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Файл:Ординатура / Хирургия / Библиотека им академика М.И. Перельмана / Книга_3063_Библиотеки_им_академика_М_И_Перельмана
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Assessment
The patient presents with an acute onset of jaundice and severe anemia, suggestive of
hemolysis or liver dysfunction with associated bleeding. There is no clinical evidence of
bleeding, coagulopathy, or hepatomegaly suggestive of a primary hepatic process.
CCS NOTE
The case simulations are liberal in accepting extra ordered diagnostic tests. Patients
with fatigue should have a CBC. Jaundiced patients should have all LFTs.
The presence of markedly elevated serum indirect bilirubin and hemoglobin-positive urine in
the absence of RBC is consistent with acute hemolysis with spillage of hemoglobin into the
urine. Hemolytic anemia results from the premature destruction of circulating RBCs and is
characterized by elevation of the reticulocyte count, lactate dehydrogenase, and, unconjugated
bilirubin, and a decrease in haptoglobin.
Hemolysis may occur in the extravascular or intravascular space. The former generally
presents in a subacute manner and results from premature destruction of RBC in the spleen and
liver. This may occur in the setting of splenomegaly as a result of liver disease, infection, or
hematologic malignancy. Extravascular hemolysis may be caused by autoantibodies directed
against RBCs and is seen in the setting of autoimmune disease, lymphoproliferative disease, or
drugs such as penicillin or alpha-methyldopa. The presence of autoantibodies bound to RBC
membranes results in a positive direct Coombs test, whereas excess antibody in the serum
leads to a positive indirect test. Extravascular hemolysis may also be caused by membrane
No urobilinogen; hemoglobin-positive; no RBC or WBC
U/S normal
301
abnormalities, such as hereditary spherocytosis, which renders RBCs more susceptible to
splenic destruction.
The acute onset of symptoms in this patient with a dramatic drop in hematocrit is more
suggestive of intravascular hemolysis. It is characterized by the presence of hemoglobinemia,
which results in hemoglobinuria, hemosiderinuria, and a marked decrease in serum
haptoglobin. Intravascular hemolysis may be caused by microangiopathic processes such as
thrombotic thrombocytopenic purpura, hemolytic uremic syndrome, disseminated intravascular
coagulation, and malignant hypertension, which are characterized by the presence of
schistocytes on peripheral smear. Other potential causes include complement-mediated lysis,
toxin-mediated lysis (Clostridium perfringens sepsis), and oxidant-mediated lysis (G6PD
deficiency). The latter may be precipitated by exposure to oxidant stresses, such as fava beans,
that the patient likely ingested. The most common type of oxidant stress causing hemolysis in
G6PD deficiency is infection.
Basic Science Correlate
Mechanism of Heinz bodies and bite cells:
Mechanism of cold agglutinin disease:
Mechanism of PNH:
Oxidized Hg precipitates in RBC membrane as Heinz bodies
Spleen “bites” out a piece of the membrane as bite cell
IgM destroys RBCs in Kupffer cells of liver
This is why neither steroids nor splenectomy is an effective treatment
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Why are there no fragmented cells on smear in G6PD hemolysis?
Further Management Plan/Results
Positive
Low/absent
Negative
Heinz bodies
CCS NOTE
Genetic defect leads to loss of PIG-A which is where complement-removing factor
anchors to prevent cell destruction by C5
Measure this as decreased CD55/59 by flow cytometry
Acidosis increases complement activation at night in PNH
Because the cells “melt” like ice in hot water from oxidant stress from infection
They are not “broken” into fragments as in TTP, HUS, or DIC
Urine for hemosiderin and hemoglobin
Haptoglobin
Coombs test
Supravital stain (crystal violet or methylene blue) of peripheral smear
Hydration to prevent renal failure from hemoglobinuria
303
Test results appear automatically as you advance the clock in the exam.
Discussion
Glucose-6-phosphate dehydrogenase (G6PD) is the most common enzyme abnormality of
RBCs and is thought to affect hundreds of millions of people worldwide. It is an X-linked
disorder and therefore clinical disease is more prevalent in men. G6PD is an important enzyme
in the hexose monophosphate shunt. This pathway is important in generating reduced
glutathione in response to oxidant stresses, thus protecting hemoglobin from having sulfhydryl
groups activated and causing precipitation. G6PD activity normally declines as the cell ages.
This process is accelerated in patients with the deficiency and there are many degrees of
severity.
The A-variant of this deficiency is found commonly in central Africans and in 15% of African
Americans. In general, these patients have a mildly decreased red-blood-cell survival time but
are not anemic. However, when an exposure to an oxidant stress occurs (such as infection,
sulfa drugs, diabetic ketoacidosis, antimalarials, or accidental ingestion of mothballs) acute
hemolysis can occur. Other medications that can cause hemolysis are dapsone, primaquine, and
nitrofurantoin.
Another population with a high incidence of G6PD deficiency is that of the Mediterranean
basin. These patients tend to have a more severe form with lower enzyme levels and greater
sensitivity to oxidants. Some of these individuals display a marked sensitivity to fava beans.
Clinically, patients present with signs of acute hemolysis, including indirect hyperbilirubinemia
without the presence of bilirubin in the urine because unconjugated bilirubin is tightly bound to
albumin. Haptoglobin binds free hemoglobin, but when this is overwhelmed, free hemoglobin
is filtered by the glomeruli and is converted to hemosiderin in tubular cells. When this system
is overwhelmed, free hemoglobin is put out in the urine, leading to a reddish-brown color.
