Iron deficiency anemia is the most common form of anemia. Although
in many developing countries dietary deficiency of iron can occur,
in developed nations the main cause is loss of iron, almost always
through blood loss from the GI or genitourinary tracts.
Because of recurrent menstrual blood loss, premenopausal women
represent the population with the highest incidence of iron deficiency.
The incidence in this group is even higher because of iron losses
during pregnancy, because the developing fetus efficiently extracts
maternal iron for use in its own hematopoiesis. In men or in postmenopausal
women with iron deficiency, GI bleeding is usually the cause. Blood
loss in this case may be due to relatively benign disorders, such
as peptic ulcer, arteriovenous malformations, or angiodysplasia (small
vascular abnormalities along the intestinal walls). More serious
causes are inflammatory bowel disease or malignancy. Endoscopic
investigation to exclude malignancy is mandatory in patients without
a known cause of iron deficiency.
There are other less common causes of iron deficiency, but almost
all are related to blood loss: Bleeding disorders, hemoptysis, and
hemoglobinuria are the chief possibilities.
Body iron stores are generally sufficient to last several years, but
there is a constant loss of iron in completely healthy persons,
such that iron balance depends on adequate intake and absorption.
Dietary iron is primarily absorbed in the duodenum. Absorption is
increased in the setting of anemia, hypoxia, and systemic iron deficiency.
Iron is also recycled from senescent erythrocytes via macrophage
phagocytosis and lysis. The export of iron to plasma from these
cellular sites is regulated by hepcidin, a 25-amino
acid peptide produced by the liver. Hepcidin binds to ferroportin,
a transmembrane protein, inducing its internalization and lysosomal
degradation. When iron stores are low, hepcidin production is reduced
and ferroportin molecules are expressed on the basolateral membrane
of enterocytes, where they transfer iron from the cytoplasm of enterocytes
to plasma transferrin. Conversely, when iron stores
are adequate or elevated, hepcidin production is increased, resulting
in the internalization of ferroportin and reduced export of iron
into plasma. In inflammatory states, hepcidin production is increased,
leading to the internalization of ferroportin on macrophages
and the trapping of recycled iron within macrophage stores.
Iron is stored in most body cells as ferritin, a
combination of iron and the protein apoferritin. It is also stored
as hemosiderin, which is ferritin partly stripped of
the apoferritin protein shell. Iron is transported in blood bound
to its carrier protein transferrin. Because of the complex interactions between
these molecules, a simple measurement of serum iron rarely reflects
body iron stores (see later discussion).
Iron is found predominantly in hemoglobin and is present also
in myoglobin, the oxygen-storing protein of skeletal muscle.
The main role for iron is as the ion in the center of the body’s
oxygen-carrying molecule, heme. Held stably in the ferrous
form by the other atoms in heme, iron reversibly binds oxygen. Each
protein subunit of hemoglobin contains one heme molecule; because
hemoglobin exists as a tetramer, four iron molecules are needed
in each hemoglobin unit. When there is iron deficiency, the final
step in heme synthesis is interrupted (Figure
6–6). In this step, ferrous iron is inserted into
protoporphyrin IX by the enzyme ferrochelatase; when heme synthesis
is interrupted, there is inadequate heme production. Globin biosynthesis
is inhibited by heme deficiency through a heme-regulated translational
inhibitor (HRI). Elevated HRI activity (a result
of heme deficiency) inhibits a key transcription initiation factor
for heme synthesis, eIF2. Thus, less heme and fewer globin chains
are available in each red cell precursor. This directly causes anemia,
a decrease in the hemoglobin concentration of the blood.
Heme synthesis, emphasizing the role of iron and the
insertion of heme into individual globin chains to make hemoglobin,
and the role of the heme-regulated translational inhibitor (HRI)
of globin synthesis. Normal concentrations of heme keep the activity
of HRI low, preserving normal globin synthesis.
As noted, heme is also the oxygen acceptor in myoglobin; therefore,
iron deficiency will also lead to decreased myoglobin production.
Other proteins also are dependent on iron; most of these are enzymes.
Many use iron in the heme molecule, but some use elemental iron.
Although the exact implications of iron deficiency on their activity
is not known, these enzymes are crucial to metabolism, energy production,
DNA synthesis, and even brain function.
As iron stores are depleted, the peripheral blood smear pattern evolves.
In early iron deficiency, the hemoglobin level of the blood falls
but individual erythrocytes appear normal. In response to a falling
oxygen level, erythropoietin levels rise and stimulate the marrow,
but the hemoglobin level cannot rise in response because of the
iron deficiency. Other hormones are presumably also stimulated,
however, and the resulting “revved-up” marrow
usually causes an elevated blood platelet count. An elevated white
cell count is less common. Reticulocytes are notably absent.
Eventually, the hemoglobin concentration of individual cells
falls, leading to the classic picture of microcytic, hypochromic
erythrocytes (Figure 6–5). This
is most commonly found as an abnormally low MCV of red cells on
the automated hemogram. There is also substantial anisocytosis and poikilocytosis,
seen on the peripheral smear, and target cells may
be seen. The target shape occurs because there is a relative excess
of red cell membrane compared with the amount of hemoglobin within
the cell, so that the membrane bunches up in the center.
Laboratory results are often confusing. A low serum ferritin level
is diagnostic of iron deficiency, but even in obvious cases, levels
can be normal; ferritin levels rise in acute or chronic inflammation
or significant illnesses, which can themselves be the cause of iron
(blood) loss. Serum iron levels fall in many illnesses, and levels
of its serum carrier, transferrin, fluctuate as well, so neither
of them is a consistent indicator of iron deficiency, nor is their
ratio, the transferrin saturation. If ferritin levels are not diagnostic,
clinical practice now focuses on measuring soluble transferrin receptor
(sTfR) in the serum. Transferrin receptors (TfRs) are membrane glycoproteins
that facilitate iron transport from plasma transferrin into body cells.
Erythroid precursors increase their expression of membrane TfR in
the setting of iron deficiency but not anemia of chronic disease.
Some membrane TfR is released into the serum as sTfR. The amount
of sTfR in the serum reflects the amount of membrane TfR. A high
ratio of sTfR to ferritin predicts iron deficiency when ferritin
is not diagnostically low.
Other than observing a hematologic response to empiric iron supplementation,
bone marrow biopsy can be used to confirm a diagnosis of iron deficiency.
Iron is normally found in the macrophages of the marrow, where it
supplies erythrocyte precursors; intracellular hemosiderin is easily
visualized with Prussian blue stain. These macrophages do not stain
at all if there is iron deficiency.
