedure, anticipated blood loss, and preexisting comorbid situations. As noted, the risk of deep vein thrombosis (DVT) can be as high as 3% in the general surgical population; the risk may be higher in patients predisposed to VTE secondary to a thrombophilia such as Antithrombin Deciency. Preoperative and postoperative prophylaxis with unfractionated (UFH) or low-molecularweight heparin (LMWH) or Antithrombin concentrates may be absolutely indicated in this patient population except in trauma or non-trauma cases with signicant anticipated blood loss– although the exclusion in the latter group is still under debate. Intraoperative management is usually routine and uneventful except in the setting of blood transfusions, most notably red blood cell (RBC) transfusions. Blood transfusions may impair the balance between coagulation factors and the inammatory cascade triggering a hypercoagulable state. While the exact mechanisms are unknown, it is clear that there is a dose response effect between the number of RBCs transfused and the risk of a VTE [6]. In the setting of a known thrombophilia, such as Antithrombin Deciency, this can be problematic and potentially lethal. Consideration should be given to blood sparing techniques when possible as blood transfusions are not without risks. In patients that require blood transfusions, the use of Antithrombin concentrates may be given to minimize the risk of a VTE.

ral anticoagulant system; Protein S serves as the binding protein for activated Protein C to form an anticoagulant complex on cell surfaces. Congenital Protein S deciency (mild) is estimated to occur in 1 per 500 individuals; severe deciency is rare, prevalence is unknown, and is associated with a myriad of life-threatening symptoms from birth. It is an autosomal dominant disease caused by a mutation in the PROS1 gene. It has variable penetrance and may be divided into type I-III based on how the PROS1 gene mutation affects Protein S.Type I disease is characterized by a quantitative defect in both total and free Protein S, whereas type II is characterized by a qualitative defect with normal levels; type III has normal total levels, but low free protein levels. Types I and III are the most common and have similar symptomology. Acquired Protein S deciency can occur to a lesser extent with liver disease, vitamin K deciency, and pregnancy [

Perioperative management of these patients is based on the severity of the disease, complexity of the procedure, and comorbid diseases. The occurrence of VTE in protein Cand/or S-decient patients is considered to be less than that of patients with Antithrombin Deciency; however, the combination of surgery and a preexisting protein C and/or S deciency is believed to increase one’s risks of perioperative VTE above the 3% occurrence rate of otherwise healthy surgical patients. The mainstay of preoperative treatment is UFH or LMWH to reduce this increased risk [ at higher risk– decreased ambulation, other comorbid disease states, anticipated RBC transfusion – prophylactic administration of protein C concentrates and/or fresh-frozen plasma (no protein S concentrate exists) may be given to further reduce the risk of VTE [2].

1, 5, 7].

7]. In patients

Protein C andS Deciency

Protein C deciency causes impaired deactivation of Factors Va and VIIIa, leading to increased production of thrombin and brin. Inherited deciency is estimated at about 1 per 200– 500in the general population and up to 15–30 per same number in patients with VTE.It is an autosomal dominant disease with variable penetrance and, like Antithrombin, may be divided into two general forms. Type I deciency is characterized by a quantitative reduction in Protein C with a proportionate reduction in functional activity; type II deciencies are due to a qualitative abnormality in Protein C with a variable reduction in functional activity. Protein C deciency may also be acquired in certain disease states such as liver disease, disseminated intravascular coagulation (DIC), and sepsis [1, 5].

Protein S deciency causes decreased activity of activated Protein C, thus leading to increased production of thrombin and brin. Protein S and protein C work in concert as a natu-

Factor V Leiden (Activated Protein C Resistance)

Factor V is a protein of the coagulation system that once activated works in conjunction with activated Factor X to convert prothrombin to thrombin. Factor V Leiden (FVL) is caused by a point mutation in the gene that renders the protein resistant to activated Protein C resulting in decreased breakdown of thrombin and an increased risk of VTE [1].

