·
Trousseau
syndrome is a chronic form of DIC.
When onset of DIC is slow, as is seen in some patients with cancer,
compensation can occur. In these patients, a procoagulant state exists, and the
patient has a predisposition for arterial and venous thrombosis (unlike in the
acute forms of DIC, in which bleeding predominates). The typical laboratory abnormalities associated with acute DIC
(thrombocytopenia, elevations in levels of coagulation factors,
microangiopathic hemolytic anemia, decreased fibrinogen levels, and elevated
D-dimer levels) are usually not present in patients with the chronic form; the
exception to this is an elevated D-dimer level. Therapy is directed
at the underlying disease. This patient with Trousseau syndrome and DVT should
receive subcutaneous heparin if its use is not contraindicated.
·
The deletion of the long arm of chromosome 5 is
present in some acute myeloid leukemias and is
associated with older age at diagnosis.
The inversion of
chromosome 16
is typically present in acute myelomonocytic leukemia
(M4 subtype).
The translocation
of the long arms of chromosomes 15 and 17 is the mutation associated with acute promyelocytic anemia that results in arrest of
cellular differentiation that can be treated with pharmacologic doses of ATRA.
Finally, trisomy 12 is
one of several mutations that may result in the development of chronic lymphocytic leukemia.
·
The cryoglobulin
associated with hepatitis C
typically contains a monoclonal IgMk with rheumatoid factor activity that binds
to polyclonal IgG, hence the term ‘mixed cryoglobulin’. The cryoglobulin in CLL usually represents the monoclonal
protein produced by the malignant lymphocyte clone. The cryoglobulin in hepatitis B and lupus reflects the immune
complexes in the condition and is typically small and polyclonal. Cryoglobulins
are not associated with CML.
·
Antithrombin
deficiency is an autosomal dominant
condition present in 0.02 - 1.1% of the population and is found in 4% of
subjects that present with a thromboembolism.
Factor V leiden is a possibility although
seems less likely as the inheritance pattern seems more likely to be AD. Similarly as the son had a DVT this would be
far less likely with FVLeiden than ATIII as
thrmobosis is more often precipitated in females on the OCP.
·
PT (extrinsic)––factors II, V, VII, and X.
·
PTT (intrinsic)––all factors except VII.
·
The peritubular
interstitial cells located in the inner cortex and outer medulla of
the kidney are the primary sites for erythropoietin
production.
·
The proliferation
and maturation of platelets take longer than those of either red
blood cells (7 to 10 days) or white blood cells (10 to 14 days) and thus are
the slowest to recover from an acute bone marrow injury, such as occurs
with chemotherapy.
·
In Hemochromatosis,
If phlebotomy therapy removes the iron load before diabetes mellitus or
cirrhosis develops, the patient’s life expectancy is normal. If cirrhosis develops, however, the risk of
hepatocellular carcinoma is increased by more than 200-fold.
·
Serum folic acid levels are less reliable than
red blood cell folic acid levels. A serum folic
acid level of less than 2 ng/ml is consistent with folic acid
deficiency, as is a red blood cell folic acid level of less than 150 ng/ml.
Because the combination of folic acid and iron
deficiency is common, full expression of megaloblastosis is often
blocked, and the patient will have a dimorphic anemia rather than the easily
identifiable macro-ovalocytosis.
·
The mutation associated with PNH results in a deficiency of the
membrane-anchoring protein phosphatidylinositol
glycan class A. Normal human erythrocytes, and probably platelets and
neutrophils, modulate complement attack by at least three glycosylphosphatidylinositol
(GPI) membrane-bound proteins: DAF (CD55),
C8-binding protein (C8BP), and MIRL (CD59). Because the defective synthesis of GPI
affects all hematopoietic cells, patients with PNH may have variable degrees of
anemia, neutropenia, or thrombocytopenia, or they may have complete bone marrow
failure. Recurrent venous occlusions lead to pulmonary embolism and hepatic and
mesenteric vein thrombosis, possibly resulting from the release of procoagulant
microparticles derived from platelets. Diagnosis is made by specific tests
based on fluorescence-activated cell sorter analysis using antibodies that
quantitatively assess DAF (CD55) and particularly MIRL (CD59) on the
erythrocyte or on the leukocyte surface.