All anemias lead to classic symptoms of decreased oxygen-carrying
capacity (ie, fatigue, weakness, and shortness of breath, particularly
dyspnea on exertion), and iron deficiency is no exception. Decreased
oxygen-carrying capacity leads to decreased oxygen delivery to metabolically
active tissues, which nonetheless must have oxygen; this leads directly
to fatigue. The compensatory mechanisms of the body lead to additional
symptoms and signs of anemia. Some patients appear pale not only
because there is less hemoglobin per unit of blood (oxygenated hemoglobin
is red and gives color to the skin) but also because superficial
skin blood vessels constrict, diverting blood to more vital structures.
Patients may also respond to the anemia with tachycardia. This increased
cardiac output is appropriate because one way to increase oxygen
delivery to the tissues is to increase the number of times each
hemoglobin molecule is oxygenated in the lungs every hour. This
tachycardia may cause benign cardiac murmurs due to the increased
Abnormalities of the GI tract occur because iron is also needed
for proliferating cells. Glossitis, where the normal tongue
papillae are absent, can occur, as can gastric atrophy with achlorhydria (absence
of stomach acid). The achlorhydria may compound the iron deficiency
because iron is best absorbed in an acidic environment, but this
complication is quite unusual.
In children, there may be significant developmental problems,
both physical and mental. Iron-deficient children, mostly in developing
regions, perform poorly on tests of cognition compared with iron-replete
children. Iron therapy can reverse these findings if started early
enough in childhood. The exact mechanism of cognitive loss in iron
deficiency is not known. Another unexplained but often observed
phenomenon in severe iron deficiency is pica, a craving
for nonnutritive substances such as clay or dirt.
Many patients have no specific symptoms or findings at all, and
their iron deficiency is discovered because of anemia noted on a
blood count obtained for another purpose. It is of interest that
mild anemias (hemoglobins of 11–12 g/dL) may be
tolerated very well because they develop slowly. In addition to
the physiologic compensatory mechanisms discussed previously (increased
cardiac output, diversion of blood flow from less metabolically
active areas), there is a biochemical adaptation as well. The ability
to transfer oxygen from hemoglobin to cells is partly dependent
on a small molecule in erythrocytes called 2,3-biphosphoglycerate (2,3-BPG).
In high concentrations, the ability to unload oxygen in the tissues
is increased. Chronic anemia leads to elevated 2,3-BPG concentrations
Other patients who do not present with symptoms directly related
to the anemia present instead with symptoms or signs related directly
to blood loss. Because the most common site of unexpected (nonmenstrual)
blood loss is the GI tract, patients often have visible changes
in the stool. There may be gross blood (hematochezia),
which is more common with bleeding sites near the rectum, or black,
tarry, metabolized blood (melena) from more proximal
sites. Significant blood loss from the urinary tract is very uncommon.
- 11. What is the most common form
of anemia and its most likely cause in a premenopausal woman? In
- 12. Why is the serum ferritin level
often not a good indicator of whether anemia is due to iron deficiency?
- 13. What are some disorders associated
with iron deficiency anemia?
- 14. What are the physiologic adaptations
to slowly developing iron deficiency anemia?
Pernicious anemia is a megaloblastic anemia in which there is abnormal
erythrocyte nuclear maturation. Unlike in many other types of anemia
such as that resulting from iron deficiency, hemoglobin synthesis
is normal. Pernicious anemia is the end result of a cascade of events
that are autoimmune in origin. The ultimate effect is a loss of
adequate stores of vitamin B12 (cobalamin), which is a
cofactor involved in DNA synthesis. Rapidly proliferating cells
are those most often affected, predominantly bone marrow cells and
those of the GI epithelium. The nervous system is also affected,
demonstrating that this is a systemic disease. Anemia is merely
the most common manifestation.
Besides pernicious anemia, cobalamin deficiency can also be due
to bacterial overgrowth in the intestine (because bacteria compete
with the host for cobalamin), intestinal malabsorption of vitamin
B12 involving the terminal ileum (such as in Crohn’s
disease), surgical removal of the antrum of the stomach (gastrectomy),
and, rarely, dietary deficiency, which occurs only in strict vegetarians.
In the diet, cobalamin is found only in animal products.
Pernicious anemia is most common in older patients of Scandinavian
descent but is found in a wide variety of ethnic groups. In the
United States, black females are one of the most common groups.
Pernicious anemia accounts for only a small percentage of patients
with anemia, however.
The initial events in the pathogenetic cascade begin in the stomach
(Figure 6–7). The gastric parietal
cells are initially affected by an autoimmune phenomenon that leads
to two discrete effects: loss of gastric acid (achlorhydria)
and loss of intrinsic factor. Pernicious anemia interferes
with both the initial availability and the absorption of vitamin
B12: Stomach acid is required for the release of cobalamin
from foodstuffs, and intrinsic factor is a glycoprotein that binds
cobalamin and is required for the effective absorption of cobalamin
in the terminal ileum. Both stomach acid and intrinsic factor are
made exclusively by parietal cells.
Pathogenesis and effects of pernicious anemia (autoimmune
(Redrawn, with permission, from Chandrasoma P,
Taylor CR. Concise Pathology, 3rd ed. Originally
published by Appleton & Lange. Copyright © 1998 by
the McGraw-Hill Companies, Inc.)
Evidence for the autoimmune destruction of parietal cells is strong:
Patients with pernicious anemia have atrophy of the gastric mucosa,
and pathologic specimens show infiltrating lymphocytes, which are
predominantly antibody-producing B cells. In addition, 90% or
more of patients have antibodies in their serum directed against
parietal cell membrane proteins. The major protein antigen appears
to be H+-K+ ATPase, the proton
pump, which is responsible for the production of stomach
acid. Cytotoxic T cells whose receptors recognize H+-K+ ATPase
may also contribute to the gastric atrophy. More than half of patients
also have antibodies to intrinsic factor itself or the intrinsic
factor-cobalamin complex. Furthermore, patients with pernicious
anemia have a higher incidence of other autoimmune diseases, such
as Graves’ disease. Lastly, corticosteroid therapy, used
as first-line therapy for many autoimmune disorders, may reverse
the pathologic findings in pernicious anemia. Despite this evidence,
the exact mechanism of the inciting event remains unknown.
Complete vitamin B12 deficiency develops slowly, even
after total achlorhydria and loss of intrinsic factor occur. Liver stores
of vitamin B12 are adequate for several years. However, the
lack of this vitamin eventually leads to alterations in DNA synthesis
and in the nervous system, altered myelin synthesis.