Heterozygous FVL is very common in individuals of Caucasian descent. It is present in about 5% of healthy individuals and up to 40–50% in individuals presenting with or for evaluation of VTE. The homozygous form is rare, but carries a 10-fold increase in the risk of thrombosis. Most FVL patients are asymptomatic and usually require another “hit” or predisposing factor to present with a VTE [5].

Surgery and/or blood transfusions may be the other “hit” to increase the occurrence of VTE.Standard perioperative VTE prophylaxis should be followed in these patients;

6 Hypercoagulation andThrombotic Disorders

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special considerations should be given to those patients with a previous history of VTE.No specic guidelines or recommendations currently exist for blood transfusions in the setting of FVL.As noted, most patients are asymptomatic even in the setting of blood product administration. In fact, current studies suggest a benecial link between FVL and reduced blood loss in cardiovascular surgery. Those same studies have raised concerns about antibrinolytic therapy and the increased potential for thrombosis in FVL patients.

FVL may also occur in pregnancy. Whether as a primary or secondary (acquired) condition, FVL is found in 20–45% of women with pregnancy-associated VTE. Homozygous patients carry the highest risk of VTE during pregnancy when compared to heterozygous patients; the risk of thrombosis during pregnancy is almost 50% greater in FVL patients as compared to non-FVL patients [1]. Prophylactic anticoagulation is usually not recommended in patients with no previous history of VTE; anticoagulation is recommended in the setting of pregnancy, FVL, and previous VTE [3]. All patients should be counseled about the risks and benets of these therapies during pregnancy. Additionally, high-risk patients should consider a 4- to 6-week course of anticoagulation during the postpartum period. No current recommendations exist for FVL, pregnancy, and blood product administration.

Table 6.2 Relative risk– rst episode of VTE– Inherited States

Risk factor Relative risk Factor V Leiden Homozygous 25 Heterozygous 5 Antithrombin deciency 5 Protein C deciency 3 Protein S deciency 2 Hyperhomocysteinemia 2

Table 6.3 Secondary hypercoagulable states (thrombophilias)

1. Deciency of coagulation inhibitors (a) Malignancy (b) Surgery (c) Immobilization

2. Increased prothrombotic proteins (a) Trauma (b) Pregnancy (c) Medications (OCP/HRT) (d) Antiphospholipid Syndrome

product administration carries its own risk of thrombosis; any treatment that lowers homocysteine levels should be considered for procedures where blood product administration is anticipated.

Hyperhomocysteinemia

Homocysteine is an intermediary amino acid formed by the metabolism of methionine. Congenital alterations in this pathway, as well as acquired deciencies in various vitamins and certain disease states, can produce elevated levels of homocysteine in the blood. Hyperhomocysteinemia may predispose individuals to arterial and venous thrombosis [5].

The incidence of hyperhomocysteinemia has been reported to be as high as 10%; however, the cause is multifactorial and varies greatly across different ethnicities and geographic regions. Homocysteinemia is suspected to cause endothelial dysfunction and promote an imbalance between procoagulant and antithrombotic activity; decreases in protein C activation, endothelial resistance to thrombosis, and nitric oxide may play a key role in this thrombotic disorder [8].

Perioperative management usually consists of standard DVT prophylaxis– LMWH and placement of pneumatic lower extremity compression devices. In the patient with elevated homocysteine levels, administration of pyridoxine, methylcobalamin, and folic acid may help to reduce homocysteine levels and the risk of a thrombotic event. Maintenance of euvolemia and avoidance of nitrous oxide are also recommended for these patients. As noted, blood

Other Primary Hypercoagulable States

A number of other congenital thrombophilia exists such as Prothrombin Gene Variant, increased levels of specic coagulation factors (VII, XI, IX, and vWF) and tissue plasminogen activator deciency [7]. Many of these other hypercoagulable states have a much lower occurrence rate (<2–3% incidence across all populations). Thus, studies and recommendations are limited regarding management of these disease states during surgery and in the setting of blood product administration. As always, treatment should be patient specic (Table6.2).