·
Risk factors that
predispose to painful crises in Sickle Cell Anemia include a
hemoglobin level greater than 8.5 g/dl, pregnancy, cold weather, and a high
reticulocyte count.
·
Erythrocytes sensitized to IgG alone are usually removed in the spleen, whereas RBCs sensitized to IgG plus complement or to complement alone
are generally destroyed in the liver,
because hepatic Kupffer cells carry receptors specific for complement component
C3b.
Both an
idiopathic variety of autoimmune hemolytic
anemia and a variety that occurs secondary to other disorders have
been described. Such primary disorders include systemic
lupus erythematosus, non-Hodgkin lymphoma (especially chronic lymphocytic
leukemia), Hodgkin disease, cancer, myeloma, dermoid cyst, HIV infection,
angioimmunoblastic lymphadenopathy with dysproteinemia, hepatitis C infection,
and chronic ulcerative colitis.
·
Patients with
alpha-thalassemia tend to have lower levels of MCHC and, thus, decreased
concentrations of HbS.
·
Some unstable hemoglobins, such as HbE, are susceptible to hemolysis from oxidative
stress. This hemoglobinopathy is diagnosed by hemoglobin electrophoresis.
However, this disease is seen almost exclusively in individuals from Southeast
Asia (Cambodia, Thailand, and Vietnam).
·
Gaisböck syndrome,
also known as relative polycythemia, is
usually found in men from 45 to 55 years of age; they are most often obese,
hypertensive men who may also be heavy smokers.
·
Patients with polycythemia vera who are older
than 70 years should be treated with a myelosuppressive agent such as
hydroxyurea in combination with phlebotomy.
·
The criteria used to diagnose HES are an unexplained eosinophil count of
greater than 1,500/mm3 for longer
than 6 months and signs or symptoms
of infiltration of eosinophils into tissues. The condition may be caused by
excessive IL-5 production by a T cell clone. Manifestations are multisystemic:
fever, rash, cough and dyspnea, diarrhea, congestive heart failure, and
peripheral neuropathy. The most severe complications involve the heart and CNS.
Careful evaluation is necessary to exclude other causes of eosinophilia. Endomyocardial fibrosis (Löffler endocarditis) is
a cardiac manifestation of hypereosinophilic syndrome. Eosinophilic deposits
may lead to direct injury of the endocardium, followed by platelet thrombi and
fibrosis. The cardiac apices can become obliterated, creating a characteristic
finding on echocardiography. The mitral and tricuspid valves are affected by
the same fibrotic process, resulting in valvular regurgitation.
·
Basophilia
(i.e., a basophil count of greater than 150/mm3) is seen in MPDs such as CML, PV, and myeloid
metaplasia; after splenectomy; in some hemolytic
anemias; and in Hodgkin disease. The basophil count can also be increased in
patients with ulcerative colitis or varicella infection.
·
Although less common than leukemoid reactions in
adults, leukoerythroblastosis reflects
serious marrow stimulation or dysfunction and should prompt bone marrow
aspiration and biopsy, unless it occurs in association with severe hemolytic
anemia, sepsis in a patient with hyposplenism, or massive trauma.
·
Large granular
lymphocyte syndrome is a clonal expansion of CD2+, CD3+, CD8+, CD16+, and CD57+ cells and is frequently
associated with rheumatoid arthritis. Patients present with neutropenia,
infections, and possibly splenomegaly and may be misdiagnosed as having Felty
syndrome. Unlike patients with Felty syndrome, however, these patients present
at an older age. Their neutropenia may develop within months of the onset of arthritis and is usually
associated with a normal or elevated blood leukocyte
(mostly lymphocytes) count.
·
Prevalence of
bleeding increases significantly below a threshold of about 10,000
platelets/µl in otherwise asymptomatic patients.
·
Until the cause
of the hemolytic transfusion reaction is identified, the patient may only
receive type O red cells or AB plasma.
·
Acetaminophen or, if the rigors are
particularly severe, meperidine is helpful in the management of febrile transfusion reaction but should be
preceded by discontinuance of the infusion.
