Hematologic Challenges in the Critically Ill

© Springer International Publishing AG, part of Springer Nature 2018

Aryeh Shander and Howard L. Corwin (eds.)Hematologic Challenges in the Critically Illhttps://doi.org/10.1007/978-3-319-93572-0_1

1. Anemia in the Critically Ill

Jens Meier¹  

(1)

Kepler Universitätsklinikum GmBH, Klinik für Anästhesiologie und Intensivmedizin, Linz, Austria

Jens Meier

Email: Jens.Meier@kepleruniklinikum.at

Keywords

AnemiaBlood lossHemoglobinopathyErythropoiesisIron deficiencyTransfusionIronErythropoietinFerritinTransferrin saturation

Introduction

Anemia is a common, worldwide health-care problem, and as a consequence patients suffering from anemia are treated by physicians all over the world on a daily basis. Depending on the region examined, up to 50% of all humans are anemic [1]; thus anemia has become one of the most prevalent and burdensome diseases. Anemia is characterized by a decreased quantity of red blood cells, often accompanied by diminished hemoglobin levels or altered red blood cell morphology. According to the definition of the World Health Organization (WHO), anemia is a condition in which the number of red blood cells or their oxygen-carrying capacity is insufficient to meet physiological needs, which vary by age, gender, altitude, smoking, and pregnancy status. Several years ago, the WHO has also published thresholds that define the limits of normal and abnormal hemoglobin concentrations. A hemoglobin concentration of 13 g/dL in men and a hemoglobin concentration of 12 g/dL in women are the lower threshold for the definition of anemia [1].

Anemia is pathophysiologically diverse and often multifactorial. Iron deficiency is thought to be the most common cause of anemia globally, although other conditions, such as folate, vitamin B12 and vitamin A deficiencies, chronic inflammation, parasitic infections, and inherited disorders can all cause anemia.

Many physicians judge anemia as a symptom and not as a disease per se. However, since anemia has gained an increase of interest in the last few years, more and more investigations describe anemia not solely as a symptom but as a pathological entity, which is an independent risk of morbidity and mortality.

What holds true for the common population is even more pronounced for patients admitted to an intensive care unit (ICU) . It is a well-known fact that nearly all ICU patients are either anemic at the time point of admission or become so after a few days of ICU stay [2]. The reasons for anemia in this situation are manifold and range from underlying diseases being the reason for ICU admission to the problem of a high number and probably unnecessary blood draws. As a consequence, most of the patients that leave the ICU remain anemic according to the WHO definition and by that are endangered by the risks associated with anemia risks that persist beyond their time in the ICU [2]. These include, but are not limited to, hypoxia, infection, myocardial infarction, stroke, etc. This extended risk profile very often results in the transfusion of allogeneic red blood cells during and after the ICU stay [3, 4]. However, within the last 20–30 years, it has been clearly demonstrated that not only anemia but also the transfusion of allogeneic red blood cells is independently associated with important risks and adverse effects. Therefore, anemia in the ICU is not only a side issue but a very important driver of ICU morbidity and mortality that determines the outcome of critically ill patients.

Pathophysiology of Anemia of Critical Illness

There are three main categories of anemia: anemia due to blood loss, anemia due to decreased red blood cell production, and anemia due to increased red blood cell breakdown [5]. Furthermore, anemias are often categorized by a different approach based on RBC morphology and further parameters like, e.g., mean cellular volume (MCV).

Blood Loss-Induced Anemia

In contrast to the other types of anemia, anemia of blood loss is characterized by a reduced hemoglobin concentration with initial normal RBC indices, whereas anemias associated with normocytic and normochromic red cells and an inappropriately low reticulocyte response (reticulocyte index <2–2.5) are called hypoproliferative anemias.

Blood losses are very common in patients that have been admitted to an ICU: either severe, massive bleeding is the reason for admission to the ICU or less severe bleeding will occur during the duration of the stay due to several reasons, including occult bleeding, diagnostic blood tests, etc.

Massive Bleeding

Massive bleeding of many different etiologies still endangers patients in different clinical settings. It is currently defined by (a) indices of its rate and extent and (b) the magnitude of the consequent blood components transfused [6]. Depending on the clinical situation, these definitions might differ. At the onset of massive bleeding, the organism is endangered by severe hypovolemia and in the end by hypoperfusion and a syndrome of hemorrhagic shock. Hemorrhagic shock is defined as a condition in which tissue perfusion is not capable of sustaining aerobic metabolism due to a loss of circulation blood [7]. Significant loss of intravascular volume may lead sequentially to hemodynamic instability, decreased tissue perfusion, cellular hypoxia, organ damage, and death. However, it is important to note that hemorrhagic shock is not defined by the presentation of anemia, or defined as a low hemoglobin concentration, but is a result of severe bleeding-induced hypovolemia and hypoperfusion. As a consequence, in the early phase of hemorrhagic shock, the hemoglobin concentration may remain constant (since red blood cells and fluids are lost in a balanced manner), masking the occurrence of blood loss in situation of occult bleeding. As events progress the course of hemorrhagic shock compensatory mechanisms (e.g., diffusion of interstitial and intracellular fluids into the blood vessels) will finally result in a decline of the hemoglobin concentration by dilution of the remaining circulating red blood cells. Furthermore, the standard treatment of hemorrhagic shock (i.e., the application of crystalloids and colloids) pronounces development of acute anemia by the same dilutional mechanism.

