Anemia of prematurity

Anemia of prematurity means that a baby born early (prematurely) does not have enough red blood cells. Red blood cells carry oxygen to the body. Preterm infants with birth weight <1.0 kg (commonly designated as extremely low birth weight or ELBW, infants) have completed ≤29 weeks of gestation, and nearly all will need red blood cell (RBC) transfusions during the first weeks of life. Every week in the United States, approximately 10,000 infants are born prematurely (ie, <37 weeks of gestation), with 600 (6%) of these preterm infants being extremely low birth weight ¹. Approximately 90% of extremely low birth weight neonates will receive at least one red blood cell transfusion ².

All babies have some anemia (decrease in hemoglobin concentration) when they are born. In healthy term infants, the nadir hemoglobin value rarely falls below 10 g/dL at an age of 10 to 12 weeks ³. This is normal and is called “physiological anemia of infancy”. For the term infant, a physiologic and usually asymptomatic anemia is observed 8-12 weeks after birth. But in premature babies, the number of red blood cells may decrease faster and go lower than in full-term babies. This may happen because:

• A premature baby may not make enough red blood cells.
• A premature baby may need tests that require blood samples. It may be hard for the baby to produce enough red blood cells to make up for the blood that’s taken out and used in the tests.
• A baby’s red blood cells don’t live as long as an older child’s red blood cells.

Anemia of prematurity is an exaggerated, pathologic response of the preterm infant to this transition. Anemia of prematurity is a normocytic, normochromic, hyporegenerative anemia characterized by a low serum erythropoietin (EPO) level, often despite a remarkably reduced hemoglobin concentration ⁴. Nutritional deficiencies of iron, vitamin E, vitamin B-12, and folate may exaggerate the degree of anemia, as may blood loss and/or a reduced red cell life span.

The anemia of prematurity is caused by untimely birth occurring before placental iron transport and fetal erythropoiesis are complete, by phlebotomy blood losses taken for laboratory testing, by low plasma levels of erythropoietin due to both diminished production and accelerated catabolism, by rapid body growth and need for commensurate increase in red cell volume/mass, and by disorders causing red blood cell losses due to bleeding and/or hemolysis ³.

The risk of anemia of prematurity is inversely related to gestational maturity and birthweight ⁴. As many as half of infants of less than 32 weeks gestation develop anemia of prematurity. Anemia of prematurity is not typically a significant issue for infants born beyond 32 weeks’ gestation.

Race and sex have no influence on the incidence of anemia of prematurity.

Testosterone is believed to be at least partially responsible for a slightly higher hemoglobin level in male infants at birth, but this effect is of no significance with regard to risk of anemia of prematurity. The nadir of the hemoglobin level is typically observed 4-10 weeks after birth in the tiniest infants, with hemoglobin levels of 8-10 g/dL if birthweight was 1200-1400 grams, or 6-9 g/dL at birth weights of less than 1200 grams and to approximately 7 g/dL in infants with birth weights <1 kg ⁴.

Anemia of prematurity is usually not serious. Anemia of prematurity spontaneously resolves in many premature infants within 3-6 months of birth ⁴. In others, however, medical intervention is required, because the low oxygen levels in a premature infant can make other problems worse, such as heart and lung problems. Most infants with birth weight <1.0 kg are given multiple red blood cell (RBC) transfusions within the first few weeks of life ³.

Red blood cell transfusions are the mainstay of therapy for anemia of prematurity with recombinant human erythropoietin (EPO) largely unused because it fails to substantially diminish red blood cell transfusion needs despite exerting substantial erythropoietic effects on neonatal marrow.

Figure 1. Blood composition

Footnote: Blood consists of a liquid portion called plasma and a solid portion (the formed elements) that includes red blood cells, white blood cells, and platelets. When blood components are separated by centrifugation, the white blood cells and platelets form a thin layer, called the “buffy coat,” between the plasma and the red blood cells, which accounts for about 1% of the total blood volume. Blood cells and platelets can be seen under a light microscope when a blood sample is smeared onto a glass slide.

Figure 2. Red blood cells (normal red blood cells)

Anemia of prematurity causes

The three basic mechanisms for the development of anemia of prematurity include:

1. Inadequate red blood cell production,
2. Shortened red blood cell life span,
3. Blood loss.

Taken together, the premature infant is at risk for the development of anemia of prematurity because of limited red blood cell synthesis during rapid growth, a diminished red blood cell life span, and an increased loss of red blood cells.

Inadequate red blood cell production

The first mechanism of anemia is inadequate red blood cell production for the growing premature infant. The location of erythropoietin (EPO) and red blood cell production changes during gestation. Erythropoietin (EPO) synthesis initially occurs in the fetal liver but gradually shifts toward the kidney as gestation advances. By the end of gestation, however, the liver remains the major source of erythropoietin (EPO).

Fetal erythrocytes are produced in the yolk sac during the first few weeks of embryogenesis. The fetal liver becomes more important as gestation advances and, by the end of the first trimester, has become the primary site of erythropoiesis. Bone marrow then begins to take on a more active role in producing erythrocytes. By about 32 weeks’ gestation, the burden of erythrocyte production in the fetus is shared evenly by liver and bone marrow. By 40 weeks’ gestation, the marrow is the sole erythroid organ. Premature delivery does not accelerate the ontogeny of these processes.

Although erythropoietin (EPO) is not the only erythropoietic growth factor in the fetus, it is the most important. Erythropoietin (EPO) is synthesized in response to anemia and consequent relative tissue hypoxia. The degree of anemia and hypoxia required to stimulate erythropoietin (EPO) production is far greater for the fetal liver than for the fetal kidney. Erythropoietin (EPO) production may not be stimulated until a hemoglobin concentration of 6-7 g/dL is reached. As a result, new red blood cell production in the extremely premature infant, whose liver remains the major site of erythropoietin (EPO) production, is blunted despite what may be marked anemia. In addition, erythropoietin (EPO), whether endogenously produced or exogenously administered, has a larger volume of distribution and is more rapidly eliminated by neonates, resulting in a curtailed time for bone marrow stimulation.

Erythroid progenitors in premature infants are quite responsive to erythropoietin (EPO), but the response may be blunted if iron or other substrate or co-factor stores are insufficient. Another potential problem is that while the infant may respond appropriately to increased erythropoietin (EPO) concentrations with increased reticulocyte counts, rapid growth may prevent the appropriate increase in hemoglobin concentration.

Shortened red blood cell life span or hemolysis

Also important in the development of anemia of prematurity is that the average life span of a neonatal red blood cell is only one half to two thirds that of an adult red blood cell. Cells of the most immature infants may survive only 35-50 days. The shortened red blood cell life span of the neonate is a result of multiple factors, including diminished levels of intracellular adenosine triphosphate (ATP), carnitine, and enzyme activity; increased susceptibility to lipid peroxidation; and increased susceptibility of the cell membrane to fragmentation.

Blood loss

Finally, blood loss may contribute to the development of anemia of prematurity. If the neonate is held above the placenta for a time after delivery, fetal-placental transfer of blood may occur. Conversely, delayed cord clamping may lessen the degree of anemia of prematurity ⁵, although a study by Elimian et al ⁶ did not find this to be true. More commonly, because of the need to closely monitor the tiny infant, frequent samples of blood are removed for various tests. These losses are often 5-10% of the total blood volume.

Anemia of prematurity differential diagnoses

Conditions to consider in the differential diagnosis of anemia of prematurity are those which diminish red cell production, increase red cell destruction, or cause blood loss.

• Acute Anemia
• Birth Trauma
• Chronic Anemia
• Head Trauma
• Hemolytic Disease of the Newborn
• Parvovirus B19 Infection
• Intraventricular Hemorrhage in the Preterm Infant

Conditions that diminish red blood cell synthesis are as follows:

• Bone marrow infiltration
• Bone marrow depression (eg, pancytopenia, drugs)
• Diamond-Blackfan anemia
• Substrate deficiencies (eg, iron, vitamin E, folic acid)
• Congenital fetal infections (eg, cytomegalovirus, parvovirus, syphilis)

Conditions that cause hemolysis are as follows:

• Congenital fetal infections (eg, cytomegalovirus, parvovirus, syphilis)
• Acute systemic infections (leading to disseminated intravascular coagulation)
• Abnormal red blood cells (spherocytosis, elliptocytosis)
• Nonspherocytic hemolytic anemias (eg, G6PD deficiency, kinase and isomerase deficiencies)
• Hemolytic disease of the newborn (Rh, ABO, other major blood-group incompatibilities between mother and fetus)

Conditions that reduce blood volume are as follows:

• Twin-to-twin transfusion syndrome (donor twin)
• Iatrogenic (eg, excessive blood sampling)
• Hemorrhage (eg, gastrointestinal, central nervous system, subcutaneous tissues)

Anemia of prematurity symptoms

Many clinical findings have been attributed to anemia of prematurity, but they are neither specific nor diagnostic. These symptoms may include the following:

• Poor weight gain despite adequate caloric intake
• Cardiorespiratory symptoms such as tachycardia, tachypnea, and flow murmurs
• Decreased activity, lethargy, and difficulty with oral feeding
• Pallor
• Increase in apneic and bradycardic episodes, and worsened periodic breathing
• Metabolic acidemia – Increased lactic acid secondary to increased cellular anaerobic metabolism in relatively hypoxic tissues

Anemia of prematurity diagnosis

The following are useful laboratory studies:

• Complete blood count (CBC) – White blood cell (WBC) and platelet values are normal in anemia of prematurity. Low hemoglobin values, below 10 g/dL, are found. They may descend to a nadir of 6-7 g/dL. Lowest levels are generally observed in the smallest infants. Red blood cell indices are normal (eg, normochromic, normocytic) for age.
• Reticulocyte count – The reticulocyte count is low when the degree of anemia is considered, as a result of the low levels of erythropoietin (EPO). Conversely, an elevated reticulocyte count is not consistent with the diagnosis of anemia of prematurity.
• Peripheral blood smear – Red blood cell morphology should be normal. Red blood cell precursors may appear to be more prominent.
• Maternal and infant blood typing; direct antibody test (Coombs) – The direct Coombs test result may be coincidentally positive. Despite this, it is important to ensure an immune-mediated hemolytic process related to maternal-fetal blood group incompatibility (hemolytic disease of the newborn) is not present.
• Serum bilirubin – An elevated serum bilirubin level should suggest other possible explanations for the anemia. These would include hemolytic entities, such as G-6-PD deficiency or other kinase/isomerase/enzyme deficiencies, or more common causes such as infection or hemolytic disease of the newborn.
• Lactic acid – Elevated lactic acid levels have been suggested by some to be useful as an aid to determine the need for transfusion.

Anemia of prematurity treatment

Medical treatment options are blood transfusion(s), recombinant erythropoietin (EPO) treatment, and observation.

Observation may be the best course of action for infants who are asymptomatic, not acutely ill, and are receiving adequate nutrition. Adequate amounts of vitamin E, vitamin B-12, folate, and iron are important to blunt the expected decline in hemoglobin levels in the premature infant. Periodic measurements of the hematocrit level in infants with anemia of prematurity are necessary after hospital discharge. Once a steady increase in the hematocrit level has been established, only routine checks are required.

Packed red blood cell transfusions

Packed red blood cell transfusions are the mainstay of therapy for anemia of prematurity. The frequency of blood transfusion varies with gestational age, degree of illness, and, interestingly, the hospital evaluated. Unfortunately, there is considerable disagreement about the indication, timing, and efficacy of packed red blood cell transfusion.

Guidelines for transfusing red blood cells to preterm neonates are controversial, and practices vary greatly ⁷. This lack of a universal approach stems from limited knowledge of the cellular and molecular biology of erythropoiesis during the perinatal period, an incomplete understanding of infant physiological/adaptive responses to anemia, and contrary/controversial transfusion practice guidelines as based on results of randomized clinical trials and expert opinions. Generally, red blood cell transfusions are given to maintain a level of blood hemoglobin or hematocrit believed to be optimal for each neonate’s clinical condition. Guidelines for red blood cell transfusions, judged to be reasonable by most neonatologists to treat the anaemia of prematurity, are listed by Table 1. These guidelines are very general, and it is important that terms such as “severe” and “symptomatic” be defined to fit local transfusion practices/policies. Importantly, guidelines are not mandates for red blood cell transfusions that must be followed; they simply suggest situations when an red blood cell transfusion would be judged to be reasonable/acceptable.