·
The best results with allogeneic transplantation for AML
are obtained in patients undergoing transplantation in first remission, in whom
a cure rate of 40% to 70% is reported. As with AML, allogeneic
transplantation can cure 15% to 20% of patients with ALL who fail induction therapy or in whom
chemotherapy-resistant disease develops; thus, these patients are candidates
for the procedure. Allogeneic and syngeneic marrow transplantations are the
only forms of therapy known to cure CML.
Time from diagnosis influences the outcome of transplantation during the
chronic phase. The best results are obtained in patients who receive
transplants within 1 year of diagnosis; progressively worse results are seen
the longer the procedure is delayed. Use of marrow
transplantation in CLL has received only limited attention, probably
because of the indolent nature of the disease and its propensity to occur in
older patients.
·
Veno-occlusive
disease typically occurs in the first few
weeks after transplantation. Pathologically, there is cytotoxic
injury to the hepatic venulae and sinusoidal endothelium, resulting in
vascular blockage (the clinical picture is similar to that of Budd-Chiari
syndrome). There is a high mortality, and research continues in the fields of
treatment and prevention.
·
The genes that encode
HLA class I and II antigens are tightly linked and are typically
inherited together. Therefore, there is a one-in-four chance of
inheriting the identical haplotype of a sibling.
·
GVHD
is quite common in patients receiving allogeneic
transplants. The most common manifestation is that of a
maculopapular rash, frequently
involving the palms and soles. The second most common organ affected is the liver. Symptoms of liver involvement typically
include an elevation in levels of transaminase, alkaline phosphatase, and
conjugated bilirubin; these changes are the result of damage to the small bile
ducts. GI symptoms include diarrhea, anorexia, and crampy abdominal pain.
Efforts to prevent GVHD include the use of immunosuppressive agents in the
early posttransplantation period. GVHD is most frequently treated with
glucocorticoids. It does not cause ARF.
·
Platelets are
activated at the site of vascular injury to form a plug to stop
bleeding. Platelet activation involves four
distinct processes: adhesion, aggregation, secretion, and procoagulant
activity. Platelet adhesion is primarily
mediated by the binding of GPIb-IX-V complex to von Willebrand protein. Aggregation involves binding of fibrinogen to the
platelet fibrinogen receptor GPIIb-IIIa. Congenital deficiency of GPIIb-IIIa or
fibrinogen leads to Glanzmann thrombasthenia and afibrinogenemia. The
GPIIb-IIIa fibrinogen pathway is the final common course for platelet
aggregation. Platelet protein secretion
occurs after platelet stimulation, with the release of granules containing
serotonin and adenosine diphosphate (ADP), which stimulate and recruit more
platelets. Platelet procoagulation
involves the assembly of the enzyme complexes in the clotting cascade on the
platelet surface. Tissue plasminogen activator is a fibrinolytic factor; its
deficiency causes a hypercoagulable state.
·
Antithrombin III, protein C, and protein S are
important components of the control mechanisms that modulate coagulation. Protein S circulates in two forms: a free form, in which it is active as an anticoagulant; and a bound,
inactive form, in which it is complexed to
C4b-binding protein of the complement system. C4b-binding protein acts as an acute phase reactant. The
resultant increase in inflammatory state reduces the activity of free protein
S, enhancing the likelihood of thrombosis. In this patient, advanced HIV
disease is causing an inflammatory state in which the levels of free functional
protein S are decreased.
·
Bleeding time should not be used as a general
screening test in a preoperative setting. Although once used commonly
for screening of platelet disorders, bleeding time has been replaced by the
PFA-100. PFA-100 is a newly developed automated test of platelet function. Citrated blood
from the patient is aspirated onto a membrane coated with collagen and
epinephrine or collagen and ADP in which a central aperture is made. The time
it takes for blood flow through the membrane to stop is denoted as the closure
time and is a measure of platelet function. The closure time is prolonged in
patients with von Willebrand disease or other platelet functional defects.
PFA100 should be considered the first-line test for
platelet function disorders. Thrombin time
is used to test for abnormalities of the conversion of fibrinogen to fibrin.
