Hemolytic Anemia
diagnostic of Fe
Clinical features: splenomegaly, pigmented gallstones ( bilirubin), dark urine, chronic ankle ulcers,
aplastic crises (associated with parvovirus B19), folate requirement
Laboratory features:
1. Increased formation of RBCs
Blood: rets, MCV, circulating NRBCs
Bone marrow: erythroid hyperplasia, reduced M:E ration (more erythroid than myeloid)
Bone: increased marrow production frontal bossing
2. Increased destruction of RBCs general hemolysis
Biochemical: LDH levels, unconjugated bilirubin
Physical: scleral icterus, jaundice
Intravascular hemolysis:
Reduced serum haptoglobin
Hemoglobinemia
Hemoglobinuria
Hemosiderinuria
Hereditary Spherocytosis membrane defect
- most common defect leading to anemia, AD
- membrane defect in spectrin or ankyrin
- Spherocytes bits of membrane are pinched off by spleen lack central pallor, more spherical due to
loss of membrane
Dx:
osmotic fragility
Tx:
folate supplementation
Splenectomy spherocytes will persist, but hemolysis will abate
G6PD Deficiency enzyme defect
- deficiency is X-linked enzyme variant A- is unstable and has low activity
- 10-14% of African-Americans have this disorder, Mediterraneans also have low-activity variant
- agents to avoid: anti-malarials, sulfa, dapsone, Vit K, naptha compounds, fava beans
Pathophysiology:
Low G6PD activity results in low levels of NADPH and reduced glutathione, which are required
to protect hemoglobin from oxidative damage.
In the absence of adequate reducing ability (provided by G6PD), oxidizing agents convert
hemoglobin to methemoglobin, then denature it, causing it to precipitate as Heinz bodies.
The spleen pinches off the Heinz body and the overlying membrane, leaving a bite cell or
blister cell
Clinical features:
- hemolysis triggered by drugs or infection
- anemia is maximal 7-10d after exposure
- A- individuals compensate with ret formation
- immediate after hemolytic episode, G6PD levels may be normal because only the newly formed cells are
present
Immune-mediated hemolytic anemia acquired hemolytic anemia
Pathophysiology:
Red cells react with antibody, with or without complement fixation, leading to RBC destruction.
IgG-coated RBCs interact with Fc receptors on macrophages, leading to complete or partial
phagocytosis, with spherocyte formation (extravascular hemolysis).
C3-coated red cells interact with C3 receptors on macrophages, with phagocytosis (extravascular
hemolysis).
Alternatively, complement cascade can be completed, with complement-mediated RBC lysis
(intravascular hemolysis).
TTP/HUS
DIC
Malignant hypertension
Ecclampsia, HELLP syndrome
Vasculitis
Other, including metastatic cancer, scleroderma renal crisis, solid organ transplant
rejection
Hemoglobinopathies
Definition: caused by a mutation resulting in an amino acid substitution or deletion on one of the globin
chains
Effects: no detectable effect, instability of hemoglobin molecule, increase or decrease in O2 affinity,
inability to maintain the heme iron is its active, reduced state (methemoglobinemia), decreased solubility of
the hemoglobin molecule
globin genes on Chromosome 16, non- globin genes on Chromosome 11
Types:
1. Unstable hemoglobinopathy: H2O able to reach heme pocket, leading to denaturation of heme and
formation of Heinz bodies
2. Alteration in Hb-O2 affinity: mutation stabilizes either the oxy or deoxy conformation
- increase in O2 affinity left-shift in O2 saturation curve individuals exhibit erythrocytosis
(increased RBCs - need increased O2 carrying) ex. Hb Bethesda
- decrease in O2 affinity right shift in O2 saturation curve individuals typically
somewhat anemic (decreased RBCs)
3. Inability to maintain heme iron in active, reduced state: methemoglobinemia HbM disorders occur
when there is a substitution at locus of proximal or distal histidine Hb with iron in oxidized (Fe 3+) state is
incapable of binding O2 patients with HbM disease are typically cyanotic
4. Decreased solubility of hemoglobin molecule:
Sickle cell anemia is autosomal co-dominant mutation - At the 6-position of the Beta-chain of
hemoglobin, you have a gluval substitution, which leads to polymerization of the Hb molecule
sickle-cell trait = roughly equal amounts of HbA and HbS, asymptomatic
compound heterozygotes express significant disease
presence of HbS decreases solubility and tendency of this abnormal Hb to polymerize
when it is in the deoxy conformation allows Hb to form polymers
Clinical features affects virtually every organ in body - Associated with gallstones, nonhealing leg ulcers (probably b/c of vaso-occulusion), acute chest syndrome which
increases morbidity and mortality, heart problems (dilation, hypertrophy), pulmonary htn
Tx: reactivate fetal Hb products with hydroxyurea HbF increases the solubility in deoxy
form
Thalassemia
- characterized by imbalance in the production of a-globin and non a-globin chains
- excess, unpaired globin tetramers become denatured and precipitate within red cells forming Heinz bodies
or target cells
- small, poorly hemoglobinized red cells (microcytosis and hypochromia)
Coagulation Defects
Hemophilia A - 85% of Hemophilias
X-linked diseasemostly boys affected
classified Severe (<1% of normal factor VIII levels), Moderate (2-5%), Mild (6-30%).