Although anemia due to massive bleeding is often described by the decline of the hemoglobin concentration, it has to be noted that all other components of blood are diluted as well by the mechanisms described above. Therefore, hemorrhagic shock does not only result in a decline of the hemoglobin concentration but also in a decline of proteins, coagulation factors, and other cellular elements of blood, resulting in hypoalbuminemia, coagulopathy, and thrombocytopenia. Furthermore, activation of an extensive network of proinflammatory mediator pathways by the innate immune system plays a significant role in the progression of hemorrhagic shock and contributes importantly to the development of multiple organ injury, multiple organ dysfunction (MOD), and multiorgan failure (MOF) and the highest risks of mortality [8].

There are a multitude of humoral mediators that are activated during shock and tissue injury. The complement cascade, activated through both the classic and alternate pathways, generates the anaphylatoxins C3a and C5a. Activation of the coagulation cascade causes microvascular thrombosis, with subsequent fibrinolysis leading to repeated episodes of ischemia and reperfusion. Components of the coagulation system (e.g., thrombin) are potent proinflammatory mediators that cause expression of adhesion molecules on endothelial cells and activation of neutrophils, leading to microvascular injury. Coagulation also activates the kallikrein-kininogen cascade, contributing and aggravating the presence of hypotension.

Therefore, massive bleeding-induced anemia is not only characterized by the decline of the hemoglobin concentration but has to be understood predominantly as a multifactorial, complicated pathophysiological event influencing oxygen, transport, tissue oxygenation, coagulation, and inflammation . Therefore, proper treatment is not limited to restoration of the circulating red cell mass but has also to include all the other side effects that are adjunctive to the sole hemoglobin loss.

Protracted and Low-Volume Bleeding During the ICU Stay

The reasons for mild to moderate blood losses during an ICU stay are manifold. First of all, nearly half of the patients that are admitted to a general ICU suffer from some level of a coagulopathy [9] and by that are prone to bleeding complications of many different kinds. Some of these coagulopathies have their sources in the underlying diseases, whereas a relevant number of patients suffer from iatrogenic coagulopathies since nowadays many patients are under oral antithrombotic therapy due to several reasons. Irrespective of the underlying pathophysiology, these coagulopathies result from overt and diffuse bleeding that might be responsible for significant and ongoing blood loss.

A second reason for moderate blood losses during the ICU stay is ICU-induced ulcers of the upper gastrointestinal tract. Stress ulcers typically occur in the gastric body, esophagus, or duodenum, sometimes resulting in severe gastrointestinal (GI) bleeding. Earlier studies reported overt GI bleeding in 5–25% of critically ill patients. In contrast, the incidence of clinically important GI bleeding is much lower, estimated between 1% and 4% [10]; however, it is found to be associated with increased ICU mortality and increased length of stay. As a consequence, recent guidelines strongly encourage perioperative GI ulcer prophylaxis at the ICU for the prevention of GI stress ulcers and the resultant bleeding.

The most frequent and probably most important reason for mild to moderate blood loss in the ICU is the standard blood tests that are usually drawn on a regular basis every morning while in the ICU. Most physicians are accustomed to the routine of checking the most recent laboratory values on morning rounds, and therefore frequent mutational blood sampling is one of the physicians’ rituals that has become an integral part of our daily work.

It has been demonstrated by several investigators that after 2 weeks in the ICU, more than 1 L of blood will be drawn depending on the underlying disease and the policy of the hospital [11, 12]. Therefore, even if other blood losses are absent, regularly drawing blood samples is a common risk factor for ICU-associated anemia, since typically 50 mL or more are drawn for one specific determination of a set of laboratory parameters [11, 12]. Although several guidelines urge physicians not to perform unnecessary laboratory tests, the approach described above is very common, and it seems as if it is very difficult to deter physicians from this deep cultural event.

Decreased Red Blood Cell Production

Nutritional Deficiency Anemia

Although nutritional deficiency anemia is the most important type of anemia worldwide [1], its prevalence in modern ICUs is lower than for many people outside the ICU [2]. It has been demonstrated by Lasocki and coworkers that less than 10% of ICU patients suffer from iron deficiency when they are discharged from the ICU, whereas 100% of them were anemic in this situation. However, 6 months later 25% of them developed severe iron deficiency due to the high iron demand during recovery [2].

