Chapter 3 First Pillar of PBM—Optimization of the Red Blood Cell Volume



10.1055/b-0036-129705

Chapter 3 First Pillar of PBM—Optimization of the Red Blood Cell Volume



3.1 Definition, Diagnosis, and Consequences of Preoperative Anemia

G. Lanzer

3.1.1 Definition, Causes, and Prevalence of Anemia


The term anemia is derived from the ancient Greek (αvα℩µοζ [anaimos]) and means “bloodless” (αv[an] “without,” α℩µα [haima] “blood”). As the red blood cell (RBC) mass is very difficult to measure—it requires the use of radioisotopes (Fairbanks et al1996)—the quantitative deficiency in the oxygen carrier molecule hemoglobin, stored in RBCs, is used instead.


Hemoglobin thresholds. In the majority of cases, the thresholds published in a WHO report on nutritional anemia in 1968 continue to be valid: < 13 g/dL for men, < 12 g/dL for menstruating women, and < 11 g/dL for pregnant women. These thresholds were calculated based on average values in the normal population at sea level and have no pathophysiological relevance (WHO 1968). Other authors have suggested a lower limit of normal of 13.7 g/dL for men younger than 60 years, 13.2 g/dL for men aged 60 years and older, and 12.2 g/dL for women (Beutler and Waalen 2006). Additional adjustments must be made for children, adults aged 65 years and older, and people of different races. Further details on the distribution of hemoglobin concentrations are given in Fig. 3.1 .

Fig. 3.1 Distribution of hemoglobin concentrations in the general Caucasian population and their relationship to the WHO definition of anemia (Dallman et al 1996). Hb, hemoglobin; NHANES III, National Health and Nutrition Examination Survey III.

Causes. Anemia can be congenital (e.g., in hemoglobinopathy) or acquired. The possible causes include blood loss, malnutrition, hemolysis, auto-immune diseases, hematopoietic disorders, kidney and liver diseases, hormone imbalances, toxins and drugs, parasites, and chronic inflammatory diseases, including various malignancies.


Anemia is rarely a single disease entity. It is predominantly the result of an iron-deficiency state, in particular in the preoperative setting. However, it can also be of multifactorial etiopathogenesis, and there are “idiopathic” forms of anemia, especially among elderly people, e.g., anemia due to age-mediated changes in stem cell physiology, diminished erythropoietin reactivity, or senescent hormonal changes (Guralnik et al 2004).


Prevalence. A WHO report states that 1.62 billion people worldwide have anemia of various etiologies. Those affected include, in particular, children of preschool age (prevalence: 47.4 %) and women of reproductive age (prevalence among pregnant women: 30.2 %). This underestimated health problem is not confined to developing countries; it is also widespread in industrialized countries (McLean et al 2009).


In light of the current demographic trends—in particular in industrialized countries and in pre-operative settings—the clinical picture of multifactorial “anemia” is now mainly identified in a multimorbid, previously treated population aged 65 years and older (Patel 2008, Tettamanti et al 2010) ( Table 3.1 ). The high prevalence of preoperative anemia (Patel and Carson 2009, Gombotz et al 2011b) must be taken into account in diagnostic and treatment algorithms and must have consequences for preoperative medical management approaches.

























































Table 3.1 Prevalence of preoperative anemia (Source: Gombotz et al 2011a)

Preoperative anemia


Prevalence (%)


Based on underlying disease


Diabetes


14–15


Heart failure


10–80


Acute myocardial infarction


6–18


Infections


up to 95


Malignancies


up to 77


Autoimmune disease


up to 71


Kidney disease


up to 50


Chronic obstructive lung disease


23


Preoperative


ASA I und ASA II


1


Knee and hip operations


20–35


General surgical procedures


up to 40


Colon surgery


25–70


Cardiovascular operations


16–40


Abbreviation: ASA, American Society of Anesthesiologists.