Factor VIII deficient
o Produced in the liver, along with the other coagulation factors
Not a protease itself, but rather a cofactor that helps to accelerate the coagulation
reaction.
o APTT will be prolonged. Factor VIII is part of the intrinsic pathway.
Target jointsbleeds into specific joints
o Symptoms usually precede evidence of bleeding
o Can use radio-synovectomy to get rid of synovium and minimize bleeding
Can use factor as prophylaxis in severe casescan administer via Port-A Cath
Factor VIII replacement now is recombinant product, with only human albumin used to stabilize
the factor. In the past, human factor was used. This resulted in 80-90% of hemophilia patients
getting HIV.
Vaccinate patients for HepA
This disease is a good candidate for Gene Therapy!
o
Hemophilia B
a deficiency of factor IX. About 15% of hemophilias
Good candidate for gene therapysmaller gene than factor VIII
For both, potential for formation of antibodies against factor (aka inhibitor)
o Factor recognized as non-self and B-cells form antibodies that get rid of it
o In normal individuals (ie, those without hemophilia), treat with rituxan, which latches on to
CD20+ B-cells and neutralizes them.
o In hemophiliacs, try to de-sensitize by giving MASSIVE infusions twice daily.
Generally in little kids
Must be religiously adhered to, or the immunity is reactivated
von Willebrand Disease (VWD)
Differs from classical hemophilia: vWF important in both primary hemostasis (platelet adhesion via
GPIb receptor) and secondary hemostasis (via Factor VIII)
(1) Suffer from mucocutaneous hemorrhage rather than hemarthroses like in hemophilia.
(2) Autosomal inheritance trait, so men and women have similar prevalence, rather than X-linked like
hemophilia.
(3) Consistently had prolonged bleeding times unlike the normal bleeding times in hemophilia. Also have
prolonged APTT (involvement of Factor XIII)
Thrombocytopenia
Symptoms of platelet hypofunction - epistaxis, gum bleeding, bruising, heavy menses, petechiae,
i.e. mucocutaneous bleeding. Oozing and bruising NOT hematomas or bleeding into joints.
Three causes:
1. underproduction inadequate megakaryocytes in the marrow due to failure, invasion, injury
(especially EtOH), congenital
2. peripheral destruction DIC, TTP, ITP - non-immune mechanisms, immune mechanisms (drugs,
HIV)
3. splenic sequestration - Splenic enlargement, from any cause, can lead to displacement of platelets
from peripheral circulation into splenic pool
DIC
Definition: A process, characterized by abnormal activation of coagulation, generation of thrombin,
consumption of clotting factors, destruction of platelets, and activation of fibrinolysis.
Dx:
Elevated PT first - due to consumption of Factor VII, which has the shortest half-life (4 hrs) of all
clotting factors.
Coagulation tests are elevated
When advanced, the APTT can be prolonged as well, as the other clotting factor levels fall.
Low platelets
Low/falling fibrinogen
Elevated fibrin degradation products (FDPs/FSPs) or D-Dimers
Can see a few schistocytes on the peripheral smear in most cases.
Tx:
Can be associated with gram negative sepsis, severe burns, obstetrical disasters, certain leukemias or
tumors, shock, insect or snake venoms
TREAT THE UNDERLYING CAUSE
Supportive measures can include transfusion of platelets, clotting factors, fibrinogen, +/- low dose
heparin to halt thrombin generation.
TTP Thrombotic Thrombocytopenic Purpura
Definition: A process, characterized by abnormal activation of platelets and endothelial cells, with fibrin
deposition in the microvasculature, and peripheral destruction of platelets and red cells.
Causes:
May be associated with an antibody against or a deficiency of the protease which cleaves the very
high molecular weight multimers of von Willebrands factor
Can be induced by drugs, including ticlopidine, quinine, cyclosporine, FK-506, mitomycin C
Increased incidence with pregnancy or HIV
Dx: MAHA, low platelets, schistocytes
Microangiopathic Hemolytic Anemia (MAHA)
Elevated LDH, elevated bilirubin
Schistocytes on the peripheral smear
MUST BE PRESENT
Low platelets - MUST BE PRESENT
Fever not always seen
Neurologic Manifestations not always seen
- headache, sleepiness, confusion, stupor, stroke, coma, seizures
Renal Manifestations not always seen
Heparin
Abciximab (ReoPro)
Heparin induced thrombocytopenia
Definition: Conditions in which there is disordered maturation in 1 or more cell lines, usually producing
cytopenias. Usually found in the elderly
Dx: abnormal CBC, macrocytosis of RBC, large platelets, PMNs hypogranular or bilobed nucleus
Bone marrow: megaloblastic erythropoiesis, ringed sideroblasts, small megakaryocytes
Monosomy 5, 7, 8 can be seen