Secondary (Acquired) Hypercoagulable States

Secondary hypercoagulable states encompass a variety of conditions that may predispose individuals to thrombotic events. The pathophysiology of these states is usually complex, multifactorial, and poorly understood. Most individuals with acquired hypercoagulable states are at risk for both arterial and venous thrombosis due to suspected abnormalities in all parts of Virchow’s triad of thrombogenesis (Table6.3).

S. J. Shah et al.

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Pregnancy/Puerperium

Pregnancy and puerperium are well-recognized and wellstudied hypercoagulable states. The risk of VTE during pregnancy/puerperium is six to eight times greater than in non-pregnant women; however, VTEs are still only seen in approximately 1% of pregnancies [1, 5]. The increased risk is present for 8–10weeks postpartum and can present with life- threatening symptoms to both the mother and fetus [9].

The pathophysiology of hypercoagulability during pregnancy and the postpartum period involves a number of anatomical, physiological, and biochemical changes that may predispose an individual to thrombotic events. There is an increased concentration of various factors within the coagulation cascade, increased platelet count, and decreased brinolysis [10, 11]. This imbalance within the coagulation cascade coupled with stasis from a gravid uterus on lower extremity venous return increases one’s thrombogenic potential [12–14].

Concomitant genetic risk (primary), older age, previous VTE, higher parity, and preeclampsia are independent risk factors that may further increase one’s predisposition for a thrombotic event [1, 5, 15].

Diagnosis and management of VTEs in pregnancy can be challenging. Overlapping signs and symptoms as well as limited radiologic and laboratory testing can complicate timely diagnosis of a VTE.Previous history or high suspicion of current VTE is to be treated with anticoagulation for up to 8weeks postpartum [16, 17]. LMWH or UFH are the mainstays of therapy as they do not cross the uteroplacental barrier and allow for timely discontinuation for neuraxial anesthesia administration [18]. Warfarin is reserved for highrisk cases due to its teratogenic effects and potential for fetal bleeding. Blood product administration should be judicious with reasonably high transfusion triggers, reserving administration for the most high-risk patients (placenta accreta, severe anemia, DIC, etc.) [19–21].

Oral Contraceptives andHormone Replacement Therapy

The administration of estrogen is associated with a twofold to six fold increase in the incidence of VTE in individuals with no other predisposing thrombotic factors [22–24]. Use of oral contraceptive pills (OCP)/hormone replacement therapy (HRT) is associated with increased levels of Factor VII and decreased activity of protein S and thrombomodulin [25]. Smoking, obesity, Polycystic Ovary Syndrome, older age, and immobilization, as well as a primary hypercoagulable disease, may signicantly increase the risk of VTE in the setting of OCP/HRT [26].

Table 6.4 Relative risk– rst episode of VTE– acquired states

Risk factor Relative risk Pregnancy 4 Recent postpartum 14 OCP/HRT 3 Antiphospholipid antibody 9 Immobilization 10 Surgery 6

Data from Liem and Deloughery, Seminars in Vasc Surg 2008

Individuals who are considered high risk for VTE or have previously had a VTE should be candidates for anticoagulation while on OCP/HRT [27, 28]. Prophylaxis with either LMWH or UFH is recommended and the mainstay of treatment. Blood product administration should be clinically indicated with reasonable triggers as no additional therapies exist to reduce the incidence of VTE from blood transfusions in the setting of OCP/HRT (Table6.4).

Antiphospholipid Syndrome

Antiphospholipid Syndrome (APS) is a thrombotic disorder mainly associated with auto antibodies toward plasma proteins on the surface of phospholipids [5, 29]. Two main subsets of auto antibodies exist in APS – anticardiolipin and lupus anticoagulant associated with lupus erythematosus [7,

30]. There are secondary states that may be acquired in the

setting of infections, drugs, or collagen vascular diseases. Regardless of the etiology, venous or arterial thromboembolic phenomenon may occur in up to one-third of individuals with APS [31].