Erythropoiesis consists of two distinct steps, one of them is iron dependent, whereas the other is erythropoietin dependent. Erythropoietin is a hormone that is produced in adulthood by the kidneys. It is upregulated when oxygen delivery to the tissues and when regional oxygen tension fall below a specific value. As long as body iron storages are sufficient to produce enough erythrocytes in the bone marrow from erythroid progenitor cells, the hematocrit will reach physiological levels. However, as soon as iron depletion occurs, erythropoiesis will be insufficient, and this condition will result in the production of smaller and fewer RBCs that contain a reduced amount of hemoglobin, resulting in hypochromic anemia. Hypochromic anemia may be caused by low iron intake, diminished iron absorption, or excessive iron loss. It can also be caused by infections (e.g., hookworms) or other diseases, therapeutic medications, copper toxicity, and lead poisoning. Sources of blood loss can include heavy menstrual periods (HMP), childbirth, uterine fibroids, stomach ulcers, colon cancer, and urinary tract bleeding. A poor ability to absorb iron may occur as a result of Crohn’s disease or a gastric bypass. In the developing world, parasitic worms, malaria, and HIV/AIDS increase the risk of decreased iron absorption. In the developed world, dietary restrictions are becoming more and more important. Especially the cutoff values for iron deficiency anemia might differ in this situation, since ferritin is an acute-phase protein [13].

Anemia of Chronic Disease

Most of the iron that is stored in the body is incorporated into hemoglobin in developing erythroid precursor cells and mature RBCs. In contrast to patients with nutritional deficiency anemia, patients with anemia of chronic disease do not have depleted iron stores but lack the ability to utilize the iron which is theoretically available in the body. The key player of iron hemostasis in this situation is the hormone hepcidin. It is encoded by the HAMP gene and is the key regulator of iron metabolism in mammalian cells. Hepcidin inhibits iron absorption and transport by binding to the iron export channel ferroportin that is located on the basolateral surface of gut enterocytes and the plasma membrane of reticuloendothelial cells. Furthermore, hepcidin breaks down the transporter protein in the lysosome [14]. As long as ferroportin is inhibited, iron export from the cells is impossible, resulting in a situation which prevents iron from being released to the blood stream and results in sequestration of iron in the cells [15]. During sepsis proinflammatory cytokines like IFN-γ, TNFα, IL-1β, and IL-6 induce the release of hepcidin, and as a consequence erythropoiesis is reduced due to lack of available serum iron, although theoretically enough iron is stored in the cells [16]. Beyond that the inflammatory cytokines also inhibit erythropoietin release from the kidneys and erythroid proliferation in the bone marrow further reducing erythropoiesis.

Additionally, the release of inflammatory cytokines leads to activation of RBC destruction by macrophages, which not only decreases the absolute number of RBCs but also reduces RBC life span. Several studies were able to demonstrate that iron status as well as erythropoiesis are altered in non-bleeding ICU patients who are post-surgery, trauma, or are septic [17]. However, one has to be aware of the fact that anemia of chronic disease might be accompanied by other forms of anemia and that can be complicated making the diagnosis of complex anemia challenging.

Anemia Due to Increased Red Blood Cell Breakdown

There is a huge amount of hematological diseases that might result in increased red blood cell breakdown; however, the most important reasons for hemolytic anemia at the ICU are immune hemolytic anemias. Two different mechanisms are responsible for immune hemolytic anemias: [1] there is a true autoantibody directed against a red cell antigen, i.e., a molecule present on the surface of red cells, or [2] there is an antibody directed against a certain molecule (e.g., a drug). If that antibody reacts with that molecule, red cells may get caught in the reaction, whereby they are damaged and/or destroyed.

While the first pathophysiology is mainly treated by hematologists and is seldomly an acute problem at the ICU, the second one is quite often induced by different medications that can lead to anemia by causing hemolysis via this immunologic pathway. Although drug-induced hemolytic anemia is relatively rare, serious adverse effect of therapeutic medications might play a role in the ICU under specific circumstances. The three most often identified medications as causing drug-induced hemolytic anemia are piperacillin, cefotetan, and ceftriaxone [18]. The most important modality to treat drug-induced anemia is the immediate withdrawal of these agents. However, since ICU patients are treated with a multitude of different medications, it is sometimes quite challenging to discover which medication should be omitted in order to stop or prevent hemolysis.

Anemia and Hemoglobinopathies in the Critically Ill

Hemoglobinopathies are disorders affecting the structure, function, or production of hemoglobin. These conditions are usually inherited and range in severity from asymptomatic laboratory abnormalities to death in utero. With approximately 7% of the worldwide population being carriers, hemoglobinopathies are the most common monogenic diseases and one of the world’s major health problems. They were originally found mainly in the Mediterranean area and large parts of Asia and Africa. International migration has spread them from those areas all over the world, and therefore they can be found in many ICUs mainly in large cities. Today, in many parts of Europe and the USA, hemoglobin (Hb) defects are classified as endemic diseases [19]. The most clinically relevant variant hemoglobins polymerize abnormally, as in sickle cell disease or exhibit altered solubility or oxygen-binding affinity. There are five major classes of hemoglobinopathies: [1] structural hemoglobinopathies (i.e., hemoglobins with altered amino sequences like, e.g., sickle cell disease), [2] thalassemias, [3] thalassemic hemoglobin variants (structurally abnormal Hb associated with coinherited thalassemic phenotype), [4] structurally abnormal Hb associated with coinherited thalassemic phenotype, and [5] acquired hemoglobinopathies. Thalassemias are the most common genetic disorders in the world, affecting nearly 200 million people worldwide underlining the relevance of this type of anemia.

The most important diagnostic tool for the detection of hemoglobinopathies is electrophoretic techniques, although it is not always conclusive since some significant variants of hemoglobinopathies (such as some variants of thalassemia) are electrophoretically silent. In these cases, the mutant hemoglobins can usually be detected by mass spectroscopy, which is gaining more traction as the standard diagnostic test.