In DNA synthesis, cobalamin, along with folic acid, is crucial
as a cofactor in the synthesis of deoxythymidine from deoxyuridine
(Figure 6–8). Cobalamin accepts
a methyl group from methyltetrahydrofolate, which leads to the formation
of two important intracellular compounds. The first is methylcobalamin,
which is required for the production of the amino acidmethionine
from homocysteine. The second is reduced tetrahydrofolate, which
is required as the single-carbon donor in purine synthesis. Thus,
cobalamin deficiency depletes stores of reduced tetrahydrofolate
and impairs DNA synthesis because of lowered purine production.
In cobalamin deficiency, other reduced folates may substitute for
tetrahydrofolate (and may explain why pharmacologic doses of folic
acid can partially reverse the megaloblastic blood cell changes,
but not the neurologic changes, seen in pernicious anemia). However,
methyltetrahydrofolate, normally the methyl donor to cobalamin,
accumulates. This folate cannot be retained intracellularly because
it cannot be polyglutamated; the addition of multiple
glutamate residues leads to a charged compound that does not freely
diffuse out of the cell. Therefore, there is relative folate deficiency
in pernicious anemia as well. In addition, methionine may serve
as a principal donor of methyl groups to these other “substituting” reduced
folates; because methionine cannot be produced in cobalamin deficiency,
this compounds the problems in purine synthesis.
Role of cobalamin (vitamin B12) and folic acid in
nucleic acid and myelin metabolism. Lack of either cobalamin or
folic acid retards DNA synthesis (A) and lack of cobalamin
leads to loss of folic acid, which cannot be held intracellularly
unless polyglutamated. Lack of cobalamin also leads to abnormal
myelin synthesis, probably via a deficiency in methionine production
(Redrawn, with permission, from Chandrasoma P,
Taylor CR. Concise Pathology, 3rd ed. Originally
published by Appleton & Lange. Copyright © 1998 by
the McGraw-Hill Companies, Inc.)
The exact mechanism of the neurologic consequences of pernicious
anemia, with demyelination (loss of the myelin sheaths
around nerves), is not known. Defects in the methionine synthase
pathway have been suggested but not proven experimentally. Instead,
observations in cobalamin-deficient gastrectomized rats implicate
an imbalance of cytokines and growth factors as a potential mediator
of nerve damage. The synthesis of the cytokine tumor necrosis
factor (TNF) is regulated by S-adenosyl-methione, a product
of methionine. Deficiency of methionine may indirectly lead to neuropathy
via unregulated production of TNF, a myelinolytic cytokine, among
The production of succinyl-coenzyme A (CoA) is also dependent
on the presence of cobalamin. It is not clear whether a decrease
in the production of succinyl-CoA, which may affect fatty acid synthesis,
is also involved in the demyelinating disease.
The gastric disorders associated with pernicious anemia are dominated
by the picture of chronic atrophic gastritis (Figure 6–7). The normally tall columnar
epithelium is replaced by a very thin mucosa, and there is obvious
infiltration of plasma cells and lymphocytes. Pernicious anemia
also increases the risk for gastric adenocarcinoma. Thus, pathologic
examination may also reveal cancer.
The peripheral blood smear picture (Figure
6–5) varies, depending on the length of time the patient
has been cobalamin deficient. In early stages, the patient may have
mild macrocytic anemia, and large ovoid erythrocytes (macro-ovalocytes)
are commonly seen. In full-blown megaloblastic anemia, however,
there are abnormalities in all cell lines. The classic picture reveals
significant anisocytosis and poikilocytosis of the red cell line,
and there are hypersegmented neutrophils, revealing the nuclear
dysgenesis from abnormal DNA synthesis (Figure
6–9). In severe cases of pernicious anemia, the red
and white cell series are easily mistaken for acute leukemia because
the cells look so atypical.
Megaloblastic hematopoiesis: morphologic changes visible
with microscopic examination of bone marrow or peripheral blood.
(Redrawn, with permission, from Chandrasoma P,
Taylor CR. Concise Pathology, 3rd ed. Originally
published by Appleton & Lange. Copyright © 1998 by
the McGraw-Hill Companies, Inc.)
The bone marrow, however, is less suggestive of acute leukemia,
and megaloblastic changes—nuclei that are too large and
immature in cells with mature, hemoglobin-filled cytoplasm—are
seen at each stage of erythrocyte development. These cells are not
seen in the peripheral blood because the abnormal erythrocytes generally
are destroyed in the marrow (intramedullary hemolysis)
by unexplained processes. This compounds the anemia. Megaloblastic
changes can be seen in the marrow even in the absence of obvious
changes on the peripheral blood smear.
Spinal cord abnormalities consist of demyelination of the posterolateral
spinal columns, called subacute combined degeneration. Peripheral
nerves may also show demyelination. Demyelination eventually results
in neuronal cell death, which is also obvious on pathologic examination.
Because neurons do not divide, new neurons cannot replace the dead
Laboratory findings include elevated lactate dehydrogenase (LDH)
and, sometimes, indirect bilirubin consistent with the hemolysis
occurring in the bone marrow. LDH is directly released from lysed
red cells, and free hemoglobin is metabolized to bilirubin. Serum
vitamin B12 levels are usually low, revealing the deficient
state. Antibodies to intrinsic factor are usually detectable. Serum
elevations of both methylmalonic acid (MMA) and homocysteine together
(see Figure 6–8) are highly predictive
of B12 deficiency. The Schilling test, which assesses the
oral absorption of vitamin B12 with and without added intrinsic
factor, is no longer used, because of lack of availability of radioactively
labeled vitamin B12. Typically, the approach is to first
measure serum B12 and, if equivocal, to obtain serum levels
of MMA and homocysteine.
The clinical presentation consists of one or more symptoms related
to the underlying deficiency. Anemia is the most commonly encountered
abnormality and is often very severe; hemoglobin levels of 4 g/dL
(less than a third of normal) can be seen. This degree of anemia
is rare with other causes, such as iron deficiency. Typical symptoms
are fatigue, dyspnea, or dizziness, because a decreased red cell
mass equals decreased oxygen-carrying capacity of the blood. High-output
congestive heart failure is relatively common, with tachycardia
and signs of left ventricular failure (Chapter 10). Because oxygen demands are constant (or rise with exercise)
and oxygen-carrying capacity is falling, the only way to maintain
tissue oxygenation in anemia is to increase cardiac output (ie,
the number of times per minute each red cell is fully oxygenated
by the lungs). Eventually, however, the left ventricle fails.
However, symptoms may be mild because the anemia develops slowly
as a result of the extensive liver storage of vitamin B12.
Patients with anemia usually adapt over time to slow changes in
oxygen-carrying capacity. The same changes in 2,3-BPG that encourage
oxygen delivery to the tissues from the hemoglobin in red cells
in other anemias occur in vitamin B12 deficiency.