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The above patient is Greek and recently ate in a restaurant that might have served fava beans.
Confirmation of the diagnosis is difficult in the acute situation because of the hemolysis of
older RBC and the presence of only circulating young RBC and reticulocytes. These cells may
have normal G6PD activity because it is a biased young population. The diagnosis may require
repeating the test once the acute hemolytic period is over.
Follow-up Management and Prevention
Basic Science Correlate
Why do you have to wait 2 months to check a G6PD level?
Mechanism of hemolysis in G6PD deficiency:
Final Diagnosis
Consider transfusional support if necessary
Avoid offending drugs or foods in future
Move clock forward 2 months and check G6PD level
Levels of G6PD are normal just after an episode of acute hemolysis
The older cells with lower levels have already been destroyed, and all there is to
test are younger cells with higher level
Infection is most common oxidant stress
Infection uses up small amount of G6PD in the cell and then it is destroyed
prematurely
305
Acute hemolysis due to glucose-6-phosphate dehydrogenase (G6PD) deficiency
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Case 2
Chief Complaint
Nose bleed
History and Physical Examination
A 25-year-old previously healthy woman comes to the local emergency department with
epistaxis for several hours that has finally responded to pressure and elevation. The
patient is bleeding from both nostrils. She denies fever, chills, and recent upper
respiratory symptoms. She had noted multiple “spots” on both ankles, and she has gingival
bleeding. A CBC is drawn which reveals platelet count 10,000/mm
3
(normal 150,000–
400,000/mm
3
). The patient takes no medications and has no significant past medical
history.
Her blood pressure is 110/86 mm Hg and pulse 88/min. She is afebrile. Physical
examination shows no focal lesion in the nasal mucosa. The oropharynx is not infected.
Multiple petechiae are seen on both ankles. The remainder of the examination is
unremarkable.
Differential Diagnosis
Immune thrombocytopenic purpura (ITP)1.
Acute leukemia2.
Disseminated intravascular coagulation (DIC)3.
Drug-related thrombocytopenia4.
307
Initial Management
Setting: emergency department
Diagnostic/Therapeutic Plan
Test Results
Assessment
The patient has the acute onset of thrombocytopenia without systemic symptoms.
Thrombocytopenia results from a failure of platelet production or premature destruction. This
distinction may be made by performing a bone-marrow examination in which the presence of
increased numbers of megakaryocytes suggests peripheral consumption of platelets. The former
is associated with marrow suppressive states and pancytopenia. Potential etiologies include
drugs such as sulfa antibiotics, marrow failure due to aplastic anemia, vitamin B12 and folate
deficiency, and marrow infiltrative disorders, such as hematologic malignancy, metastatic solid
Aplastic anemia
5.
von Willebrand disease (vWD)
6.
Marrow infiltration (malignancy)
7.
Systemic lupus erythematosus
8.
CBC, differential, peripheral smear
PT/PTT
Fibrinogen
WBC 5,000/mm
3
, hemoglobin 13 mg/dL, 67% granulocytes, 23% lymphocytes, 10%
monocytes, no abnormal cells seen; large platelets (10,000/mm
3
) noted
PT 11 seconds (normal)/PTT 33 seconds (normal)
Fibrinogen normal
308
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tumors, and disseminated mycobacterial or fungal infection. Because the patient is not acutely
ill, is not on medications, and has no abnormalities on peripheral smear, these causes are
unlikely.
CLINICAL PEARL
Patients with a bleeding problem should have their PT checked and a CBC. Do not
worry if the test results are normal. What matters is that the tests could have been
abnormal.
Increased platelet destruction may be due to microangiopathic processes, such as disseminated
intravascular coagulation, thrombotic thrombocytopenia purpura, or hypersplenism. However,
isolated thrombocytopenia is more likely to be platelet autoantibodies. This may be seen in the
setting of systemic lupus erythematosus, HIV, or lymphoproliferative diseases such as chronic
lymphocytic leukemia, (CLL). Infections such as Cytomegalovirus, herpes, and hepatitis can
also cause antibody-mediated thrombocytopenia. In addition, drugs such as heparin, penicillin,
or quinidine may stimulate antibodies that are cross-reactive with platelets or may bind as
antigen/antibody complexes to the platelet surface (innocent bystander effect). If no clear
underlying condition can be identified, it is most likely antibody-mediated thrombocytopenia,
also known as ITP (diagnosis of exclusion).
Further Management Plan/Results
Negative
Prednisone orally
HIV test
309
Platelet count 12,000, increased mean platelet
volume
No specific recommendations are made
Normocellular, normal erythroid and myeloid
maturation; normal M:E ratio; markedly
increased numbers of megakaryocytes with
some immature megakaryocytes
Negative
Normal-sized spleen
CCS NOTE
If a patient has a serious problem, always initiate therapy and do not wait for specific
test results. In this otherwise healthy patient with isolated thrombocytopenia and a
normal spleen, initiating prednisone is more effective than waiting for specific tests.
Discussion
Antibody-mediated thrombocytopenia (ITP) is characterized by immune destruction of
circulating platelets by autoantibodies. In adults, it is seen more commonly in women. Immune-
related thrombocytopenia may be triggered by medications, or it could be associated with
collagen-vascular disease or lymphoproliferative diseases. Diagnosis of antibody-mediated
thrombocytopenia is suggested by severe thrombocytopenia in the presence of increased
Repeat CBC
Hematology consult
Bone marrow biopsy
ANA
Abdominal U/S
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