Since hemoglobinopathies are prevalent and complex in both diagnosis and management, a detailed description is beyond this book chapter. Consultation with a hematologist should be always considered if microcytic hypochromic anemia is detected after iron deficiency has been ruled out, chronic hemolytic anemia has been diagnosed, vascular obliteration crises of unclear etiology in patients from areas in which HbS and/or HbC is widespread occur, drug-induced anemia is considered, and erythrocytosis and cyanosis caused by hematological factors are seen. Generalized hemoglobin electrophoresis for all cases of anemia cannot be justified on the basis of expediency or financial considerations, particularly in those with no background of migration [19].

Evaluation and Treatment

Evaluation

Anemia is easily diagnosed by the determination of the hemoglobin concentration (Hb) or the hematocrit (hct). However, the solely diagnosis of anemia yields no information about the causes of anemia or the underlying disease. Several algorithms have been developed for the differential diagnosis of different types of anemia. However, most of them aim at the diagnosis of anemia of ambulatory patients and are therefore are not very helpful for patients that have been admitted to the ICU.

In daily clinical practice, typically two different types of anemia may occur: [1] either a patient is suffering from significant blood loss after trauma or surgery or due to occult bleeding or [2] a patient is anemic in the ICU with signs of severe anemia but without any signs of overt or occult blood losses. While in the first case diagnosis and treatment of anemia are relatively straightforward, the latter case requires an extensive and thoughtful workup of acute anemia.

Diagnosis of Anemia Due to Overt or Occult Bleeding

If the reason for anemia is overt or occult acute bleeding, the evaluation of anemia can be reduced to some very basic laboratory values. Acute blood loss is defined as a concurrent loss of plasma and red blood cells. Therefore, in the acute phase of bleeding and blood loss, the hemoglobin concentration will not necessarily decline; however, in all cases a decline of the hemoglobin concentration is seen either due to resorption from interstitial or intracellular fluid or due to the infusion of crystalloids or colloids in the further course of treatment. Taking this into account, it is an accepted practice that the hemoglobin concentration (Hb) or the hematocrit (hct), the parameters that are most often used for description and quantification of acute bleeding, is an inappropriate measure for the estimation of the severity of blood losses in the acute phase of bleeding but is very useful later on to determine the Hb deficit. It has been demonstrated that in many clinical scenarios, determination of lactate concentration, arterial base excess, pH, or lactate clearance is more useful for estimation of blood loss and prediction of mortality in this situation [20–22]. However, after termination of the acute phase of bleeding and subsequent restoration of the volume lost, the hemoglobin concentration is then used to determine the oxygen transport capacity of blood. Furthermore, in daily clinical practice, the hemoglobin concentration is the most common parameter for the indication of red blood cell (RBC) transfusions, although this single dimensional practice can result in substantial and unnecessary transfusions in many clinical situations [3, 4, 23].

Diagnosis of Anemia in Patients Without Overt or Occult Bleeding

Diagnosis of anemia in patients without overt or occult bleeding is much more difficult than in the group of patients described above. In this situation, the hemoglobin concentration or the hematocrit is the key parameter to help in diagnosing the evolving anemia. However, since the reason for anemia is unknown in this setting, further tests are needed for a proper workup of anemia in this situation. First, efforts should focus on ruling out any cause of bleeding not considered so far. Typically, patients in the ICU suffer from occult GI bleeding, a pathophysiology that should be diagnosed by gastroscopy or colonoscopy. Furthermore, chest tubes and drains give a hint for occult bleeding, although even drainage of the operation site is not necessarily a useful parameter for the exclusion of occult bleeding. Sometimes computer tomography can help in identifying the source of bleeding.

In order to determine the type of anemia in patients without overt or occult bleeding, a set of laboratory determination is used to diagnose the type of anemia.

Since more than 80 years, MCV has been the most used parameter to distinguish microcytic, normocytic, and macrocytic anemia [24]. Although MCHC played a major role in earlier times for differentiation of hypochromic, normochromic, or hyperchromic anemia, nowadays anemias are very seldomly classified using this parameter [25]. In addition to MCV, the reticulocyte count should be determined, which enables a classification of anemia by a kinetic approach [25]. The reticulocyte count is clinically important both for the pathophysiological classification of anemia (due to an inadequate production of erythrocytes by the bone marrow, in which case there is a decreased number of reticulocytes, or to an excessive loss or the destruction of erythrocytes, in which there is an increase in reticulocyte count) and for the early identification of the normalization of erythropoiesis by the bone marrow after therapeutic intervention (iron, cobalamin, folic acid, ESAs, etc.), after spontaneous or pharmacologically induced aplasia of the marrow, or following bone marrow transplantation. However, it has to be stated that the reticulocyte count should be determined using a modern analyzer, since manual counts of reticulocytes are prone to severe inaccuracies. The latest generation of hematology analyzers provides some reticulocyte indices analogous to the equivalent RBC indices. Among these, the most promising from a clinical point of view are the hemoglobin content of reticulocyte and the mean reticulocyte volume [25].