GI symptoms are less prevalent and include malabsorption, muscle
wasting (unusual), diarrhea (more common), and glossitis (most
common). In glossitis, the normal tongue papillae are absent regardless
of whether the tongue is painful, red, and “beefy” or
pale and smooth.
Neurologic symptoms are least likely to improve with cobalamin
replacement therapy. As with other neuropathies involving loss of
myelin from large peripheral sensory nerves, numbness and tingling
(paresthesias) occur frequently and are the most common
symptoms. Demyelination and neuronal cell death in the posterolateral “long
tracts” of the spinal cord interfere with delivery of positional
information to the brainstem, cerebellum, and sensory cortex. Patients,
therefore, complain of loss of balance and coordination. Examination
reveals impaired proprioception (position sense) and
vibration sense. True dementia may also occur when demyelination
involves the brain. Importantly but somewhat unexpectedly, neurologic symptoms
may occur in the absence of any changes in the peripheral blood
smear suggestive of pernicious anemia.
- 15. Name two crucial cofactors
in DNA synthesis whose deficiency results in pernicious anemia.
In what specific biochemical pathways do they participate?
- 16. Why neurologic defects are observed
in prolonged pernicious anemia?
- 17. Why symptoms of pernicious anemia
are usually relatively mild?
- 18. Are changes in the peripheral
blood smear necessary for neurologic effects of vitamin B12 deficiency?
The most important leukocyte abnormalities are the malignant
disorders leukemia and lymphoma. They are discussed in Chapter 5.
Absolute neutropenia, characterized by neutrophil counts less than
1500–2000/μL (> 2 SD below the
mean in normals) is a commonly encountered problem in medicine and
can be due to a large number of disease entities (Table
6–5). Cyclic neutropenia, however, is rare. It is
of interest because it provides insight into normal neutrophil production
and function. It is characterized by a lifetime history of neutrophil
counts that decrease to zero or near zero for 3–5 days
at a time every 3 weeks and then rebound. Interestingly, the peripheral
blood neutrophil counts and monocyte counts oscillate in opposite phases
on this 3-week cycle.
Classic, childhood-onset cyclic neutropenia results from mutations
in the gene, ELA2, which encodes for a single enzyme, neutrophil
elastase (NE). NE is found in the primary azurophilic granules of
neutrophils and monocytes. There are approximately 100 cases in
the literature, most of which are consistent with an autosomal dominant
inheritance. However, sporadic adult cases also occur, and these
are associated with neutrophil elastase mutations. There does not
seem to be a racial predilection or gender bias in incidence.
The neutrophil count in blood is stable in normal individuals, reflecting
the fact that there is a large storage pool of granulocytes in the
marrow. The marrow reserve exceeds the circulating pool of neutrophils
by 5- to 10-fold. This large pool is necessary because it takes
nearly 2 weeks for the full development of a neutrophil from an
early stem cell within the bone marrow, yet the average life span
of a mature neutrophil in blood is less than 12 hours.
In cyclic neutropenia, the storage pool is not adequate. Daily
measurements of neutrophil counts in the blood reveal striking variations
in their number. Studies of neutrophil kinetics in affected patients
reveal that the defect is in abnormal production, rather than abnormal
disposition of neutrophils. Neutrophil production occurs in discrete
waves even in normal individuals. As neutrophils differentiate from
an early progenitor cell, they produce neutrophil elastase, which
is thought to inhibit the differentiation of myeloblasts in a negative
feedback loop. This results in an oscillatory wave with peaks and
troughs of neutrophil production. As neutrophil numbers increase
in the marrow, a peak is obtained where enough neutrophil elastase
causes a drop in neutrophil differentiation. Then, as the number
of neutrophils drops again to a nadir, the production of neutrophil
elastase also declines, allowing the number of neutrophils to climb
once again. In cyclic neutropenia, it is hypothesized that the mutant
neutrophil elastase may have an excessive inhibitory effect, causing prolonged
trough periods and inadequate storage pools to maintain a normal
peripheral neutrophil count. However, once they are extruded from
the marrow, the neutrophils appear to have a normal life span (Figure
Feedback loop hypothesis to explain hematopoietic cycling.
Neutrophil elastase (NE) is postulated to inhibit further differentiation
by a myeloblast. Blue sinewave denotes neutrophil count oscillations.
In this model, NE is produced by the terminally differentiating cohort
of neutrophils and ultimately feeds back to inhibit further production
of neutrophils, which results in loss of the inhibitory cycle—at
least for a while, until production of the neutrophils resumes,
followed again by the inhibitory action of NE in a cyclic manner.
(Redrawn from: Horwitz MS et al. Neutrophil elastase
in cyclic and severe congenital neutropenia. Blood.
2007 Mar 1;109(5):1817–24. Copyright American Society of
The myeloid progenitor for neutrophil can also produce monocytes.
Therefore, during neutrophil nadirs, the myeloid progenitor cell
can preferentially differentiate to the monocyte lineage, giving
the opposing oscillatory waves of neutrophils and monocytes seen
in these patients (see Figure 6–11).
Regular cyclic variation of monocytes, reticulocytes,
and neutrophils in a patient with cyclic neutropenia. Note that
monocytes and reticulocytes tend to rise when the neutrophils fall.
(Redrawn, with permission, from Dale D, Hammond
WP. Cyclic neutropenia: A clinical review. Blood Rev. 1988;2:178.)
The waves are remarkably constant in their periodicity. Almost
every patient has a cycle between 19 and 22 days, and each patient’s
cycle length is constant during his or her lifetime. Neutrophils
and monocytes are not the only marrow elements that cycle. Platelet
and reticulocyte counts also cycle with the same cycle length, but,
in contrast to the blood neutrophil count, clinically significant
decreases are not observed. This is presumably because the blood
life spans of these elements are so much longer than the life span
of neutrophils. Because multiple cell lines are seen to cycle, it
is believed that neutrophil elastase mutations accelerate the process
of apoptosis (programmed cell death) in early progenitor cells,
as well, unless they are “rescued” by G-CSF.
Clinically, administration of pharmacologic doses of G-CSF (filgrastim)
to affected individuals has three interesting effects that partially
overcome the condition. First, although cycling continues, mean
neutrophil counts increase at each point in the cycle, such that
patients are rarely neutropenic. Second, cycling periodicity decreases
immediately from 21 days to 14 days. Third, other cell line fluctuations
change in parallel; their cycle periodicity also decreases to 14
days, suggesting that an early progenitor cell is indeed at the
center of this illness. However, the fact that cycling does not
disappear demonstrates that there are other abnormalities yet to
be discovered. It also suggests that there may be an inherent cycling
of all stem cells in normal individuals that is modulated by multiple
cytokines in the marrow.