3.1.2 Diagnosis of Anemia


For the diagnosis of anemia, the medical history, clinical picture, clinical examination, and laboratory tests go hand in hand.



Medical History and Clinical Examination

The clinical picture of anemia often goes unnoticed by those affected—depending on the underlying disease—or it is ignored or perceived only after a long delay.



Note


Anemia is often an incidental finding (e.g., it is diagnosed during a routine test or during pre-operative assessment).


Medical history. Conventional medical history taking is of paramount importance for the (differential) diagnosis, and should be used to classify the multifaceted symptoms on the basis of the subjective complaints ( Table 3.2 ).

































Table 3.2 Multifaceted symptoms in patients with iron deficiency or resultant anemia

Organ systems and symptoms


General symptoms




  • Fatigue, exhaustion, weakness, sensitivity to cold


Immune system




  • Infection susceptibility due to impaired functioning of the cells of the immune system


Gastrointestinal tract




  • Loss of appetite, nausea


Cardiorespiratory system




  • Shortness of breath, exertional dyspnea



  • Tachycardia



  • Palpitations



  • Arrhythmias



  • Stenocardia, dyscardia


Vascular system




  • Low skin temperature



  • Paleness



  • Vertigo, tendency to collapse


Central nervous system




  • Impaired cognitive function, lack of concentration



  • Absentmindedness



  • Despondency, depression


Next, concurrent issues should be clarified; this goes well beyond the determination of hemoglobin values:




  • Preexisting illnesses: kidneys, liver, endocrinopathies, infections; treatment requirements (e.g., because of bleeding), operations, malignancies.



  • Bleeding: abnormal menstruation, melena, hematemesis, hemoptysis, hematuria.



  • Dietary abnormalities, exposure to toxins, alcohol abuse, medications, drug abuse.



  • Previous diagnostic results (e.g., blood count), blood donations, RBC transfusions.



  • Unintentional and unexplained weight loss.


Physical examination. The accompanying physical examination should focus on:




  • Skin/mucosal paleness?



  • Signs of cardiorespiratory decompensation?



  • Heart murmurs (changes to blood flow and blood viscosity)?



  • Bleeding signs (purpura, petechiae)?



  • Icteric skin?



  • Impaired metabolism (thyroid gland)?



  • Hepatomegaly, splenomegaly, lymphadenopathy?



  • Reflexes, deep sensibility?


Lastly, urine and stool tests should be performed.


Any diagnostic measures aimed at identifying the cause of pathologic blood loss must take account of any iatrogenic blood loss (blood donor?) and interventional blood loss (e.g., due to routine blood draws in intensive care units or cardiac catheter examination).



Laboratory tests

Laboratory tests are an important adjunct to medical history taking and meticulously recorded clinical findings. In addition to obtaining a full blood count and iron metabolism parameters, the stepwise diagnostic workup may include the determination of biochemical parameters, relevant vitamin levels, and/or immunohematology parameters (e.g., antibody screening), and—as a last resort—a bone marrow biopsy.


The full blood count includes the RBC count, RBC indices, reticulocyte parameters, white blood cell count, platelet count, and differential blood count.



Red Blood Cell Count and Indices

The RBC count is measured in accordance with the principles of light scatter or impedance. The hematology analyzer also measures the RBC volume and the hemoglobin concentration (based on the hemoglobincyanide method), and calculates other RBC indices from the results obtained (Thomas 2008):




  • MCV: mean corpuscular volume (Hct/RBC count) in femtoliters (fL, 10−15 L); reference range in adults: 80–96 fL (an MCV-based algorithm for the evaluation of anemia is illustrated in Fig. 3.2 ).



  • RDW: RBC distribution width, MCV distribution, a measure of anisocytosis (RDW = [standard deviation of MCV/mean MCV] × 100); reference range: < 15 %.



  • MCH: mean corpuscular hemoglobin (Hb/RBC count) in picograms (10 12 g)/cell; reference range: 28–33 pg.