If anemia is present despite a lack of overt or occult bleeding, one should consider the potential prevalence of the different kinds of hemoglobinopathies described above. However, it has to be stated that generalized hemoglobin electrophoresis for all cases of anemia cannot be justified particularly in those with no background of migration. Therefore, knowledge about the local population prevalence of specific hemoglobinopathies is essential for tailored screening and diagnosis in these patients.

While anemia can occur as an expression and a side effect of many diseases, it may also result from pharmacological treatment. Unfortunately, there is no easy, specific diagnostic test that is evidentiary for medications being the cause of anemia in a specific patient. As a consequence, only a treatment-free interval can be used for the diagnosis of drug-induced anemia. In daily clinical practice, this is often impossible, and many patients leave the ICU without a clear proof for the tentative diagnosis of drug-induced anemia.

Probably the most important kind of anemia prevalent in ICUs is a hybrid form of iron deficiency anemia and anemia of chronic disease. The diagnosis of iron deficiency anemia typically focuses on two different laboratory values, the transferrin saturation and the ferritin level in the blood. However, no specific test confirms the diagnosis of IDA in all patients because serum ferritin may be falsely normalized/elevated and transferrin saturation may be reduced in inflammatory states. If the ferritin level is low, then the iron stores of the organism are thought to be depleted, but there are many clinical situations, especially in the postoperative phase where iron stores are depleted and the ferritin level is high. Therefore, a multitude of different ferritin levels have been published as cutoff for iron deficiency anemia [13].

Newer markers, such as serum transferrin receptor and reticulocyte hemoglobin (Hb) content, have been advocated as additional tools for the discrimination of iron deficiency/chronic disease anemia for a while. Serum transferrin receptor levels as a diagnostic tool for IDA are still a test that is infrequently available. In contrast, reticulocyte hemoglobin content is becoming ubiquitous but requires the clinician awareness of the test and a separate order [26]. Furthermore, measurements of serum hepcidin appear to be promising and worth pursuing in larger diagnostic and therapeutic trials [27], but hepcidin levels have not attained the level of a standard clinical tool [15]. In daily clinical practice, many physicians use mainly the Hb , the transferrin saturation, and the ferritin level together with the C-reactive protein to determine the presence of IDA [13].

Treatment

Iron and/or Erythropoietin Therapy

Although the transfusion of red blood cells seems to be the most common treatment modality for anemia in ICU patients, there are effective treatment modalities especially for patients with IDA or anemia of chronic disease that must be entertained. Since both types of anemia occur often in ICU patients, and the prevalence of both pathophysiologies overlaps often, iron and exogenous erythropoietin (EPO) as the standard treatment of this entity are administered regularly in this situation.

As described above the diagnosis of iron deficiency can be difficult in ICU patients, since the most important laboratory parameter for iron deficiency, the ferritin concentration, is elevated in inflammatory states. Despite this diagnostic obstacle, iron is regularly used in daily clinical practice in ICU patients. Although it has been demonstrated that per os (oral) iron can reduce the likelihood of RBC transfusion [28], it has to be stated that nowadays typically intravenous application of iron is the standard route of administration especially for the stressed ICU patient. However, the results for the efficacy of intravenous iron are mixed. In trauma patients it has been demonstrated that the application of intravenous iron reduced the number of RBC transfusions [29], whereas in a very similar study, this effect has not been confirmed [30]. However, taking a look at the most recent meta-analysis, it has to be stated that although not being significant all outcomes are in favor of the application of iron [31].

It has been argued that iron, especially intravenous preparation, might significantly increase the risk of postoperative infections. Although the underlying mechanisms are very plausible, in daily clinical practice, this phenomenon seems to play a minor role. Two large meta-analyses performed could not demonstrate an increase of postoperative infection rates [32, 33]. Furthermore, a transfusion of one pack RBCs results in an addition of heme iron (not present in commercial preparations) content of 200 mg, a different iron modality that may be associated with increased postoperative infectious risks [34].

Nowadays erythropoietin is used seldomly in the ICU. The first study that described EPO usage in the ICU with the aim to reduce perioperative transfusion needs has been published by Corwin in 2007 [35]. Although this study failed in terms of the main outcome parameter (transfusion), it could be clearly demonstrated that some secondary outcome parameters were significantly better in the treatment group. Especially, survival was significantly better in the EPO group. Since EPO is thought to increase the risk for perioperative thrombosis, the interest in this compound diminished over the years for this indication, although it has been demonstrated that EPO obviously has no negative short-term effects on survival [36, 37].

There are also some other deficiencies that might result in anemia, e.g., folate deficiency, or Vit-B12 deficiency, etc. Recently, Rodriguez and colleagues reported iron deficiency in 9% of ICU patients; 2% of the patients were deficient in vitamin B12, and another 2% suffered from folic acid deficiency [38]. However, whether proper treatment of these pathologies results in a reduction of the transfusion rate during the ICU stay remains unknown.