The decision to give a transfusion should not be made lightly, because significant infectious, hematologic, immunologic, and metabolic complications are possible. Late-onset necrotizing enterocolitis has been reported in stable-growing premature infants electively transfused for anemia of prematurity ⁸. Transfusions also transiently decrease erythropoiesis and EPO levels. There is also agreement that the number of transfusions, as well as the number of donor exposures, should be reduced as much as possible.

Clinical trials designed to determine the efficacy of blood transfusions in relieving symptoms ascribed to anemia of prematurity have produced conflicting results ⁹. Improved growth has been an inconsistent finding. While some studies have demonstrated a decrease in apneic episodes after blood transfusion, others have found similar results with simple crystalloid volume expansion.

Subjective improvement in activity, decreased lethargy, and improved feeding have been described in some studies. Blood transfusions have been documented to decrease lactic acid levels in otherwise healthy preterm infants who are anemic. Blood transfusions have reduced tachycardia in anemic infants who are transfused.

Some medical professionals have suggested using lactate levels as an aid in determining the need for transfusion.

Table 1. Allogeneic red blood cell transfusions for the anemia of prematurity

Transfuse to maintain the blood hematocrit per each clinical situation:

• > 40% (35 to 45% ^*) for severe cardiopulmonary disease
• > 30% for moderate cardiopulmonary disease
• > 30% for major surgery
• >25% (20 to 25% ^*) for symptomatic anemia
• > 20% for asymptomatic anemia

*Reflects practices that vary among neonatologists. Thus, any value within range is acceptable for local practices.

Reducing the number of transfusions

Studies from individual centers have documented a marked decrease in the administration of packed red blood cell transfusions in the past decades, even before the use of EPO became more frequent. This decrease in transfusions is almost certainly multifactorial in origin. Adoption of standardized transfusion protocols that take various factors into account, including hemoglobin levels, degree of cardiorespiratory disease, and traditional signs and symptoms of pathologic anemia, are acknowledged as an important factor in this reduction. A restricted transfusion protocol may decrease the number of transfusions while also decreasing the hematocrit at discharge ¹⁰.

A 2011 study ¹¹ evaluated 41 preterm infants with birth weights of 500-1300 g who were enrolled in a clinical trial that compared high and low hematocrit thresholds for transfusion. A rise in systemic oxygen transport and a decrease in lactic acid after transfusion was noted in both groups; however, oxygen consumption did not change significantly in either group. In the low hematocrit group only, cardiac output and fractional oxygen extraction fell after transfusion, which shows that these infants had increased their cardiac output to maintain adequate tissue oxygen delivery in response to anemia. The results demonstrate that infants with low hematocrit thresholds may benefit from transfusion, while transfusion in those with high hematocrit thresholds may provide no acute physiological benefit ¹¹.

The Premature Infant in Need of Transfusion study ¹² showed that transfusing infants to maintain higher hemoglobin level (8.5-13.5 g/dL) conferred no benefit in terms of mortality, severe morbidity, or apnea intervention compared with infants transfused to maintain a low hemoglobin levels (7.5-11.5 g/dL).

These findings differ from the Iowa study, which found less parenchymal brain hemorrhage, periventricular leukomalacia, and apnea in infants whose transfusion criteria was not restricted and whose hemoglobin level was higher. Clearly, no universally accepted guidelines for transfusion in infants with anemia of prematurity are available at this time, and clinicians must determine their individual standardized transfusion practices.

Anemia of prematurity guidelines

No universally accepted guidelines for transfusion in infants with anemia of prematurity are available at this time, and clinicians must determine their individual standardized transfusion practices.

As an example, note the Children’s Hospital of Wisconsin Transfusion Committee guidelines for consideration:

• An infant with a hemoglobin (Hb) level of less than 8 g/dL may be transfused at the discretion of the attending physician
• A stable infant with a hemoglobin level of 8-10 g/dL without clinical symptoms or other exceptions listed below may be transfused
• An infant with a hemoglobin level of 11-13 g/dL without a supplemental oxygen or continuous positive airway pressure (CPAP) requirement, apnea/bradycardia, significant tachycardia or tachypnea, or other exceptions listed below should not be transfused
• An infant with a hemoglobin level of more than 13 g/dL without an oxygen requirement of more than 40% by hood, CPAP, or ventilator; hypotension that requires pressor medication; major surgery; or other exceptions listed below should not be transfused
• An infant with a hemoglobin level of more than 15 g/dL without cyanotic heart disease, extracorporeal membrane oxygenation (ECMO) therapy, regional oxygen saturations less than 50%, or hypotension that requires pressor medications should not be transfused
• An infant with a history of massive blood loss may be transfused at the discretion of the attending physician

It is of obvious importance to discuss with the family their child’s need for transfusion and to obtain consent before the transfusion. It is also important to discuss with parents the normal course of anemia, the criteria for and risks associated with transfusions, and the advantages and disadvantages of erythropoietin (EPO) administration. Also necessary is consideration of the family’s religious beliefs regarding transfusions.

Reducing the number of donor exposures

Reducing the number of donor exposures is also important. Preservatives and additive systems allow blood to be stored safely for as long as 35-42 days. This can be accomplished by using packed red blood cells stored in preservatives (eg, citrate-phosphate-dextrose-adenine [CPDA-1]) and additive systems (eg, Adsol). Infants may be assigned a specific unit of blood, which may suffice for treatment during their entire hospitalization and thus limit exposure to the single donor of that unit. Concerns that stored blood might increase serum potassium levels are unfounded if the transfused volume is low.

Complications

Potential complications of transfusion include the following:

• Infection (eg, hepatitis, cytomegalovirus [CMV], human immunodeficiency virus [HIV], syphilis)
• Fluid overload and electrolyte imbalances
• Exposure to plasticizers
• Hemolysis
• Posttransfusion graft versus host disease

An important tool in reducing at least one of these transfusion risks is to use all available screening techniques for infection. The risk of cytomegalovirus (CMV) transmission can be dramatically reduced by use of CMV-safe blood. This can be accomplished by using CMV serology–negative cells, along with blood processed through leukocyte-reduction filters or inverted spin technique. These methods also reduce other WBC-associated infectious agents (eg, Epstein-Barr virus, retroviruses, Yersinia enterocolitica) by yielding a leukocyte-poor suspension of packed red blood cells. The American Red Cross now provides exclusively leukocyte-reduced blood to hospitals in the United States.

Recombinant Erythropoietin treatment

Multiple investigations have established that premature infants respond to exogenously administered recombinant human EPO and supplemental iron with a brisk reticulocytosis. Subcutaneous administration of EPO may be preferred, as intravenous administration has increased urinary losses. Although EPO cannot prevent early transfusions, modest decreases in the frequency of late packed red blood cell transfusions have been documented. Additional iron supplementation is necessary during exogenous EPO treatment.

Trials have evaluated the impact of EPO treatment in populations of the most immature neonates. These studies likewise have demonstrated that infants with very low birth weight (VLBW) are capable of responding to EPO with a reticulocytosis.

Studies and a Cochrane Neonatal Systemic review suggest an association between exogenous EPO administration and retinopathy of prematurity ¹³.

Yasmeen et al ¹⁴ studied 60 preterm low birth weight infants and concluded that short-term recombinant human erythropoietin with iron and folic acid was effective in preventing anemia of prematurity.

EPO with iron does not adversely affect growth or developmental outcomes, but the impact on the number of transfusions a premature infant receives ranges from nonexistent to small.

At this time, no agreement regarding the safety, timing, dosing, route, or duration of therapy has been established. In short, the cost-benefit ratio for EPO has yet to be clearly established, and this medication is not universally accepted as a standard therapy for an infant with anemia of prematurity.

Anemia of prematurity prognosis

Spontaneous recovery of mild anemia of prematurity may occur 3-6 months after birth. In more severe, symptomatic cases, medical intervention may be required.

References

1. Martin JA, Hamilton BE, Sutton PD, et al. Births: final data for 2008 national Vital Statistics Reports. Centers for Disease Control and Prevention. 2009;57:7.
2. Maier RJ, Sonntag J, Walka MM, et al. Changing practices of red blood cell transfusions in infants with birth weights less than 1000 g. J Pediatr. 2000;136:220–224.
3. Strauss RG. Anaemia of prematurity: pathophysiology and treatment. Blood Rev. 2010;24(6):221-225. doi:10.1016/j.blre.2010.08.001 https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2981681
4. Anemia of Prematurity. https://emedicine.medscape.com/article/978238-overview
5. Ultee CA, van der Deure J, Swart J, Lasham C, van Baar AL. Delayed cord clamping in preterm infants delivered at 34 36 weeks’ gestation: a randomised controlled trial. Arch Dis Child Fetal Neonatal Ed. 2008 Jan. 93(1):F20-3.
6. Elimian A, Goodman J, Escobedo M, Nightingale L, Knudtson E, Williams M. Immediate compared with delayed cord clamping in the preterm neonate: a randomized controlled trial. Obstet Gynecol. 2014 Dec. 124 (6):1075-9.
7. dos Santos AMN, Guinsburg R, Procianoy RS, dos SR, Sadeck L, Netto AA, Rugolo LM, et al. Variability on red blood cell transfusion practices among Brazilian neonatal intensive care units. Transfusion. 2010;50:150–159.
8. Singh R, Shah BL, Frantz ID 3rd. Necrotizing enterocolitis and the role of anemia of prematurity. Semin Perinatol. 2012 Aug. 36(4):277-82.
9. Bell EF, Nahmias C, Sinclair JC, Zipursky A. Changes in circulating red cell volume during the first 6 weeks of life in very-low-birth-weight infants. Pediatr Res. 2014 Jan. 75 (1-1):81-4.
10. Bell EF, Strauss RG, Widness JA, et al. Randomized trial of liberal versus restrictive guidelines for red blood cell transfusion in preterm infants. Pediatrics. 2005 Jun. 115(6):1685-91.
11. Fredrickson LK, Bell EF, Cress GA, et al. Acute physiological effects of packed red blood cell transfusion in preterm infants with different degrees of anaemia. Arch Dis Child Fetal Neonatal Ed. 2011 Jul. 96(4):F249-53.
12. Kirpalani H, Whyte RK, Andersen C, et al. The Premature Infants in Need of Transfusion (PINT) study: a randomized, controlled trial of a restrictive (low) versus liberal (high) transfusion threshold for extremely low birth weight infants. J Pediatr. 2006 Sep. 149(3):301-307.
13. Suk KK, Dunbar JA, Liu A, et al. Human recombinant erythropoietin and the incidence of retinopathy of prematurity: a multiple regression model. J AAPOS. 2008 Jun. 12(3):233-8.
14. Yasmeen BH, Chowdhury MA, Hoque MM, Hossain MM, Jahan R, Akhtar S. Effect of short-term recombinant human erythropoietin therapy in the prevention of anemia of prematurity in very low birth weight neonates. Bangladesh Med Res Counc Bull. 2012 Dec. 38(3):119-23.

What is blood plasma

How much blood you have depends mostly on your size and weight. A man who weighs about 70 kg (about 154 pounds) has about 5 to 6 liters of blood in his body. Blood is 55% blood plasma and about 45% different types of blood cells. Blood is composed of solid particles (red blood cells, white blood cells, and cell fragments called platelets) suspended in a fluid extracellular matrix called blood plasma. Over 99% of the solid particles present in blood are cells that are called red blood cells (erythrocytes) due to their red color. The rest are pale or colorless white blood cells (leukocytes) and platelets (thrombocytes).