  • MCHC: mean corpuscular hemoglobin concentration, a measure of the hemoglobin concentration of the circulating RBC mass (MCH/MCV = Hb/Hct); reference range: 33–36 g/dL.



  • Hct: hematocrit, packed cell volume in % (RBC count × MCV); reference range in Caucasians: men 36 % to 48 %, women 40 % to 53 %.

Fig. 3.2 Diagnostic algorithm based on MCV. ACD, anemia of chronic disease; Hb, hemoglobin; MCV, mean corpuscular volume.

Additional information. Some hematology analyzers can also measure the proportions of hypochromic, microcytic, and macrocytic RBCs:




  • %HYPO: proportion of hypochromic RBCs (RBCs with hemoglobin < 28 pg); reference range: 1–5 %; used for the assessment of a potential iron deficiency—it is an earlier indicator of iron deficiency than the MCV.



  • %MICRO: proportion of microcytic RBCs; the quotient of %MICRO/%HYPO is used in the diagnosis of β-thalassemia.



  • %MACRO: proportion of macrocytic RBCs; used to test for vitamin-B12 or folic-acid deficiency anemia and for alcohol abuse.


Table 3.3 shows the classification of anemia based on the RBC indices MCV, MCH, and MCHC.





















































Table 3.3 Classification of anemia on the basis of the RBC indices MCV, MCH, and MCHC

Anemia


MCV (fL)


MCH (pg)


MCHC (g/dL)


Normocytic normochromic anemia


80–96


28–33


33–36


Normocytic hypochromic anemia


Normal


< 28


Normal


Normocytic hyperchromic anemia


Normal


> 33


> 36


Microcytic hypochromic anemia


< 80


< 28


< 33


Macrocytic normochromic anemia


> 96


Normal


Normal


Macrocytic hypochromic anemia


> 96


< 28


< 33


Macrocytic hyperchromic anemia


> 96


> 28


> 36


Abbreviations: MCH, mean corpuscular hemoglobin; MCHC, mean corpuscular hemoglobin concentration; MCV, mean corpuscular volume.


Causes. In detail, the findings may indicate the following.




  • Normocytic normochromic anemia (a more detailed diagnostic algorithm used to test for this includes the reticulocyte production index [see below]):




    • Hyporegenerative anemia occurring in the presence of chronic or malignant diseases, inflammation, or renal changes.



  • Normocytic hypochromic anemia:




    • Early iron deficiency anemia (additional indicators include the RDW, %HYPO, and CHr [see below]).



  • Normocytic hyperchromic anemia:




    • Intravascular hemolysis.



    • Incorrect determination of hemoglobin in hyperlipidemia.



    • Heinz bodies in toxic anemia.



  • Microcytic hypochromic anemia:




    • Classic iron deficiency anemia.



    • Anemia of chronic disease with functional iron deficiency.



  • Macrocytic normochromic anemia:




    • Folic-acid or vitamin-B12 deficiency anemia.



    • Alcohol abuse.



    • Cirrhosis of the liver.



    • Myelodysplastic syndrome.



  • Macrocytic hypochromic anemia:




    • Regenerative anemia (indicating treatment response).



  • Macrocytic hyperchromic anemia:




    • Possibly an incorrect result because of RBC agglutination, e.g., if cold agglutinins are present (RBC count calculated too low, MCV calculated too high).



Reticulocytes

The diagnostic tests involving RBCs—in particular those for the differential diagnosis of anemia—must be complemented by the additional assessment of reticulocytes.


Reticulocyte count. The reticulocyte count gives insights into bone marrow activity, impaired erythropoiesis, and response to treatment, e.g., erythropoietin therapy. The reticulocyte count is provided as the proportion of RBCs that are reticulocytes (reticulocytes/100 mature RBCs; reference range: 5–15 %) or expressed as an absolute value (reticulocytes/µL = [% reticulocytes × RBC count/µL]/100; reference range: 50,000–100,000 reticulocytes/µL) (Wick et al 2011).