Transfusion of Red Blood Cells

It has been demonstrated by many different investigators that anemic patients in the ICU suffer from high morbidity and mortality [39]; nevertheless this problem is often severely under-recognized [40, 41]. Since the quality of blood component has reached a high level in the last few years, it seems obvious that a low hemoglobin concentration can be easily treated by the transfusion of red blood cells [42]. However, the risks of transfusion still remain despite the quality [43], and the desired effects of blood transfusions on oxygen transport and tissue oxygenation are less predictable than expected. It has been demonstrated by a meta-analysis that the transfusion of one pack of red blood cells increases the hemoglobin concentration and by that oxygen carrying capacity in all cases but regularly fails to increase oxygen delivery and oxygen consumption resulting in a disputable risk/benefit ratio for transfusion [44]. The reason for this phenomenon might be an increase of blood viscosity that is induced by the transfusion of a single and multiple packs of RBCs, resulting in a decrease blood flow and a decrease of regional oxygen delivery [45]. Taking into account the low efficacy of blood transfusion on the one hand and the risks of transfusion on the other, one has to concur that the trade-off of transfusion versus anemia is difficult to judge. As a consequence, many clinical studies have investigated the effects of a restrictive transfusion regime (accepting lower hemoglobin values and sparing RBC transfusions) versus a liberal transfusion regime (with higher hemoglobin values but more RBC transfusions). The first of these studies has been published by Hebert and coworkers in 1999 [46]. In this landmark paper, they demonstrated that a restrictive transfusion regime is as safe as a liberal one, with the advantage that less resources are needed, and as a consequence, the costs for treatment were clearly lower. Similar experiments have been performed in the following years, with the focus set to more patient populations at the ICU.

The FOCUS trial demonstrated that a restrictive and a liberal transfusion regime are equivalent for patients with cardiac risk factors undergoing total hip replacement [47, 48]. The TRIS trial had a similar outcome in septic patients [49]. The TRACs and the TRICS-3 trial demonstrated that a restrictive transfusion regime is as safe as a liberal one in cardiac surgery patients [50, 51]. The first trial to demonstrate that a restrictive transfusion regime results in a lower mortality than a liberal transfusion regime has been published by Villanueva in patients with acute upper gastrointestinal bleeding [52].

The studies demonstrating the opposite are rare: one trial in oncologic surgery patients demonstrated superiority of a liberal transfusion regime [53], and the same result has been obtained for patients with symptomatic coronary artery disease in an inconclusive pilot study [43, 54]. While in the second case the pathophysiological reasons are obvious, the mechanism for improved outcome in the first case remains incomprehensibly.

In patients with hemoglobinopathies, transfusion of red blood cells is often the only possible therapeutic modality [55], although the efficacy of this measure is questionable for some of the indications [56]. However, even if some of the symptoms of many different hemoglobinopathies can be reduced by the transfusion of red blood cells, it has to be stated that these often recurring transfusions are associated with significant adverse events [57].

A very recent Cochrane analysis sums up the evidence for the comparison of a restrictive and a liberal transfusion regime. Transfusing at a restrictive hemoglobin concentration of between 7 and 8 g/dL decreased the proportion of participants exposed to RBC transfusion, while there was no evidence that a restrictive transfusion strategy impacts 30-day mortality or morbidity (i.e., mortality at other points, cardiac events, myocardial infarction, stroke, pneumonia, thromboembolism, infection) compared with a liberal transfusion strategy [58].

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© Springer International Publishing AG, part of Springer Nature 2018

Aryeh Shander and Howard L. Corwin (eds.)Hematologic Challenges in the Critically Illhttps://doi.org/10.1007/978-3-319-93572-0_2

2. Hemostatic Abnormalities in the Critically Ill

Michelle Sholzberg¹, ²  

(1)

Departments of Medicine and Laboratory Medicine and Pathobiology, St. Michael’s Hospital, Toronto, ON, Canada

(2)

University of Toronto, Toronto, ON, Canada

Michelle Sholzberg

Email: sholzbergm@smh.ca

Keywords

HemostasisThrombocytopeniaCoagulopathyBleedingClottingTransfusionThrombotic microangiopathyDICTTPHUSHIT

Pathophysiology of Hemostatic Abnormalities in the Critically Ill

Hemostasis involves a series of physiologic events that lead to the formation of a strong and appropriately designed blood clot to stop bleeding. Hemostasis is triggered by endothelial damage. The platelet plug forms with the help of von Willebrand factor and fibrinogen, and this phase is called primary hemostasis. Secondary hemostasis results in fibrin formation which occurs very delicately on the surface of activated platelets; clot stabilizers then strengthen the clot both structurally and by sheltering the clot from early fibrinolytic degradation.

We are evolutionarily designed to boost the release of acute-phase reactants in the face of acute systemic stress, and many acute-phase reactants are involved in hemostasis. Therefore, an appropriate, regulated response to sympathetic nervous system activation is a balanced pro-hemostatic one which protects us from potential hemorrhagic death [1, 2]. When the response is inadequate, dysregulated, or disorganized, the pro-hemostatic compensation is lost, and the patient is at risk for bleeding and/or thromboembolism [3, 4].

