Hematology Physiology Amboss Q&A
A 16-year-old girl is brought to the emergency department because of lethargy and headache for the past 6 hours. Three days ago, she was started on dapsone and rifampin for the treatment of tuberculoid leprosy. Her pulse is 115/min and respirations are 12/min. Physical examination shows bluish discoloration of the lips and nail beds. A venous blood sample appears chocolate-colored and does not change color when exposed to oxygen. Compared to a healthy child, arterial blood gas analysis in this patient is most likely to show which of the following findings? %O2 saturation O2partial pressure O2content Hbconcentration A Normal normal increased increased B Normal normal decreased decreased CDecreased normal decreased normal DDecreased decreased decreased normal E Decreased normal decreased increased In a patient undergoing treatment with dapsone, tachycardia, respiratory depression, cyanosis, and chocolate-colored blood on venous sampling should raise suspicion for acute methemoglobinemia.
C %O2 sat O2partial pres O2content Hbconc CDecreased normal decreased normal Methemoglobinemia is caused by an abundance of methemoglobin, an altered form of hemoglobin in which ferrous iron (Fe2+) is oxidized to the ferric form (Fe3+). Since Fe3+ cannot bind oxygen, arterial O2 saturation and total O2 content decrease. This leads to functional anemia, despite normal hemoglobin concentrations. Patients with methemoglobinemia show clinical signs of cyanosis due to poor tissue oxygenation. O2 partial pressure (PaO2), which reflects the concentration of dissolved oxygen in plasma, is not affected. In patients prone to developing methemoglobinemia (e.g., patients with G6PD deficiency), oxidant drugs such as dapsone and topical anesthetic drugs should be avoided. Treatment consists of converting methemoglobin to hemoglobin by using reducing agents such as methylene blue and vitamin C.
An investigator is studying the changes that occur in the oxygen-hemoglobin dissociation curve of different types of hemoglobin under various conditions. The blood obtained from a male infant shows decreased affinity for 2,3-bisphosphoglyceric acid. Which of the following is the most likely composition of the hemoglobin molecule in this sample? A blood sample taken from a young infant is most likely to have mostly fetal hemoglobin (HbF).
α2γ2 The negatively charged 2,3-BPG binds to the central space between the two beta-globin chains of deoxygenated HbA1 (α2β2) by interacting with the positively charged basic amino acids lysine and histidine. In the gamma chain of HbF (α2γ2), the histidine residue is replaced by the neutral amino acid serine, which decreases affinity of HbF for 2,3-BPG. HbF is the major type of hemoglobin in-utero and during early infancy but by 6-12 months after birth, gamma globin synthesis is negligible and HbA1 (α2β2) becomes the major type of hemoglobin.
A 9-year-old boy is brought to the emergency department by his mother because of painful swelling in his right knee that started after he collided with another player during a soccer game. He has no history of serious illness except for an episode of prolonged bleeding following a tooth extraction a few months ago. Physical examination shows marked tenderness and swelling of the right knee joint. There are multiple bruises on the lower extremities in various stages of healing. Laboratory studies show a platelet count of 235,000/mm3, partial thromboplastin time of 78 seconds, prothrombin time of 14 seconds, and bleeding time of 4 minutes (N = 2-7). Which of the following steps in coagulation is most likely directly affected by this patient's condition? Combined with a history of abnormal bleeding and prolonged PTT, acute hemarthrosis following trauma likely indicates underlying he
Conversion of factor X The conversion of factor X to factor Xa can occur via two mechanisms: a complex formed of factor VIIa and tissue factor (extrinsic pathway), or a complex formed of factor VIIIa and IXa (intrinsic pathway). The extrinsic pathway is unaffected in this patient, as evidenced by the normal PT. However, hemophilia is characterized by a deficiency of factor VIII (hemophilia A) or a deficiency of factor IX (hemophilia B), both of which affect the intrinsic pathway, causing the prolonged PTT seen in this patient. While the conversion of factor X can still occur via the extrinsic pathway, the conversion of factor X by the intrinsic pathway will be impaired. A prolonged PTT with normal PT, bleeding time, and platelet count is typical of hemophilia.
A 63-year-old man comes to the physician because of an 8-month history of progressively worsening fatigue and shortness of breath on exertion. During this time, he has noticed blood in his stool on 5 separate occasions. Physical examination shows pale conjunctivae. His hemoglobin concentration is 8.9 g/dL and mean corpuscular volume is 65 μm3. Further analysis of this patient's arterial blood is most likely to show which of the following sets of findings? %O2saturation O2partial pressure O2content O2-Hb dissoc. curve A Normal normal normal normal B Decreased normal decreased left-shift C Normal normal increased normal DNormal normal decreased normal E Decreased decreased decreased right-shift This patient has chronic blood loss that has resulted in iron deficiency anemia, which can manifest with fatigue, pale conjunctivae, and microcytic anemia (decreased hemoglobin concentration and mean corpuscular volume).