Reticulocyte index. If the reticulocyte count is elevated or the RBC count decreased, the reticulocyte index is calculated to adjust for the altered proportions and for a normal hematocrit (= 45 %):



Formula


Reticulocyte index (%) = [% reticulocytes × Hct %] / 45


This correction is recommended for the assessment of patients with anemia, and a hematologist must be consulted if there are any issues to be clarified.


Reticulocyte production index. The reticulocyte production index (RPI) is used to gain additional information, e.g., about the proliferative activity of bone marrow (Patel and Carson 2009). It takes the current hematocrit value of the patient into account:



Formula


RPI = % reticulocytes × [patient Hct/normal Hct (= 45)] × [1 / shift correction factor (= 1–2.5)]


The correction factor is 1.0 if Hct = 36–45 %; 1.5 if Hct = 26–35 %; 2.0 if Hct = 16–25 %; and 2.5 if Hct ≤ 15 %.


The term shift is used to denote the relationship between the hematocrit and the reticulocyte retention time in peripheral blood (it refers to the shift in the maturation or retention time of reticulocytes upon their release from the bone marrow into the peripheral blood). The physiological maturation time of reticulocytes is approximately 3 days in bone marrow and 1 day in peripheral blood. If the RBC production is accelerated, the retention and maturation time of reticulocytes in bone marrow will be shorter because of their accelerated release. Depending on the respective hematocrit, this will lead to a relative increase in the reticulocyte count in peripheral blood because of the shift in the maturation time and the associated prolonged retention time. Therefore, the relationship between the hematocrit and the retention time (see the shift correction factors given above) is taken into account when calculating the RPI (alternative formula: RPI = [reticulocyte count % / retention time in blood] × [patient Hct / 45] (Wick et al 2011). The RPI thus corresponds to the reticulocyte count adjusted for the maturation time and maturation site of the cells.


Hypo- and hyperproliferative anemia. The RPI is an integral part of the diagnostic algorithm in the case of normochromic normocytic (normal MCH and MCV) anemia.


A “hypoproliferative” (RPI < 2) finding calls for the additional testing of haptoglobin, creatinine, ferritin, C-reactive protein (CRP), soluble transferrin receptor (sTfR), erythropoietin, and bilirubin, from which the differential diagnoses can be inferred ( Table 3.4 ):





















































Table 3.4 Additional parameters needed to diagnose a “hypoproliferative” disorder (reticulocyte production index < 2)

Haptoglobin


Creatinine


Ferritin


CRP


sTfR


Erythropoietin


Bilirubin


Disorder


Normal


Normal






Normal


Impaired erythropoiesis



Elevated


Normal




Decreased



Kidney failure




Elevated


Elevated


Low


Decreased



Anemia of chronic disease


Abbreviations: CRP, C-reactive protein; sTfR, soluble transferrin receptor




  • Impaired erythropoiesis → next step: bone marrow biopsy.



  • Kidney failure.



  • Anemia of chronic disease.


In the event of RPI > 2 (“hyperproliferative” anemia), lactate hydrogenase (LDH) is measured additionally. The combination of a low haptoglobin level and elevated levels of LDH, bilirubin, and sTfR is suggestive of hemolytic activity. This indicates the need for a blood smear (assessment of RBC morphology) and a direct and indirect Coombs test (assessment of noncorpuscular hemolysis secondary to antibody formation against RBC surface antigens).


Other reticulocyte indices. Additional parameters give qualitative information about the cell volume of reticulocytes and their hemoglobin load (Thomas 2008):




  • MCVr: mean corpuscular reticulocyte volume; the volume of reticulocytes (reference range in adults: 92–120 fL) is around 20 % greater than that of RBCs, and the average MCVr is 106 fL (compared with 88 fL for RBCs). Macroreticulocytes (> 120 fL), known as stress reticulocytes, are a sign of accelerated hematopoiesis (e.g., after hemolysis or hyperstimulation with erythropoietin). Elevated MCVr values are found in folic-acid and vitamin-B12 deficiency anemia. Decreased MCVr values are an early indicator of iron deficiency.



