Pathology Review Ch. 14 - Red Blood Cell And Bleeding Disorders

Glucose-6-phosphate dehydrogenase deficiency is an X-linked disorder that affects about 10% of African-American
males. The lack of this enzyme subjects hemoglobin to damage by oxidants, including drugs such as primaquine,
sulfonamides, nitrofurantoin, phenacetin, and aspirin (in large doses). Infection also can cause oxidative damage to
hemoglobin. Heinz bodies damage the RBC membrane, giving rise to intravascular hemolysis. The “bite cells” result from
the attempts of overeager splenic macrophages to pluck out the Heinz bodies, adding an element of extravascular
hemolysis. Heterozygotes with α-thalassemia have no major problems, but in cases of α-thalassemia major, perinatal
death is the rule. Likewise, β-thalassemia minor and sickle cell trait are conditions with no major problems and no relation
to drug usage. Some autoimmune hemolytic anemias can be drug related, but the hemolysis is predominantly
extravascular. RBC membrane abnormalities, such as hereditary spherocytosis (caused by abnormal spectrin), typically
produce a mild anemia without significant hemolysis, and there is no drug sensitivity.

Although β-thalassemia minor and iron deficiency anemia are characterized by hypochromic and microcytic RBCs,
there is no increase in hemoglobin A2 in iron deficiency states. A normal serum ferritin level also excludes iron deficiency.
In contrast to β-thalassemia major, there is usually a mild anemia without major organ dysfunction. Diseases that produce
hemolysis and increase erythropoiesis (e.g., autoimmune hemolytic anemia, malaria) do not alter the composition of β-
globin chain production. Anemia of chronic disease may mimic iron deficiency and thalassemia minor with respect to
hypochromia and microcytosis; however, anemia of chronic disease is associated with an increase in the serum
concentration of ferritin.

Spectrin and related proteins (e.g., protein 4.1, ankyrin) are cytoskeletal proteins that are important in maintaining
the RBC shape. Hereditary spherocytosis is a condition in which a mutation affects one of several membrane cytoskeletal
proteins, such as ankyrin (most common) and band 4.2, which binds spectrin to the transmembrane ion transporter, band
3, and protein 4.1, which binds the “tail” of spectrin to another transmembrane protein, glycophorin A. Cells with such
mutant proteins are less deformable. The abnormal RBCs seem to lack central pallor on a peripheral blood smear, and
they are sequestered and destroyed in the spleen. Glucose-6-phosphate dehydrogenase deficiency is an X-linked
condition that most commonly affects black males. Thalassemias with abnormal α-globin or β-globin chains are associated
with hypochromic microcytic anemias. Iron deficiency affects the heme portion of hemoglobin, leading to hypochromia and
to microcytosis. Carbonic anhydrase in RBCs helps to maintain buffering capacity.

This patient's bleeding tendency is caused by a low platelet count. She most likely has idiopathic thrombocytopenic
purpura (ITP), in which platelets are destroyed in the spleen after being coated with antibodies to platelet membrane
glycoproteins IIb-IIIa or Ib-IX affecting both the patient's platelets and the transfused platelets. Because the spleen is the
source of the antibody and the site of destruction, splenectomy can be beneficial. There is no defect in the production of
platelets. Suppression of pluripotent stem cells gives rise to aplastic anemia, which is accompanied by pancytopenia.
Platelet functions are normal in ITP. Chronic blood loss would not lead to thrombocytopenia when normal bone marrow
function is present. Abnormal platelet-endothelial interactions are more likely to cause thrombosis.

Throughout human history, malaria has been the driving force for increasing the gene frequency of hemoglobin S.
Individuals who are heterozygous for hemoglobin S have the sickle cell trait. They are resistant to malaria because the
parasites grow poorly or die at low oxygen concentrations, perhaps because of low potassium levels caused by potassium
efflux from RBCs on hemoglobin sickling. The malarial parasite cannot complete its life cycle. Clostridium neoformans can
cause granulomatous disease in immunocompromised individuals. Borrelia burgdorferi is the spirochete that causes Lyme
disease. Treponema pallidum is the infectious agent causing syphilis. Clostridium perfringens may produce gas gangrene
after soft-tissue injuries. Trypanosoma gambiense infection causes sleeping sickness. Schistosoma haematobium
infection leads to hematuria and iron deficiency anemia.