D %O2sat O2part. press O2content O2-Hb dissoc. curve DNormal normal decreased normal Chronic blood loss (e.g., from gastrointestinal bleeding in this case) reduces serum concentrations of hemoglobin, as seen in this patient's arterial blood findings. O2 content in the blood is affected by hemoglobin concentration, PaO2, and SaO2 and will, therefore, be decreased in this case. PaO2 and SaO2 depend on the inhaled oxygen concentration, atmospheric pressure, and gas exchange in the lungs, none of which is affected by anemia. In addition, SaO2 depends on the affinity of hemoglobin for oxygen, which is affected by a number of factors, including body temperature, PaCO2, serum pH, and 2,3-BPG concentration; it is not affected by hemoglobin concentration. SaO2 and the O2-Hb dissociation curve will therefore be normal for this patient.
An investigator is studying the effects of tissue hypoxia on skeletal muscles. Skeletal muscle hypoxia is induced by decreasing oxygen delivery to peripheral tissues. Which of the following is most likely to achieve this desired effect? Oxygen delivery to the peripheral tissues decreases when hemoglobin binds more strongly to oxygen. This can be achieved if the oxygen-hemoglobin dissociation curve shifts to the left.
Decrease the serum 2,3-bisphosphoglycerate concentration A decrease in serum 2,3-bisphosphoglycerate (2,3-BPG) concentration decreases oxygen availability in the peripheral tissues. 2,3-BPG binds hemoglobin and stabilizes it in its low oxygen affinity state, which increases oxygen unloading. Therefore, decreased availability of this molecule will lead to less unloading of oxygen and induce tissue hypoxia. Other factors that shift the oxygen-hemoglobin dissociation curve to the left include decreased pCO2, increased pH, and decreased body temperature.
A 36-year-old woman is admitted to the hospital for the evaluation of progressive breathlessness. She has no history of major medical illness. Her temperature is 37°C (98.6°F), pulse is 115/min, and respirations are 22/min. Pulse oximetry on room air shows an oxygen saturation of 99%. Cardiac examination shows a loud S1 and S2. There is a grade 2/6 early systolic murmur best heard in the 2nd right intercostal space. Cardiac catheterization shows a mixed venous oxygen saturation of 55% (N = 65-70). Which of the following is the most likely cause of this patient's breathlessness? Mixed oxygen venous saturation (SvO2) is the oxygen saturation in the pulmonary artery. This is a measure of the oxygen content in the venous system compared to pulse oximetry, which is often used as a surrogate for arterial hemoglobin saturation (SaO2)
Decreased hemoglobin concentration Dyspnea, tachycardia, and evidence of hyperdynamic circulation (e.g., loud S1/S2, systolic ejection murmur due to increased blood flow) are features of severe anemia. In patients with anemia, the arterial partial pressure of oxygen (PaO2), which reflects dissolved oxygen content, and the arterial hemoglobin oxygen saturation (SaO2) remain normal. However, the total arterial oxygen content (CaO2), which is given by the formula [1.34 x SaO2 x hemoglobin concentration] + [0.003 x PaO2]), would be decreased because the total hemoglobin concentration is decreased. Therefore, the amount of oxygen delivered to tissues (DO2) is decreased and tissues extract more oxygen per gram of hemoglobin in order to meet the metabolic demands (VO2). This results in a decreased hemoglobin oxygen saturation in venous blood, which is measured by SvO2.
An otherwise healthy 23-year-old man comes to the physician because of a 3-day history of mild persistent bleeding from the site of a tooth extraction. He has no prior history of medical procedures or surgeries and no history of easy bruising. He appears well. Vital signs are within normal limits. Laboratory studies show: Hemoglobin 12.4 g/dL Platelets 200,000/mm3 Serum Prothrombin time25 seconds Partial thromboplastin time (activated) 35 seconds Deficiency of which of the following coagulation factors is the most likely cause of this patient's condition? The patient's elevated prothrombin time and normal partial thromboplastin time (activated) indicate a coagulation defect in the extrinsic pathway.
Factor VII Factor VII is the only coagulation factor listed here that is part of the extrinsic hemostatic pathway. The extrinsic pathway is activated by traumatic tissue injury, such as this patient's tooth extraction, which exposes tissue factor (factor III) located beneath the endothelium. Factor III then activates factor VII, forming a complex to trigger the common pathway by activating factor X. Hereditary factor VII deficiency is rare and is caused by a mutation of the F7 gene on chromosome 13. Factor VII deficiency presents with features similar to those of hemophilia (factor VIII or factor IX deficiency), such as bleeding following dental extraction and hemarthrosis. However, in patients with factor VII deficiency, the PT would be prolonged (due to an extrinsic pathway defect) and the aPTT would be normal. Conversely, in patients with hemophilia, the aPTT is prolonged (due to an intrinsic pathway defect) and the PT is normal.
