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
Anemia of chronic inflammation (ACI)
Chronic kidney disease (CKD)
Nutritional deficiencies (B12, folate)
Unexplained anemia of the elderly (UAE)
Recent surgery or procedures (including femoral access for coronary angiography)
GI disease (colonic polyps, peptic ulcer disease, malignancy)
Poor iron absorption due to medications, diet, or GI surgery
Recent hospitalization, phlebotomy
Total serum iron: normal or low
Total iron-binding capacity (TIBC): high normal or elevated
Transferrin saturation (TSAT): low
Reticulocyte hemoglobin content (CHr): low
CHr provides a snapshot of the iron directly available for hemoglobin synthesis and is an early indicator of the body’s iron status.
Iron dextran (low molecular weight [LMW])
Body weight (kg) × (target Hb-actual Hb) × 2.4
150 to 200 mg iron for each g/dL deficit in Hb
TSAT <10% regardless of ferritin
TSAT <20% and ferritin < 100 ng/dL
Epoetin alfa, 600 u/kg/wk × 3 weeks
Iron sucrose, 100 to 200 mg/wk × 3 weeks
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).
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.
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)
Heterozygous S + another abnormal hemoglobin (HbC or β thalassemia)
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)
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
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
TABLE 9.2 Preoperative Testing Recommendations
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
TABLE 9.4 Perioperative Evaluation: System-Based Focus
Alpha thalassemia silent carrier and alpha thalassemia trait
Healthy, occasional mild anemia
No treatment required
Alpha thalassemia intermedia (Hb H disease)
Decreased production of normal hemoglobin and increased hemolysis due to Heinz bodies
Splenomegaly, icterus, abnormal RBC indices
Treatment includes folic acid, transfusions, possible splenectomy for progressive anemia, avoidance of oxidant drugs
Alpha thalassemia major
Incompatible with life without intrauterine blood transfusion
Beta thalassemia minor
Can be asymptomatic or have mild anemia
Abnormal RBC indices, hypochromia, and microcytosis
Usually does not require treatment
Beta thalassemia intermedia and beta thalassemia major
Severe anemia (can be transfusion dependent)
Can develop heart failure secondary to severe anemia, splenomegaly, massive expansion of medullary and extramedullary erythropoietic tissue leading to skeletal deformities, abnormal facies from malar hypoplasia, growth retardation, paravertebral bone marrow expansion, diabetes mellitus, hypothyroidism, adrenal insufficiency, liver cirrhosis.
Treatment includes transfusions to keep Hb >7 g/dL, splenectomy around adolescence when transfusion requirements increase as a result of hypersplenism and sequestration, iron chelation therapy, and occasionally hematopoietic stem cell transplant (5).
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).
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
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.
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
TABLE 9.6 Other Causes of Hypercoagulable States
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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