Thrombin time is prolonged in patients with severe liver disease and DIC and
those undergoing heparin therapy. Factor VII levels are measured in patients
who have a prolonged PT; it is a test of
the extrinsic system. Factor XIII is the only clotting factor whose activity is
not assessed in PT or PTT; a deficiency should be suspected in an infant who
experiences bleeding after circumcision or in an adult with unexplained
bleeding.
·
Although most cases of ITP are idiopathic, it is well known that ITP can
be associated with a number of underlying conditions, including HIV, viral illnesses (e.g., Epstein-Barr virus [EBV]
infection), and autoimmune disease, most notably SLE. In adults, in
contrast to children, ITP can present as a smoldering disease. Therapy is
recommended for asymptomatic patients whose platelet counts are persistently
lower than 20,000 to 30,000/µl and for patients with significant bleeding
complications. Although in most patients ITP follows a relatively benign
course, serious bleeding complications are occasionally seen. Of these bleeding
complications, intracranial bleeding is the most
dreaded because it is commonly fatal. Intracranial bleeding is more
commonly seen when the platelet count drops below 10,000/µl; other risk factors
include advanced age and concomitant medical illness.
·
AT-III deficiency
is an autosomal dominant trait that affects nearly 1 in 2,000 people. There are
two types of AT-III deficiency: inherited and acquired. The inherited
form has two subsets: quantitative deficiency and qualitative deficiency. In
some cases, AT-III deficiency may be acquired, as with disseminated
intravascular coagulation or severe liver disease or through the administration
of I.V. heparin. AT-III normally inactivates factor Xa and thrombin; patients
with AT-III deficiency show evidence of continuous
factor X activation and thrombin generation. The typical presentation of
AT-III deficiency is similar to that of other hypercoagulable states. There is
no evidence that AT-III deficiency increases the risk of arterial thrombosis.
·
The two
hypercoagulable states more closely related to arterial thrombosis are
the antiphospholipid syndrome and hyperhomocystinemia.
·
Because the INR
(prothrombin time) is heavily dependent on factor VII, which has a
short half-life, it rises fairly quickly after warfarin is begun. However, therapeutic anticoagulation may take several days
longer because of the persistence of factor X and prothrombin.
·
DDAVP
causes the release of a number of factors
and von Willebrand factor from the liver and endothelial cells. This may be
useful for patients with mild hemophilia.
·
There are two
corrections that need to be made to the reticulocyte count when it is being used to
estimate the marrow’s response to anemia. The first correction adjusts
the reticulocyte count for the number of circulating
red cells (i.e., the percentage of reticulocytes may be increased
although the absolute number is unchanged). The absolute
reticulocyte count = reticulocyte count * (hematocrit/expected hematocrit).
Second, when there is evidence of prematurely released reticulocytes on the
blood smear (polychromatophilia), prolonged
maturation in the serum may cause a falsely high estimate of daily
red blood cell production. Correction is achieved by dividing by a “maturation
time correction,” usually 2 if the hematocrit is between 25% and 35%.
·
While the SC
route for delivery of vitamin K has long been a primary route of
correction for Warferin Overdose, a meta-analysis has shown the SC route to be no better than placebo and inferior to the
oral and IV routes, which have similar efficacy.
·
HIT
should be suspected in individuals with a fall in platelet count by >50% of
pretreatment levels. Usually the fall in platelet counts occurs 5–13 days after
starting heparin, but it can occur earlier if there is a prior exposure to
heparin, which this patient undoubtedly has because of his mechanical mitral
valve replacement. While a platelet count of <100,000/µL
is highly suggestive of HIT, in most individuals, the platelet count
rarely falls this low. HIT is caused by IgG
antibodies directed against antigens on PF4 that are exposed when
heparin binds to this protein. The IgG antibody binds simultaneously to the
heparin-PF4 complex and the Fc receptor on platelet surface and causes platelet
activation, resulting in a hypercoagulable state. Individuals with HIT are at
increased risk of both arterial and venous
thromboses, although venous thromboses are much more common.
Demonstration of antibodies directed against the heparin–platelet factor
complex is suggestive of, but not sufficient for, diagnosis because these
antibodies may be present in the absence of clinical HIT. The serotonin release assay
is the most specific test for determining if HIT is present.