Thrombosis often occurs at unusual sites and may present with a myriad of symptoms such as skin necrosis– livedo reticularis, acute renal failure, cerebrovascular pathology (strokes, ocular disturbances, etc.), or recurrent miscarriages [32]. APS is the most common cause of initial thrombosis in pregnancy when compared to other thrombophilias. Currently, no recommendations exist for anticoagulation in APS individuals with no history of thromboembolic phenomenon [33]. Individuals with other risk factors or previous VTE should be placed on long-term anticoagulation therapy; patients with “high” APS antibody titers should also consider long-term therapy even in the absence of VTE [34, 35]. The mainstay of long-term therapy is warfarin with goal INRs of 2–3; LMWH may be used in patients with allergies to warfarin [32, 36].

No current recommendations exist for blood product administration either. Individuals with APS may have a concomitant quantitative thrombocytopenia. Blood product administration should be based on reasonable transfusion triggers and the needs of the individuals.

6 Hypercoagulation andThrombotic Disorders

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Other Secondary Hypercoagulable States

Thromboembolic phenomenon may occur in individuals with gastrointestinal disorders such as inammatory bowel disease and Behcet’s disease. Intestinal inammation, which may occur cyclically in these disease states, may activate the coagulation system and increase the risk of thrombosis [5].

Nephrotic Syndrome may lead to an acquired Antithrombin III deciency through the excess excretion of protein. Myeloproliferative disorders can create a myriad of acquired thrombotic disorders [37, 38].

Hemolytic diseases or diseases with abnormal RBCs, such as sickle cell disease, may lead to alterations in the surface of RBCs that promote increased thrombin formation.

Summary

Hypercoagulable states, or thrombophilias, are disease states that predispose individuals to thrombotic phenomenon; these disease states are either congenital or acquired and may present with no symptoms or be life-threatening. The occurrence of thromboembolic events is usually complex and multifactorial; laboratory testing and treatment will vary based on the severity of the disease and concomitant co morbidities. The administration of blood products increases the incidence of thrombotic events. While specic recommendations do not exist for blood transfusions in many of these disease states, caution and judicious practices should be used to minimize any risks for VTE in predisposed individuals.

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29. Finazzi G, Brancaccio U, Moia M, etal. Natural history and risk factors for thrombosis in 360 patients with antiphospholipid anti-

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Diseases or Conditions ofPlatelet

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Disorders

GeorgeM.Jeha, AlexD.Pham, IvanUrits, LuSun, DallasL.Domangue, KarinaCharipova, KyleGress, ElyseM.Cornett, andAlanDavidKaye

Introduction

Platelets are small, anucleate cells circulating in the blood at concentrations of approximately 150,000–400,000/μL.They form from projections known as proplatelets off megakaryocytes in the bone marrow. Thrombopoietin is important in the process of megakaryopoiesis and stimulation ofother stems cells in the bone marrow [1, 2]. The typical lifespan of a platelet is 10days before they are removed from circulation by the spleen [3]. Platelets primarily function in hemostasis. Platelets contain alpha granules and dense granules, which play major roles in coagulation. The alpha granules contain larger proteins (e.g., von Willebrand factor) while the dense granules contain small non-protein particles (e.g., ADP) [3]. Platelets are involved in inammation and atherosclerosis related to their production of inammatory mediators (e.g., thromboxanes) and aid in cancer progression by impeding the immune system. They may even be involved in the progression of Alzheimer’s dementia given their ability to carry amyloid precursor protein. Platelet dysfunction has been

G. M. Jeha · A. D. Pham · D. L. Domangue Department of Anesthesiology, LSUHSC New Orleans, New Orleans, LA, USA

I. Urits Beth Israel Deaconess Medical Center Harvard Medical School, Boston, MA, USA

L. Sun · E. M. Cornett ( LSU Health Shreveport, Department of Anesthesiology, Shreveport, LA, USA e-mail: ecorne@lsuhsc.edu

K. Charipova · K. Gress Georgetown School of Medicine, Washington, DC, USA

A. D. Kaye Departments of Anesthesiology and Pharmacology, Toxicology, and Neurosciences, Louisiana State University School of Medicine-Shreveport, Shreveport, LA, USA

LSU Health Shreveport School of Medicine, New Orleans, LA, USA

Tulane School of Medicine, New Orleans, LA, USA

noted in various other systemic diseases such as diabetes mellitus, liver disease, and renal disease, which can all lead to plasma membrane alterations that affect their function [4].

