Hematologic Disorders



Hematologic Disorders





9.1 Anemia

Lori B. Heller

It has long been recognized that anemia in the general population is associated with longer and more frequent hospitalizations as well as an increase in mortality (1,2). However, until recently preoperative anemia was thought to have relatively limited significance other than as an indication to have blood available for transfusion. Preoperative anemia has emerged to be one of the major factors associated with perioperative morbidity and mortality (3,4,5). It is estimated that over one-third of patients presenting for surgery meet the WHO criteria for anemia. These estimates differ based on the population and surgeries studied and vary from 10% to 80% (6).

WHO definition of anemia:



  • Women: Hematocrit (Hct) <36 g/dL


  • Men: Hct <39 g/dL

While blood transfusion is the easiest and most expeditious treatment for anemia, transfusion is associated with perioperative morbidity and mortality (7,8). For this and other reasons, it is not considered appropriate therapy for preoperative anemia management in elective surgery patients. Preoperative anemia is one of the major risk factors for transfusion, and is now identified as an independent risk factor for perioperative morbidity and mortality, regardless of transfusion (3,4). Several studies found that the increased risk does not require profound or even moderate levels of anemia. The perioperative risk begins when Hct falls below the WHO definition of anemia (36 and 39 g/dL for women and men respectively) and increases linearly as the Hct declines (3,4). Because preoperative anemia is often an easily modifiable factor it needs to be identified and treated like any other comorbidity.


PREOPERATIVE ANEMIA EVALUATION

In some instances, the evaluation of anemia is complicated, extensive, and out of the scope of practice for an anesthesiologist. However, perioperative physicians’ goals are to identify anemia and increase red blood cell (RBC) mass to decrease perioperative risk. Evaluation and treatment algorithms do not need to be complex (Fig. 9.1).

Certain circumstances prompt a referral to a primary care physician (PCP) or hematologist. This does not have to result in a delay of surgery. Ideally, the referral is
done concurrently with the initial evaluation and treatment of the anemia. For other patients it may be acceptable to pursue follow-up postoperatively.






Figure 9.1 Anemia management algorithm—Swedish Hospital.

Hgb, hemoglobin; Fe, iron; TIBC, total iron binding capacity; TSAT, Transferrin saturation; GI, gastrointestinal; PCP, primary care physician; CHr, Reticulocyte hemoglobin content; IV, intravenous; GFR, glomerular filtration rate; ESA, erythrocyte stimulating agent; MCV, mean corpuscular volume; TSH, thyroid stimulating hormone

*No recent surgery/procedure involving blood loss, menstruation. Evaluation can be concurrent or completed.

ˆIf significant time prior to surgery, can give a trial of oral iron

**ESA – epoetin alpha 600 u/kg/wk x 1-3 weeks, consider referral to nephrologist



  • Indications for PCP referral



    • Iron-deficiency anemia (IDA) in postmenopausal women or any man not explained by recent blood loss or surgery.



    • IDA can be associated with malignancies such as gastrointestinal (GI), kidney, uterine, or hematologic and needs to be investigated preoperatively.


  • Indications for hematology referral



    • Concurrent abnormalities in other cell lines (thrombocytopenia, leukopenia)


    • Abnormalities on peripheral smear


    • Suspicion of hemolytic anemia


    • Suspicion of hematologic malignancy


ETIOLOGY

There are five major causes of preoperative anemia



  • IDA


  • Anemia of chronic inflammation (ACI)


  • Chronic kidney disease (CKD)


  • Nutritional deficiencies (B12, folate)


  • Unexplained anemia of the elderly (UAE)


Iron-Deficiency Anemia

Iron deficiency is the cause of anemia 20% to 55% of the time, depending on the type of surgery and the population studied (6). The causes of IDA vary and include:



  • Recent surgery or procedures (including femoral access for coronary angiography)


  • Menstruation


  • GI disease (colonic polyps, peptic ulcer disease, malignancy)


  • Poor iron absorption due to medications, diet, or GI surgery


  • Recent hospitalization, phlebotomy

Iron is particularly challenging to absorb and the vast majority of the iron source for RBC production comes from recycling of old RBCs that have reached the end of their 120-day lifespan. Dietary and supplemental iron absorption requires a mildly acidic environment which is not present in patients on H2 blockers or proton pump inhibitors (PPIs). In addition, phytates (found in nuts and whole grains) and tannins (found in wine, chocolate, and tea) also interfere with iron absorption.


Assessment of Iron Deficiency

The diagnosis of iron deficiency is based on laboratory values of average RBC size or mean corpuscular volume (MCV) and an assessment of iron stores. Also helpful is a history of known blood loss (recent surgery, menstruation). Laboratory studies include:



  • Total serum iron: normal or low


  • Total iron-binding capacity (TIBC): high normal or elevated


  • Transferrin saturation (TSAT): low


  • Ferritin: low


  • MCV: low


  • Reticulocyte hemoglobin content (CHr): low

Iron parameters (serum iron, TIBC, ferritin, TSAT) can be difficult to interpret especially after recent iron administration or in the setting of acute illness which can result in elevated ferritin. Therefore, measurement of the CHr can be helpful. Reticulocytes are the most immature RBC found in circulation. The measurement of
CHr provides a snapshot of the iron directly available for hemoglobin synthesis and is an early indicator of the body’s iron status.


