Authors: Payal Bhandari M.D., Hailey Chin, Madison Granados 

Contributors: Vivi Chador, Amer Džanković, Emilia Feria, Nigella Umali Ruguian 

Key Insights

Blood contains red blood cells (RBCs), white blood cells (WBCs), and platelets. RBCs transport oxygen via hemoglobin, WBCs defend against infections and maintain immune balance, and platelets prevent blood loss by forming clots and aiding tissue repair . 

Figure 1: Blood is divided into three parts: 55% is plasma, which comprises of water (93%), salts, proteins, lipids, and glucose; 45% are red blood cells; and 1% are WBCs and platelets. 

What are the Hemoglobin and Hematocrit Blood Tests? 

Hemoglobin

The Hgb test measures the amount of hemoglobin in RBCs and helps estimate how much oxygen is reaching the body’s tissues. Hgb is a protein found only in RBCs, making up 96-97% of their dry weight and giving blood its bright red color. The most common type of hemoglobin is Hgb A. Figure 2 illustrates the makeup of an element of Hemoglobin.

Figure 2: Hemoglobin structure. 

Hemoglobin (Hgb) consists of two alpha and two beta globin chains, each with a heme group containing an iron atom (Fe²⁺). With help from vitamins B12 and B9 (folate), oxygen binds to the iron, forming oxyhemoglobin. Each Hgb molecule can carry up to four oxygen molecules. Vitamin B9 and B12 are regulated by the stomach, while iron is absorbed in the small intestine.

Hematocrit

The Hematocrit test, also known as a packed cell volume (PCV) test, measures the total amount of RBCs in the blood sample and provides vital information about the transport of oxygen in relation to the whole blood volume. This test involves collecting a blood sample and centrifuging it to separate its components. The heavier red blood cells (RBCs) settle at the bottom, while the lighter plasma rises to the top. The hematocrit percentage is determined by comparing the volume of RBCs to the total blood sample4. Measuring Hct helps identify polycythemia (high RBC) and anemia (low RBC) to aid in disease detection, guiding treatment, and management. 

Role of Hemoglobin

RBCs transport O₂ from the lungs to tissues and remove CO₂ during exhalation. Hgb carries most of the oxygen, as only a small amount dissolves in plasma. RBCs use O₂, H, and CO₂ for energy production through cellular respiration.

As RBCs develop in the bone marrow, they produce their own Hgb. RBCs lack a nucleus or mitochondria, creating more space for Hgb and preventing oxygen from being delivered to tissues. Once in the bloodstream, the Hgb content of RBCs remains constant throughout their lifespan.

Figure 3:  RBCs main job is to carry O2 to tissue and release the waste product, CO2 during exhalation. RBCs contain around 640 million Hgb molecules per cell. 

Figure 4: 98% to 99% of oxygen in the blood binds to Hgb in red blood cells and is transported to tissue throughout the body.

Regulation of Hemoglobin and Hematocrit 

The production of Hgb and RBCs is regulated by the body’s ability to produce energy (ATP) through cellular respiration.

Figure 5: Cellular respiration is a series of chemical reactions that convert energy from food (originally from plants through photosynthesis) into high-energy molecules like ATP (adenosine triphosphate), NADH, and FADH. These reactions also produce carbon dioxide (CO₂) as a waste product, which is exhaled by the lungs. This process happens in three main stages: glycolysis, the Krebs cycle, and the electron transport chain, with most energy (34 ATP) being made in the mitochondria during the electron transport chain.

The body typically produces ATP from glucose through glycolysis. In low-energy states like fasting, intense exercise, or diabetes, it uses ketogenesis, breaking down stored fats and proteins into amino acids, lactic acid, and glycerol. Since the brain cannot use fat directly, glycerol is converted into glucose to meet its energy needs. 

Figure 6: Circadian rhythm (sleep-wake cycle) genes control the production of glucose and ketones in the liver to create energy (ATP). This is done by breaking down fatty acids, amino acids, glycerol, and other materials in fat cells (adipocytes), the liver, and skeletal muscles. Ketones provide energy during fasting, intense exercise, low insulin, or high brain energy demands. Ketogenesis produces more ATP (34) than glucose (2-4), stabilizing blood sugar, improving insulin sensitivity, and reducing carb dependence. It can lower hunger, stabilize mood, reduce hormonal imbalances, and decrease inflammation from oxidative stress.