These patients have sickle cell disease with hemoglobin S. During infancy, the amount of fetal hemoglobin being
produced is sufficient to prevent most complications of the disease, such as vaso-occlusive crises and infections. After
infancy, the amount of hemoglobin F declines, but drugs such as hydroxyurea can induce increased production of
hemoglobin F. Hemoglobin A1 is the normal adult hemoglobin that is absent with homozygous sickle cell anemia.
Hemoglobin A2 is not produced in sufficient quantities to ameliorate the effects of hemoglobinopathies. Hemoglobins C and
E when homozygous produce anemia much milder than hemoglobin S disease, and when heterozygous help ameliorate
hemoglobin S, but there is no differential production of hemoglobin C or E in infancy.

In patients with hereditary spherocytosis, spheroidal cells are trapped and destroyed in the spleen because the
abnormal RBCs have reduced deformability. Splenectomy is beneficial because the spherocytes are no longer detained by
the spleen. Splenectomy has no effect on the synthesis of spectrin or RBC deformability as a result; the RBCs in
spherocytosis are not killed by opsonization. In warm antibody hemolytic anemias, opsonized RBCs are removed by the
spleen. Reactive oxygen species do not play a role in anemias.

This patient has cold agglutinin disease, with antibody (usually IgM) coating RBCs. The IgM antibodies bind to the
RBCs at low temperature and fix complement; however, complement is not lytic at this temperature. With an increase in
temperature, the IgM is dissociated from the cell, leaving behind C3b. Most of the hemolysis occurs extravascularly in the
cells of the mononuclear phagocyte system, such as Kupffer cells in the liver, because the coating of complement C3b
acts as an opsonin. Raynaud phenomenon occurs in exposed, colder areas of the body, such as the fingers and toes. The
patient probably has an elevated cold agglutinin titer. IgE is present in allergic conditions, and histamine is released in type
I hypersensitivity reactions. IgG is typically involved in warm antibody hemolytic anemia, which is chronic and is not
triggered by cold. Fibronectin is an adhesive cell surface glycoprotein that aids in tissue healing.

Platelet number and function in this case are normal, and there is no detectable abnormality in the extrinsic or
intrinsic pathways of coagulation as measured by the prothrombin time or partial thromboplastin time. Petechiae and
ecchymoses can result from increased vascular fragility, a consequence of nutritional deficiency (e.g., vitamin C), infection
(e.g., meningococcemia), and vasculitic diseases. Liver disease would affect the prothrombin time. Chronic renal failure
may depress platelet function. Meningococcemia is an acute illness. Metastatic disease does not directly affect
hemostasis, although extensive marrow metastases could diminish platelet production.

Children and adults with sickle cell anemia may benefit from hydroxyurea therapy, which can increase the
concentration of hemoglobin F in RBCs, which interferes with the polymerization of hemoglobin S. However, the
therapeutic response to hydroxyurea often precedes the increase in hemoglobin F levels. Hydroxyurea also has an antiinflammatory
effect, increases the mean RBC volume, and can be oxidized by heme groups to produce nitric oxide.
Because hemoglobin F levels are high for the first 5 to 6 months of life, patients with sickle cell anemia do not manifest the
disease during this period. Because both β-globin chains are affected, no hemoglobin A1 is produced. Globin synthesis
decreases with the thalassemias. The hemolysis associated with sickling promotes erythropoiesis, but the concentration of
hemoglobin S is not changed. Hydroxyurea does not shift the oxygen dissociation curve or change the oxygen affinity of
the various hemoglobins.

This is an example of disseminated intravascular coagulation (DIC) with associated microangiopathic hemolytic
anemia. The DIC developed in the setting of a mucin-secreting adenocarcinoma. Howell-Jolly bodies are small, round
inclusions in RBCs that appear when the spleen is absent. Teardrop cells are most characteristic of myelofibrosis and
other infiltrative disorders of the marrow. Macro-ovalocytes are seen in megaloblastic anemias, such as vitamin B12
deficiency. Target cells appear in hemoglobin C disease or severe liver disease.

The presence of thrombocytopenia, increased prothrombin and partial thromboplastin times, and fibrin split
products, and the low fibrinogen concentration all suggest disseminated intravascular coagulation (DIC), which was most
likely caused by a retained dead fetus, an obstetric complication that can lead to DIC through release of thromboplastins
from the fetus. This release causes widespread microvascular thrombosis and consumes clotting factors and platelets.
There is no damage to the vascular endothelium or vascular wall. Platelet production is normal, but platelets are
consumed by widespread thrombosis of small vessels. There is no defect in platelet function.