A 7-year-old boy is brought to the physician for a follow-up examination after the removal of a tooth. During the procedure, he had prolonged bleeding that did not resolve with pressure and gauze packing and eventually required suture placement. His older brother had a similar episode a year ago, but his parents and two sisters have never had problems with prolonged bleeding. Physical examination shows no abnormalities. Genetic analysis confirms an X-linked recessive disorder. Which of the following is most likely deficient in this patient? This patient most likely has hemophilia A.
Factor VIII Hemophilias are hereditary disorders of secondary hemostasis that can manifest with prolonged bleeding after surgery (e.g., tooth extraction), hemarthrosis, and hematomas. Depending on the severity of clotting factor deficiency, bleeding may occur spontaneously or in response to trauma. Hemophilia A, which is caused by deficiency of factor VIII, and hemophilia B, which is caused by deficiency of factor IX, both follow an X-linked recessive pattern of inheritance. Since hemophilia A (∼ 80% of cases) is much more common than hemophilia B (∼ 20% of cases), this patient most likely has hemophilia A.
An 11-year-old boy is brought to the physician by his mother because of worsening fatigue. His mother reports that he seems to have trouble keeping up with his older brothers when playing outside. Physical examination shows conjunctival pallor. A hemoglobin electrophoresis is performed. This patient's results are shown in comparison to those of a patient with known sickle cell anemia and a child with normal hemoglobin. Based on this electrophoresis, which of the following types of hemoglobin are dominant in this patient's blood? Hemoglobin electrophoresis separates different types of hemoglobin based on their charge. The more negatively charged a hemoglobin molecule is, the further it will migrate toward the positively charged anode.
HbS and HbC HbA (α2β2), which is the predominant form of hemoglobin by the age of 6 months, migrates farther than HbS, which is the predominant hemoglobin of patients with sickle cell disease. This is because HbS contains a neutral valine residue at position 6 within the beta subunit in place of the normal, negatively charged glutamic acid residue. HbS, in turn, migrates farther than HbC because HbC contains a positively charged lysine residue in the same position. The thin band between HbS and HbA in the sickle cell patient's sample is HbF (α2γ2), which is slightly less negatively charged than HbA but more negatively charged than HbS. HbF is normally present in negligible quantities by early childhood but patients with sickle cell disease often have increased levels of HbF. This patient's hemoglobin electrophoresis shows one band at the position of the HbS band and the other at a position closer to the cathode than HbS. Therefore, this patient has HbSC disease. HbSC patients have milder symptoms than those with homozygous sickle cell anemia (HbSS).
A 27-year-old man comes to the physician for a follow-up evaluation. Two days ago, he was involved in a physical altercation and sustained a bruise on his left arm and an injury to his left shoulder. Initially, there was a reddish-purple discoloration on his left upper arm. A photograph of the left upper arm today is shown. Which of the following enzymes is most likely responsible for the observed changes in color? The change from reddish-purple to a greenish color reflects a step in the breakdown of hemoglobin.
Heme oxygenase Immediately after trauma, blood collects outside of the blood vessel (released hemoglobin), which results in a red hematoma. After 24-96 hours, the hematoma darkens and can appear purple or blue/black. This is due to blood coagulation and the degradation of hemoglobin into bile pigment. After 4-7 days, the hematoma becomes dark green as the heme part of hemoglobin is broken down into biliverdin by the enzyme heme oxygenase. After 7 days, biliverdin is broken down into bilirubin by the enzyme biliverdin reductase and the hematoma appears yellow or brownish.
An investigator is conducting a study on hematological factors that affect the affinity of hemoglobin for oxygen. An illustration of two graphs (A and B) that represent the affinity of hemoglobin for oxygen is shown. Which of the following best explains a shift from A to B? Right shift of the oxygen-hemoglobin dissociation curve represents a decreased affinity of hemoglobin for oxygen.
Increased body temperature Increased body temperature, e.g., from fever or exercise, would explain the right shift in the oxygen-hemoglobin dissociation curve. Increased temperature weakens the bond between oxygen and hemoglobin and increases the amount of oxygen available to tissues for consumption. Other factors that shift the oxygen-hemoglobin dissociation curve to the right include increased pCO2, decreased pH, increased 2,3-BPG, exercise, and altitude.