The pathologic features of cyclic neutropenia are seen mostly in
the laboratory. The peripheral blood smear appears normal except
for the paucity of neutrophils—mature or immature—during
the nadirs of each cycle. Individual neutrophils appear normal.
The bone marrow, however, shows striking differences depending on
the day of the cycle on which it is examined. During the nadir of
each cycle, there are increased numbers of early myeloid precursors
such as promyelocytes and myelocytes, and mature neutrophils are
rare. This picture is similar to that seen in acute leukemia, but
10 days later, as circulating neutrophil counts are rising, an entirely
normal-appearing marrow is typical.
In general, neutropenia from any cause places patients at risk for
severe bacterial infections, generally from enteric organisms, because
of the alteration in host defenses in the gastrointestinal tract.
This is especially true when the neutropenia is due to administration
of chemotherapeutic agents, because chemotherapy also affects the
lining of the GI tract. Neutrophils, with their ability to engulf
bacteria and deliver toxic enzymes and oxidizing free radicals to
sites of infection, normally serve as the first line of host defenses
against the bacteria that inhabit the gut. Such patients are also
at risk for fungal infections if the neutropenia lasts more than
several days; this is because it takes longer for fungi to reproduce
and invade the bloodstream. Untreated infections of either type
can be rapidly fatal, particularly if the neutrophil count is less
than about 250/μL.
In cyclic neutropenia, then, recurrent infections are to be expected,
and deaths from infections with intestinal organisms have been reported.
Each cycle is characterized by malaise and fever coincident with
the time neutrophil counts are falling. Cervical lymphadenopathy
is almost always present as are oral ulcers. These symptoms usually
last for about 5 days and then subside until the next cycle.
When infections occur, the site is usually predictable. Skin infections,
specifically small superficial pyogenic abscesses (furunculosis)
or bacterial invasion of the dermis or epidermis (cellulitis),
are the most common and respond to antibiotic therapy with few sequelae.
The next most common infection site is usually the gums, and chronic
gingivitis is evident in about half of patients. It is also the
most noticeably improved problem when patients receive therapy with filgrastim.
Other infections are unusual, but any neutropenic patient is at
risk for infection from organisms that reside in the GI system.
In the few patients who have required abdominal surgery during their
neutropenia, ulcers similar to those seen in the mouth have been
noted; this destruction of the normal mucosal barrier presumably
eases entry of intestinal bacteria into the bloodstream. Because
the period of greatest susceptibility to infection is only a few
days in each cycle, most patients grow and develop normally.
- 19. How long does it take for
a neutrophil to develop from a stem cell in the bone marrow? Once
fully mature, what is its life span?
- 20. At what level of neutropenia does
the incidence of infection dramatically increase?
- 21. What are the most common sites
and types of infections observed in neutropenic patients?
- 22. What is the probable underlying
abnormality in cyclic neutropenia?
Thrombocytopenia, defined as the occurrence of platelet levels below
the normal laboratory range, is a commonly encountered abnormality.
Although there are many causes (Table 6–7),
the possibility of a drug-induced immune thrombocytopenia should
always be considered.
Many drugs have been associated with this phenomenon, and the
most common ones are listed in Table 6–9.
In practice, the association between a given drug and thrombocytopenia
is usually made clinically rather than with specific tests. Thrombocytopenia
usually occurs at least 5–7 days after exposure to the
drug, if given for the first time. The suspect drug is stopped and
platelet counts rebound within a few days. Rechallenge with the
drug, which is rarely done, almost always reproduces the thrombocytopenia.
Table 6–9 Common Drugs that May Cause Thrombocytopenia. |Favorite Table|Download (.pdf)
Table 6–9 Common Drugs that May Cause Thrombocytopenia.
|Amiodarone||Iodinated contrast agents|
|Aspirin||Nonsteroidal antiinflammatory drugs|
|Ethanol||Sulfonamides (antibiotics and hypoglycemics)|
Heparin is the most important cause of thrombocytopenia because
of its frequent use in hospitalized patients; its use also carries
the potential to cause a life-threatening thrombotic syndrome. The
pathophysiology of the thrombocytopenia caused by heparin is also
the most completely described.
Although the phenomenon of drug-induced thrombocytopenia has
been known for decades to be immune in nature, the specific mechanisms
have long been controversial. The association of antibodies with
platelets leads to their destruction via the spleen. The spleen
acts as the major “blood filter” and recognizes
platelets bound to antibodies as abnormal and thus removes them.
Spleen removal also occurs in autoimmune (idiopathic) thrombocytopenia,
which is relatively common and difficult to distinguish clinically
from drug-induced thrombocytopenia.
There are various mechanisms underlying drug-induced immune thrombocytopenia.
Quinine- or NSAID-induced thrombocytopenia involves the tight binding
of antibody to normal platelets only in the presence of the sensitizing
drug. The antibody usually targets epitopes on the glycoprotein
IIb/IIIa or Ib/IX complexes, the major platelet
receptors for fibrinogen and von Willebrand factor, respectively.
Penicillin and cephalosporin antibiotics are believed to lead to
platelet destruction via hapten-dependent antibodies. The drug acts
as a hapten, a small molecule that only elicits an immunologic response
when it is bound to a large carrier molecule or protein. Some drugs
(gold salts, procainamide, and possibly sulfonamides) can induce
autoantibodies that are capable of binding to and destroying platelets even
in the absence of the sensitizing drug.
For heparin, there is clear evidence of binding to a platelet protein,
platelet factor 4 (PF4). PF4 resides in the alpha granules of platelets
and is released when they are activated. It binds back onto the
platelet surface through a specific PF4 receptor molecule, further
increasing platelet activation. It also binds with high affinity
to heparin and to heparin-like glycosaminoglycan molecules present
on the vascular endothelium. This non–immune-based adhesion
to PF4 can lead to mild thrombocytopenia via promotion of platelet
binding to fibrinogen and subsequent aggregation, known as heparin-induced
thrombocytopenia (HIT) type I. This
can happen in 30% of patients exposed to heparins without
clinical sequelae. However, the combination of heparin with PF4
can also act as an antigenic stimulus that provokes the production
of immunoglobulin G (IgG) directed against the combination. This immunologic
response is known as heparin-induced thrombocytopenia (HIT) type
II. These antibodies can occur in 17% of patients
treated with unfractionated heparin and 8% of those treated
with low-molecular-weight heparins. About 20% of these
patients with heparin-PF4 antibodies will develop a serious clinical
syndrome, which paradoxically involves both thrombocytopenia 5–10
days after drug exposure and a prothrombotic state via increased
Thrombocytopenia occurs in HIT type II after a series of steps.