The findings point to Coombs-positive immune hemolytic anemia. Cold agglutinin immunohemolytic anemia can be
seen with lymphoid neoplasms and infections such as Mycoplasma, Epstein-Barr virus, HIV, influenza virus, and
cytomegalovirus. IgM binds to RBCs at cooler peripheral body regions, then fixes complement. At warmer central regions,
the antibody is eluted, but the complement marks the RBCs for extravascular destruction in the spleen, and there is
minimal intravascular hemolysis. The increased RBC turnover increases the MCV and the bilirubin, which is mainly
indirect. Chemotherapy can suppress bone marrow production, but more likely all cell lines, and without an immune
component. This patient has CMV infection, but hepatitis would likely increase direct and indirect bilirubin, and not account
for anemia. Folate deficiency could account for macrocytosis, but not a positive Coombs test. Non-Hodgkin lymphomas do
not often involve colon, but this might account for gastrointestinal bleeding with features of iron deficiency and
microcytosis.

This patient has hepatitis C with severe hepatocyte damage. Many of the clotting factors that are instrumental in the
in vitro measurement of the extrinsic pathway of coagulation, as measured by the prothrombin time, are synthesized in the
liver. Von Willebrand factor is produced by endothelial cells, not hepatocytes. The platelet count is not affected directly by
liver disease. Increased fibrin split products suggest a consumptive coagulopathy, such as disseminated intravascular
coagulation. Platelet aggregation is a measure of platelet function, which is not significantly affected by liver disease.

An inherited bleeding disorder with normal platelet count and prolonged bleeding time suggests von Willebrand
disease, confirmed by the ristocetin-dependent bioassay for von Willebrand factor (vWF). Von Willebrand disease is a
common bleeding disorder, with an estimated frequency of 1%. In most cases, it is inherited as an autosomal dominant
trait. In these cases, a reduction in the quantity of vWF impairs platelet adhesion to damaged vessel walls, and hemostasis
is compromised. Because vWF acts as a carrier for factor VIII, the level of this procoagulant protein (needed for the
intrinsic pathway) is diminished, as in this case. The levels of factor VIII rarely are reduced enough, however, to be
clinically significant. Prolonged partial thromboplastin time corrected by normal plasma is a reflection of factor VIII
deficiency. Because the disease is not a disorder of stem cells, transplantation is not helpful. Joint hemorrhages are a
feature of hemophilia A and B, not von Willebrand disease. Patients with von Willebrand disease are not prone to
thrombosis, as are individuals with factor V (Leiden) mutation or other inherited disorders of anticoagulation. Splenectomy
is useful in cases of idiopathic thrombocytopenic purpura, but the platelets are not consumed in von Willebrand disease.

The high MCV indicates a marked macrocytosis, greater than would be accounted for by a reticulocytosis alone.
The two best-known causes for such an anemia (also known as megaloblastic anemia when characteristic megaloblastic
precursors are seen in the bone marrow) are vitamin B12 and folate deficiency. Because vitamin B12 is absorbed in the
terminal ileum, its removal can cause vitamin B12 deficiency. Hemolytic anemia is unlikely several weeks after blood
transfusion. Chronic blood loss and iron deficiency produce a microcytic pattern of anemia, as does dietary iron deficiency.
Anemia of chronic disease is generally a normocytic anemia. Inflammatory bowel diseases (e.g., Crohn disease) increase
the risk of malignancy, but myelophthisic anemias (from space-occupying lesions of the marrow) are usually normocytic to
mildly macrocytic (from reticulocytosis).

This patient has aplastic crisis, precipitated by a parvovirus infection. In adults who do not have a defect in normal
RBC production, such as hereditary spherocytosis or sickle cell anemia, or who are not immunosuppressed, parvovirus
infection is self-limited and often goes unnoticed. When RBC production is shut down by parvovirus, there is no
reticulocytosis. Disseminated intravascular coagulation gives rise to thrombocytopenia, bleeding, and the appearance of
fragmented RBCs in the blood smear. Reticulocytosis would be prominent with RBC antibodies. Iron deficiency does not
occur in hemolytic anemias because the iron that is released from hemolyzed cells is reused.