The patients in the hospital at highest risk for hemostatic complications are those admitted to the intensive care unit (ICU), and ICU patients with hemostatic abnormalities have a higher risk of death [5–7]. To understand hemostatic abnormalities associated with critical illness, we must first appreciate that nearly all coagulation factors involved in secondary hemostasis are made in the liver (with the notable exception of factor VIII which is also made by the endothelium), that platelets arise from megakaryocytes in the bone marrow, and that an increasing proportion of patients admitted to the ICU will be on some antithrombotic medication given the increase in therapeutic indications and prevalence of age-related conditions requiring anticoagulation. Nearly all hemostatic abnormalities encountered in ICU patients are acquired and can be divided into the following categories: (1) deficiencies of coagulation factors and platelets and (2) inhibition or dysfunction of coagulation factors and platelet function.

Deficiencies of Coagulation Factors and Platelets

Deficiencies in coagulation factors are mostly caused by diminished or altered hepatic synthesis, massive consumption, and/or loss. Impaired synthesis of clotting factors in the liver occur in the context of liver failure or vitamin K deficiency which interferes with the appropriate activation (gamma carboxylation) of vitamin K-dependent coagulation factors (II, VII, IX, X, protein C, and protein S). Vitamin K antagonists (e.g., warfarin) specifically interfere with the gamma carboxylation step, and when patients are on therapeutic doses of warfarin, their vitamin K-dependent clotting factor activity ranges between 20% and 40% of normal. Risk factors for vitamin K deficiency include chronic antibiotic use, malnutrition, and cholestasis – all of which can occur in patients admitted to the ICU.

Liver dysfunction is a relatively common occurrence in this patient population and can be due to acute infection, hypoperfusion, medication effect, or direct injury. Liver dysfunction can be differentiated from vitamin K deficiency by assessment of non-vitamin K-dependent clotting factor activity (e.g., factor V), and if normal then vitamin K deficiency is suggested [8]. One should expect to first detect diminished activity of the clotting factor with the shortest half-life (i.e., factor VII) in vitamin K deficiency since its activity and ability to accumulate will be affected earliest. Almost all coagulation factors are produced in the liver; therefore acute organ failure commonly results in diminished production of many coagulation factors, with the exception of factor VIII since it is also made by the endothelium. Thrombocytopenia is also a feature of liver disease due to decreased thrombopoietin production and release.

Massive losses of coagulation factors and platelets can occur during and after massive hemorrhage in surgical patients or in those who have experienced major trauma. Cold temperature, acidosis, and rapid, dilutional intravascular volume replacement with crystalloids, colloids, and red blood cells will aggravate the bleeding tendency. Furthermore, surgical causes for bleeding and acute coagulopathy of trauma, a hypocoagulable and hyperfibrinolytic state thought to be triggered by systemic activation of protein C, may contribute. Consumption due to disseminated intravascular coagulation (DIC ), the most common thrombotic microangiopathy, may also contribute to the bleeding tendency. DIC can be differentiated from liver disease by diminished or inappropriately normal factor VIII as factor VIII is expected to rise with acute illness (in the absence of DIC) since it is an acute-phase reactant. DIC will be discussed in detail later in this chapter.

Thrombocytopenia is a common occurrence in patients admitted to the ICU with a reported prevalence at the time of admission between 8.3% and 67.6% [9, 10]. The incidence of thrombocytopenia during the ICU admission is between 14% and 44% [9, 10]. Factors associated with thrombocytopenia in the ICU patient include illness severity, organ dysfunction, sepsis, vasopressor use, and acute kidney injury [9, 11]. Sustained, severe thrombocytopenia is associated with prolonged ICU stay and mortality [6, 7, 9, 12–20]. Thrombocytopenia of any severity also appears to associate with bleeding and transfusion risk [9, 11, 21, 22], while recovery of the platelet count in the critically ill is positively correlated with survival [7].

There are many contributing mechanisms to thrombocytopenia in the critically ill, and the exact mechanisms remain incompletely understood. Thrombocytopenia typically occurs on the basis of consumption from bleeding and/or platelet activation/adhesion/aggregation, presumed diminished production from bone marrow suppression or insult (although never critically evaluated/proven), increased destruction from directed clearance or toxicity, dilution in the context of resuscitation, or any combination thereof.

Thrombocytopenia from consumption in critically ill patients is by far the most common cause and therefore warrants additional discussion. Consumption was classically thought to be due solely to thrombin-medicated platelet activation, but novel mechanisms involving excessive platelet adhesion and aggregation from high von Willebrand factor (and diminished ADAMTS13), histone release, hemophagocytosis, and complement activation have been described [23, 24]. In fact, the mechanisms involved in thrombocytopenia associated with sepsis are multiple and probably interactive, but the relative contribution of each mechanism may vary per patient and even within a given patient over time. Moreover, in patients with septic shock with thrombocytopenia, platelet count recovery typically occurs several days after vasopressor independence [25].

Thrombocytopenia commonly accompanies deficiencies of coagulation factors, and therefore their co-occurrence may not be particularly helpful in narrowing the differential diagnosis; thus thrombocytopenia must always be analyzed in the clinical context to clarify the underlying pathophysiologic mechanism. There are certain clues however that may help identify a cause of thrombocytopenia in the critically ill, and these are described in Fig. 2.1. See Table 2.1 for the approach to the differential diagnosis of thrombocytopenia in the ICU.