Treatment of Iron Deficiency

Iron supplementation is provided orally or intravenously (IV). While repletion by oral supplementation has a lower cost, the response is slower and not as reliable. Many patients are noncompliant due to the high rate of GI intolerance. Many patients on PPIs and H2 blockers will not absorb iron adequately due to lack of acid. IV iron is often a more effective strategy. The various formulations of iron differ in maximum dosing and side effect profiles. The most common reactions include allergic flushing, pruritus, urticaria, rash and hypotension. Hypotension is usually associated with rapid infusion. The most common IV preparations include:



  • Iron dextran (low molecular weight [LMW])


  • Iron sucrose


  • Ferric gluconate


  • Ferric carboxymaltose

Iron dextran has the benefit of repleting the entire iron deficit in one sitting, whereas the other preparations require repeat divided doses with a maximum weekly dosage restriction. However, iron dextran requires a test dose and carries a black box warning, in part due to the high adverse effects that were associated with the high-molecular-weight preparation that was previously available (9). Two adverse events can uncommonly occur with LMW dextran, both without residual sequelae, but can make it a less desirable choice for many patients. The first is the acute onset of chest and back pain without hypotension, tachypnea, tachycardia, or wheezing. The second occurs in approximately 10% of patients and consists of arthralgias and myalgias, usually occurring 24 hours after the infusion (10). Total repletion doses with dextran require pretreatment with methylprednisolone. For these reasons, iron sucrose, ferric gluconate, and ferric carboxymaltose have gained favor as treatments of choice in many anemia management programs. They do not contain the dextran moiety and the incidence of anaphylactic reactions is much lower than with iron dextran, but do require multiple visits for repeat infusions. Ferric carboxymaltose can be given at a higher total single dose than either iron sucrose or ferric gluconate; however, it can be cost prohibitive. In general, IV supplementation begins to take effect in 1 week with the peak effect seen in 2 weeks post repletion (Fig. 9.2).

IV iron repletion is straightforward. The patient’s iron deficit and total iron dose is calculated by formulas based on blood volume and current hemoglobin (Hg) levels. Either of the following calculations can be used:



  • Body weight (kg) × (target Hb-actual Hb) × 2.4


  • 150 to 200 mg iron for each g/dL deficit in Hb

For both of the above formulas: add 500 to 800 mg to replace depleted iron stores in patients with the following:



  • TSAT <10% regardless of ferritin

    OR


  • TSAT <20% and ferritin < 100 ng/dL







Figure 9.2 Iron preparations.

LMW, low molecular weight

In patients with normal Hg but decreased ferritin, IV iron can be given. This is particularly useful for postoperative recovery in surgeries with high expected blood loss. In this instance, the dosage of IV iron can be calculated with the following formula:

[100-ferritin (ng/mL)] × 10


Anemia of Chronic Inflammation

ACI is estimated to be the cause of anemia in 25% to 33% of patients (6). In certain chronic disease states, increased iron accumulation and reduced enteric iron absorption occurs, primarily due to excessive amount of the liver enzyme, hepcidin. In addition, patients with ACI have a decreased marrow responsiveness to erythropoietin, a hormone produced by the kidneys that induces RBC production. The diagnosis of ACI involves assessment of RBC size and iron stores. Differentiation between ACI and iron deficiency is shown in Figure 9.3. Both disease processes result in low serum iron and TSAT. ACI has normal or elevated iron stores, and normal or decreased TIBC.


Treatment of Anemia of Chronic Inflammation

The treatment of ACI is exogenous erythropoietin (Epo) and IV iron supplementation. The IV iron circumvents the issue of decreased enteric iron absorption as well as the diminished release of iron stores and provides iron availability for RBC production. However, care is taken to not cause iron overload by assessing ferritin levels.

A typical treatment plan may be:



  • Epoetin alfa, 600 u/kg/wk × 3 weeks


  • Iron sucrose, 100 to 200 mg/wk × 3 weeks

Epo is approved for perisurgical adjuvant therapy without auto donation since 1996 and its use is advocated by the American Society of Anesthesiologists’ Task Force on Perioperative Blood Management (11). Epo has been shown to be effective
in reducing the need for transfusion (12). In 2007, FDA placed a black box warning on erythrocyte stimulating agents in the setting of malignancies or renal failure. The studies showing a safety signal for oncology had Hg targets >13 g/dL and up to 15 g/dL which is generally higher than standard preoperative thresholds (13,14). The FDA has recommended that prophylactic anticoagulation be “strongly considered” in patients using Epo in the perioperative setting although there is conflicting data over the risk of VTE. Several studies looking at the preoperative use of Epo and risk of VTE did not specifically target anemic patients and the resulting Hg levels were higher than what is generally now advocated in the perioperative setting (15).






Figure 9.3 Comparison of laboratory data for iron deficiency and anemia of chronic inflammation.


Anemia of Chronic Kidney Disease

CKD is a common cause of perioperative anemia. Patients with moderately impaired kidney function (stage 3, glomerular filtration rate <50 mL/min/1.73 m2) do not produce adequate erythropoietin, and require supplemental erythropoietin. Concomitant iron therapy is administered because of the increased demand for iron with erythropoiesis.


Nutritional Deficiencies and Unexplained Anemia of the Elderly

Less common causes of preoperative anemia include B12 and folate deficiencies (3% to 5%) and medications (inhibited erythropoiesis or anticoagulant-associated bleeding) (6). Nutritional deficiencies such as B12 and folate can occur due to decreased dietary intake or after weight loss surgery, and can be subclinical, typically resulting from a “tea and toast” diet. Some patients have normal B12 levels and the deficiency is only detected by an elevation in B12 metabolites (methylmalonic acid and homocysteine). These deficiencies can be replaced with oral supplementation. Even pernicious anemia can be treated with oral B12, despite the common practice of giving B12
intramuscularly. UAE, which is often mild and multifactorial and associated with renal insufficiency, androgen deficiency, myelodysplasia, chronic inflammation, and stem cell aging, make up the majority of the remaining preoperative anemias. UAE is characterized by low erythropoietin levels and unlike ACI, with low levels of proinflammatory markers as well as low lymphocyte counts (16). UAE is treated similarly to ACI.