The blood plasma is the clear, straw-colored, liquid portion of the blood in which the cells (red blood cells, white blood cells) and platelets are suspended. It is
approximately 92% water and less than 8% is dissolved substances, mostly proteins, a complex mixture of organic and inorganic biochemicals. Functions of plasma include transporting gases, vitamins, and other nutrients; helping to regulate fluid and electrolyte balance; and maintaining a favorable pH. Blood plasma also contain antibodies to fight infections (part of the immune system), glucose, amino acids and the proteins that form blood clots (part of the hemostatic system)..

Blood plasma contains electrolytes that are absorbed from the intestine or released as by-products of cellular metabolism. They include sodium, potassium, calcium, magnesium, chloride, bicarbonate, phosphate, and sulfate ions. Sodium and chloride ions are the most abundant. Bicarbonate ions are important in maintaining the pH of plasma. Like other plasma constituents, bicarbonate ions are regulated so that their blood concentrations remain relatively stable.

Blood transports a variety of materials between interior body cells and those that exchange substances with the external environment. In this way, blood helps maintain stable internal environmental conditions.

Hemostasis refers to the process that stops bleeding, which is vitally important when blood vessels are damaged. Following an injury to the blood vessels, several actions may help to limit or prevent blood loss. These include vascular spasm, platelet plug formation, and blood coagulation.

Platelets adhere to any rough surface, particularly to the collagen in connective tissue. When a blood vessel breaks, platelets adhere to the collagen underlying the endothelium lining blood vessels. Platelets also adhere to each other, forming a platelet plug in the vascular break. A plug may control blood loss from a small break, but a larger break may require a blood clot to halt bleeding.

Coagulation, the most effective hemostatic mechanism, forms a blood clot in a series of reactions, each one activating the next. Blood coagulation is complex and utilizes many biochemicals called clotting factors. Some of these factors promote coagulation, and others inhibit it. Whether or not blood coagulates depends on the balance between these two groups of factors. Normally, anticoagulants prevail, and the blood does not clot. However, as a result of injury (trauma), biochemicals that favor coagulation may increase in concentration, and the blood may coagulate. The resulting mass is a blood clot, which may block a vascular break and prevent further blood loss. The clear, yellow liquid that remains after the clot forms is called serum. Serum is plasma minus the clotting factors.

Note: Blood is a complex mixture of formed elements in a liquid extracellular matrix, called blood plasma. Note that water and proteins account for 99% of the blood plasma.

Figure 1. Blood composition

Note: Blood consists of a liquid portion called plasma and a solid portion (the formed elements) that includes red blood cells, white blood cells, and platelets. When blood components are separated by centrifugation, the white blood cells and platelets form a thin layer, called the “buffy coat,” between the plasma and the red blood cells, which accounts for about 1% of the total blood volume. Blood cells and platelets can be seen under a light microscope when a blood sample is smeared onto a glass slide.

Blood Plasma Proteins

Blood plasma proteins are the most abundant of the dissolved substances (solutes) in plasma. These proteins remain in the blood and interstitial fluids, and ordinarily are not used as energy sources. The three main types of blood plasma proteins—albumins, globulins, and fibrinogen—differ in composition and function.

Albumins are the smallest plasma proteins, yet account for about 60% of them by weight. Albumins are synthesized in the liver.

Plasma proteins are too large to pass through the capillary walls, so they are impermeant. They create an osmotic pressure that holds water in the capillaries, despite blood pressure forcing water out of capillaries by filtration. The term colloid osmotic pressure is used to describe this osmotic effect due to the plasma proteins. Because albumins are so plentiful, they are an important determinant of the colloid osmotic pressure of the plasma.

By maintaining the colloid osmotic pressure of plasma, albumins and other plasma proteins help regulate water movement between the blood and the tissues. In doing so, the blood plasma proteins help control blood volume, which, in turn, directly affects blood pressure.

If the concentration of plasma proteins falls, tissues swell. This condition is called edema. As the concentration of plasma proteins drops, so does the colloid osmotic pressure. Water leaves the blood vessels and accumulates in the interstitial spaces, causing swelling. A low plasma protein concentration may result from starvation, a protein-deficient diet, or an impaired liver that cannot synthesize plasma proteins.

Globulins make up about 36% of the plasma proteins. They can be further subdivided into alpha, beta, and gamma globulins. The liver synthesizes alpha and
beta globulins, which have a variety of functions. The globulins transport lipids and fat-soluble vitamins. Lymphatic tissues produce the gamma globulins, which are a type of antibody.

Fibrinogen constitutes about 4% of the plasma proteins, and functions in blood coagulation (clotting). Fibrinogen is synthesized in the liver, fibrinogen is the largest of the plasma proteins.

Plasma products and their uses

Plasma products can be grouped into three main types:

• clotting or coagulation factors
• albumin solutions
• immunoglobulins

Coagulation or clotting factors

Coagulation is the name for the complex process of blood clotting. Clotting factors are proteins that work together with platelets to clot blood.

People need clotting factors for their blood to successfully clot. Missing one or more of these factors leads to blood clotting disorders such as haemophilia and Von Willebrand disease.

In the US, hemophilia is commonly treated with ‘recombinant factors’ that are manufactured in a laboratory and do not come from donated plasma.

Other blood clotting disorders that are treated with coagulation factors made from donated plasma.

Albumin

Albumin is the most common protein in blood plasma. It helps to:

• carry substances around the body
• maintain the right amount of fluid circulating in the body

If the circulation is working properly, vital hormones, cells and enzymes are transported to the right parts of the body to do their job.

If it’s not working properly, the circulatory system starts to break down, with serious consequences such as fluids being retained in the cells.

This can be treated by using human albumin solution which makes sure that the right amount of fluid is circulating in the blood stream.

Albumin can also be used to treat people with some types of liver or kidney disease and patients who have suffered burns.

Immunoglobulins

Immunoglobulins are protective antibodies which are produced by the body to fight against invading viruses or bacteria. There are two different types of immunoglobulins, specific and non-specific.

Specific immunoglobulins

Specific immunoglobulins contain high levels of antibody to a particular illness. These are given to people who have been exposed to a specific infection.

Antidotes to tetanus, rabies, chickenpox and hepatitis are all examples of specific immunoglobulins.

For example, a donor who has had chicken pox will have high levels of chicken pox antibodies. So their plasma would be ideal to treat a child with leukaemia who has been exposed to chicken pox.

Non-specific immunoglobulins

Non-specific immunoglobulins contain a wide variety of antibodies. These are given to people:

• who make faulty antibodies, or can’t make their own antibodies
• who are having treatments for diseases like cancer, where the treatment harms their ability to make antibodies

People with a faulty immune system need these products to live. Over 1,000 donations of plasma contribute to a single dose of an immunoglobulin product that contains all the necessary antibodies.

Table 1 summarizes the characteristics of the blood plasma proteins.

Table 1. Blood plasma proteins

Protein	Percentage of Total	Origin	Function
Albumins	60%	Liver	Help maintain colloid osmotic pressure
Globulins	36%
Alpha globulins		Liver	Transport lipids and fat-soluble vitamins
Beta globulins		Liver	Transport lipids and fat-soluble vitamins
Gamma globulins		Lymphatic tissues	Constitute the antibodies of immunity
Fibrinogen	4%	Liver	Plays a key role in blood coagulation

Separating plasma products

Plasma is first tested to be sure it’s safe to use, in the same way that whole blood is tested.

Many chemical and physical processes (e.g., spinning and heat treatments) are then carried out to separate the individual proteins. This is known as the fractionation process.

This process is fully automated and takes up to five days to complete.

Solvent or detergent treatment, dry heat treatment, filtration and pasteurization are also used to kill or remove any viruses that may be present.

The finished products are then tested again to make sure they contain the right biological make-up.

Once processing and testing is complete, the products are labeled, coded and packed, ready to be used by hospitals, clinics and doctors’ surgeries.

The total number of products that can be made with plasma fractionation runs into hundreds.

Blood Plasma Gases and Nutrients

The most important blood gases are oxygen (O2) and carbon dioxide (CO2). Blood plasma also contains a considerable amount of dissolved nitrogen, which ordinarily has no physiological function.

The plasma nutrients include amino acids, simple sugars, nucleotides, and lipids, all absorbed from the digestive tract. For example, blood plasma transports glucose from the small intestine to the liver, where it may be stored as glycogen or converted to fat. If blood glucose concentration drops below the normal range, glycogen may be broken down into glucose.

Blood plasma also carries recently absorbed amino acids to the liver, where they may be used to manufacture proteins, or deaminated and used as an energy source.

Blood plasma lipids include fats (triglycerides), phospholipids, and cholesterol. Because lipids are not water-soluble and plasma is almost 92% water, these lipids are carried in the plasma attached to proteins.

Blood Plasma Nonprotein Nitrogenous Substances

Molecules that contain nitrogen atoms but are not proteins comprise a group called nonprotein nitrogenous substances. In plasma, this group includes amino acids, urea, uric acid, creatine and creatinine. Amino acids come from protein digestion and amino acid absorption. Urea and uric acid are products of protein and nucleic acid catabolism, respectively. Creatinine results from the metabolism of creatine. In the skeletal muscle creatine is part of creatine phosphate in muscle tissue, where it stores energy in phosphate bonds.

Blood Plasma Electrolytes

Blood plasma contains electrolytes that are absorbed from the intestine or released as by-products of cellular metabolism. They include sodium, potassium, calcium, magnesium, chloride, bicarbonate, phosphate, and sulfate ions. Sodium and chloride ions are the most abundant. Bicarbonate ions are important in maintaining the pH of plasma. Like other plasma constituents, bicarbonate ions are regulated so that their blood concentrations remain relatively stable.

Blood plasma donation

Plasmapheresis is the standard procedure by which blood plasma is separated from whole blood and collected ¹. Blood flows through a single needle placed in an arm vein, into a machine that contains a sterile, disposable plastic kit. The plasma is isolated and channeled out into a special bag, and red blood cells and other parts of the blood are returned to you through the same needle.

Is Plasmapheresis Safe ?

Absolutely. The machine and the procedure have been evaluated and approved by the Food and Drug Administration (FDA), and all plastics and needles coming into contact with you are used once and discarded ¹. At no time during the procedure is the blood being returned to you detached from the needle in your arm, so there is no risk of returning the wrong blood to you.

Who Is Eligible to Participate in the AB Plasma Program ?

Donors must have blood group AB and must be male, because men lack plasma proteins (antibodies) directed against blood cell elements ¹. Otherwise, eligibility for plasmapheresis procedures is the same as that for whole-blood donation. The interval between consecutive group AB plasmapheresis donations at National Institutes of Health Blood Bank is 1 month.

How Long Does Plasmapheresis Take ?

Plasmapheresis procedures take about 40 minutes, but you should allow another 20 minutes for staff to obtain your medical history ¹.

What is blood plasma used for

Blood plasma is the pale yellow liquid part of whole blood. It is enriched in proteins that help fight infection (part of the immune system) and aid the blood in clotting (part of the hemostatic system). AB plasma is plasma collected from blood group AB donors. It is considered “universal donor” plasma because it is suitable for all recipients, regardless of blood group. Due to its value as a transfusion component, it is sometimes referred to as “liquid gold.”

Blood plasma products available in the United States include fresh frozen plasma and thawed plasma that may be stored at 33.8 to 42.8°F (1 to 6°C) for up to five days ². Blood plasma contains all of the coagulation factors. Fresh frozen plasma infusion can be used for reversal of anticoagulant effects. Thawed plasma has lower levels of factors V and VIII and is not indicated in patients with consumption coagulopathy (diffuse intravascular coagulation) ³.

Blood plasma transfusion is recommended in patients with active bleeding and an International Normalized Ratio (INR) greater than 1.6, or before an invasive procedure or surgery if a patient has been anticoagulated ⁴, ⁵. Blood plasma is often inappropriately transfused for correction of a high INR when there is no bleeding. Supportive care can decrease high-normal to slightly elevated INRs (1.3 to 1.6) without transfusion of plasma. Table 2 gives indications for plasma transfusion ⁴, ⁵, ⁶.