This patient has a microcytic anemia, which is typical of iron deficiency. Iron deficiency is the most common form of
anemia worldwide. The lack of iron impairs heme synthesis. The marrow response is to “downsize” the RBCs, resulting in
a microcytic and hypochromic anemia. At this patient's age, bleeding from an occult malignancy should be strongly
suspected as the cause of iron deficiency. An autoimmune hemolytic anemia would appear as a normocytic anemia or as a
slightly increased MCV with pronounced reticulocytosis. Thalassemias may result in a microcytosis, but β-thalassemia
major causes severe anemia soon after birth, and survival to age 73 years is unlikely. Macrocytosis would accompany a
history of chronic alcoholism, probably because of poor diet and folate deficiency. Vitamin B12 deficiency also results in a
macrocytic anemia. By this patient's age, hemophilia A would result in joint problems; because the bleeding is mainly into
soft tissues without blood loss, the iron is recycled.

Reduced numbers of platelets can result from decreased production or increased destruction. Marrow examination
in this case shows numerous megakaryocytes, which excludes decreased production. Accelerated destruction can be caused by hypersplenism, but there is no splenomegaly in this case. Peripheral platelet destruction is often
immunologically mediated and can result from well-known autoimmune diseases such as systemic lupus erythematosus, or
it can be idiopathic. When all known causes of thrombocytopenia are excluded, a diagnosis of idiopathic (immune)
thrombocytopenic purpura (ITP) can be made. This patient seems to have no other symptoms or signs and has no history
of drug intake or infections that can cause thrombocytopenia. ITP is most likely. Thrombotic thrombocytopenic purpura
(TTP) is another entity to be considered, but TTP produces a microangiopathic hemolytic anemia (MAHA) that typically is
associated with fever, neurologic symptoms, and renal failure. Disseminated intravascular coagulation is another form of
MAHA. Hemophilia B, similar to hemophilia A, leads to soft-tissue bleeding, and the partial thromboplastin time is
prolonged, but the platelet count is normal. Metastases can act as a space-occupying lesion in the marrow to reduce
hematopoiesis, but this is unlikely to be selective with megakaryocytes, and in this case, there is a megakaryocytic
hyperplasia. Vitamin K deficiency prolongs the prothrombin time initially and the partial thromboplastin time if severe, but
does not affect platelets. In von Willebrand disease, bleeding is due to abnormal platelet adhesion, but platelet numbers
are normal.

This patient has a warm autoimmune hemolytic anemia secondary to systemic lupus erythematosus (SLE). A
positive Coombs test result indicates the presence of anti-RBC antibodies in the serum and on the RBC surface. Most
cases of warm autoimmune hemolytic anemia are idiopathic, but one fourth occur in individuals with an identifiable
autoimmune disease, such as SLE. Some are caused by drugs such as α-methyldopa. The immunoglobulin coating the
RBCs acts as an opsonin to promote splenic phagocytosis. Nucleated RBCs can be seen in active hemolysis because the
marrow compensates by releasing immature RBCs. Infections such as mononucleosis and Mycoplasma are associated
with cold autoimmune hemolytic anemia (with an elevated cold agglutinin titer). The increased RBC destruction in
hereditary spherocytosis is extravascular and not immune mediated. Septicemia is more likely to lead to a
microangiopathic hemolytic anemia.

The increased ferritin concentration and reduced total iron-binding capacity are typical of anemia of chronic
disease, such as an autoimmune disease. Increased levels of cytokines such as interleukin-6 promote sequestration of
storage iron, with poor use for erythropoiesis. Secretion of erythropoietin by the kidney is impaired. Various underlying
diseases, including cancer, collagen vascular diseases, and chronic infections, can produce this pattern of anemia. Iron
deficiency would produce a microcytic anemia, with a low serum ferritin level. Aplastic anemia is unlikely because the
platelet count and WBC count are normal. Microangiopathic hemolytic anemias are caused by serious acute conditions
such as disseminated intravascular coagulation; these patients have thrombocytopenia caused by widespread thrombosis.
Megaloblastic anemias are macrocytic without an increase in iron stores. Thalassemia minor is uncommon and is not
associated with a positive ANA test result.

The severity of hemophilia A depends on the amount of factor VIII activity. With less than 1% activity, there is
severe disease, and joint hemorrhages are common, leading to severe joint deformity and ankylosis. Mild (1% to 5%) and
moderate (5% to 75%) activity is often asymptomatic except in severe trauma. The bleeding tendency is not associated
with splenomegaly. Petechiae, seen in patients with thrombocytopenia, are not a feature of hemophilia. Factor VIII
deficiency does not affect the life span of RBCs. Because individuals with factor VIII deficiency do not depend on RBC
transfusions, iron overload is not a usual consequence.