There are various inherited and acquired disorders associated with platelets. Inherited platelet disorders are typically rare compared to the acquired platelet disorders (with the exception of inherited versus acquired vWF disease) [1]. The inherited platelet disorders have increased in prevalence in part due to routine blood counts but are still often misdiagnosed as an acquired platelet disorder or aresimply notclassied, making accurate measurements of prevalence difcult [2]. These disorders can cause alterations in platelet number (quantitative) or function (qualitative). The qualitative changes involve impairment in platelet adhesion, activation, secretion, or aggregation. The quantitative changes can predispose to thrombosis or bleeding depending on the presence of thrombocytosis or thrombocytopenia, respectively. The bleeding from platelet disorders usually involves mucocutaneous bleeding, epistaxis, petechiae, and postsurgical bleeding. This contrasts with the larger and deeper bleeds associated with hemophilia [1, 3]. Given that several genes involved with inherited platelet disorders (e.g., WAS, MYH9, GP2B) arealso utilized by other cell lines, multisystem disease is common with platelet disorders [2, 3].

Related tothe systemic involvement of plateletsin hemostasis and the effects of other diseases on them, platelet disorders are an important consideration for aficted patients. Up to 25% of the population has thrombocytopenia, which can cause mild bleeding at plateletconcentrations lower than 100,000/μL [1]. Screening tools in the form of questionnaires have been utilized to screen for platelet disorders without signicant success, deferring to the patient’sability to recount a history of bleeding and multisystem involvement as the primary screening modality [1, 3]. When an inherited disorder is suspected, ow cytometry is commonly implemented, taking advantage of the fact that platelets do not contain DNA [4]. Various other tests are used to assess platelet function (e.g., Aggregation tests) [3]. Many different

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G. M. Jeha et al.

drugs, foods, and supplements are known to affect platelet function (e.g., aspirin). Patients with platelet disorders must therefore be identied and educated on their bleeding risk and advisedto avoid compounds which could increase their risk. The role of platelets should be carefully considered by the physician when evaluating patients. This chapter focuses on summarizing platelet disorders,as well as their diagnosis, management, and perioperative considerations,for the clinical anesthesiologist.

Types ofDisorders

Platelets play an important role in hemostasis, initiation of blood coagulation, and wound healing [4–7]. Disorders of platelet function, whether inherited or acquired, can range in clinical expression from asymptomatic to mild bruising, mild mucocutaneous bleeding, and even acute lifethreatening bleeding [7–9]. Patients with platelet counts less than 150×10

per μL 10 but greater than 50× 103 per μL may be clinically asymptomatic. As platelet count continues to decline, patients may experience petechiae, purpura, and ecchymoses. Severely low platelet counts can lead to bleeding with minimal trauma and eventually spontaneous bleeding [9, 10].

Platelet disorders encompass a vast spectrum of disease, varying from syndromes with abnormally decreased platelet numbers (thrombocytopenia), abnormally increased platelet numbers (thrombocythemia or thrombocytosis), or abnormal platelet function [6].

Thrombocytopenia

Thrombocytopenia is a commonly encountered clinical entity with a multitude of potential etiologies, making diagnosis challenging [11–13]. Potential causes include decreased platelet production in the bone marrow, increased platelet destruction or consumption in the periphery, enhanced splenic sequestration, and hemodilution [14, 15].

Consumptive thrombocytopenic disorders involve increased consumption of platelets in the periphery, such as that which occurs in disseminated intravascular coagulation (DIC), septicemia, and thrombotic microangiopathies such as thrombotic thrombocytopenic purpura and hemolytic- uremic syndrome [15–17]. Platelet destruction often refers to the clearance of platelets via platelet-reactive antibodies, alloantibodies, or drug-dependent antibodies [15, 18, 19].