Table 2. Indications for Transfusion of Blood Plasma Products

Indication	Associated condition/additional information
International Normalized Ratio > 1.6	Inherited deficiency of single clotting factors with no virus-safe or recombinant factor available—anticoagulant factors II, V, X, or XI
	Prevent active bleeding in patient on anticoagulant therapy before a procedure
	Active bleeding
Emergency reversal of warfarin (Coumadin)	Major or intracranial hemorrhage
	Prophylactic transfusion in a surgical procedure that cannot be delayed
Acute disseminated intravascular coagulopathy	With active bleeding and correction of underlying condition
Microvascular bleeding during massive transfusion	≥ 1 blood volume (replacing approximately 5,000 mL in an adult who weighs 155.56 lb [70 kg])
Replacement fluid for apheresis in thrombotic microangiopathies	Thrombotic thrombocytopenic purpura; hemolytic uremic syndrome
Hereditary angioedema	When C1 esterase inhibitor is unavailable

[Source ²]

Cryoprecipitate

Cryoprecipitate is prepared by thawing fresh frozen plasma and collecting the precipitate. Cryoprecipitate contains high concentrations of factor VIII and fibrinogen ². Cryoprecipitate is used in cases of hypofibrinogenemia, which most often occurs in the setting of massive hemorrhage or consumptive coagulopathy. Indications for cryoprecipitate transfusion are listed in Table 3 ⁷, ⁸. Each unit will raise the fibrinogen level by 5 to 10 mg per dL (0.15 to 0.29 μmol per L), with the goal of maintaining a fibrinogen level of at least 100 mg per dL (2.94 μmol per L) ⁸. The usual dose in adults is 10 units of pooled cryoprecipitate ³. Recommendations for dosing regimens in neonates vary, ranging from 2 mL of cryoprecipitate per kg to 1 unit of cryoprecipitate (15 to 20 mL) per 7 kg ⁷.

Table 3. Indications for Transfusion of Cryoprecipitate

Adults

Hemorrhage after cardiac surgery

Massive hemorrhage or transfusion

Surgical bleeding

Neonates

Anticoagulant factor VIII deficiency*

Anticoagulant factor XIII deficiency

Congenital dysfibrinogenemia

Congenital fibrinogen deficiency

von Willebrand disease*

---

[Source ²]

Blood plasma for patients undergoing surgery on the heart or blood vessels

Cardiovascular surgery includes many types of major surgery on the heart and major blood vessels, including procedures such as: heart valve replacements, coronary artery bypass grafts, aortic aneurysm repairs and corrections or congenital abnormalities of the heart. Cardiovascular surgery is associated with a significant risk of bleeding, with 8% of patients losing more than 2 ml/kg/hour of blood postoperatively ⁹. A number of features make patients undergoing cardiovascular surgery more likely to bleed ¹⁰, ¹¹:

• These patients may be taking drugs that predispose towards bleeding, such as aspirin or clopidogrel.

• Patients undergoing major heart surgery will often require a cardiopulmonary bypass, where a circuit is formed by removing the heart from the circulation by passing a catheter into the aorta and the pulmonary artery while a cardiopulmonary bypass machine circulates blood round the body and ensures that it is adequately oxygenated. Heparin is used to prevent the cardiopulmonary bypass circuit from clotting. Heparin is an anticoagulant and can predispose patients to bleeding. When cardiopulmonary bypass is complete, heparin is neutralised with protamine.

• Hypothermia and acidosis during the procedure may also contribute towards excess bleeding.

• Dilution of clotting factors with administration of intravenous fluid; this is a particular problem in the paediatric setting.

• When acute bleeding develops, clotting factors are consumed, resulting in a coagulopathy and predisposing the patient towards further bleeding.

In some cases these patients will have a clearly defined bleeding risk. They may already be haemorrhaging and, if this is the case, treatments to reduce bleeding would be considered therapeutic. Alternatively they may have abnormal blood results, such as a prolonged prothrombin time, suggesting that clotting factors may be deficient. Lastly, in some cases it may be presumed that a coagulopathy may develop and that prophylactic treatment before this event would reduce the risk of bleeding.

Treatment strategies to reduce bleeding include optimising surgical technique to minimise blood loss; antifibrinolytic agents such as tranexamic acid; careful monitoring and neutralisation of heparin; optimising the management of anticoagulant and antiplatelet drugs; and blood components such as fresh frozen plasma ¹².

Fresh frozen plasma obtained from whole blood from blood donors, is a source of procoagulant factors, including fibrinogen and is used for either the treatment or prophylaxis of bleeding ¹³. Many audits indicate that patients undergoing major cardiac and vascular surgery receive a significant proportion of all clinical plasma transfusions. Some studies have reported wide variation in the use of clinical plasma for cardiac surgery and in critical care among centres within the same country ¹⁴.

Fresh frozen plasma contains a number of factors that help blood to clot. The risk of bleeding in open heart surgery or surgery on the main blood vessels in the body is high. Fresh frozen plasma is sometimes administered to these patients to reduce bleeding. It can be administered prophylactically (to prevent bleeding) or therapeutically (to treat bleeding). However, there are risks of side effects from fresh frozen plasma, such as severe allergic reactions or breathing problems ¹⁵.

However a 2015 Cochrane Review found no evidence for the efficacy of fresh frozen plasma for the prevention of bleeding in heart surgery and it found some evidence of an increased overall need for red cell transfusion in those treated with fresh frozen plasma ¹⁵. There were no reported adverse events due to fresh frozen plasma transfusion. Overall the evidence for the safety and efficacy of prophylactic fresh frozen plasma for cardiac surgery is insufficient. The trials focused on prevention of bleeding and did not address prevention of bleeding for patients with abnormal blood clotting or for the treatment of bleeding patients.

Blood plasma for critically ill patients

Plasma transfusions are a frequently used treatment for critically ill patients, and they are usually prescribed to correct abnormal coagulation tests and to prevent or stop bleeding ¹⁶. Plasma transfusions have been used since 1941 ¹⁷. In 2008, 4,484,000 plasma units were transfused in patients in the United States ¹⁸. More than 10% of critically ill patients, both adults and children, receive a plasma transfusion during their hospital stay, making plasma transfusion a frequently used treatment modality ¹⁹, ²⁰, ²¹. In current practice, plasma transfusions are widely used in critical care; they are administered most often to correct abnormal coagulation tests or to prevent bleeding ²².

In situations in which active bleeding is attributable to a coagulation factor deficiency, plasma transfusions can constitute a life-saving intervention by improving coagulation factor deficit ²³, especially in patients requiring massive transfusion ²⁴. Although plasma transfusions are frequently prescribed for critically ill patients, some of the reasons for their use are not supported by evidence from medical research. Some research has found an association of plasma transfusions with worse outcomes, and other studies have suggested that plasma transfusions do not help to return blood to its normal thickness ²⁵.

Blood plasma for chronic inflammatory demyelinating polyradiculoneuropathy

Chronic inflammatory demyelinating polyradiculoneuropathy is a disease that causes progressive or relapsing and remitting weakness and numbness. At least one or two cases per 100,000 of the population and may be as high as 8.9 per 100,000 ²⁶. It is probably caused by an autoimmune process. Chronic inflammatory demyelinating polyradiculoneuropathy is an uncommon disease that causes weakness and numbness of the arms and legs. The condition may progress steadily or have periods of worsening and improvement. Although not proven, chronic inflammatory demyelinating polyradiculoneuropathy is generally considered to be an autoimmune disease caused by either humoral or cell-mediated immunity directed against myelin around individual nerve fibres or Schwann cell antigens which have not been identified ²⁷. In severe cases, the disease affects the actual nerve fibres themselves. There has been debate as to whether people with the clinical features of an acquired demyelinating neuropathy and a systemic disease, such as cancer, diabetes mellitus, systemic lupus erythematosus, and other connective tissue diseases should be categorised as having chronic inflammatory demyelinating polyradiculoneuropathy ²⁸.

Immunosuppressive or immunomodulatory drugs would be expected to be beneficial. According to Cochrane systematic reviews, three immune system treatments are known to help. These are corticosteroids (‘steroids’), plasma exchange (which removes and replaces blood plasma), and intravenous immunoglobulin (infusions into a vein of human antibodies). Moderate- to high-quality evidence from two small trials shows that plasma exchange provides significant short-term improvement in disability, clinical impairment, and motor nerve conduction velocity in chronic inflammatory demyelinating polyradiculoneuropathy but rapid deterioration may occur afterwards ²⁹. Adverse events related to difficulty with venous access, use of citrate, and haemodynamic changes are not uncommon.

Blood plasma for generalised myasthenia gravis

Myasthenia gravis is an autoimmune disease caused by antibodies in the blood which attack the junctions (against the nicotinic acetylcholine receptor) between nerves and muscles they stimulate. Less than five per cent of patients have auto-antibodies to a muscle tyrosine kinase. Myasthenia gravis is characterised by weakness and fatigability of voluntary muscle, which changes over time. Acute exacerbations are life-threatening because they can cause swallowing difficulties or respiratory failure. Historically, with treatment – including thymectomy, steroids, and immunosuppressive drugs – after one to 21 (mean 12) years, 6% of patients went into remission, 36% improved, 42% were unchanged, and 2% were worse ³⁰. In recent years, expert opinion has highlighted the greater efficacy of combined immunosuppressive treatments ³¹. A new subtype of myasthenia is associated with autoantibodies to a muscle specific kinase and these antibodies are also pathogenic on passive transfer ³².

Plasma exchange was introduced in 1976 as a short-term therapy for acute exacerbations of myasthenia gravis ³³. It is thought to work because the exchange removes circulating anti-AChR (anti-acetylcholine receptor) antibodies. However, improvement has also been reported in so-called seronegative myasthenia gravis (where no anti-AChR antibodies can be detected) following plasma exchange ³⁴. A symposium held in 1978 ³⁵, and numerous papers have recognised the short-term benefit of plasma exchanges ³⁶. The use of repeated plasma exchange over a long period in refractory myasthenia gravis has also been reported ³⁷. Plasma exchange is used worldwide for the treatment of myasthenia gravis but despite the published case series and the conferences of experts many questions remains unanswered concerning its efficacy for the treatment of chronic, more or less severe, myasthenia gravis as well as of myasthenic exacerbation or crisis and its efficacy in comparison with other treatments. Few randomised controlled trials have been published ³⁸, ³⁹. Plasma exchange removes these circulating auto-antibodies. Many case series suggest that plasma exchange helps to treat myasthenia gravis. However, two Cochrane Reviews 2002 ⁴⁰ and 2003 ⁴¹, both found no adequate randomised controlled trials have been performed to determine whether plasma exchange improves the short- or long-term outcome for chronic myasthenia gravis or myasthenia gravis exacerbation. However, many case series studies convincingly report short-term benefit from plasma exchange in myasthenia gravis, especially in myasthenic exacerbation or crisis. In severe exacerbations of myasthenia gravis one randomised controlled trial did not show a significant difference between plasma exchange and intravenous immunoglobulin. Further research is need to compare plasma exchange with alternative short-term treatments for myasthenic crisis or before thymectomy and to determine the value of long-term plasma exchange for treating myasthenia gravis.

Blood plasma for the prevention of ovarian hyperstimulation syndrome

Ovarian hyperstimulation syndrome is an iatrogenic, serious and potentially fatal complication of ovarian stimulation which affects 1% to 14% of all in vitro fertilisation (IVF) or intracytoplasmic sperm injection (ICSI) cycles ⁴². Ovarian hyperstimulation syndrome may be associated with massive ovarian enlargement, extracellular exudate accumulation combined with profound intravascular volume depletion, ascites, hydrothorax, haemoconcentration, liver dysfunction and renal failure ⁴³. It can lead to cancellation of an IVF cycle and prolonged bed rest or hospitalisation, which may have significant emotional, social, and economic impacts ⁴⁴. Ovarian hyperstimulation syndrome can be classified into an early form that is related to the ovarian response and exogenous human chorionic gonadotrophin (hCG) administration, and is detected three to nine days after hCG administration. A late form of ovarian hyperstimulation syndrome, diagnosed 10 to 17 days later, is due to endogenous hCG ⁴⁵ and is categorised as mild, moderate, severe or life-threatening. The aetiology of ovarian hyperstimulation syndrome is not completely clear at this moment; however the syndrome is strongly associated with serum hCG and certain vasoactive substances ⁴⁶ are not elevated during gonadotropin stimulation in in vitro fertilization (IVF) patients developing ovarian hyperstimulation syndrome (OHSS): results of a prospective cohort study with matched controls. European Journal of Obstetrics, Gynecology, and Reproductive Biology 2001;96:196-201. https://www.ncbi.nlm.nih.gov/pubmed/11384807)).