First, PF4 is released from platelets either by heparin itself or
by other stimuli. Heparin then binds to PF4, forming an antigenic
complex that results in the production of IgG antibodies that can
bind directly to this compound. The new complex of IgG-heparin-PF4
binds to platelets through the platelet Fc receptor, via its IgG
end. Platelets bound with this antibody complex are then destroyed
by the spleen.
Despite the resulting thrombocytopenia, HIT type II leads to a
prothrombotic state via the additional binding of the heparin-PF4
portion to the PF4 receptor on platelets, promoting platelet cross-linking,
activation, and aggregation (Figure 6–12).
Pathogenesis of heparin-induced thrombocytopenia (HIT).
IgG is the autoantibody against the heparin-PF4 complex. Platelets
can bind to each other and become activated via either the IgG-Fc
receptor interaction or the PF4-PF4 receptor interaction or both.
Aggregation and thrombus formation may thus occur. Furthermore,
IgG may bind to endothelial cell bound heparan-PF4 construct and cause
vascular damage, which may also provoke thrombus formation.
Because each end of this IgG-heparin-PF4 molecule can bind to
a platelet, it is possible that platelets can become cross-linked
by a single molecule. Many platelets could actually interact in
this fashion, leading to further platelet aggregation and activation.
Clinically, this decreases the numbers of circulating platelets,
but it may also lead to creation of a thrombus at the site of activation.
Thus, despite the fact that heparin is the most commonly used anticoagulant,
in this case it may actually provoke coagulation. Furthermore, the
activation of platelets via this mechanism leads to increased amounts
of circulating PF4, which can bind to more heparin and continue
the cycle. The excess PF4 can also bind to the endothelial surface
via the heparin-like glycosaminoglycans described earlier. It is
thus possible that the antibodies to the heparin-PF4 construct could
bind to the endothelial cells as well, which may lead to endothelial
cell injury, further increasing the risk of local thrombosis by
generating tissue factor and ultimately thrombin. Lastly, there
is some evidence that macrophages may release tissue factor in response
to these antibodies, further stimulating the coagulation cascade.
The peripheral blood smear is not strikingly abnormal unless platelet
counts are less than about 75,000/μL,
and then it is usually abnormal only because relatively few platelets
are seen. Platelet morphology, however, is usually normal, although large
platelets can be seen. These large platelets are less mature and
are a bone marrow compensation for a low peripheral platelet count,
with platelet production from megakaryocytes being increased. Although
drugs—heparin in particular—may cause platelet
aggregation in vivo and in vitro, this is usually not apparent on
review of the blood smear.
The bone marrow usually appears normal, although the megakaryocyte
number may be relatively increased, presumably reflecting an attempt
to increase the number of platelets (megakaryocyte fragments) in
the circulation. In a few cases of immune-mediated thrombocytopenia,
however, there may be decreased numbers of megakaryocytes. There
are many hypotheses as to why this may occur, but it most likely
means that the antigenic combination of drug-platelet protein is
also occurring on megakaryocytes, so that they as well as the platelets
in the peripheral circulation are being immunologically destroyed.
This destruction would not involve the spleen, of course, but would
require antibody-dependent cell killing.
In patients who develop heparin-induced thrombocytopenia and
thrombosis, thrombi are seen that are relatively rich in platelets
when compared with “typical” thrombi seen in other
situations. They are described as “white clots.” The thrombi
may be either arterial or venous.
Despite that the platelet count in immune-mediated thrombocytopenia
can be extremely low (< 10,000/μL,
compared with a normal value of over 150,000/μL),
significant bleeding is unusual. More often there is easy bruising
with minimal trauma. With platelet counts of less than about 5000/μL,
pinpoint hemorrhages (petechiae) may spontaneously
occur in the skin or mucous membranes. These are self-limited because
the plasma coagulation factors are still intact, and only a small number
of aggregated platelets are needed to provide adequate phospholipid
for the clotting cascade.
The relationship between the likelihood of bleeding and the platelet
count is not linear. The bleeding time test used clinically
to evaluate platelet function does not even begin to be abnormally
prolonged until the platelet count is less than 90,000/μL.
Spontaneous bleeding is unlikely until platelet counts are less
than 20,000/μL but is still uncommon until counts
are less than about 5000/μL. This assumes
that patients do not have other abnormalities of hemostasis, which
is not always true. For example, aspirin inhibits platelet aggregation and
increases the likelihood of bleeding. When bleeding from thrombocytopenia
does occur, it is most often mucosal or superficial in the skin.
This is most commonly seen as a nosebleed (epistaxis), but bleeding
of the gums, GI tract, or bladder mucosa may be seen.
As mentioned, however, when immune thrombocytopenia occurs as
a result of heparin, paradoxical clotting may occur instead of bleeding.
This may cause a very confusing picture, because the heparin may
have been given therapeutically for another thrombosis; it may be
difficult to determine whether the new thrombosis is an extension
of the initial clot or a new one referable to the heparin. However,
the occurrence of the simultaneous thrombocytopenia provides a clue.
When heparin-induced thrombocytopenia and thrombosis do occur,
the clinical manifestation of the new thrombosis will depend on
the site of the thrombus. Most studies of this disorder suggest
that when thrombosis occurs, it is at the site of previous vascular
injury or abnormality. Thus, in patients with atherosclerotic vascular
disease, arterial thromboses are much more common than venous clots.
Patients have the rapid onset of severe pain, usually in an extremity,
with a cool, pale limb. Pulses are absent. This can be life threatening
or at least extremity threatening because oxygen flow to the affected
area is cut off, and emergency clot removal or vascular bypass surgery
may be necessary. Venous clots also occur in a manner similar to
typical venous clots (see later discussion). In addition to stopping
heparin, patients with type II HIT need anticoagulation to prevent
and treat thrombosis formation. Direct thrombin inhibitors, (argatroban,
lepirudin, or bivalirudin) provide a direct means of blocking the
effects of thrombin, a primary mediator of the coagulation cascade.
- 23. What is the most common category
of cause of thrombocytopenia?
- 24. Name the antibodies to which platelet
protein are implicated in the pathogenesis of heparin-induced thrombocytopenia?
- 25 By what mechanism can heparin-induced
thrombocytopenia actually increase clot formation?
- 26. Why is major bleeding unusual
in drug-induced thrombocytopenia?