This patient has glucose-6-phosphate dehydrogenase deficiency. A drug that leads to oxidative injury to the RBCs,
such as primaquine, can induce hemolysis. Oxidant injury to hemoglobin produces inclusion of denatured hemoglobin
within RBCs. The inclusions damage the cell membrane directly, giving rise to intravascular hemolysis. These cells have
reduced membrane deformability, and they are removed from the circulation by the spleen. The remaining mechanisms
listed are not directly drug dependent. Mechanical fragmentation of RBCs is typical of microangiopathic hemolytic
anemias, such as disseminated intravascular coagulation. Complement lysis is enhanced in paroxysmal nocturnal
hemoglobinuria, which results from mutations in the PIGA gene. Impaired RBC nuclear maturation occurs as a result of
vitamin B12 or folate deficiency. Impaired globin synthesis occurs in thalassemias. Hemolytic anemias with antibody coating
RBCs can occur with autoimmune diseases, prior transfusion, and erythroblastosis fetalis. Reduced RBC membrane
deformability is seen in patients with abnormalities in cytoskeletal proteins, such as spectrin; the latter causes hereditary
spherocytosis.

The RBCs display hypochromia and microcytosis, consistent with iron deficiency. The most common cause of this in
elderly patients is chronic blood loss that originates from a gastrointestinal source (e.g., carcinoma, ulcer disease). At age
69, this patient is not menstruating, and vaginal bleeding is likely to be noticed as a “red flag” for a gynecologic
malignancy. Pernicious anemia from vitamin B12 deficiency would result in a macrocytic anemia. The RBCs are generally
normocytic in patients with aplastic anemia. Microcytosis may accompany thalassemias, but the patient would be unlikely
to live to the age of 69 years with β-thalassemia major. Autoimmune hemolytic anemias usually produce a normocytic
anemia, or the MCV can be slightly elevated, with a brisk reticulocytosis.

The pancytopenia and absence of a reticulocytosis strongly suggest bone marrow failure. Aplastic anemia has no
apparent cause in half of all cases. In other cases, drugs and toxins may be identified; drugs such as chemotherapeutic
agents are best known for this effect. A preceding viral infection may be identified in some cases, but bacterial infections
rarely cause aplastic anemias. Individuals with pancytopenia are subject to bleeding disorders because of the low platelet count and to infections because of the low WBC count. Dietary history would not be helpful because this patient's clinical
and laboratory picture is not characteristic of iron deficiency or vitamin B12 deficiency. Menstrual history would be relevant
if the patient had hypochromic microcytic anemia. The only known familial cause of aplastic anemia (Fanconi anemia) is
rare.

The diagnosis of thrombotic thrombocytopenic purpura (TTP) is based on finding a classic pentad: transient
neurologic problems, fever, thrombocytopenia, microangiopathic hemolytic anemia, and acute renal failure. The diagnosis
is confirmed by demonstration of von Willebrand factor monomers in the serum. These abnormalities are produced by
small platelet-fibrin thrombi in small vessels in multiple organs. The heart, brain, and kidney often are severely affected. Of
the other choices, only disseminated intravascular coagulation is a microangiopathic hemolytic anemia, but the pentad of
TTP is missing.

The crescent-shaped RBCs (sickled RBCs) are characteristic of hemoglobin SS. This disease is most common in
individuals of African and eastern Arabian descent. The sickled RBCs are susceptible to hemolysis (mainly vascular, in the
spleen), but they also can cause microvascular occlusions anywhere in the body, most commonly bone, lungs, liver, and
brain, leading to ischemia and severe pain. Vascular occlusions in the lungs are often accompanied by infection and lead
to the “acute chest syndrome.” The cell membranes of reversibly sickled cells are abnormally “sticky,” and they adhere to
capillary endothelium, especially in lungs. Vasoconstriction is caused by depletion of NO by free hemoglobin. Adhesion of
RBCs to endothelium retards blood flow, creates hypoxia, and precipitates local sickling and vascular occlusion. Chronic
tissue hypoxia does occur in sickle cell anemia, but it produces insidious impairment of function in organs such as heart,
kidneys, and lungs. Defects in the alternative pathway of complement activation predispose to infection with encapsulated
bacteria, such as Haemophilus influenzae and Streptococcus pneumoniae.