  • CHCMr: mean corpuscular hemoglobin concentration of reticulocytes (reference range: 27–33 g/dL) (Thomas and Thomas 2002); it is measured by suitably equipped hematology analyzers as the hemoglobin concentration in the reticulocyte fraction and is used for the calculation of the reticulocyte hemoglobin content (CHr, see next bullet point).



  • CHr, Ret-Hb: reticulocyte hemoglobin content; the CHr is the mathematical product of the MCVr and the CHCMr (MCVr × CHCMr) and hence a measure of reticulocyte hemoglobinization. It is expressed in picograms (pg, 10 12 g) and is a marker used in the differential diagnosis of anemia to identify changes in iron metabolism, e.g., to monitor treatment with erythropoietin. In adults it has a reference range of 8–35 pg (Thomas 2008).



Note


The insights gained from the evaluation of reticulocyte parameters expand the scope of the differential diagnosis of anemia through the addition of categories such as hypo-, normo-, and hyperregenerative anemia and hypo-, normo-, and hyperproliferative anemia.



Blood smear

Occasionally, additional information can be gained from the morphology of RBCs—e.g., information about target cells, schistocytes (fragmented cells), and spherocytes—and from the differential blood count (e.g., information about granulocytes, platelets).



Iron Parameters

Iron metabolism is highly complex ( Fig. 3.3a–d ) and is often difficult to evaluate in clinical practice.

Fig. 3.3 Iron metabolism. (Reproduced with kind permission of Vifor Pharma. Illustrations: Descience, A. Ulrich & N. Stadelmann). (a) Iron is absorbed in the duodenum and upper jejunum in the form of reduced Fe2+ only. To that effect, the iron salts must be soluble in the acidic pH of the stomach. Iron ions are transported across the cells lining the duodenum by a series of carrier proteins: apical absorption after reduction by ferrireductase (duodenal cytochrome b, Fe3+ → Fe2+), then cell-membrane passage of Fe2+ via DMT 1 and shuttle transport via mobilferrin (not illustrated here), with possible iron transfer to ferritin. This is followed by the basolateral release by ferroportin and the transfer to ferroxidase (hephaestin, Fe2+ → Fe3+), with subsequent binding of Fe3+ to transferrin. The nutritive iron in hemoglobin enters the enterocytes via HCP1 as an intact metalloporphyrin; from there, it is either transported further in the manner described, or transferred via the heme exporter protein (HEP, not illustrated here) to transferrin in the blood circulation. Transferrin is a bilobed molecule that can be present in di-, mono-, or apoferric (without a load) form; when loaded with Fe3+, it binds to the ubiquitously distributed transferrin receptors. Dcytb, duodenal cytochrome b; DMT 1, divalent metal transporter 1; HCP1, heme carrier protein 1. (b) The TfR–transferrin complex enters the target cells via endosomes; in the endosomes, Fe3+ is reduced to Fe2+; via DMT 1 and the cytosolic iron store, it reaches its main site of use, the mitochondria (e.g., production of the iron-sulfur clusters in enzymes of the electron transport chain)—unless it is stored in ferritin. Other target sites of cytoplasmic iron are heme and nonheme proteins (enzymes) as well as iron receptor proteins, which are important in iron hemostasis. The soluble TfR (TfR portion after cleavage from the intracellular part of the TfR) and apoferritin (the protein component of ferritin) are removed from the cell and enter the bloodstream. DMT 1, divalent metal transporter 1; TfR, transferrin receptor. (c) Erythropoiesis (iron absorption and EPO-mediated stimulation of proerythroblasts; hemoglobin synthesis in erythroblasts) and RBC breakdown in the RES. At the end of their lifespan, RBCs undergo phagocytosis by RES macrophages, and their iron is stored in ferritin or hemosiderin (a heterogeneous group of ferritin breakdown products). To recycle the iron taken up by macrophages, its release via ferroportin is inhibited by hepcidin. EPO, erythropoietin; RES, reticuloendothelial system. (d) During inflammatory processes, interleukin-6 stimulates the synthesis of hepcidin (hepatic bactericidal protein) in the liver. Hepcidin inactivates ferroportin in enterocytes (no release of iron), macrophages, and the liver (intracellular iron blockade), resulting in impaired iron distribution, as seen for example in anemia of chronic disease. IRP, iron regulatory protein.

