Download Hematology: Inherited blood disorders

Hematology: Inherited blood
disorders, case histories and review
Michael R. Jeng, MD
Tuesday, August 2, 2005
Case A
• HPI: A 14 year old Nigerian boy, who is
visiting the bay area, presented to the ED
with severe chest pain, fever, and shortness
of breath for 2 days.
• Past Medical History: This boy has been
admitted to the hospital in the past for pain
of the arms and legs, but there is no
diagnosis. He is on no current medications.
• PE: 40.0 C, 100, 40, 120/76
– Mild respiratory distress, uncomfortable
– Mildly icteric eyes
– Resp: Crackles at LLL
– CV: 3/6 SM at LLSB
– Abd: unremarkable. No HSM
• Labs:
– Chemistry Panel: T Bili: 2.5 mg/dL
– WBC: 10.5 K/uL, Plts: 594 K/uL
– Hgb: 8.5 gm/dL, Retic: 15%, ARC: 485 K/uL
– HPLC: SF, Hgb S: 96%:, Hgb F: 4%
– CXR: LLL and RLL infiltrates
Peripheral Blood Smear
Normal Smear
Sickle Smear
SCD: Pathophysiology
• Most common mutation is the substitution of a
valine for glutamine at the 6-position.
• The resulting abnormal hemoglobin, (Hb S),
easily precipitates and crystallizes. When this
occurs, the red blood cells change shape, into a
sickle shape.
• Dehydration, low PH, deoxygenation, stress can
lead to crystallization/precipitation.
• This change in conformation causes occlusion of
blood vessels, which leads to the complications of
sickle cell disease.
SCD: Pathophysiology
Normal vs. Sickle Hemoglobin
Normal
• disc-Shaped
• soft(like a bag of jelly)
• easily flow through
small blood vessels
• lives for 120 days
Sickle
• sickle-Shaped
• hard (like a piece of
wood)
• often gets stuck in
small blood vessels
• lives for < 20 days
SCD: Diagnosis
• Types of screening:
– Sickle Prep / morphology
– Hemoglobin electrophoresis
– HPLC (gas chromatography)
– DNA testing
•
•
•
•
•
Electrophoresis/HPLC:
AS trait: 55-65% A, 40-45% S, 1-2% A2
SS disease: 80-100% S, 0-20% F
SC disease: 50% S, 50% C
S – Thal: 75-100% S, 0-20% F: 3-6% A2,
some 1-15% A
Epidemiology
• Sickle cell disease is an inherited disease.
• It is the most common genetic (inherited) disease
due to a single amino acid substitution in the USA.
• 1 in 10 African Americans carry the gene, and
approx. 1 in 300 have the disease.
• Most common mutation is the substitution of a
valine for glutamine at the 6-position.
• Heterozygotes with this mutation are thought to
have a selective advantage due to protection from
cerebral malaria.
Epidemiology
• There are about 50,000 - 70,000 persons with
sickle cell disease in the USA.
• More rare, Indian, Middle Eastern, Latin
American, and Caucasian persons may be
affected.
• 48 states have newborn screening for
hemoglobinopathies. 2 states do not screen for
sickle cell disease: Idaho, South Dakota.
(?Montana-pilot program)
• The current lifespan for people with sickle cell
disease is about 45-50 years for men, and 50-55
years for women in the USA.
Probability of Survival to Age 20 years in Patients with Hb SS, Hb
SC, and All Others entered in Cooperative Study of Sickle Cell
Disease at <20 years of age
Proportion Surviving
1.0
0
.95
.90
.85
.80
SS
SC
ALL
.75
2M
1Y
3Y
Age
6Y
10Y
20Y
Probability of Survival for Male and Female Patients
with SS Compared with Black Males and Females
1.0
0.9
0.8
Probability of Survival
0.7
0.6
0.5
0.4
0.3
0.2
Females with SS
Males with SS
Black females
Black males
0.1
0
0
10
20
30
40
Age (Years)
50
60
70
Medical Complications – Acute
Management
• Although there are many different complications,
classically there are 4 crises:
– Vaso-occlusive Crisis: Dactylitis, Priapism, CVA
– Acute Chest Syndrome/Crisis
– Aplastic Crisis
– Splenic Sequestration Crisis
– Fever/Infections
– Other Clinical Issues: Fever, Gallstones, Ocular
damage
Vaso-occlusive Crisis
• Usually begin at 8-10 months of age
• Dactylitis if often first symptom (Hand-foot) **
• Priapism – emergency
• Pain
• Stroke – emergency (most serious complication)
Vaso-Occlusive Crisis
• Pain Episodes: Most common VOC.
• Treat with fluids, pain medications, warm
compresses, time. . . .
• Try to avoid transfusions
• Stroke: 11% of patients by 18 years of age, most
serious complication
• Treat with exchange transfusion with goal of Hb
around 10 gm/dL, and %Hb S at less than 30%
• Rehabilitation
Aplastic Crisis
•
•
•
•
•
Usually associated with Parvo B19 infection
Sudden drop in Hgb, no reticulocytosis
Often contagious (family)
Phenomenon due to shortened red cell half life
DX: severe anemia, low reticulocyte,
parvovirus B19 titers
• RX: Close observation or simple transfusion,
monitor family members with SCD
Splenic Sequestration Crisis
• Acute drop in hemoglobin
• Sickling in efferent venules can cause balloon like
phenomenon
• All patients taught to monitor spleen size
• DX: clinical - May be associated with fever, pain,
respiratory symptoms, sudden trapping of blood within
the spleen
• Circulatory collapse and death can occur in less than
thirty minutes.