The formation of blood clots in otherwise normal vessels is distinctly
abnormal because the coagulation system in mammalian species is
both positively and negatively balanced by so many factors. Nonetheless,
there are a number of diseases that result in abnormal clotting
(thrombosis). Abnormal clotting states may be either
primary, in that the abnormalities are due to genetic predispositions
involving the coagulation factors themselves, or secondary (ie,
acquired) because of changes in coagulation factors, blood vessels,
or blood flow.
As first noted by the pathologist Virchow more than 150 years
ago, there are three possible contributors to formation of an abnormal
clot (thrombus): decreased blood flow, vessel injury or inflammation,
and changes in the intrinsic properties of the blood. Persistent
physiologic changes in any of these three factors (Virchow’s
triad) are referred to as the “hypercoagulable states.”
The primary, or inherited, hypercoagulable states are all autosomal
dominant genetic defects. This means that carriers (heterozygotes)
are affected. Except for hyperprothrombinemia, all lead to only
moderate (50%) decreases in the levels of the relevant
factors. Despite the relatively modest fall, affected individuals
are predisposed to abnormal thrombosis. These disorders are relatively
rare in the general population, but they do account for a significant
percentage of young patients who come to medical attention with
thromboses. The specific states to be discussed are activated protein
C resistance (the most commonly encountered abnormality), protein
C deficiency, protein S deficiency, antithrombin deficiency, and
the prothrombin 20210 AG abnormality. Hyperhomocystinemia, an inborn
error of metabolism, is also an inherited hypercoagulable state,
but because it does not involve the coagulation cascade, it is not
further discussed here.
In the coagulation cascade, activated factor V (Va) plays a pivotal
role (Figure 6–13). It is required
for significant activation of factor X (to Xa), which is the central
control factor involved in the entire cascade. Factor Va thus makes
an excellent negative control point, so that once clot formation
has begun, it does not go on unchecked.
Central role of factor V in the control of the coagulation
cascade. The action of each of the negative control factors: protein
S, protein C, and antithrombin, is shown in color.
Protein C is the major inhibitor of factor Va. Although it is an
anticoagulation factor, its production is contingent on vitamin
K-dependent γ-carboxylation, just like the coagulation factors
II, VII, IX, and X. Protein C, when activated by the presence of
clotting that generates thrombin, cleaves factor Va into an inactive
form, and activation of factor X is thus slowed. By itself, however,
protein C only weakly influences factor Va; its negative effect
on factor Va is enhanced by a protein cofactor, protein S.
Factor V does not provide the only negative control point, however.
Protein C also inhibits activated factor VIIIa. Factors II, IX,
X, XI, and XII (the serine proteases) are inhibited by a different
molecule, antithrombin (AT). The action of AT itself is also regulated
and is highly dependent on the binding of an accelerator, heparin,
or similar molecules that are present in abundance along the endothelial
cells that line the vasculature. Evidence suggests that AT may also
inhibit the factor VII–tissue factor complex.
The fact that deficiencies of protein S, protein C, and antithrombin
activity cause clinically significant thrombosis demonstrates an
important concept: It is the lack of adequate anticoagulant activity
rather than the overproduction of procoagulant activity that characterizes
most of the hypercoagulable states.
Protein C Resistance
Activated protein C resistance is the most common inherited hypercoagulable
state, with as many as 2–5% of the general population
heterozygous for the abnormality. Up to 25% of patients
who have venous thrombosis without an inciting event are found to
have activated protein C resistance in a large patient series. Most
of the cases are due to a single DNA base pair mutation in the factor V
gene, where guanine (G) is replaced by adenine (A). This single
base change leads to substitution of the amino acidglutamine for
arginine at position 506, and the altered factor V is referred to
as “factor V Leiden,” named for the town in the Netherlands
where it was discovered. This amino acid change alters the three-dimensional
conformation of the cleavage site within factor Va, where activated
protein C normally binds to inactivate it. Thus, factor Va molecules
can continue to enhance factor Xa’s conversion of prothrombin
to thrombin (factor IIa), and coagulation is not inhibited.
Protein C deficiency is common; up to 1 of every 200 individuals
in the population is a heterozygote. Yet thrombosis is uncommon
among these individuals. The families that are thrombosis prone
are thought to carry additional genetic factors, in addition to
protein C deficiency, that increase their risk for thrombosis.
As noted earlier, protein C inactivates factors Va and VIIIa but
requires protein S for its own action. Protein C is also dependent
on the presence of platelet phospholipid and calcium. In protein
C deficiency, there is less inhibition of the prothrombinase complex,
leading to relatively unrestricted clot formation. Normally, some
of the thrombin generated in the cascade binds to an endothelial
cell protein, thrombomodulin, and this complex activates protein
C in the first place. This “negative feedback loop” is
thus lost in protein C deficiency.
Protein C deficiency is not all one disease, however, unlike the
factor V Leiden abnormality discussed previously. Type I deficiency
refers to individuals with decreased levels of protein C. Type II
deficiency denotes cases with normal protein C levels but low protein
Protein S deficiency is also an uncommon heterogeneous disorder.
Type I protein S deficiency refers to cases with low free and total
protein S levels. Type II deficiency, which is the least encountered,
refers to an abnormal functioning protein S. Type III deficiency
refers to only low levels of free protein S. In the coagulation
cascade, when factors Va and Xa are complexed together, the inactivation
site on factor Va is “hidden” from protein C.
Protein S, not a protease itself, exposes this site so that protein
C can cleave Va. Because protein S is so crucial, deficiency of
protein S also leads to the unregulated procoagulant action of factor
Antithrombin (AT) deficiency is less common than any of the previously
discussed disorders, with approximately 1 in 2000 cases in the general population.
AT binds to and inhibits not just thrombin (whence its name) but
also the activated forms of factors IX, X, XI, and XII and perhaps
the factor VII–tissue factor complex as well. Unlike protein
C’s proteolytic cleavage of factor Va, AT binds to each
factor, directly blocking their activity; it is not an enzyme. This
action is accelerated—up to 2000 times—in a reversible
manner by the anticoagulant molecule heparin, which binds to AT
via its pentasaccharide sequence. The anticoagulant fondaparinux
is a synthetic version of this five-saccharide sequence, and thus,
it can also bind to AT. In AT deficiency, then, multiple coagulation
steps are unbalanced, and the coagulation cascade may proceed unrestrained.
More than 100 different AT mutations have been reported. Type I molecular
defects involve a parallel decrease in antigen and activity, while
Type II defects involve a dysfunctional molecule that has decreased
activity, but normal or near-normal antigen levels.
A mutation in the untranslated region of the prothrombin gene
(a single base pair mutation, called 20210 AG) is associated with
elevated plasma prothrombin levels and an increased risk of thrombosis.