Patients should not be switched to
low-molecularweight heparin (LMWH). While the incidence of HIT is
lower with LMWH, there is cross-reactivity with heparin-PF4 antibodies, and
thrombosis can occur. Choice of anticoagulation should be with either a direct
thrombin inhibitor or a factor Xa inhibitor. The direct thrombin inhibitors
include lepirudin, argatroban, and bivalirudin. Argatroban is the
appropriate choice in acute renal failure in association with contrast dye
administration for the cardiac catheterization. Argatroban is hepatically metabolized and is safe to give in renal failure,
whereas lepirudin is renally metabolized. The factor Xa
inhibitors, fondaparinux or danaparoid, are also possible treatments for
HIT, but renal metabolism is there. Finally, warfarin
is contraindicated as sole treatment for HIT as the fall in vitamin
K–dependent anticoagulant factors, especially factor C, can further increase
risk of thrombosis and trigger skin necrosis.
·
Embryonic stem
cells tend to develop abnormal karyotypes and have the potential to
form teratomas. Umbilical
cord blood stem cells have less
graft-versus-host disease than marrow-derived stem cells and are less likely to be contaminated by the herpes virus.
Organ-specific multipotent stem
cells are easy to isolate from the marrow
but are difficult to isolate from tissues such as the heart and brain.
Early studies of bone marrow mesenchymal stem cells have shown that the
transplanted cells fuse with cells resident in the organ.
·
Dysfibrinogenemia
refers to a constellation of disorders that involve mutations that alter the
release of fibrinopeptides, affect the rate of polymerization of
fibrin monomers, or alter the sites of fibrin cross-linking.
Dysfibrinogenemia is either inherited in an autosomal dominant fashion or
acquired. Patients with liver disease, hepatomas,
AIDS, and lymphoproliferative disorders may develop an acquired form of
dysfibrinogenemia. The presence of altered partial thromboplastin time (PTT) and prothrombin time (PT)/INR
reflects an abnormality in coagulation from the prothrombinase complex
downstream to fibrin. Correction with a mixing study eliminates factor
inhibition as a cause of the coagulation disorder. Other causes of prolongation
of the PT and PTT include factor deficiencies in factor V or X,
afibrinogenemia or dysfibrinogenemia, and consumption of
coagulation factors from DIC.
·
In “mixing study”
the patient’s
plasma is mixed with pooled plasma. Correction of the aPTT
reflects a deficiency of factors that are replaced by the pooled
sample. Failure to correct the aPTT reflects the presence of a
factor inhibitor or phospholipid inhibitor. Common causes of a failure
to correct include the presence of heparin in the sample, factor inhibitors
(factor VIII inhibitor being the most common), and the presence of antiphospholipid
antibodies.
·
The differentiation between DIC and severe liver disease is challenging.
Both entities may manifest with similar laboratory findings: elevated
fibrinogen degradation products, prolonged aPTT and PT, anemia, and
thrombocytopenia. When suspecting DIC, these
tests should be repeated over a period of 6–8 hours because
abnormalities may change dramatically in patients with severe DIC. In contrast,
these tests should not fluctuate as much in patients with severe liver
disease.
·
The discovery that spectrin
deficiency is the sine qua non of hereditary spherocytic red cells
led some to hypothesize that primary defects in spectrin would be found in most
cases of hereditary spherocytosis. Surprisingly, mutations in a-spectrin
(autosomal recessive hereditary spherocytosis) and ß-spectrin (autosomal
dominant hereditary spherocytosis) are each present in only about 10%
of patients with hereditary spherocytosis. Instead, mutations in ankyrin (autosomal dominant and recessive
hereditary spherocytosis; about 40 to 50% of cases) and band 3 (autosomal dominant hereditary
spherocytosis; about 20% of cases) are much more common. Mutations in protein 4.2 (autosomal recessive hereditary
spherocytosis) are relatively rare except in Japan, where a number of families
have been described.
Molecular
defects in spectrin, ankyrin, band 3, and protein 4.2 lead to spectrin deficiency as the “final common pathway”
that characterizes all red cells with hereditary spherocytosis.
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