REFERENCES

1. Kikuchi M, Inagaki T, Shinagawa N. Five-year survival of older people with anemia: variation with hemoglobin concentration. J Am Geriatr Soc. 2001;49(9):1226-1228.

2. Salive ME, Cornoni-Huntley J, Guralnik JM, et al. Anemia and hemoglobin levels in older persons: relationship with age, gender, and health status. J Am Geriatr Soc. 1992;40(5):489-496.

3. Beattie WS, Karkouti K, Wijeysundera DN, et al. Risk associated with preoperative anemia in noncardiac surgery: a single-center cohort study. Anesthesiology. 2009;110(3):574-581.

4. Wu WC, Schifftner TL, Henderson WG, et al. Preoperative hematocrit levels and postoperative outcomes in older patients undergoing noncardiac surgery. JAMA. 2007;297(22): 2481-2488.

5. Karkouti K, Wijeysundera DN, Beattie WS; Reducing Bleeding in Cardiac Surgery (RBC) Investigators. Risk associated with preoperative anemia in cardiac surgery: a multicenter cohort study. Circulation. 2008;117(4):478-484.

6. Muñoz M, Gómez-Ramírez S, Campos A, et al. Pre-operative anaemia: prevalence, consequences and approaches to management. Blood Transfus. 2015;13(3):370-379.

7. Engoren MC, Habib RH, Zacharias A, et al. Effect of blood transfusion on long-term survival after cardiac operation. Ann Thorac Surg. 2002;74(4):1180-1186.

8. Bernard AC, Davenport DL, Chang PK, et al. Intraoperative transfusion of 1 u to 2 u packed red blood cells is associated with increased 30-day mortality, surgical-site infection, pneumonia, and sepsis in general surgery patients. J Am Coll Surg. 2009;208(5): 931-937.

9. Chertow GM, Mason PD, Vaage-Nilsen O, et al. Update on adverse drug events associated with parenteral iron. Nephrol Dial Transplant. 2006;21(2):378-382.

10. Auerbach M, Ballard H, Glaspy J. Clinical update: intravenous iron for anaemia. Lancet. 2007;369(9572):1502-1504.

11. American Society of Anesthesiologists Task Force on Perioperative Blood Management. Practice guidelines for perioperative blood management: an updated report by the American Society of Anesthesiologists Task Force on Perioperative Blood Management. Anesthesiology. 2015;122(2):241-275.

12. Stowell CP, Jones SC, Enny C, et al. An open-label, randomized, parallel-group study of perioperative epoetin alfa versus standard of care for blood conservation in major elective spinal surgery: safety analysis. Spine (Phila Pa 1976). 2009;34(23):2479-2485.

13. Glaspy J, Crawford J, Vansteenkiste J, et al. Erythropoiesis-stimulating agents in oncology: a study-level meta-analysis of survival and other safety outcomes. Br J Cancer. 2010;102(2):301-315.

14. Bennett CL, Silver SM, Djulbegovic B, et al. Venous thromboembolism and mortality associated with recombinant erythropoietin and darbepoetin administration for the treatment of cancer-associated anemia. JAMA. 2008;299(8):914-924.

15. Singh AK, Szczech L, Tang KL, et al. Correction of anemia with epoetin alfa in chronic kidney disease. N Engl J Med. 2006;355(20):2085-2098.

16. Ferrucci L, Guralnik JM, Bandinelli S, et al. Unexplained anaemia in older persons is characterized by low erythropoietin and low levels of pro-inflammatory markers. Br J Haematol. 2007;136(6):849-855.



9.2 Sickle Cell Disease

Lori B. Heller

Sickle cell disease (SCD) is a hereditary hemoglobinopathy that is associated with significant morbidity and mortality. Worldwide about 300,000 infants are born each year with sickle cell anemia and about 100,000 people in the United States are affected (1). SCD is the result of a mutation in chromosome 11 which produces an abnormal beta-globulin chain. Under certain conditions the red cells can deform and cause sickling crises with vaso-occlusive phenomena and hemolysis. Vaso-occlusion results in recurrent painful episodes and organ system complications. Circumstances that can result in crisis are:



  • Hypoxia


  • Venous stasis


  • Hypothermia


  • Dehydration


  • Surgical stress

Surgical procedures can also be a precipitant of acute chest syndrome, which is an acute pneumonia-like complication of SCD that is characterized by a new pulmonary infiltrate, chest pain, pyrexia, tachypnea, wheezing, or cough.


AFFECTED ORGAN SYSTEMS

Several organ systems may be involved in SCD, including:



  • Pulmonary: Acute chest syndrome, progressive lung disease


  • Neurologic: Hemorrhagic or ischemic stroke, retinopathy, neuropathy, chronic pain


  • Renal: Renal insufficiency


  • Gastrointestinal: Cholelithiasis, viral hepatitis (transfusion related)


  • Orthopedic: Osteonecrosis

Pulmonary and neurologic diseases are the leading causes of morbidity and mortality. Although several organ systems can be involved in a chronic and progressive disease process, most deaths are not the result of chronic organ failure, but occur during an acute episode of pain, respiratory failure, or stroke (2).


GENOTYPES

The following genotypes occur (where A represents normal hemoglobin):



  • Homozygous (HbSS)


  • Heterozygous (HbAS)


  • Heterozygous S + another abnormal hemoglobin (HbC or β thalassemia)

Sickle cell trait (HbAS) is generally benign, requiring extremely hypoxic or acidotic conditions for sickling to occur. Patients with HbAS have a low risk of surgical complications. Homozygous (HbSS) or doubly heterozygous (HbSC or HbS β thalassemia) forms produce chronic, incurable illness.