The attachment of sugar molecules to the beta chains of Hgb affects its stability and its ability to deliver oxygen efficiently to tissues 11-12  . When more glucose and other sugars attach to Hgb, it reduces the ability of RBCs to carry oxygen. This lowers energy production and increases levels of harmful molecules called reactive oxygen species (ROS). This condition, known as hypoxia, allows ROS to damage RBC membranes (hemolysis), releasing free Hgb into the bloodstream and leading to higher Hgb levels on a blood test 7. 

When hypoxia causes RBC damage (hemolysis), the kidneys respond by producing the hormone erythropoietin (EPO). EPO signals the bone marrow to create more RBCs and Hgb, leading to higher Hct levels in the blood.

However, if hypoxia-induced hemolysis continues untreated, the reactive oxygen species (ROS) can damage the kidneys. This damage lowers EPO production, reducing RBC and Hb production in the bone marrow. As a result, both Hct and Hgb levels decrease over time. 

Clinical Significance of Low Hemoglobin and Hematocrit Levels

Low hemoglobin (Hgb) and hematocrit (Hct) levels, known as anemia, can result from reduced RBC production in the bone marrow (true anemia) or increased plasma volume, which dilutes RBC concentration (relative anemia).

Dehydration thickens the blood, reducing oxygen delivery and energy production while damaging cells . Dehydration thickens the blood, reducing oxygen delivery and energy production while damaging cells. Water loss causes RBCs to shrink, impairing oxygen transport and leading to hypoxia. The brain detects this and triggers thirst and the release of vasopressin to conserve water. Despite these efforts, dehydration harms RBCs and disrupts energy production. Severe drops in blood oxygen levels suppress the liver enzyme ALA synthase, slowing heme production, a vital component of Hgb. This reduces Hgb and Hct levels, further impairing oxygen transport .       

Figure 7: Effects of water osmosis on the integrity and function of blood cells. Osmosis moves water across cell membranes based on solute concentration. In a hypotonic solution, water flows into the cell. In an isotonic solution, water moves in and out equally. In a hypertonic solution, water leaves the cell.

Dehydration temporarily raising the Hb and Hct levels can occur due to the following mechanisms24:

• burns 

• diarrhea 

• excessive use of diuretics or laxatives 

• sweating from strenuous exercise or heat stroke 

• inadequate water intake

• inadequate breast milk consumption in newborns

• excess blood loss due to:

• heavy menstrual cycle 

• excess tissue injury associated with chronic inflammation (e.g., inflammatory bowel disease, ulcerative colitis, stomach ulcers, celiac disease, cancer), surgery, or trauma

• excess blood donation, such as in blood draws

Anemia of chronic inflammation (ACI) is associated with decreased Hgb and RBC production. This often happens because chronic dehydration interferes with food digestion, nutrient absorption, and the removal of cellular waste. The resulting anemia triggers a chain of reactions in the body: 

1. Excess undigested food particles like proteins, glucose, and fats, along with toxins in the bloodstream, thicken the blood, reducing oxygen delivery to tissues.

2. Cells die prematurely. 

3. White blood cells, platelets, and smooth muscle cells repair wounds and form new blood vessels through angiogenesis. This trauma response, called atherosclerosis, produces reactive oxygen species (ROS) and inflammatory proteins, reducing arterial blood flow, raising blood pressure, and causing blood to back up into organs, leading to enlargement and dysfunction. 

4. Chronic inflammation disrupts immune function, redirecting nutrients from fighting infections to tissue repair. White blood cells may produce antibodies that attack the body, causing autoimmune disorders. Dormant pathogens can activate, leading to infections and cancer growth.

Figure 8: Atherosclerosis causes artery walls to thicken as fat, plaque, and oxidized LDL cholesterol build up, with platelets forming clots. 

Figure 9: Anemia of chronic inflammation increases the activity of white blood cells (leukocytes) and platelets (thrombocytes), which collaborate with pathogens and tumor cells to prevent excessive bleeding and aid in wound repair. Platelets recruit tumor cells and pathogens to absorb free hemin and iron, helping them grow and spread. Neutrophils help stabilize blood vessel integrity by releasing proinflammatory proteins,27 activating platelets through tumor cells,  and promoting new blood vessel formation (angiogenesis). At the same time, natural killer (NK) cells are blocked from destroying tumor cells and pathogens. This allows pathogens to release toxins that damage red blood cells, steal nutrients like iron and oxygen from organs, and contribute to infections and tumor growth. 