Blood plasma albumin has both osmotic and transport functions. It contributes about 75% of the plasma oncotic pressure and administration of 50 g human albumin solution will draw more than 800 mL of extracellular fluid into the circulation within 15 minutes ⁴⁷. It has been suggested that the binding and transport properties of human albumin play a major role in the prevention of severe ovarian hyperstimulation syndrome, as albumin may result in binding and inactivation of the vasoactive intermediates responsible for the pathogenesis of ovarian hyperstimulation syndrome. The osmotic function is responsible for maintaining the intra-vascular volume in the event of capillary leakage, thus preventing the sequelae of hypovolaemia, ascites and haemoconcentration ⁴⁸. A 2016 Cochrane Review concluded that there is some eEvidence suggesting that the plasma expanders assessed in this review (human albumin, hydroxyethyl starch and mannitol) reduce rates of moderate and severe ovarian hyperstimulation syndrome in women at high risk. Adverse events appear to be uncommon, but were too poorly reported to reach any firm conclusions ⁴⁸.

References

1. AB Plasma Donor Program. National Institutes of Health Blood Bank. https://clinicalcenter.nih.gov/blooddonor/donationtypes/ab_plasma.html
2. Transfusion of Blood and Blood Products: Indications and Complications. Am Fam Physician. 2011 Mar 15;83(6):719-724. http://www.aafp.org/afp/2011/0315/p719.html
3. King KE, Bandarenko N. Blood Transfusion Therapy: A Physician’s Handbook. 9th ed. Bethesda, Md.: American Association of Blood Banks; 2008:236.
4. Practice parameter for the use of fresh-frozen plasma, cryoprecipitate, and platelets. Fresh-Frozen Plasma, Cryoprecipitate, and Platelets Administration Practice Guidelines Development Task Force of the College of American Pathologists. JAMA. 1994;271(10):777–781.
5. Holland LL, Brooks JP. Toward rational fresh frozen plasma transfusion: the effect of plasma transfusion on coagulation test results. Am J Clin Pathol. 2006;126(1):133–139.
6. Liumbruno G, Bennardello F, Lattanzio A, Piccoli P, Rossetti G; Italian Society of Transfusion Medicine and Immunohaematology (SIMTI) Work Group. Recommendations for the transfusion of plasma and platelets. Blood Transfus. 2009;7(2):132–150.
7. Poterjoy BS, Josephson CD. Platelets, frozen plasma, and cryoprecipitate: what is the clinical evidence for their use in the neonatal intensive care unit? Semin Perinatol. 2009;33(1):66–74.
8. Callum JL, Karkouti K, Lin Y. Cryoprecipitate: the current state of knowledge. Transfus Med Rev. 2009;23(3):177–188.
9. Vuylsteke A, Pagel C, Gerrard C, Reddy B, Nashef S, Aldam P, et al. The Papworth Bleeding Risk Score: a stratification scheme for identifying cardiac surgery patients at risk of excessive early postoperative bleeding. European Journal of Cardiothoracic Surgery 2011;39(6):924-30. https://www.ncbi.nlm.nih.gov/pubmed/21094051
10. Bevan DH. Cardiac bypass haemostasis: putting blood through the mill. British Journal of Haematology 1999;104(2):208-19. https://www.ncbi.nlm.nih.gov/pubmed/10050700
11. Hartmann M, Sucker C, Boehm O, Koch A, Loer S, Zacharowski K. Effects of cardiac surgery on hemostasis. Transfusion Medicine Reviews 2006;20(3):230-41. https://www.ncbi.nlm.nih.gov/pubmed/16787830
12. Davidson S. State of the art: how I manage coagulopathy in cardiac surgery patients. British Journal of Haematology 2014;164(6):779-89. https://www.ncbi.nlm.nih.gov/pubmed/24450971
13. Desborough M, Stanworth S. Plasma transfusion for bedside, radiologically guided, and operating room invasive procedures. Transfusion 2012;52(Suppl 1):20S-9S. https://www.ncbi.nlm.nih.gov/pubmed/22578367
14. Stanworth SJ, Grant-Casey J, Lowe D, Laffan M, New H, Murphy MF, et al. The use of fresh-frozen plasma in England: high levels of inappropriate use in adults and children. Transfusion 2011;51(1):62-70. https://www.ncbi.nlm.nih.gov/pubmed/20804532
15. Desborough M, Sandu R, Brunskill SJ, Doree C, Trivella M, Montedori A, Abraha I, Stanworth S. Fresh frozen plasma for cardiovascular surgery. Cochrane Database of Systematic Reviews 2015, Issue 7. Art. No.: CD007614. DOI: 10.1002/14651858.CD007614.pub2. http://onlinelibrary.wiley.com/doi/10.1002/14651858.CD007614.pub2/full
16. Plasma transfusion strategies for critically ill patients. National Center for Biotechnology Information, U.S. National Library of Medicine. https://www.ncbi.nlm.nih.gov/pubmedhealth/PMH0061586/
17. Schmidt PJ. The plasma wars: a history. Transfusion 2012;52(S1):2S-4S.
18. Office of the Assistant Secretary for Health. The 2009 National Blood Collection and Utilization Survey Report. Washington, DC: US Department of Health and Human Services, 2011.
19. Luk C, Eckert KM, Barr RM, Chin-Yee IH. Prospective audit of the use of fresh-frozen plasma, based on Canadian Medical Association transfusion guidelines. Canadian Medical Association Journal 2002;166(12):1539-40. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC113799/
20. Puetz J, Witmer C, Huang Y, Raffini L. Widespread use of fresh frozen plasma in US children’s hospitals despite limited evidence demonstrating a beneficial effect. Journal of Pediatrics 2012;160(2):210-5.
21. Stanworth SJ, Walsh TS, Prescott RJ, Lee RJ, Watson DM, Wyncoll D. A national study of plasma use in critical care: clinical indications, dose and effect on prothrombin time. Critical Care 2011;15(2):R108.
22. Vlaar AP, in der Maur AL, Binnekade JM, Schultz MJ, Juffermans NP. A survey of physicians’ reasons to transfuse plasma and platelets in the critically ill: a prospective single-centre cohort study. Transfusion Medicine 2009;19(4):207-12.
23. Stanworth SJ, Hyde CJ, Murphy MF. Evidence for indications of fresh frozen plasma. Transfusion Clinique et Biologique 2007;14(6):551-6. https://www.ncbi.nlm.nih.gov/pubmed/18430602
24. Zink KA, Sambasivan CN, Holcomb JB, Chisholm G, Schreiber MA. A high ratio of plasma and platelets to packed red blood cells in the first 6 hours of massive transfusion improves outcomes in a large multicenter study. American Journal of Surgery 2009;197(5):565-70. https://www.ncbi.nlm.nih.gov/pubmed/19393349
25. Karam O, Tucci M, Combescure C, Lacroix J, Rimensberger PC. Plasma transfusion strategies for critically ill patients. Cochrane Database of Systematic Reviews 2013, Issue 12. Art. No.: CD010654. DOI: 10.1002/14651858.CD010654.pub2. http://onlinelibrary.wiley.com/doi/10.1002/14651858.CD010654.pub2/full
26. Mahdi-Rogers M, Hughes RA. Epidemiology of chronic inflammatory neuropathies in southeast England. European Journal of Neurology 2014;21(1):28-33. https://www.ncbi.nlm.nih.gov/pubmed/23679015
27. Köller H, Kieseier BC, Jander S, Hartung HP. Chronic inflammatory demyelinating polyneuropathy. New England Journal of Medicine 2005;352(13):1343-56. https://www.ncbi.nlm.nih.gov/pubmed/15800230
28. Van den Bergh PY, Hadden RD, Bouche P, Cornblath DR, Hahn A, Illa I, et al. European Federation of Neurological Societies, Peripheral Nerve Society. European Federation of Neurological Societies/Peripheral Nerve Society guideline on management of chronic inflammatory demyelinating polyradiculoneuropathy: report of a joint task force of the European Federation of Neurological Societies and the Peripheral Nerve Society – first revision. Journal of the Peripheral Nervous System : JPNS 2010; Vol. 17, issue 3:356-63.
29. Mehndiratta MM, Hughes RAC, Pritchard J. Plasma exchange for chronic inflammatory demyelinating polyradiculoneuropathy. Cochrane Database of Systematic Reviews 2015, Issue 8. Art. No.: CD003906. DOI: 10.1002/14651858.CD003906.pub4. http://onlinelibrary.wiley.com/doi/10.1002/14651858.CD003906.pub4/full
30. Grob D, Brunner NG, Namba T. The natural course of myasthenia gravis and effect of therapeutic measures. Annals of the New York Academy of Science 1981;377(1):652-69. https://www.ncbi.nlm.nih.gov/pubmed/6951490
31. Oosterhuis HJGH. Myasthenia gravis. Groningen: Groningen Neurological Press, 1997.
32. Cole RN, Reddel SW, Gervasio OL, Phillips WD. Anti-MuSK patient antibodies disrupt the mouse neuromuscular junction.. Ann Neurol 2008;63(6):782-9. https://www.ncbi.nlm.nih.gov/pubmed/18384168
33. Pinching AS, Peters DK. Remission of myasthenia gravis following plasma exchange. Lancet 1976;2(8000):1373-6. https://www.ncbi.nlm.nih.gov/pubmed/63848
34. Miller RG, Milner-Brown HS, Dau PC. Antibody-negative acquired myasthenia gravis. Successful therapy with plasma exchange (letter). Muscle and Nerve 1981;4(3):255. https://www.ncbi.nlm.nih.gov/pubmed/7242562
35. Dau PC. Plasmapheresis and the immunology of myasthenia gravis. Boston: Hougton-Mifflin, 1979.
36. NIH Consensus Conference. The utility of therapeutic plasmapheresis for neurological disorders. NIH Consensus Development.. Journal of the American Medical Association 1986;256(10):1333-7. https://www.ncbi.nlm.nih.gov/pubmed/3747048
37. Rodnitzky RL, Bosch EP. Chronic long-interval plasma exchange in myasthenia gravis. Archives of Neurology 1984;41(7):715-7. https://www.ncbi.nlm.nih.gov/pubmed/6743060
38. Rønager J, Ravnborg M, Hermansen I, Vorstrup S. Immunoglobulin treatment versus plasma exchange in patients with chronic moderate to severe myasthenia gravis. Artificial Organs 2001;25(12):967-73. https://www.ncbi.nlm.nih.gov/pubmed/11843764
39. Kamel A, Essa M. Effectiveness of prethymecthomy plasmapheresis on short-term outcome of non-thymomatous generalized myasthenia gravis. Egyptian Journal Neurology, Psychiatry and Neurosurgurgery 2009;46(1):161-8.
40. Gajdos P, Chevret S, Toyka KV. Plasma exchange for generalised myasthenia gravis. Cochrane Database of Systematic Reviews 2002, Issue 4. Art. No.: CD002275. DOI: 10.1002/14651858.CD002275. http://onlinelibrary.wiley.com/doi/10.1002/14651858.CD002275/full
41. Gajdos P, Chevret S, Toyka K. Intravenous immunoglobulin for myasthenia gravis. The Cochrane Database of Systematic Reviews 2003, Issue 2. Art. No.: CD002277. DOI: 10.1002/14651858.CD002277. http://onlinelibrary.wiley.com/doi/10.1002/14651858.CD002277
42. Garcia-Velasco JA, Pellicer A. New concepts in the understanding of the ovarian hyperstimulation syndrome. Current Opinion in Obstetrics and Gynecology 2003;15(3):251-6. https://www.ncbi.nlm.nih.gov/pubmed/12858114
43. Vloeberghs V, Peeraer K, Pexsters A, D’Hooghe T. Ovarianhyperstimulation syndrome and complications of ART. Best Practice & Research. Clinical Obstetrics & Gynaecology 2009;23(5):691-709. https://www.ncbi.nlm.nih.gov/pubmed/19632900
44. Engmann L, DiLugie A, Schmidt D, Nulsen J, Maier D, Benavida C. The use of gonadotropin-releasing hormone (GnRH) agonist to induce oocyte maturation after cotreatment with GnRH antagonist in high-risk patients undergoing in vitro fertilization prevents the risk of ovarian hyperstimulation syndrome: a prospective randomised controlled study. Fertility and Sterility 2008;89(1):84-91. https://www.ncbi.nlm.nih.gov/pubmed/17462639
45. Mathur RS, Jenkins JM. Is ovarian hyperstimulation syndrome associated with a poor obstetric outcome?. BJOG 2000;107:943-6. https://www.ncbi.nlm.nih.gov/pubmed/10955422
46. Enskog A, Nilsson L, Brännström M. Plasma levels of free vascular endothelial growth factor(165) (VEGF(165
47. McClelland DB. Human albumin solutions. BMJ 1990;300:35-57. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC1661866/
48. Shalev E, Giladi Y, Matilsky M, Ben-Ami M. Decreased incidence of severe ovarian hyperstimulation syndrome in high risk in-vitro fertilisation patients receiving intravenous albumin: a prospective study. Human Reproduction 1995;10:1373-6. https://www.ncbi.nlm.nih.gov/pubmed/7593499