ASSESSMENT OF SURGICAL RISK

Surgical risk is assessed by evaluating the following:



  • Type of surgical procedure: low, moderate, high (see Table 9.1)


  • Patient age (older age carries increased risk)


  • Frequency of recent complications and hospitalizations


  • Extent of chronic pulmonary disease, including history and frequency of acute chest syndrome


  • Current infection (including urinary tract and upper respiratory infections [URIs])


  • Pregnancy (higher risk)


  • Haplotype (African greater risk than Asian)

The type of surgery has a direct impact on the severity of complications. In one study tonsillectomy had an incidence of complications of 0%, hip surgery 2.9%, nonobstetrical intra-abdominal surgery 7.8%, cesarean section and hysterectomy 16.9%, and dilation and curettage 18.6%. While the study was retrospective and the type of anesthesia was not controlled, it does suggest there is a significant difference in complications based on types of surgery (3).


PREOPERATIVE TESTING

Preoperative evaluation includes evaluation of the patient’s hematologic, pulmonary, renal, and neurologic status (4). Given the frequency of alloimmunization due to previous transfusions, type and screen is recommended for antibody assessment for most surgeries. Preoperative testing recommendations are in Table 9.2. Interestingly, an abnormal chest radiograph, but not lower oxygen saturation, was associated with longer stay following cholecystectomy (5).


PREOPERATIVE TRANSFUSION AND EXCHANGE TRANSFUSION

It had previously been recommended that anemia be treated preoperatively. It had previously been recommended that anemia be treated and the HbS burden lowered to less than 30%-60% through liberal preoperative exchange transfusions in all patients with SCD. However, newer data demonstrates equal outcomes for more conservative transfusion practices, and concerns regarding the complications of transfusions have changed these more aggressive transfusion guidelines (6). The incidence of alloimmunization which is the development of non-ABO erythrocyte antibodies, in the SCD population varies from 8% to 50% and increases with the
number of transfusions (7). Importantly, this can result in an inability to find compatible red cell units in emergency hemorrhage situations. Extended cross matching for E, C, and K antigens decreases alloimmunization. Other transfusion complications seen in the SCD population are:



  • Delayed transfusion reactions, which can present as fulminant hemolysis


  • Stroke


  • Pain crisis


  • Acute pulmonary deterioration (secondary to transfusion-related acute lung injury [TRALI] and transfusion-associated circulatory overload [TACO])


  • Infection (particularly hepatitis C)








TABLE 9.1 Risk Stratification by Type of Surgery











Low Risk


Moderate Risk


High Risk


Inguinal hernia repair


Extremity surgery


Intra-abdominal


Intracranial


Thoracic









TABLE 9.2 Preoperative Testing Recommendations




















Hematocrit


Blood urea nitrogen/creatinine


Urinalysis (proteinuria and occult infection)


Chest radiography


Pulse oximetry


Type and screen


Further testing, based upon risk assessment, may include:



Pulmonary function testing


Arterial blood gas


Liver function tests


Neurologic imaging


Electrocardiogram


Cross-match


Recent studies indicate that prophylactic transfusion to hematocrits >30 (not exchange transfusion) may be beneficial in moderate and high-risk cases (6). However, the efficacy has not been clearly demonstrated by a randomized trial and remains controversial. A recent Cochrane review demonstrated no difference in all-cause mortality, acute chest syndrome, vaso-occlusive crisis, serious infection, or perioperative transfusion-related complications when comparing aggressive versus conservative transfusion practices or preoperative transfusion versus no transfusion (8). However, they concluded that there is not enough evidence to identify specific recommendations. Use of transfusion for mild cases of acute chest syndrome is also controversial, although transfusion in severe cases improves arterial oxygenation (9).





REFERENCES

1. Piel FB, Steinberg MH, Rees DC. Sickle cell disease. N Engl J Med. 2017;376(16):1561-1573.

2. Platt OS. Mortality in sickle cell disease. Life expectancy and risk factors for early death. N Engl J Med. 1994;330(23):1639-1644.

3. Koshy M, Weiner SJ, Miller ST, et al. Surgery and anesthesia in sickle cell disease. Cooperative study of sickle cell diseases. Blood. 1995;86(10):3676-3684.

4. Firth PG, Head A. Sickle cell disease and anesthesia. Anesthesiology. 2004;101(3): 766-785.

5. Haberkern CM, Neumayr LD, Orringer EP, et al. Cholecystectomy in sickle cell anemia patients: perioperative outcome of 364 cases from the National Preoperative Transfusion Study. Preoperative Transfusion in Sickle Cell Disease Study Group. Blood. 1997;89(5):1533-1542.

6. Vichinsky EP, Neumayr LD, Haberkern C, et al. The perioperative complication rate of orthopedic surgery in sickle cell disease: Report of the National Sickle Cell Surgery Study Group. Am J Hematol. 1999;62(3):129-138.

7. Davies SC. Blood transfusion in sickle cell disease. Curr Opin Hematol. 1996;3(6): 485-491.

8. Estcourt LJ, Fortin PM, Trivella M, et al. The Cochrane database of systematic reviews. 2016;4:CD003149.

9. Vichinsky EP, Neumayr LD, Earles AN, et al. Causes and outcomes of the acute chest syndrome in sickle cell disease. National Acute Chest Syndrome Study Group. N Engl J Med. 2000;342(25):1855-1865.


9.3 Thalassemia

Justin N. Lipper

Normal adult hemoglobin (Hb A) is comprised of one pair of alpha globin (α) chains and one pair of beta globin (β) chains, produced in a 1:1 ratio. A reduction or absence in the production of one or more globin chains results in thalassemia. There are approximately 15 million people with thalassemia in the world, but only a small percent of those live in the United States. The etiology is a genetic mutation associated with ancestry in areas endemic to malaria, so the majority of cases occur in people of African, Mediterranean, and Southeast Asian descent (1). Thalassemias are inherited in an autosomal recessive manner.