Clinical Significance of High Hemoglobin and Hematocrit Levels

High Hgb and Hct levels indicate polycythemia. True polycythemia occurs when the bone marrow overproduces RBCs, while relative polycythemia results from decreased plasma volume, often due to dehydration, temporarily raising Hct levels.

Thicker blood in polycythemia reduces oxygen delivery (hypoxia) and shortens RBC lifespans (hemolysis). RBC breakdown releases toxic byproducts like free Hgb and iron, triggering inflammation. White blood cells remove toxins, while platelets and smooth muscle cells repair tissues. Low oxygen levels cause the kidneys to release hormones like EPO, stimulating the bone marrow to produce more RBCs, platelets, and WBCs, increasing Hct levels . 

Figure 10: Polycythemia (excess red blood cell production by the bone marrow)

Figure 11: RBC destruction, or hemolysis, involves quickly removing toxic byproducts like free Hgb and iron from the bloodstream and transporting them to the liver. Transporter proteins like haptoglobin and hemopexin bind to hemoglobin and heme, allowing macrophages in the liver and spleen to engulf them33. Heme is broken down by heme oxygenase, releasing iron, which is stored in ferritin or transported by ferroportin to organs like the pancreas, bone marrow, and muscles . Heme is converted to bilirubin in the liver and excreted in bile, stool, or urine. The liver recycles globulin for protein production. Hemolysis increases hepcidin and ferritin levels, which block ferroportin, limiting iron release and absorption. Excess iron storage can cause hemochromatosis, while reduced oxygen levels can oxidize LDL cholesterol, contributing to atherosclerosis . 

Platelets are vital for wound repair and preventing bleeding. Despite chronic hemolysis reducing RBC and platelet production, platelets form when blood flow shears parts of megakaryocytes (MKs) in the bone marrow. In chronic inflammation, MKs escape the bone marrow, travel to low-oxygen areas in the lungs, and form active platelets, which clot RBCs and aid vessel repair. To manage this, the lungs produce thrombopoietin (TPO) to destroy circulating MKs, reducing platelets and increasing RBC breakdown.

Figure 12: Hypoxia-induced red blood cell (RBC) destruction triggers the liver and kidneys to produce hormones that boost RBC and platelet production in the bone marrow. However, if the underlying cause of the destruction isn’t resolved, ongoing tissue damage in various organs leads to increased RBC and platelet breakdown.The kidneys produce erythropoietin (EPO), while the liver produces thrombopoietin (TPO) and colony-forming unit (CFU-meg). These hormones stimulate the production of red blood cells (RBCs) and megakaryocytes (MKs), respectively.. Anemia of chronic inflammation damages kidney and liver cells, reducing the hormones needed to make RBCs and platelets. Sometimes, whole megakaryocytes (MKs) escape the bone marrow and settle in the lungs, where low oxygen levels keep them from turning into platelets. During high-stress times, when oxygen levels in the lungs rise, these MKs are activated and converted into platelets . To prevent excessive tissue damage, the lungs produce thrombopoietin (TPO) and CFU-meg, which bind to and destroy circulating megakaryocytes (MKs), reducing platelet production in the bone marrow. 

Prevalence and Statistics on Abnormal Hemoglobin and Hematocrit Levels

High levels of hemoglobin (Hgb) and hematocrit (Hct) indicate polycythemia, a condition affecting 44 to 57 per 100,000 people in the U.S., mostly those over 60. Younger individuals have a much lower risk. Polycythemia can be primary (polycythemia vera, PV) or secondary, often due to chronic hypoxia. Most PV cases involve a JAK2 gene mutation (JAK2V617F), which increases red blood cell and platelet production.

Low levels of Hgb and Hct cause anemia, affecting one-third of the global population. Acute anemia is often due to blood loss or rapid RBC destruction, while chronic anemia is more common and can signal other health issues. Iron deficiency anemia, the most prevalent type, accounts for 50% of cases and results from blood loss, poor iron intake, absorption issues, or gastrointestinal bleeding.

Conclusion

Hct and Hgb levels are important for understanding overall health and are used to diagnose and manage many medical conditions. Hct measures the percentage of blood made up of RBCs, while Hgb shows how well these cells can carry oxygen. High Hct or Hgb levels may point to conditions like polycythemia vera or chronic lung and heart disease, while low levels can indicate anemia caused by chronic inflammation, low plasma volume, or problems with the bone marrow, kidneys, liver, spleen, or small intestine.

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