Several medications have the potential to lead to thrombocytopenia by either inducing destruction of platelets via antibody-mediated processes or inhibiting production of platelets in the bone marrow. Drugs with known potential for

causing drug-induced thrombocytopenia include beta-lactam antibiotics such as penicillins and cephalosporins, vancomycin, phenytoin, piperacillin, trimethoprim-sulfamethoxazole, sulfonamides, rifampin, quinine, quinidine, carbamazepine, abciximab, eptibatide, and tiroban; drugs with the potential for dose-dependent bone marrow suppression include valproic acid, linezolid, daptomycin, and gold compounds [

20–29].

Heparin-induced thrombocytopenia (HIT) is a lifethreatening condition related to heparin exposure caused by antibodies recognizing complexes of platelet factor 4 and heparin. These antibodies also activate platelets and lead to arterial and venous thrombosis which can be fatal in up to 20% of untreated cases [30, 31].

Acquired causes of decreased bone marrow platelet production include malignancies, chemical agents, or infectious agents [14]. Thrombocytopenia is a common nding in patients with solid tumors and may be related to several factors such as tumor inltration of thebone marrow and spleen, chronic DIC, microangiopathy, alterations in cytokine proles, and the use of chemotherapeutic agents [

32, 33]. In

patients with leukemias, impaired hematopoiesis, abnormalities in hematopoietic cell morphology, and inltration of bone marrow can lead to thrombocytopenia [34]. Chronic myeloid leukemia may be the cause of thrombocytopenia when neutrophilia is also present and infectious etiologies have been excluded [10]. Signicant elevations in white blood cell counts accompanying thrombocytopenia may suggest the presence of lymphoid malignancy [35].

If thrombocytopenia is present in the context of neutrophilia, an infectious process should be considered [10]. Several infectious agents are associated with thrombocytopenia, with the most common mechanisms being immunemediated destruction, bone marrow suppression, and consumption. Some viruses may inuence platelet and megakaryocyte function and induce the generation of antiplatelet antibodies [36]. Infection with viruses such as Epstein-Barr, mumps, rubella, parvovirus, varicella, and hepatitis C virus may lead to thrombocytopenia.

Thrombocytopenia has also been reported after Zika virus infection [37]. Since thrombopoietin is produced in the liver, any viral infection leading to severe hepatitis may potentially cause thrombocytopenia [38, 39]. In thrombocytopenia related to chronic hepatitis C infection, bone marrow inhibition, hypersplenism, and auto-immunogenicity are also contributory factors [38, 40].

Mild platelet dysfunction has been associated with consumption of several food products and supplements including onion, cumin, turmeric, curcumin, clove, garlic, sh oil, and vitamin E, with possible etiologies related to decreased synthesis of thromboxane A2, decreased metabolism of arachidonic acid, and inhibition of brinogen binding to platelets [41–43].

7 Diseases or Conditions ofPlatelet Disorders

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Thrombocythemia andThrombocytosis

Thrombocytosis, often dened as a platelet count greater than 450×109/L, has numerous potential causes which can generally be organized as spurious, reactive, or clonal in nature [44–46]. Reactive etiologies are the most common, comprising up to 97% of cases of thrombocytopenia [47,

48]. Patients with thrombocytosis may be at risk of both

thrombotic complications and paradoxical bleeding [46, 49,

50].

A major branchpoint in the diagnostic evaluation of thrombocytosis involves determining whether a reactive or clonal process is taking place [46]. Common causes of reactive thrombocytosis include infection, tissue damage, chronic inammatory disorders, iron deciency anemia, and malignancy [46–48, 51].

After excluding reactive thrombocytosis, a clonal etiology should be investigated. The most common clonal causes of thrombocytosis are essential thrombocythemia, CML, polycythemia vera, and primary myelobrosis [46].

Spurious thrombocytosis occurs when non-platelet structures in peripheral blood, such as cryoglobulin crystals, cell fragments, or bacteria, are counted as platelets by automated blood counters. This can be avoided by evaluation of a peripheral blood smear [46].