CLASSIFICATION

Being a heterogeneous group of microcytic anemias, thalassemias are further classified by the genotype (Table 9.3). This classification has a direct correlation with severity of disease and clinical manifestations, ranging from a silent carrier of a genetic mutation to transfusion dependency and death.

There are two genes responsible for the production of alpha globin and one gene responsible for beta globin (2). At least two alleles need to be abnormal to produce a clinically significant decrease in alpha globin production and a concomitant proliferation of beta globin, which results in alpha thalassemia. This increased ratio of beta to alpha causes the formation of tetramers of beta globin creating Hb H. Hb H
is unstable and has impaired oxygen association. It is also very insoluble and results in inclusion (Heinz) bodies in circulating RBCs which cause hemolytic anemia (3). In utero, gamma globin precedes the production of and is replaced by beta globin, which distinguishes fetal hemoglobin (Hb F) from Hb A. Similar to Hb H, Hb Barts is the result of four gamma globin chains coming together. This is why measuring Hb Barts is a useful screening tool for neonates suspected of having altered alpha globin synthesis (4).








TABLE 9.3 Classification of Thalassemias





















































Disorder


Genotype


Anemia


MCV


Hb Types


Alpha thalassemia silent carrier


α α/α –


None


Normal


Normal <3% Hb Barts at birth


Alpha thalassemia minor


α α/- – or α -/α –


Mild


Low


Normal


3-8% Hb Barts at birth


Hb H disease


α -/- –


Moderate


Low


5-30% Hb H in adults


20-40% Hb Barts at birth


Alpha thalassemia major (hydrops fetalis)


– -/- –


Fatal


Low


Hb Barts, Hb H


Hb A, Hb F. Hb A2 absent


Beta thalassemia minor


β/β0 or β/β+


Mild


Low


Decreased Hb A


Increased Hb F


Beta thalassemia Intermedia


β+/β+ or β+/β0


Moderate


Low


Decreased Hb A


Increased Hb F


Beta thalassemia major


(Cooley anemia)


(β0/β0


Severe


Low


Hb A absent


Only Hb A2 and Hb F


Adapted from Benz EJ Jr. Clinical manifestations and diagnosis of the halassemias. Post TW, ed. UpToDate. Waltham, MA: UpToDate Inc. www.uptodate.com (Accessed on Jan 08, 2018.)


Whereas each alpha globin allele can either make normal alpha globin or nothing at all, abnormal beta globin alleles can have partial synthesis of normal beta globin chains. Therefore, beta globin alleles that are abnormal but still produce beta globin are referred to as β+, while the ones that do not produce any are referred to as β0. Even if there is a homozygous β0 mutation (beta thalassemia major), this is still compatible with life due to a low level of delta globin (δ) being produced after birth which can join with alpha globin to form Hb A2. As there is no substitute for alpha globin, alpha thalassemia major results in death in utero (hydrops fetalis). Similar to alpha thalassemias, the clinical pathology seen as a result of beta thalassemia is due to impaired erythroid maturation with dysfunctional or absent beta chains as well as the concomitant proliferation of alpha chains.









TABLE 9.4 Perioperative Evaluation: System-Based Focus

































System


Effect


Evaluation


HEENT


Malar hypoplasia


Airway examination


Cardiovascular


Heart failure, arrhythmia, pericarditis


CV examination, assess exercise tolerance, ECG, further evaluation if history suggests underlying pathology


Pulmonary


Restrictive lung disease


Lung examination, assess exercise tolerance, possible PFTs


Hematologic


Anemia, splenomegaly, alloimmunization, coagulopathy


History of blood transfusions, CBC, type and screen, coagulation studies (PT, aPTT)


Hepatic


Cirrhosis


LFTs, prothrombin time, platelets


Endocrine


Diabetes mellitus, hypothyroidism, adrenal insufficiency


Fasting glucose, HbA1c, thyroid function test, cortisol determination


HEENT, head, eyes, ears, nose, throat; CV, cardiovascular examination; ECG, electrocardiogram; PFTs, pulmonary function tests; CBC, complete blood count; PT, prothrombin time; PTT, partial thromboplastin time; LFTs, liver function tests; HbA1c, glycosylated hemoglobin





REFERENCES

1. Global Burden of Disease Study 2013 Collaborators. Global, regional, and national incidence, prevalence, and years lived with disability for 301 acute and chronic diseases and injuries in 188 countries, 1990-2013: a systematic analysis for the Global Burden of Disease Study 2013. Lancet. 2015;386(9995):743-800.

2. Kumar V, Abbas A, Aster J. Thalassemia. In: Kumar V, Abbas A, Aster J, Perkins J, eds. Robbins Basic Pathology. 10th ed. Philadelphia, PA: Elsevier; 2018; 447. Available at www.clinicalkey.com/dura/browse/bookChapter/3-s2.0-C20140017194. Accessed May 1, 2017

3. Sheeran C, Weekes K, Shaw J, et al. Complications of HbH disease in adulthood. Br J Haematol. 2014;167(1):136-139.

4. Lorey F, Cunningham G, Vichinsky EP, et al. Universal newborn screening for Hb H disease in California. Genet Test. 2001;5(2):93-100.

5. Taher AT, Musallam KM, Cappellini MD, et al. Optimal management of β thalassaemia intermedia. Br J Haematol. 2011;152(5):512-523.