Blood donation rules

Blood donation rules and requirements vary a lot between countries. For example, in the the United States (US) you must be at least 17 years old to donate blood at the National Institutes of Health Blood Bank ¹. In Australia the minimum age to donate blood is 16 years with an upper limit of 70 years of age ². In the US there is no upper age limit for donation ¹.

The temperature of blood in the body is 38° C, which is about one degree higher than body temperature ³. How much blood you have depends mostly on your size and weight. A man who weighs about 70 kg (about 154 pounds) has about 5 to 6 liters of blood in his body.

The volume of blood removed during a donation (450 mL ± 10% of blood) represents only about 10% of the total blood mass of a subject weighing 70 Kg.

Blood is 55% blood plasma and about 45% different types of blood cells. The blood plasma is a light yellow liquid. Over 90% of blood plasma is water, while less than 10% is dissolved substances, mostly proteins. Blood plasma also contains electrolytes, vitamins and nutrients such as glucose and amino acids. Over 99% of the solid particles present in blood are cells that are called red blood cells (erythrocytes) due to their red color. The rest are pale or colorless white blood cells (leukocytes) and platelets (thrombocytes).

Note: Blood is a complex mixture of formed elements in a liquid extracellular matrix, called blood plasma. Note that water and proteins account for 99% of the blood plasma.

Figure 1. Blood composition

Note: Blood consists of a liquid portion called plasma and a solid portion (the formed elements) that includes red blood cells, white blood cells, and platelets. When blood components are separated by centrifugation, the white blood cells and platelets form a thin layer, called the “buffy coat,” between the plasma and the red blood cells, which accounts for about 1% of the total blood volume. Blood cells and platelets can be seen under a light microscope when a blood sample is smeared onto a glass slide.

Blood has three important functions:

• Transportation

The blood transports oxygen from the lungs to the cells of the body, where it is needed for metabolism. The carbon dioxide produced during metabolism is carried back to the lungs by the blood, where it is then exhaled. Blood also provides the cells with nutrients, transports hormones and removes waste products, which the liver, the kidneys or the intestine, for example, then get rid of.

• Regulation

The blood helps to keep certain values of the body in balance. For instance, it makes sure that the right body temperature is maintained. This is done both through blood plasma, which can absorb or give off heat, as well as through the speed at which the blood is flowing. When the blood vessels expand, the blood flows more slowly and this causes heat to be lost. When the environmental temperature is low the blood vessels can contract, so that as little heat as possible is lost. Even the so-called pH value of the blood is kept at a level ideal for the body. The pH value tells us how acidic or alkaline a liquid is. A constant pH value is very important for bodily functions.

• Protection

If a blood vessel is damaged, certain parts of the blood clot together very quickly and make sure that a scrape, for instance, stops bleeding. This is how the body is protected against losing blood. White blood cells and other messenger substances also play an important role in the immune system.

Blood donation eligibility ⁴

You can donate blood if you:

• Are healthy
• Are at least 17 years of age
• Weigh at least 110 pounds (50 kgs). There is no upper weight limit.

The tables below address specific situations affecting donation eligibility.

Table 1. Medical Condition

Medical Condition	Eligibility
Acquired Immune Deficiency Syndrome (AIDS), individuals at high risk and their partners	cannot donate
Colds and flu within 2 days	cannot donate
Diabetes, on or off medication and under control. If well-controlled by diet, oral medication, or insulin, you can donate. *However, the use of insulin made from beef is a cause for permanent deferral.	can donate
Hepatitis or jaundice after age 11	cannot donate
Pregnancy. You cannot donate until six weeks after the conclusion of the pregnancy.	cannot donate
Pregnancy, after delivery, miscarriage, abortion	6-week wait
Menstruation	can donate
Cancer, treatment complete and disease-free; most types	2-year wait

[Source ¹]

Table 2. Medical Procedures

Medical Procedures	Eligibility
Surgery, without transfusion (except for autologous blood)	can donate
Surgery, with transfusion	1-year wait

[Source ¹]

Table 3. Vaccinations

Vaccinations	Eligibility
Measles (rubella); measles, mumps, and rubella (MMR); chicken pox (varicella)	1-month wait
Flu	can donate
Hepatitis A or B	can donate

[Source ¹]

Table 4. Other Possible Restrictions

Other Possible Restrictions	Eligibility
Ear/Body piercing, sterile procedure/equipment used	can donate
Ear/Body piercing, nonsterile procedure/equipment used	1-year wait
Tattooing	1-year wait
Travel outside the United States or Canada	Contact the National Institutes of Health Blood Bank

[Source ¹]

If you have traveled to other countries

There is a slight risk of exposure to infectious agents outside the United States that could cause serious disease. Donor deferral criteria for travel outside the US are designed to prevent the transmission of three specific organisms from donor to recipient:

• Malaria. Malaria is caused by a parasite that can be transmitted from mosquitoes to humans. It is found in several hundred countries, and is one of the leading causes of death from infectious diseases world-wide. Donors who have traveled to areas listed by the Centers for Disease Control ⁵ as malarial risk areas are deferred for 1 year after their travel ends ¹.

• Bovine Spongiform Encephalopathy (BSE). BSE is commonly referred to as “Mad Cow disease” and is caused by an abnormal, transmissible protein called a prion. In the 1990s, the United Kingdom experienced an epidemic of the disorder in cows, with subsequent cow-to-human transmission, presumably through the food chain. BSE-infected cattle were also detected in other countries in Western Europe. Transfusion-transmission of BSE among donor-recipient pairs has been documented in a handful of cases ¹. Donors who have spent more than three months in the United Kingdom from 1980-1996, and donors who resided in Western Europe for greater than five years since 1980, are permanently deferred from blood donation ⁶.

Other blood donation restrictions

• If you have low Hemoglobin (Hb) or anemia, female donors must have a hemoglobin level of at least 12.5g/dL and male donors are required to have a minimum level of 13.0g/dL. The deferral is 30 days for both whole blood and apheresis donations. The most common reason for low hemoglobin is iron deficiency, and you will be given information about maintaining a healthy iron balance.
• If you have sickle cell disease, you cannot donate if you have sickle cell disease. You should not donate whole blood if you have sickle cell trait, because your blood will clog the filter that is applied to whole blood units. You can donate platelets if you are a sickle cell trait carrier.
• If you have received a blood transfusion, you must wait one year to donate.
• You cannot donate if you are currently experiencing severe allergy symptoms.

• Taking antibiotics,  you can donate 24 hours after the last dose if you have no further signs of infection. You may donate while taking antibiotics for acne.
• You cannot donate while taking narcotics to relieve pain.
• You may donate blood while taking nonnarcotic pain relievers.
• Aspirin interferes with platelet function and should be discontinued prior to platelet donation as follows. You cannot donate platelets if you have taken aspirin in the last 48 hours.
  • Special Caution: Many medications contain aspirin, so check the container carefully before making a platelet donation,
• Nonaspirin: You can donate platelets if you have taken ibuprofen or other nonaspirin, nonsteroidal anti-inflammatory drugs (NSAIDS).
• You can donate if you had skin cancer (basal cell or squamous cell) or cervical cancer in situ and the surgical site is completely healed.
• If you had another type of cancer, you can donate two years after the date of surgery or other definitive therapy, as long as your doctor informs you that there is no evidence of persistent or recurrent cancer.
• You are permanently deferred if you had leukemia or lymphoma.
• If you have a cold or the flu, you can donate once you have been symptom-free for 48 hours.
• If you have had dental work, there is a 24-hour waiting period after a routine cleaning and a 72-hour wait after extractions, root canals, or oral surgery.
• If you have epilepsy, you can donate if you have been seizure free for at least one week.
• If you have high blood pressure, you can donate if your blood pressure is controlled by medication.
• If you have low blood pressure, you can donate with low blood pressure.
• If you have heart disease or had a heart attack, in some situations, you may donate if you have heart disease or have had a heart attack. Contact the National Institutes of Health Blood Bank ⁷ for more details.
• If you have had angioplasty, you will need to contact the National Institutes of Health Blood Bank ⁷ for more details.
• If you had major surgery, you must wait until you have completely recovered and returned to normal activity before donating.
• If you have had hepatitis, you cannot donate if you have had hepatitis after age 11.
• If you received the hepatitis vaccine, you can donate if you have received the hepatitis vaccine (a series of three vaccinations).
• You must wait one year if you received Hepatitis B Immune Globulin or if you experienced a needlestick injury contaminated with untested blood.
• If you have herpes, you cannot donate with herpes or a cold sore when the lesions are active. You can donate if the lesions are dry and almost healed.
• If you have had malaria, you may donate if you have been asymptomatic of malaria for more than 3 years while residing in a non-endemic country.

Benefits of blood donation

There is no substitute for human blood. Human blood cannot be manufactured. People are the only source of blood. Much of the medical care of an National Institutes of Health patient depends on the steady supply of blood from healthy, caring individuals like yourself. No miracle of modern medicine can help the patients who need blood if blood is not available. The blood you donate at the National Institutes of Health Blood Bank is used to support the many patients who come from all over the world to receive treatment.

Blood in the umbilical cord at birth is rich in stem cells that can be used to treat a variety of disorders, including leukemias, sickle cell disease and other hemoglobin abnormalities, and certain inborn errors of metabolism. The United States and the United Kingdom have public umbilical cord blood banks that provide stem cells for free. For many illnesses it is more effective to receive donor stem cells, because receiving one’s own could reintroduce the disease.

Types of Blood Donations

You can make the following types of donations:

Blood components for transfusion

• Whole blood
• Red cells by apheresis
• Platelets by apheresis
• Granulocytes by apheresis
• AB Plasma by apheresis

Hemochromatosis donations

Hemochromatosis is a relatively common inherited condition in which the body absorbs excess iron. Over many years, iron overload can develop, with deposition of excess iron in body tissues and organs. Disabling arthritis, glandular failure, and severe liver disease can occur if the disorder is not treated. The treatment is phlebotomy therapy, or removal of 1 unit (1 pint) of blood every 1 – 16 weeks, depending on the level of iron overload. One pint of blood contains 250 mg of iron. Serial frequent phlebotomy sessions are a highly effective way to lower body iron levels. The National Institutes of Health Blood Bank has a protocol for treatment of hemochromatosis by phlebotomy therapy, which uses a simple and easy method to determine the pace of therapy.