Just under 80 % of all anemia cases are caused by absolute or relative iron deficiency. The WHO states that > 30 % of the world’s population have iron deficiency anemia (WHO 1968). Iron deficiency anemia means that an iron deficiency state has already progressed to an advanced stage. This condition is preceded by ferritin (stored iron) deficiency (prelatent if ferritin is in the range of 35–12 µg/L; latent if ferritin < 12 µg/L) and functional iron deficiency. The latter two states are mostly clinically silent, but nonetheless of paramount importance in the postoperative phase.


The diagnosis of anemia and the closely related iron deficiencies is based on the medical history, the clinical picture, and any additional diagnostic measures needed, and rests on four pillars: the blood count and related blood cell diagnostic tests as described above, the measurement of ferritin (and CRP, to rule out inflammation), the calculation of the “ferritin index,” and possibly—depending on the laboratory equipment available—the determination of transferrin saturation.


Ferritin and C-reactive protein. The serum ferritin concentration is a measure of the amount of stored iron. It should not be used as a sole diagnostic indicator because ferritin is not only an acute-phase protein but is also released during cell disintegration (e.g., in inflammation or malignancies). Therefore, to clarify any issues relating to iron metabolism, the CRP concentration must also be measured.


CRP is synthesized in the liver and released in response to inflammatory cytokines such as interleukin-6. It is the most suitable and most commonly used acute-phase protein for the diagnosis of infection. Against that background, it has broad clinical application and its role in the diagnosis of anemia is restricted to interpreting elevated levels of acute-phase ferritin. The CRP reference value is < 0.5 mg/dL.


Soluble transferrin receptor. Iron deficiency triggers an increased synthesis of the transferrin receptor, which in turn leads to an increase in soluble transferrin receptor (sTfR)—a cleaved portion of the transferrin receptor—in the patient’s serum. Elevated levels of sTfR are suggestive of a hyperproliferative form of anemia (expansion of erythropoiesis, e.g., after a hemolytic event).


Ferritin index. The quotient of sTfR (mg/L) divided by the logarithm of serum ferritin (µg/L) has proved to be a useful anchor point in the diagnosis of iron metabolism disorders. The higher this index, the greater the functional iron deficiency!


Transferrin saturation. The transferrin saturation (in %) is the quotient of serum iron (µg/dL) divided by transferrin (mg/dL) multiplied by the factor 70.9.


A summary of iron metabolism parameters indicative of anemia is given in Table 3.5 .























Table 3.5 Iron metabolism parameters indicative of anemia

Parameter


Suggestion of anemia


Ferritin


< 12 µg/L


Soluble transferrin receptor


> 5 mg/L (method-dependent)


Ferritin index


> 3.2 (method-dependent)


Transferrin saturation


< 15 %


Additional tests. Other biochemical tests that can support the diagnosis of anemia include:




  • Kidney, liver, thyroid parameters.



  • Direct and indirect bilirubin.



  • LDH.



  • Haptoglobin.

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Jun 7, 2020 | Posted by in EMERGENCY MEDICINE | Comments Off on Chapter 3 First Pillar of PBM—Optimization of the Red Blood Cell Volume
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