9.4 Thrombocytopenia

Ross G. Gaudet

Thrombocytopenia is defined as a platelet count <150,000 mm3. Normal platelet counts vary for individuals across the population and it is important to obtain previous platelet counts to compare and trend. Pathophysiologic causes of thrombocytopenia include: primary immune idiopathic thrombocytopenia, drug-induced immune thrombocytopenia (ITP), quinine containing foods/beverages, infections, hypersplenism, alcohol, nutrient deficiencies, pregnancy, or myelodysplasia.

The first step in identifying the cause of thrombocytopenia is to confirm the decrease in platelet count by repeating the complete blood count (CBC) in EDTA-free
tubes and reviewing a peripheral blood smear. The next step in the differential diagnosis is the setting in which thrombocytopenia is found. Asymptomatic mild thrombocytopenia may be ITP, liver disease, human immunodeficiency virus (HIV) infection, myelodysplastic syndromes, or a congenital disorder. The most common diagnosis is ITP, but patients should be screened for HIV, hepatitis, and pregnancy. If the patient has an underlying immunodeficiency, congenital causes are sought. The patient’s medication list should be thoroughly reviewed for drugs, which can cause thrombocytopenia (e.g., acetaminophen, NSAIDs, penicillins, cimetidine, vancomycin).

Idiopathic (autoimmune) thrombocytopenic purpura (ITP) is a diagnosis of exclusion. ITP presents with a reduced platelet count, increased peripheral destruction, and normal bone marrow production. Autoantibodies bind to platelet antigens and trigger removal by the reticuloendothelial system in the spleen. However, testing for these autoantibodies is unwarranted and diagnosis is made by clinical manifestation alone. Treatment of ITP is supportive, not curative, with corticosteroids, but other treatments include splenectomy, gamma globulin, or platelet transfusion.

The differential diagnosis in acutely ill patients who present with thrombocytopenia includes infection, sepsis, liver disease, disseminated intravascular coagulation (DIC) and heparin-induced thrombocytopenia (HIT) (Fig. 9.4). Further characterization is obtained with blood, urine and sputum cultures, liver function tests, and coagulation studies (e.g., PT, INR, partial thromboplastin time [PTT], and fibrinogen). Treatment of thrombocytopenia is aimed at the underlying conditions and supportive treatments, such as transfusions or mechanical ventilation if warranted.

HIT usually presents 5 to 10 days after initiation of heparin and has a decrease in platelet counts >50% from their baseline levels. About 20% of cases present within 24 hours of heparin exposure and may develop significant thrombosis of arteries and veins, which can be deadly. Risk scoring to estimate the likelihood of diagnosis can be done utilizing the 4 T score (thrombocytopenia, timing of heparin exposure, presence of thrombosis, and other causes of thrombocytopenia) available in online calculators. Most centers first test for the presence of platelet-function 4 (PF4) antibodies using enzyme-linked immunosorbent assay (ELISA) testing and confirm the diagnosis with
a serotonin release assay. Treatment of HIT includes withholding heparin and using other anticoagulants (i.e., bivalirudin, lepirudin, argatroban) if warranted. Platelet counts usually return to normal within 7 to 10 days, but PF4 antibodies can persist for 2 to 3 months.






Figure 9.4 Differential diagnosis in patients presenting with thrombocytopenia. ITP, Idiopathic thrombocytopenic purpura

Platelets are usually transfused to a certain target, but the ultimate decision lies with the surgeon and anesthesiologist for surgical procedures. The typical platelet count acceptable for open or endoscopic general surgery is >50,000 mm3. Notable exceptions are neurosurgery, ocular surgery, and inner ear surgery with recommendations >100,000 mm3. Recommendations for epidural or spinal anesthesia is >80,000 mm3 and central line insertion >20,000 mm3. One six-pack of platelets will raise the platelet count by 30-50,000 mm3. If the patient requires transfusion of platelets they are given before surgery and additional platelets are transfused during surgery based on surgical bleeding.



SUGGESTED READINGS

Arnold DM, Lim W. A rational approach to the diagnosis and management of thrombocytopenia in the hospitalized patient. Semin Hematol. 2011;48(4):251-258.

Hui P, Cook DJ, Lim W, et al. The frequency and clinical significance of thrombocytopenia complicating critical illness: a systematic review. Chest. 2011;139(2):271-278.

Neunert C, Lim W, Crowther M, et al; American Society of Hematology. The American Society of Hematology 2011 evidence-based practice guideline for immune thrombocytopenia. Blood. 2011;117(16):4190-4207.

Reese JA, Li X, Hauben M, et al. Identifying drugs that cause acute thrombocytopenia: an analysis using 3 distinct methods. Blood. 2010;116(12):2127-2133.


9.5 Thrombocytosis

Ross G. Gaudet

Thrombocytosis is defined as platelet counts >450,000 mm3 and extreme thrombocytosis is when platelet counts are >1,000,000 mm3. The causes of thrombocytosis can be broken down into reactive, autonomous, and essential.

Reactive thrombocytosis is a physiologic response to periods of bodily stress. Cytokine release increases bone marrow megakaryocyte development, which increases platelet counts substantially. This is most commonly seen in pregnancy, asplenia, iron-deficiency anemia, postoperative states, or overwhelming infection/sepsis. Further testing can identify the etiology of reactive thrombocytosis such as transferrin and iron levels to diagnose iron-deficiency anemia, identification of Howell-Jolly bodies for asplenia, or neutrophil counts for infection. Treating the underlying cause and close observation is the usual management strategy.

Autonomous thrombocytosis is secondary to a myeloproliferative or myelodysplastic disorder. Examples include chronic myeloid leukemia, primary myelofibrosis, polycythemia vera, myelodysplastic syndrome variants, or acute myeloid leukemia. These disorders can be diagnosed via bone marrow examination, staining, and cytogenetic studies. Essential thrombocytosis is a diagnosis of exclusion and will be discussed further along in this section. See Figure 9.5 for a diagnostic algorithm.