Fig. 2.1

Clues for the diagnosis of thrombocytopenia in critically ill patients. ITP immune thrombocytopenia, HIT heparin-induced thrombocytopenia, PTP posttransfusion purpura. PT prothrombin time. aPTT activated partial thromboplastin time. DIC disseminated intravascular coagulation [27]. (Used with permission)

Table 2.1

Mechanisms of thrombocytopenia in the critically ill [27]

Used with permission

It is worthy of mention that platelets and coagulation factors have roles beyond hemostasis and thrombosis, and this is particularly relevant in the patient with sepsis and/or compromised tissue integrity. In fact, platelets are now recognized as critical players of the innate immune response; they contribute to inflammation, microorganism attack, and tissue repair [28–33]. Coagulation factors and platelets often contribute to both vascular and tissue injury via inflammation while also contributing to resolution of inflammation and repair (see Fig. 2.2). These opposing (and sometime concurrent) actions of the hemostatic systems in relation to the endothelium have been extensively described and are thought to be related to complications of sepsis in particular [30, 34, 35].

Fig. 2.2

Platelets are integral players in the immune response , linking hemostasis, thrombosis, inflammation, pathogen clearance, and tissue repair: a schematic representation. A growing body of evidence highlights a role for platelets beyond the confines of hemostasis and thrombosis. Some of platelet interfaces in innate immune response are schematized. Platelets are activated at sites of infection/tissue injury. Platelets and platelet-derived mediators contribute to arrest bleeding, to clear pathogens directly or indirectly by acting on various steps of the immune response, and to drive vascular/tissue repair by providing matrix building blocks and a multiplicity of signals that remodel matrix, attracting tissue progenitor cells and reconstructing the vascular frame. In doing so, platelets provide a coherent biological response contributing to cure infection and reestablish tissue architecture and homoeostasis. Scales are arbitrary. Platelet-derived microparticles (PMPs) recapitulate several of activated platelet functions. ECM extracellular matrix, MN monocytes, PMN polymorphonuclear neutrophils, MΦ macrophages [36]. (Used under Creative Commons license)

Pharmacologic Inhibition of Coagulation Factors and Platelet Function

Coagulation factors can be inhibited either directly or indirectly by anticoagulants. Heparins (unfractionated and low molecular weight heparins) are indirect anticoagulants as they exert their function by enhancing the natural inhibitory activity of endogenous antithrombin. Antithrombin is an inhibitor of serine proteases which account for nearly all coagulation factors. Antithrombin, however, preferentially inhibits activated factor X and II, and in doing so it disables the rate-limiting and final effector enzymes of secondary hemostasis (i.e., formation of the insoluble fibrin clot). Heparins convert antithrombin from a slow to a rapid inhibitor; therefore, they make antithrombin more efficient at what it does naturally.

Direct inhibitors however do not require an intermediary to facilitate their anticoagulant effect. Instead, they directly inhibit clotting factors. Argatroban, bivalirudin, hirudin, and dabigatran directly inhibit factor IIa, while rivaroxaban, apixaban, and edoxaban directly inhibit factor Xa. While warfarin is an anticoagulant, it is not an inhibitor. Instead it results in the deficiency of vitamin K-dependent clotting factor activity (factors II, VII, IX, X, proteins C, and S).

Platelet function can also be inhibited by directed pharmacotherapy. There are many different drugs that target different platelet function pathways , and they are listed in Fig. 2.3. Inhibitors of coagulation whether involving the platelet or the coagulation factors often contribute to the bleeding phenotype in critically ill patients, particularly given the expanding indications for antithrombotic therapy and the rising prevalence of conditions requiring antithrombotic therapy in the aging population.

Fig. 2.3

Antiplatelet therapy targets [37]. (Used with permission)

Thrombotic Microangiopathy

Thrombotic microangiopathies (TMAs) are a constellation of disorders that are characterized by micro- or macro-vasculopathy and are often accompanied by microangiopathic hemolytic anemia and thrombocytopenia. Organ dysfunction due to ischemia is characteristic of TMAs and can occur to the brain, kidneys, heart, pancreas, liver, lungs, eyes, and even skin [38]. Relatively common etiologies of TMA in the ICU patient include disseminated intravascular coagulation (DIC), sepsis, malignant hypertension, TMA of pregnancy, thrombotic thrombocytopenic purpura (TTP), hemolytic uremic syndrome (HUS), atypical hemolytic uremic syndrome (aHUS), drug-induced TMA, and cancer-associated TMA. The most common TMA is DIC [39]. ADAMTS13, complement biomarkers, and coagulation testing provide important information as they will rule out TTP and suggest HUS or DIC, respectively. General diagnostic tests required in patients with suspected TMA include the following: complete blood count, peripheral blood film, reticulocyte count, lactate dehydrogenase, haptoglobin, bilirubin, activated partial thromboplastin time, prothrombin time, and fibrinogen. Tests to assess for the presence of secondary organ damage could include the following: serum electrolytes, creatinine, urinalysis, liver function, troponin, electrocardiogram, lactic acid, lipase or amylase, and brain imaging studies. The remainder of testing should be guided by features specific to the patient (e.g., beta-human chorionic gonadotropin) or by the suspected specific type of underlying TMA (e.g., ADAMTS13). Care of non-TTP