The blood units removed therapeutically may be made available for transfusion into others if the donor (the hemochromatosis subject) meets standard blood donor eligibility criteria. Phlebotomy therapy and medical care for hemochromatosis are offered free of charge to all study participants. All persons with hemochromatosis are eligible for participation in this study, regardless of whether they meet blood donor criteria.

Hemochromatosis patients participating in the NIH Blood Bank Hemochromatosis Donor Program may donate:

• Whole blood
• Double red cells

Blood components for laboratory research use

Donated blood is never wasted. It is used every day of the year to treat patients who are participating in the medical treatment and research programs of the National Institutes of Health. If your blood is not required for immediate use, it may be frozen and stored. Fractions of blood that cannot be used for transfusion are used for research. Occasionally, the blood you give may not be required for a patient here but may be sent to another hospital, where it can be used to help save a life.

What is Whole Blood ?

Whole blood consists of red blood cells, white blood cells, and platelets suspended in a protective yellow liquid known as plasma. Most patients receiving transfusions do not need all of these elements.

Red blood cells have no nucleus, in contrast to many other cells. Each red blood cell contains hemoglobin, which can transport oxygen. In tiny blood vessels in the lung the red blood cells pick up oxygen from inhaled air and carry it through the bloodstream to all parts of the body. When they reach their goal, they release it again. The cells need oxygen for metabolism, which also creates carbon dioxide as a waste product. The red blood cells then pick up the carbon dioxide and transport it back to the lung. There we exhale it when we breathe out.

Red blood cells can also pick up or release hydrogen and nitrogen. When picking up or releasing hydrogen they help to keep the pH level of the blood steady; by releasing nitrogen the blood vessels expand, and blood pressure falls. Red blood cells have a life cycle of about 120 days. When they are too old or damaged they are broken down in the bone marrow, spleen or liver.

All solid parts of the blood originate from common parent cells, the so-called stem cells. In adults blood cells are produced mainly in the bone marrow. The various blood cells develop in several stages from stem cells to blood cells or blood platelets. White blood cells such as lymphocytes do not mature only in the bone marrow, but also in the lymph nodes. When the cells are completed, they are released into the bloodstream. In addition to these mature cells, the blood still contains a small number of precursor cells.

Figure 2. Blood cell development. A blood stem cell goes through several steps to become a red blood cell, platelet, or white blood cell

Certain messenger substances regulate the production of blood cells. The hormone erythropoietin, which is produced in the kidneys, promotes the production of red blood cells, while so-called cytokines stimulate the production of white blood cells.

One pint (473 ml) of whole blood is usually processed by a spinning method into:

• Red blood cells, which carry the oxygen needed by patients who are anemic;
• Platelets: Platelets are small cells that help the blood to clot. Manufactured in the bone marrow and stored in the spleen, their job is to rush to the site of an injury. Once there, they form a barrier, help the damaged organ or blood vessel stop bleeding, and give the body a chance to begin healing. Platelets needed by patients who are bleeding.
• Plasma: Plasma is the pale yellow liquid part of whole blood, in which the cellular elements are suspended. It is enriched in proteins that help fight infection and aid the blood in clotting. AB plasma is plasma collected from blood group AB donors. It is considered “universal donor” plasma because it is suitable for all recipients, regardless of blood group. Due to its value as a transfusion component, it is sometimes referred to as “liquid gold.” Plasma is transfused to patients whose blood is not clotting.

Therefore, one donation of whole blood can treat three different patients!

Used for:

• Cancer, blood diseases, haemophilia, anaemia, heart disease, stomach disease, kidney disease, childbirth, operations, blood loss, trauma, burns.

Is it Safe to Give Whole Blood ?

Absolutely. Many safeguards are taken to assure that no harm comes to you during or after donation. First, we obtain a medical history and check your blood pressure, pulse, and temperature to assure that you are in good health. We take a small sample of blood from your finger to confirm that you have an ample number of red cells to share. All equipment used to collect your blood is sterile and disposable. After donation, we provide delicious snacks and drinks.

Who is Eligible to Give Whole Blood?

Please see detailed description of donor criteria above (Tables 1-4 plus eligibility criteria and restrictions).

How often can you donate whole blood ?

You must wait 56 days between whole-blood donations to allow the number of red blood cells in your body to return to a predonation level.

How long does blood donation take ?

15 minutes to donate, 45 minutes for the appointment.

How Do You Arrange to Donate ?

You can contact the National Institutes of Health Blood Bank ⁷ for more details.

What is Donating Red Cells by Apheresis

Double Red Cell Apheresis (DRCA) is a procedure that allows a donor to give 2 units of red cells at the same time. This is done by a procedure called “apheresis,” which separates whole blood into component parts such as red blood cells, platelets, and plasma ⁸. To remove red cells, a needle is placed in your arm, and the blood flows into a sterile, disposable plastic kit installed in a machine designed specifically for this purpose. As blood enters the machine, the bowl is spinning at high speed. This causes the components of the blood to separate so that the red blood cells can be siphoned into a blood bag. Plasma and other parts of the blood are then returned to you through the same needle. The process is repeated to collect 2 units of red blood cells.

Is Double Red Cell Apheresis Safe ?

Absolutely. The machine and the procedure have been evaluated and approved by the Food and Drug Administration (FDA), and all plastics and needles coming into contact with you are used once and discarded ⁸. At no time during the procedure is the blood being returned to you detached from the needle in your arm, so there is no risk of returning the wrong blood to you.

What Are The Double Red Cell Apheresis Donor Requirements ?

Because you will be losing more red blood cells than usual during this procedure, donor criteria differ from those for whole blood donation:

Men

• Minimum weight – 130 pounds (59 kgs)
• Minimum height – 5’1″

Women

• Minimum weight – 150 pounds (68 kgs)
• Minimum height – 5’5″

Donors must have a slightly higher red cell count, specifically, a fingerstick hemoglobin level of at least 13.3 gm/dL. To assure that you do not become anemic, the interval between Double Red Cell Apheresis and subsequent blood donation is 4 months ⁸.

How Long Does Double Red Cell Apheresis Procedure Take ?

The time required to remove 2 units of reds cells is about 45 minutes ⁸. Because you’ll be with us longer, there will be time to watch TV, read, or just chat with staff and other donors. Every effort will be made to make the experience relaxing and enjoyable.

What is Donating Platelets by Apheresis

Plateletpheresis is the standard procedure by which platelets are separated from whole blood, concentrated, and collected ⁹. To remove platelets, a needle is placed in each arm. Blood flows through a needle into a machine that contains a sterile, disposable plastic kit specifically designed for this purpose. The platelets are isolated and channeled out into a special bag, and red blood cells and other parts of the blood are returned to you through a needle in the opposite arm. There is also a plateletpheresis procedure that can be performed with a single needle.

Is Plateletpheresis Safe ?

Absolutely. The machine and the procedure have been evaluated and approved by the Food and Drug Administration, and all plastics and needles coming into contact with you are used once and discarded ⁹. At no time during the procedure is the blood being returned to you detached from the needle in your arm, so there is no risk of returning the wrong blood to you.

Who Is Eligible to Give Platelets ?

The interval between consecutive platelet donations at National Institutes of Health Blood Bank is 1 month. However, because the body replaces platelets within a few days, you are allowed to give more frequently when you are donating for a relative or for a patient who responds particularly well to your platelets. In addition to standard donor eligibility requirements, platelet donors should refrain from taking aspirin for 48 hours prior to donation.

How Long Does Plateletpheresis Take ?

Plateletpheresis procedures take about 90 minutes ⁹, but you should allow another 30 minutes for staff to obtain your medical history.

What is Plasmapheresis ?

Plasmapheresis is the standard procedure by which plasma is separated from whole blood and collected ¹⁰. Blood flows through a single needle placed in an arm vein, into a machine that contains a sterile, disposable plastic kit. The plasma is isolated and channeled out into a special bag, and red blood cells and other parts of the blood are returned to you through the same needle.

Is Plasmapheresis Safe ?

Absolutely. The machine and the procedure have been evaluated and approved by the Food and Drug Administration (FDA), and all plastics and needles coming into contact with you are used once and discarded ¹⁰. At no time during the procedure is the blood being returned to you detached from the needle in your arm, so there is no risk of returning the wrong blood to you.

Who Is Eligible to Participate in the AB Plasma Program ?

Donors must have blood group AB and must be male, because men lack plasma proteins (antibodies) directed against blood cell elements ¹⁰. Otherwise, eligibility for plasmapheresis procedures is the same as that for whole-blood donation. The interval between consecutive group AB plasmapheresis donations at National Institutes of Health Blood Bank is 1 month.

How Long Does Plasmapheresis Take ?

Plasmapheresis procedures take about 40 minutes, but you should allow another 20 minutes for staff to obtain your medical history ¹⁰.

What is Granulocytes by Apheresis

A granulocyte is a type of white blood cell which fights bacteria and fungi. Patients with bone marrow failure syndromes, or those undergoing chemotherapy or marrow transplantation, often do not make enough of their own granulocytes to prevent serious infections. Such patients may benefit from a course of granulocyte transfusions.

What is Granulocytapheresis ?

Granulocytapheresis is the process by which granulocytes are collected from a healthy donor ¹¹. Similar to plateletpheresis, blood is withdrawn from a vein and directed into a machine that contains a sterile disposable kit. Granulocytes are separated by a spinning process and concentrated in a plastic bag. The remaining parts of the blood are returned to the donor through a second needle.

Is Granulocytapheresis Safe ?

Yes. The machine and the procedure used for granulocyte collection are approved by the Food and Drug Administration, and all plastics and needles coming into contact with the donor are discarded after use ¹¹. Two medications are given to the donor the day before collection to boost the donor’s granulocyte count. These medications are approved for donor use under an NIH protocol.

Who Is Eligible to Give Granulocytes ?

Granulocyte donors are healthy, unpaid volunteers between the age of 18 and 75 who meet the criteria for blood and platelet donors described below ¹¹. Granulocyte donors must meet some additional criteria described in the protocol. Granulocyte donors should refrain from taking aspirin for 48 hours prior to donation.

How Long Does Granulocytapheresis Take ?

Giving granulocytes with use of an apheresis machine takes about 2.5 hours, which is slightly longer than a plateletpheresis donation ¹¹. The donor has enough time to enjoy a full-length movie.

Blood donation side effects

Blood donors normally tolerate the donation very well, but occasionally adverse reactions of variable severity may occur during or at the end of the collection. The adverse reactions that occur in donors can be divided into local reactions and systemic reactions. In a small study involving 4,906 donors (3,716 male and 1,190 female), only 63 donors (1.2% of all the volunteers) suffered some kind of adverse reaction: 59 (1.08% of the subjects) had mild reactions (agitation, sweating, pallor, cold feeling, sense of weakness, nausea), and only 4 (3 males and 1 female, 0.2%) had more severe disorders, including vomiting, loss of consciousness, and convulsive syncope.

The statistical probability of an episode of complete loss of consciousness was equivalent to an incidence of 0.1%, that is, one case every 1,000 donors ¹².

Of the 63/4,906 (1.2%) donors who had adverse reactions to blood donation, only 40 (0.8%) were administered oral vasopressors (a drug or other agent which causes the constriction of blood vessels), while the other 23 (0.4%) recovered from the vasovagal reaction simply from being placed in the antishock position. Of the 63 donors who had a vasovagal reaction, only 18 (0.36%) were given crystalloid solutions, while less than five (0.1%) required additional therapy with cortisone ¹². In no case was re-animation based on oxygen therapy or administration of adrenaline needed.

The greatest number of reactions occurred during or after donations of whole blood, with there being fewer after donations of other blood components.

Local reactions

Local reactions occur predominantly because of problems related to venous access ¹². They are usually haematomas due to extravasation from the veins, caused by incorrect placement of the needle during the venipuncture. Pain, hyperaemia and swelling may develop at the site of the extravasation. Other local events include pain due to slight trauma to the subcutaneous nerve endings. In most cases, however, these are banal complications that do not require any treatment. Local phlebitis and thrombophlebitis are more serious complications than the foregoing, but are very rare.