Figure 9.5 Diagnosis of essential thrombocytosis.

The most common complaint is vasomotor symptoms such as flushing, headache, and sweating. These complaints are usually treated with low dose aspirin (81 to 100 mg) therapy, but some patients may require cytoreductive therapy. Bleeding may occur with thrombocytosis due to platelet dysfunction. The first step in bleeding patients is to stop all antiplatelet agents unless there is a significant risk of thromboembolism. Next steps are to rule out disseminated intravascular coagulation and coagulation factor deficiencies by evaluating PT, INR, aPTT, fibrinogen, and individual factor levels.

Thrombosis is a concern with platelet counts >800,000 mm3. If patients present with thrombosis, treatment involves immediate platelet apheresis, evaluation for additional thrombotic disorders, and anticoagulation therapy for at least 3 months whether or not platelet counts are lowered via apheresis. If patients are found to have additional thrombotic disorders, therapy may be extended for 6 months or greater.

Essential thrombocytosis is a diagnosis of exclusion (Fig. 9.5). The incidence of essential thrombocytosis is about 2.5 new cases/100,000 population per year with a female to male ratio of 2:1. The median age at diagnosis is 60 years old and it may be acquired or familial. The familial variant is an autosomal dominant mutation in genes for thrombopoietin TPO or its receptor, c-Mpl. There have been case reports of leukemic conversion and continued observation is important. Patients may be totally asymptomatic or present with symptoms ranging from vasomotor complaints to thrombotic events.

Thrombotic events range from digital ischemia to hepatic thrombosis or pulmonary embolism. Factors predicting high risk of thrombosis include age ≥60 years
old and history of previous thrombosis. Treatment of essential thrombocytosis is usually with hydroxyurea, which takes 3 to 5 days for effect. The dose is titrated to keep platelet counts <400,000 mm3. Another option is anagrelide, which inhibits platelet aggregation via anti-cAMP phosphodiesterase activity. Severe, life-threatening thrombosis can be treated with plateletpheresis. Overall, elective surgery should be deferred until platelet counts are less than 400,000 mm3, but in emergency situations plateletpheresis can be used to acutely lower platelet counts.



SUGGESTED READINGS

Gruppo Italiano Studio Policitemia (GISP). Low-dose aspirin in polycythaemia vera: a pilot study. Br J Haematol. 1997;97(2):453-456.

Harrison CN, Bareford D, Butt N, et al; British Committee for Standards in Haematology. Guideline for investigation and management of adults and children presenting with a thrombocytosis. Br J Haematol. 2010;149(3):352-375.

Ho KM, Yip CB, Duff O. Reactive thrombocytosis and risk of subsequent venous thromboembolism: a cohort study. J Thromb Haemost. 2012;10(9):1768-1774.

Osselaer JC, Jamart J, Scheiff JM. Platelet distribution width for differential diagnosis of thrombocytosis. Clin Chem. 1997;43(6 Pt 1):1072-1076.

Schafer AI. Thrombocytosis. N Engl J Med. 2004;350(12):1211-1219.

Schafer AI. Thrombocytosis: When is an incidental finding serious? Cleve Clin J Med. 2006;73(8):767-774.


9.6 Hypercoagulable States

Michael A. Hanak

Amir K. Jaffer

Perioperative risk assessment for hypercoagulable states focuses on identifying underlying thrombophilic conditions or other predisposing factors that increase the likelihood of postoperative VTE. Hereditary and acquired conditions can result in hypercoagulable states which can lead to thrombus formation (see Table 9.5). Approximately half of VTE episodes are healthcare-associated, and up to 70% of this cohort are considered preventable (1). One-third of VTE-related deaths among hospitalized patients occur in the postoperative setting (2). Patients with a primary underlying thrombophilia comprise a small subset of that cohort.

Routine screening of asymptomatic patients for common prothrombotic states is not recommended by leading authorities in perioperative assessment, including the American College of Cardiology/American Heart Association (ACC/AHA) guidelines on perioperative cardiovascular evaluation and the preanesthesia evaluation guidelines of the American Society of Anesthesiologists (ASA) (3,4). The Agency for Healthcare Research and Quality (AHRQ) found only low-grade evidence that positive screening leads to improved outcomes (i.e., reduced incidence of VTE), regardless of planned surgery (5). The Caprini Risk Assessment Model (see Chapter 9.15) estimates VTE risk, and considers both clinical characteristics and surgical severity (i.e., minimally invasive vs. major open surgery) along with serum measurements of known prothrombotic elements. Patients scoring ≥3 are candidates for VTE prophylaxis.

In the preoperative setting, PT and aPTT are often utilized to screen for coagulopathies. However, their routine use in screening is not recommended. Practice
guidelines by the ASA Task Force on Perioperative Blood Management recommend obtaining coagulation studies (i.e., PT, aPTT, and fibrinogen) when coagulopathy is suspected based on the history provided by the patient (6). It is important to remember that prolongation of the aPTT can be related to mild factor XII deficiency and asymptomatic lupus anticoagulant, neither of which is associated with a clotting tendency (7). Further support of this is found in the international community as the British Committee for Standards in Haematology published guidelines stating that routine coagulation testing to identify previously undiagnosed bleeding disorders is far more likely to identify a prolonged coagulation test that is not associated with a coagulopathy (7).