An investigator is studying the resting rate of oxygen consumption in the lower limbs of individuals with peripheral vascular disease. The rate of blood flow in a study subject's femoral vessels is measured using Doppler ultrasonography, and blood samples from the femoral vein and femoral artery are obtained. The blood samples are irradiated and centrifuged, after which the erythrocyte fractions from each sample are hemolyzed using 10% saline. Compared to the femoral vein, which of the following findings would be expected in the hemolysate from the femoral artery? The findings in the hemolysate will reflect differences between the intraerythrocytic compartments of the arteries and veins.
Lower chloride concentration Cell metabolism generates CO2 that is transported from tissues through the venous system (e.g., the femoral vein). CO2 in the plasma diffuses into erythrocytes. Carbonic anhydrase then converts CO2 and H2O into H2CO3 (carbonic acid), which then dissociates to form H+ and HCO3- ions. Most of the H+ is buffered by hemoglobin and other proteins. To prevent intracellular buildup of HCO3- and allow for more uptake of CO2, HCO3- is exchanged for extracellular chloride ions (Cl-) via the Cl-/HCO3- exchanger. This leads to a large shift of Cl- from the extracellular space to the intracellular space (chloride shift). Compared to venous blood, arterial blood transports less CO2. Erythrocytes in arterial blood thus have lower intracellular CO2 concentrations and less activity of the Cl-/HCO3- exchanger, which leads to a lower intraerythrocytic chloride concentration.
An investigator is studying the recycling of heme proteins in various cell types. Heat denaturation and high-performance liquid chromatography are used to carry out and observe the selective destruction of hemoglobin molecules in red blood cells. It is found that these cells are unable to regenerate new heme molecules. A lack of which of the following structures is the most likely explanation for this observation? Two enzymatic reactions (via aminolevulinate synthase and ferrochelatase) required to form heme complexes occur within this organelle.
Mitochondria Heme is synthesized in the mitochondria and the cytosol of immature RBCs. Mitochondria are the site of the first and final step of heme synthesis, involving aminolevulinate synthase and ferrochelatase, respectively. The absence of organelles in RBCs allows them to be maximally filled with hemoglobin and gives them their biconcave cell shape. Without mitochondria, though, RBCs are unable to regenerate new heme molecules or produce ATP from the oxygen they transport. Instead, RBCs produce ATP by glycolysis and lactic acid fermentation of the resulting pyruvate.
An investigator is studying the role of different factors in inflammation and hemostasis. Alpha-granules from activated platelets are isolated and applied to a medium containing inactive platelets. When ristocetin is applied, the granules bind to GpIb receptors, inducing a conformational change in the platelets. Binding of the active component of these granules to GpIb receptors is most likely responsible for which of the following steps of hemostasis? The factor that is stored in alpha-granules of platelets is von Willebrand factor (vWF).
Platelet adhesion After an endothelial injury, circulating vWF binds to exposed collagen and anchors platelets to collagen with the GpIb receptor. This process, which is called platelet adhesion, is the first step in thrombus formation. vWF also prevents the breakdown of factor VIII and plays a role in platelet aggregation and the regulation of angiogenesis. In addition to the alpha-granules of platelets, vWF is also stored in the Weibel-Palade bodies of endothelial cells.
An investigator is studying the affinity of hemoglobin for oxygen in different clinical settings. An illustration of an oxygen-hemoglobin dissociation curve is shown. Curve A shows the test results of one of the research participants and curve B shows a normal oxygen-hemoglobin dissociation curve. Which of the following is most likely present in this research participant? Curve A shows a left shift in the oxygen-hemoglobin dissociation curve, which indicates a higher affinity of Hb for O2 compared to a normal oxygen-hemoglobin dissociation curve.
Secondary polycythemia The left shift in the O2-Hb dissociation curve indicates that this patient's Hb has a high affinity for O2, which results in less unloading of O2 in the peripheral tissues. Chronic tissue hypoxia stimulates the release of erythropoietin, which stimulates the bone marrow to produce more erythrocytes and results in secondary polycythemia.
An investigator is studying the function of different enzymes in various human cell types. A subset of normal human cells with an elevated intracellular concentration of bisphosphoglycerate mutase is harvested and isolated. Which of the following is most likely to be absent in these cells? Bisphosphoglycerate mutase is an enzyme of the glycolytic pathway that is present only in RBCs and a specific type of placental cell.
α-ketoglutarate dehydrogenase The enzyme α-ketoglutarate dehydrogenase would not be found in RBCs because they lack mitochondria, which is where the TCA cycle takes place. The main biochemical pathways available in RBCs are the pentose-phosphate pathway, glycolysis, and glutathione reduction. 2,3-bisphosphoglycerate mutase is vital to RBCs for the conversion of 1,3-BPG, an intermediate in glycolysis, to 2,3-BPG, which binds to hemoglobin and causes a conformational change that results in oxygen release into local tissues.