Inherited Platelet Disorders

Compared to acquired causes, inherited causes of platelet disorders are less frequent but often portend a higher tendency for bleeding [52, 53]. Although rare, these inherited platelet disorders have contributed greatly to our understanding of platelet function and hemostasis.

Inherited platelet disorders may affect the number of platelets or impair normal platelet functions such as adhesion, receptor functionality, secretion, enzymatic activity, or signaling pathways [2, 54–57]. Inherited thrombocytopathies are often organized into disorders of platelet adhesion, aggregation, and secretion, [2].

Oftentimes, the platelet phenotype can be of signicance when evaluating differential diagnosis of thrombocytopenia. For example, Wiskott-Aldrich syndrome and X-linked thrombocytopenia may both lead to small platelet size [2, 58,

59]. Alternatively, abnormally large platelets may be seen in

disorders such as velocardiofacial syndrome, Mediterranean macrothrombocytopenia, platelet-type von Willebrand disease, May-Hegglin anomaly, Fechtner syndrome, Sebastian syndrome, or Epstein syndrome [2, 58, 60–64].

Bernard-Soulier syndrome and platelet-type von Willebrand disease are examples of disorders of platelet adhesion. Bernard-Soulier syndrome is an autosomal recessive bleeding syndrome involving defects of the platelet gly-

coproteins Ib, IX, and V, which form a complex to aid in the adherence of platelets to the vascular endothelium via binding of von Willebrand Factor (vWF) [

65, 66]. The syndrome

is characterized by bleeding tendency, abnormally large platelets, and thrombocytopenia [53, 66]. Homozygous mutations typically manifest after birth with purpura, epistaxis, or gingival bleeding [53]. Bleeding tendencies have been reported in heterozygous individuals, but these patients more often remain asymptomatic [67, 68]. Platelet-type von Willebrand disease is a rare autosomal dominant disorder characterized by increased afnity for glycoprotein Ib for vWF, leading to abnormal enhanced binding of vWF by platelets [69–71]. Consequently, complexes of platelets bound to high-molecular-weight multimers of vWF are removed from circulation, leading to thrombocytopenia and decreased levels of vWF multimers [72]. Platelet-type von Willebrand disease and type 2B von Willebrand disease are very similar in clinical and laboratory ndings, and diagnosis can be made using genetic analysis [

70, 72]. The former

disorder requires treatment with platelet transfusions, while the latter requires administration of exogenous vWF [71]. Due to misdiagnosis, the prevalence of platelet-type von Willebrand disease is likely underestimated [72–74].

Glanzmann’s thrombasthenia is a classic disorder affecting platelet aggregation. This is an autosomal recessive syndrome affecting the quantity or quality of the α

IIbβ3

integrin (glycoprotein IIb/IIIa) present on platelets, which is involved in platelet aggregation at the site of vessel injury [75]. The syndrome is characterized by a lack of platelet aggregation and commonly manifests at birth with bleeding symptoms such as purpura, epistaxis, and gingival bleeding [75]. Glanzmann thrombasthenia should be suspected when mucosal bleeding is accompanied by lack of platelet aggregation in the presence of normal platelet count and size; the diagnosis may be conrmed via ow cytometry [53].

Inherited disorders involving the number, contents, storage, or release of platelet granules belong to a heterogeneous group of disorders called storage pool disease (SPD). AlphaSPD, or the gray platelet syndrome, is a deciency involving alpha granules and their contents. Delta-SPDs involve abnormalities in the dense bodies, causing a deciency of adenosine diphosphate, adenosine triphosphate, and serotonin [8,

76, 77]. The most commonly known delta-SPDs include

Hermansky-Pudlak syndrome, Chediak-Higashi syndrome, and the Quebec platelet syndrome [8, 53, 78, 79].

Disorders of platelet membrane receptors affecting platelet extension and aggregation are a growing area of research [8]. Examples include defects in the P2Y12 receptor, which is necessary for adenosine diphosphate-induced platelet aggregation, defects in the glycoprotein VI platelet collagen receptor, thromboxane A2 receptor, and the epinephrine receptor [8, 80, 81].

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