TABLE 9.5 Common Thrombophilic Conditions







  • Factor V Leiden mutation



  • Prothrombin G20210A mutation



  • Antiphospholipid syndrome



  • Protein C deficiency



  • Protein S deficiency



  • Antithrombin deficiency



  • Elevated plasminogen activator inhibitor



  • Myeloproliferative neoplasms



  • Excess factors 7, 8, or 11



  • Hyperhomocysteinemia



  • Hyperfibrinogenemia









TABLE 9.6 Other Causes of Hypercoagulable States







  • Heparin-induced thrombocytopenia



  • Malignancies



  • Polycythemia vera



  • Paroxysmal nocturnal hemoglobinuria



  • Inflammatory bowel disease



  • Pregnancy or postpartum status



  • Recent surgery



  • Prolonged immobility



  • Medications:




    • Oral contraceptives



    • Chemotherapy



    • Hormonal replacement therapy



    • Thalidomide



    • Tamoxifen



    • Raloxifene




  • Antiphospholipid syndrome (APS) is the most concerning hypercoagulable state, but occurs less commonly than factor V Leiden mutation, prothrombin gene G20210A mutation, or elevated factor VIII. Tables 9.5 and 9.6 identify the most
    common hereditary and acquired risk factors and diseases that predispose a surgical patient to VTE. APS occurs in 3% to 5% of the general population and is caused by autoantibodies against phospholipid proteins, leading to activation of endothelial cells and subsequent complement-mediated thrombosis. Most common among these proteins are the lupus anticoagulants, explaining the high prevalence of APS among patients with SLE and other autoimmune connective tissue disorders. Anticardiolipin antibodies account for the second most common source of autoimmunity in APS. Importantly, 1% to 5% of the population will have antiphospholipid antibodies present at low levels which are not associated with thrombotic events (8). Thus, routine screening of asymptomatic patients do not provide additional risk stratification without known prior VTE. APS can be induced by certain medications, including hydralazine, phenothiazines, and procainamide. In the perioperative setting, it may be reasonable to screen patients for thrombophilia if they have never had prior screening yet report a past episode of VTE (especially if younger than 40 years) or recurrent pregnancy loss. Table 9.7 shows clinical characteristics that may prompt further evaluation of thrombophilia (9). Since APS confers high risk for recurrent VTE, warfarin is usually continued life-long (titrated to an INR of 2 to 3). Warfarin needs to be stopped 5 days before most surgeries with use of LMWH, such as enoxaparin or dalteparin 1 mg/kg subcutaneously q12 hours preoperatively for bridging therapy, as well as early postoperative resumption of anticoagulation.


  • The most common inherited thrombophilia is a mutation on factor V that is associated with 95% of cases of activated protein C resistance. Patients who are heterozygous carriers have a lower risk of VTE than those with the full trait, but either condition is associated with an equal severity of clot burden and is responsive to anticoagulation. Around half of patients with recurrent VTE test positive for the factor V Leiden mutation, and most will experience the most common type of VTE to occur with this condition, lower extremity deep venous thrombosis (DVT) (10).


  • Prothrombin is the precursor of thrombin, an essential component of the coagulation cascade involved with the production of fibrin used in clot formation. When affected by the G20210A mutation, prothrombin functions at an increased level of efficacy. Affected individuals have serum prothrombin at levels 30% higher (heterozygotes) than those without the mutation (11). Since the mutation is autosomal dominant, patients with the homozygous trait demonstrate an even
    higher risk of thrombosis. The mutation is relatively rare in non-Caucasian populations and much like other prothrombotic conditions should not be routinely screened for perioperatively. Even among patients with a single provoked VTE, screening is not recommended without a family history to suggest an underlying coagulopathy. In the uncommon scenario of having identified a surgical patient as a carrier of the mutation (perhaps an asymptomatic relative of an affected family member) it is advisable to follow routine anticoagulation in the postoperative setting.








    TABLE 9.7 Characteristics That May Suggest Thrombophilia









    • Age <50 years at onset of first thrombosis



    • Atypical site of thrombosis (hepatic, mesenteric, or cerebral veins)



    • History of thrombosis



    • No provoking risk factors (immobilization, travel, medications, cancer, prior surgery)



    • Positive family history for venous thromboembolism



    • Recurrent pregnancy loss



    • Repeated pregnancies with evidence of intrauterine growth restriction


    Adapted from Galioto NJ, Danley DL, Van Maanen RJ. Recurrent venous thromboembolism. Am Fam Physician. 2011;83(3):293-300.



  • Protein C and protein S deficiency occur far less commonly than other hypercoagulable conditions. Protein C is an anticoagulant protein synthesized in the liver and responsible for inactivating coagulation factors V and VIII, necessary for thrombin generation. This process is amplified by the presence of protein S. Deficiency of either protein allows the coagulation pathway to proceed, resulting in a hypercoagulable state. Warfarin (INR target 2.5 to 3.5) or other direct oral anticoagulants (DOACs) are the mainstay of management for the majority of patients with protein C deficiency. In a small number of patients with baseline low protein C levels, initiation of warfarin can exacerbate this deficiency and result in a transient hypercoagulable state, causing vascular occlusion with secondary skin necrosis. For this reason, therapeutic heparin should precede warfarin by several days, or, alternatively, the use of DOACs may be preferred. Patients with protein C or protein S deficiency are managed with long-term anticoagulation following VTE, though current antithrombotic guidelines from the American College of Chest Physicians (ACCP) recommend against daily pharmacologic prophylaxis for asymptomatic individuals (12). LMWH is recommended over UFH for prevention and treatment of VTE during pregnancy and the postpartum period after Cesarean delivery. As shown in Table 9.8, the ACCP considers a variety of criteria that include history of VTE, postpartum hemorrhage, preeclampsia, and other risk factors. Presence of major risk factors guides the selection of initiating thromboprophylaxis versus early mobilization and pneumatic compression in the perioperative environment.

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