Presumably, this leads to excess thrombin generation when the prothrombinase
complex is activated. This is probably the second most common hereditary
hypercoagulable state after factor V Leiden. It is the first hereditary
thrombophilia associated with overproduction of procoagulant factors.
The pathologic features of thrombi in hypercoagulable states are
indistinguishable from those of genetically normal individuals on
a gross anatomic or microscopic basis, except that there is a greater
likelihood in hypercoagulable states of having a clot in unusual
sites. (See Clinical Manifestations section.)
Most of the pathologic features of the hereditary hypercoagulable
states consist of laboratory abnormalities, and findings depend
on which laboratory tests are requested. In the evaluation of patients
suspected of having a hereditary hypercoagulable state, there are
two basic types of laboratory abnormalities. The first type is quantitative:
Specific immunologic assays can define the relative amount of protein
C, protein S, antithrombin, or fibrinogen present in a given patient’s serum,
but they do not evaluate the function of any of these molecules.
The second type is qualitative: The assays for protein C or protein
S activity (rather than amount) measure the ability (or inability)
of the patient’s protein C or S to prolong a clotting time
in vitro. Activated protein C resistance can be evaluated with a
different clotting assay, but generally the presence of the specific
mutation in factor V Leiden is assessed by the polymerase chain
reaction, because the full sequence of the molecule is known. The
polymerase chain reaction is also used for detecting the 20210 AG
prothrombin abnormality. Prothrombin levels can also be measured
and are consistently in the highest quartile of prothrombin levels found.
Most thromboembolic events encountered in clinical practice are
secondary, not primary. Patients have blood clots usually in the
deep veins of the legs for two reasons: (1) because of sluggish
blood flow (in high-capacity, low-flow veins) compared with other
sites, particularly when inactive (bedridden after surgery or as
a result of illness); and (2) because the extremities are more likely
to sustain injury than the trunk. Trauma causes blood vessel compression
or injury; thus, two elements of Virchow’s triad are more
readily observed in the legs than elsewhere.
These venous clots in the legs (commonly referred to as deep
venous thromboses [DVTs]) usually present with
pain, swelling, and redness below the level of the thrombus, with normal
arterial pulses and distal extremity perfusion. Because blood return
to the central circulation is blocked in these high-capacity vessels,
superficial collateral veins just under the skin may be prominent
and engorged. The swelling is mechanical, because normal arterial
blood flow continues to the extremity while venous return is compromised,
leading to engorgement. Pain occurs primarily as a result of the
swelling alone but can also occur from lactic acid buildup in the
muscles of the legs. This happens when the pressure in the legs increases
to the point that it compromises arterial blood flow and adequate
oxygen delivery to those muscles.
Pulmonary emboli, the major source of morbidity and mortality
after DVT of the lower extremity, typically present with acute-onset
shortness of breath, hypoxemia, and a history suggesting an initial
DVT that has now broken off and migrated through the right side
of the heart to the pulmonary arterial system. The presence of the
clot blocks blood flow from the heart to a portion of lung; thus,
the blood returning from the lung to the heart is not fully oxygenated. The
degree of hypoxemia depends on how much of the blood flow is blocked
and whether the patient has any underlying lung disease.
The clinical presentations of all of the hypercoagulable states
are similar, but there are some interesting differences. DVTs tend
to occur (whether there is a hypercoagulable state or not) in patients
with a history of trauma, pregnancy, oral contraceptive use, or
immobility but rarely in adolescents or young adults. The inherited
hypercoagulable states are suspected in patients who present with
a thromboembolic event, usually because they are young or have recurrent
clots. Events that occur without any specific risks, of course,
are particularly suspect. Because of the dominant pattern of inheritance, suspicion
is aroused when other family members have had clotting problems,
and this underscores the importance of taking a family history.
Despite the distinct coagulation abnormalities, most thromboses
still occur in usual sites (ie, the deep veins of the legs with
or without pulmonary embolism). Other unusual sites, however, are
much more likely than in patients without underlying coagulation
disorders, such as the sagittal sinus of the skull or the mesenteric
veins in the abdomen. The propensity for clotting notwithstanding,
arterial thromboses are extremely rare.
Interestingly, not all patients—probably not even a
majority—with an inherited hypercoagulable state develop
symptomatic thromboses; this is particularly true for heterozygotes.
Each disorder is slightly different, presumably because of the redundancy
of the factors in the coagulation cascade, and the penetrance of
each state varies in individual patients because of factors we do
not yet understand. For this reason, many patients come to medical
attention with a clot in a “usual” spot with a “typical” risk
factor: sustaining an injury, having an extremity immobilized, having
surgery, or being pregnant.
Homozygousprotein C or protein S deficiencies have the highest
likelihood of causing illness. Both conditions usually result in
thrombosis, which is fatal in early life (neonatal purpura fulminans),
although some patients may not present until their teens even with
these profound defects. Heterozygotes for protein C deficiency are
actually unlikely to develop a thrombosis over their lifetimes,
although they are about six times more likely to do so than members
of the general population. A similar propensity is true for the
heterozygous protein S state.
Antithrombin deficiency is another significant defect in terms
of the likelihood of developing thrombosis. These patients have
a lifetime 10-fold increased risk for thrombosis.
The situation is complex in the case of activated protein C resistance.
Proteins C and S can still cleave factor VIIIa and the factor V
abnormality is a relative rather than an absolute insensitivity
to activated protein C. There is still negative control of the clotting
cascade at the factor X step by tissue factor pathway inhibitor
(TFPI) as well.
Heterozygotes for activated protein C resistance probably represent
more than one third of all patients with familial thromboses. An
individual’s risk of developing a clot, however, is lower
than with protein S or protein C deficiency. Heterozygosity for
factor V Leiden results in a lifelong 5-fold increased risk for
Even homozygous factor V Leiden does not inevitably cause thrombosis.
Families in which homozygous females have had repeated pregnancies
without difficulty have been carefully described. This is somewhat
surprising because pregnancy, a hypercoagulable state itself, leads
to decreases in protein S concentration, which would be expected
to amplify the resistance to protein C. Nevertheless, case-control
studies suggest at least a 30-fold increased risk of thrombosis
versus the general population for homozygotes for factor V Leiden.
Persons with the prothrombin 20210 AG mutation are nearly all
heterozygotes, with about a threefold higher risk of thrombosis
than the general population.
- 27. What constitutes Virchow’s
triad of factors predisposing to formation of intravascular clots?
- 28. Deficiencies in what proteins
can result in clinically significant thromboses?
- 29. What is the basis for activated
protein C resistance?