Systemic reactions

The systemic reactions, in contrast to the local reactions, can be divided into mild or severe. In most cases, they are vasovagal reactions than can be triggered by the pain of the venipuncture, by the donor seeing his or her own blood, by the donor seeing another donor unwell, by the anxiety and state of tension of undergoing the donation, etc. The systemic reactions are characterised by the appearance of pallor, sweating, dizziness, gastrointestinal disorders, nausea, hypotension, and bradycardia. Therapeutic intervention must be swift, otherwise this clinical picture, typical of a vasovagal reaction, will progress into an episode of syncope, of variable severity, which may or may not be complicated by the onset of tonic-clonic muscle spasms (convulsive syncope), accompanied by vomiting and loss of sphincter control.

Systemic reactions can occur during apheresis procedures, which require the use of anticoagulants such as acid-citrate-dextrose for the collection of the blood component ¹². This anticoagulant can cause hypocalcaemia, because of chelation. The lowered concentration of calcium ions leads to episodes of paraesthesia of the lips, oral cavity and limbs. These symptoms resolve after interruption of the apheresis procedure, although it may sometimes be necessary to use a therapeutic intervention, such as the administration of calcium gluconate. Much more rarely, tremor, muscle spasms, hypotension, tachycardia, arrhythmia, convulsions and tetany develop.

There are rare reports of acute intoxication due to overdoses of acid-citrate-dextrose ¹³. Another rare complication, that can occur during apheresis procedures, is severe arrhythmias ¹².

Figure 3. Frequency of the symptoms occurring in donors during or immediately after the donation

Note: The donor population analysed consisted of 4,906 donors (3,716 male and 1,190 female). In total, 3,983 (81%) voluntaries have donated whole blood, 851 (17%) plasma from apheresis, 64 (1.3%) experienced multicomponent donation, and 8 (0.1%) were donors of plasma-platelet apheresis in the year from 24^th October, 2005 to 24^th April 2006.

[Source ¹²]

Blood Transfusions

Early attempts to transfer blood from one person to another produced varied results. Sometimes, the recipient improved. Other times, the recipient suffered a blood transfusion reaction in which the red blood cells clumped, obstructing vessels and producing great pain and organ damage.

Eventually scientists determined that blood is of differing types and that only certain combinations of blood types are compatible. These discoveries led to the development of procedures for typing blood. Today, safe transfusions of whole blood depend on two blood tests—“type and cross match.” First the recipient’s ABO blood type and Rh status are determined. Following this, a “cross match” is done of the recipient’s serum with a small amount of the donor’s red blood cells that have the same ABO type and Rh status as the recipient. Compatibility is determined by examining the mixture under a microscope for agglutination, the clumping of red blood cells. Agglutination (“clumping”) is a reaction between antigens and specific antibodies. This is what happens when antigens on mismatched donated red blood cells react with antibodies in plasma.

Blood Antigens and Antibodies

An antigen, is any molecule that triggers an immune response, the body’s reaction to invasion by a foreign substance or organism. When the immune system encounters an antigen not found on the body’s own cells, it will attack, producing antibodies. In a transfusion reaction, antigens (agglutinogens) on the surface of the donated red blood cells react with antibodies (agglutinins) in the plasma of the recipient, resulting in the agglutination of the donated red blood cells.

A mismatched blood transfusion quickly produces telltale signs of agglutination—anxiety, breathing difficulty, facial flushing, headache, and severe pain in the neck, chest, and lumbar area. Red blood cells burst, releasing free hemoglobin. Liver cells and macrophages phagocytize the hemoglobin, converting it to bilirubin, which may sufficiently accumulate to cause the yellow skin of jaundice. Free hemoglobin reaching the kidneys may ultimately cause them to fail.

Only a few of the 32 known antigens on red blood cell membranes can produce serious transfusion reactions. These include the antigens of the ABO group and those of the Rh group. Avoiding the mixture of certain kinds of antigens and antibodies prevents adverse transfusion reactions.

ABO Blood Group

The ABO blood group is based on the presence (or absence) of two major antigens on red blood cell membranes—antigen A and antigen B. A and B antigens are carbohydrates attached to glycolipids projecting from the red blood cell surface. A person’s erythrocytes have on their surfaces one of four antigen combinations: only A, only B, both A and B, or neither A nor B.

A person with only antigen A has type A blood. A person with only antigen B has type B blood. An individual with both antigens A and B has type AB blood. A person with neither antigen A nor B has type O blood. Thus, all people have one of four possible ABO blood types—A, B, AB, or O. The resulting ABO blood type is inherited. It is the consequence of DNA encoding enzymes to synthesize A or B antigens on erythrocytes in one of these four combinations.

• In the United States, the most common ABO blood types are O (47%) and A (41%). Rarer are type B (9%) and type AB (3%). These percentages vary in subpopulations and over time, reflecting changes in the genetic structure of populations.

Antibodies that affect the ABO blood group antigens are present in the plasma about two to eight months following birth, as a result of exposure to foods or microorganisms containing the antigen(s) that are not present on the individual’s red blood cells. Specifically, whenever antigen A is absent in red blood cells, an antibody called anti-A is produced, and whenever antigen B is absent on cells, an antibody called anti-B is produced. Therefore, individuals with type A blood have anti-B antibody in their plasma; those with type B blood have anti-A antibody; those with type AB blood have neither antibody; and those with type O blood have both anti-A and anti-B antibodies (Figure 4 and Table 5). The antibodies anti-A and anti-B are large and do not cross the placenta. Thus, a pregnant woman and her fetus may be of different ABO blood types, but agglutination in the fetus will not occur.

An antibody of one type will react with an antigen of the same type and clump red blood cells; therefore, such combinations must be avoided. The major concern in blood transfusion procedures is that the cells in the donated blood not clump due to antibodies in the recipient’s plasma. For this reason, a person with type A (anti-B) blood must not receive blood of type B or AB, either of which would clump in the presence of anti-B in the recipient’s type A blood. Likewise, a person with type B (anti-A) blood must not receive type A or AB blood, and a person with type O (anti-A and anti-B) blood must not receive type A, B, or AB blood.

Type AB blood does not have anti-A or anti-B antibodies, so an AB person can receive a transfusion of blood of any other type. For this reason, individuals with type AB blood are called universal recipients. However, type A (anti-B) blood, type B (anti-A) blood, and type O (anti-A and anti-B) blood still contain antibodies (either anti-A and/or anti-B) that could agglutinate type AB cells if transfused rapidly.

Consequently, even for AB individuals, using donor blood of the same type as the recipient is best (Table 6). Type O blood has neither antigen A nor antigen B. Therefore, theoretically this type could be transfused into persons with blood of any other type. Individuals with type O blood are called universal donors. Type O blood, however, does contain both anti-A and anti-B antibodies. If type O blood is given to a person with blood type A, B, or AB, it should be transfused slowly so that the recipient’s larger blood volume will dilute the donor blood, minimizing the chance of an adverse reaction.

Figure 4. ABO Blood Types and Antibodies (different combinations of antigens and antibodies distinguish blood types)

Table 5. Antigens and Antibodies of the ABO Blood Group

Blood Type	Antigen	Antibody
A	A	Anti-B
B	B	Anti-A
AB	A and B	Neither anti-A nor anti-B
O	Neither A nor B	Both anti-A and anti-B

Table 6. Preferred and Permissible Blood Types for Transfusions

Blood Type of Recipient	Preferred Blood Type of Donor	If Preferred Blood Type Unavailable, Permissible Blood Type of Donor
A	A	O
B	B	O
AB	AB	A, B, O
O	O	No alternate types

Rh Blood Group

The Rh (Rhesus) blood group was named after the rhesus monkey in which it was first studied. In humans, this group includes several Rh antigens (factors). The most prevalent of these is antigen D, a transmembrane protein.

If the Rh antigens are present on the red blood cell membranes, the blood is said to be Rh-positive. Conversely, if the red blood cells do not have Rh antigens, the blood is called Rh-negative. The presence (or absence) of Rh antigens is an inherited trait. Anti-Rh antibodies (anti-Rh) form only in Rh-negative individuals in response to the presence of red blood cells with Rh antigens. This happens, for example, if an individual with Rh-negative blood receives a transfusion of Rh-positive blood. The Rh antigens stimulate the recipient to begin producing anti-Rh antibodies. Generally, this initial transfusion has no serious consequences, but if an individual with Rh-negative blood—who is now sensitized to Rh-positive blood—receives another transfusion of Rh-positive blood some months later, the donated red cells are likely to agglutinate.

A similar situation of Rh incompatibility arises when an Rh-negative woman is pregnant with an Rh-positive fetus. Her first pregnancy with an Rh-positive fetus would probably be uneventful. However, if at the time of the infant’s birth (or if a miscarriage occurs) the placental membranes that separated the maternal blood from the fetal blood during the pregnancy tear, some of the infant’s Rh-positive blood cells may enter the maternal circulation. These Rh-positive cells may then stimulate the maternal tissues to produce anti-Rh antibodies. If a woman who has already developed anti-Rh antibodies becomes pregnant with a second Rh-positive fetus, these antibodies, called hemolysins, cross the placental membrane and destroy the fetal red blood cells. The fetus then develops a condition called erythroblastosis fetalis, or hemolytic disease of the fetus and newborn.

Erythroblastosis fetalis is extremely rare today because obstetricians carefully track Rh status. An Rh-negative woman who might carry an Rh-positive fetus is given an injection of a drug called RhoGAM at week 28 of her pregnancy and after delivery of an Rh-positive baby. Rhogam is a preparation of anti-Rh  antibodies, which bind to and shield any Rh-positive fetal cells that might contact the woman’s cells and sensitize her immune system. RhoGAM must be given within 72 hours of possible contact with Rh-positive cells—including giving birth, terminating a pregnancy, miscarrying, or undergoing amniocentesis (a prenatal test in which a needle is inserted into the uterus).

References

1. NIH BLOOD BANK. National Institutes of Health Blood Bank. https://clinicalcenter.nih.gov/blooddonor/can_i_donate.html
2. Age – How does age affect my ability to donate ? Australian Red Cross Blood Service. http://donateblood.com.au/faq/age
3. What does blood do ? National Center for Biotechnology Information, U.S. National Library of Medicine. https://www.ncbi.nlm.nih.gov/pubmedhealth/PMH0072576/
4. About Donating Blood. National Institutes of Health Blood Bank. https://clinicalcenter.nih.gov/blooddonor/about_donating_blood.html
5. Explore Travel Health with the CDC Yellow Book. Centers for Disease Control and Prevention. https://wwwnc.cdc.gov/travel/page/yellowbook-home
6. Bovine Spongiform Encephalopathy (BSE) Questions and Answers. U.S. Food and Drug Administration. https://www.fda.gov/BiologicsBloodVaccines/SafetyAvailability/ucm111482.htm
7. National Institutes of Health Blood Bank. https://clinicalcenter.nih.gov/blooddonor/index.html
8. Red Cells by Apheresis. National Institutes of Health Blood Bank. https://clinicalcenter.nih.gov/blooddonor/donationtypes/red_cells.html
9. Platelets by Apheresis. National Institutes of Health Blood Bank. https://clinicalcenter.nih.gov/blooddonor/donationtypes/platelets.html
10. AB Plasma Donor Program. National Institutes of Health Blood Bank. https://clinicalcenter.nih.gov/blooddonor/donationtypes/ab_plasma.html
11. Granulocytes by Apheresis. National Institutes of Health Blood Bank. https://clinicalcenter.nih.gov/blooddonor/donationtypes/granulocytes.html
12. Crocco A, D’Elia D. Adverse reactions during voluntary donation of blood and/or blood components. A statistical-epidemiological study. Blood Transfusion. 2007;5(3):143-152. doi:10.2450/2007.0005-07. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2535889/
13. Winters JL. Complications of donor apheresis. J Clin Apher. 2006;21:132–41. https://www.ncbi.nlm.nih.gov/pubmed/15880355