• Usually occurs in 1st 5yrs of life
• RX: follow serial hgbs, simple transfusions, follow-up
Acute Chest Syndrome
•
•
•
•
•
•
Fever
Chest Pain
Increased work of breathing
Shortness of breath
Decreased oxygen saturation
DX: new infiltrate on CXR with
above symptoms
• RX: antibiotics, oxygen,
bronchodilators, transfusion, incentive
spirometry, close monitoring
Other Clinical Issues:
FEVER/Infections
•
•
•
•
•
By age 5 years, 84% without spleen
Infections are a common complication of SCD
Patients begin prophylactic PCN by age 2-3 months
All patients with fever need evaluation
Esp. prone to encapsulated organisms (S.
pneumoniae, H. influenzae, Salmonella
(osteomyelitis), mycoplasma
• Need all Pneumococcal vaccines, H. Flu
• RX: antibiotics, follow blood cultures
Case B
• 5 week old infant was referred because of a
hemoglobin F pattern noted on the neonatal screen.
• History: 5 week old baby boy born to Vietnamese
parents. Birth history = unremarkable.
• Growing on his home regimen of breast milk and
formula.
• You have seen him twice since being discharged from
the hospital with no complications or problems at any
of these visits. There have been no fevers; abnormal
bleeding or bruising; vomiting or diarrhea.
•
•
•
•
Expected PE
What other history?
Family History?
WHAT TO DO NOW?
• Lab evaluation:
• WBC: 11; hemoglobin of 14.4; and
platelets of 497.
• Reticulocyte count was 0.98. He had a
total bilirubin of 9.3. MCV: 51 fL
• Repeat HPLC: Showed Hb F pattern
• Thalassemias:
• The thalassemias are a diverse group of
genetic blood diseases characterized by
absent or decreased production of normal
hemoglobin, resulting in a microcytic
anemia of varying degree.
• The thalassemias have a distribution
concomitant with areas where P. falciparum
malaria is common.
Affected Populations
Southeast Asian (Vietnamese, Laotian, Thai, Singaporean, Filipino,
Cambodian, Malaysian, Burmese, and Indonesian)
Chinese
East Indian
African
Middle Eastern
Greek
Italian
Transcaucasian (Georgian, Armenian, and Azerbaijani)
Malaria Belt
• Two main types: alpha or beta
thalassemia
• Alpha Thalassemia:
• 4 copies of the alpha globin genes on
Chromosome 16
• Thus, there are 4 genotypes possible
Alpha Thalassemia
• aa/aa: normal
• a-/aa: silent carrier
• a-/a- (aa/--): alpha thal trait
minor anemia, microcytosis
• a-/--: HbH disease: anemia and
microcytosis, occ. transfusions, high bili
• --/--: Hydrops fetalis
Beta Thalassemia
• Beta Thal Minor/ Beta Thal Trait
• Asymptomatic, carriers.
• Mild anemia, and microcytosis
• Beta Thal Major/Beta Thalassemia (Cooley’s
anemia)
– Transfusion Dependent, usually about 10 –
12 months of age
– At risk for bony deformities, gall stones,
splenomegaly
– Long term transfusions are used to treat
these patients
– Eventually, suffer from iron overload
Case C
• A 1 day old newborn is noted to be icteric
and jaundiced.
• Maternal history: Born to a 32 year old
G3P1 > 2 Caucasian woman, by NSVD.
Uncomplicated delivery. Little prenatal
care
• PE: normal vital signs, healthy appearing
except for jaundice and minimal pallor. No
congenital defects, normal appearing
male.
• What other history?
• Labs?
• Review of labs:
– Mother:
Rh negative, Anti-Rh antibodies
present
– CBC: WBC: 12 Hgb: 10, with spherocytes,
reticulocyte count: 16%, Platelets – 242
– Coombs positive
• RH disease
• Hemolytic Disease of the Newborn (HDN)
• Rh Alloimmune hemolytic disease
• This disorder is called erythroblastosis
fetalis when it occurs in the fetus and HDN
when it occurs in the newborn.
• Rarely seen now with anti-Rh antibody
(Rhogam). If prenatal care~!
• Wide range of clinical presentation
For Prenatal Care
• In the Rh negative patient, initial testing, if
negative, is usually followed up with
another antibody screen at 28 weeks, just
prior to administration of antenatal Rh(D)
immune globulin and after delivery. (300
mcg)
• Usually give after any procedures
• May monitor antibody titers
For Prenatal Care
• Test for Fetal-Maternal Hemorrhage
– Rosette Test
– Kleihauer-Betke Test
Treatment of infant, or known HDN
• If antibodies present, monitoring of the infant for
signs of anemia:
– Hgb/hct (by amnio/cordocentesis sampling)
– Liver size by U/S
– Doppler U/S for fetal MCA flow
• Possible intrauterine transfusions, and early
delivery may be necessary
• Postpartum monitoring and possible
transfusions
• TREATMENT of Sensitized Mother:
Of mother:
If there is anti-D in the maternal serum, and
the mother did NOT receive antenatal Rh
immune globulin, then she would NOT be
a candidate for Rh immune globulin
postpartum, since she has apparently
already been sensitized to the Rh(D)
factor.
Case D
• A 5-year, 9-month-old male was previously healthy,
was seen in the Emergency Room yesterday for
jaundice and emesis. The parents say that he had
been recently well, with no recent upper respiratory
symptoms or diarrhea.
• Yesterday, he developed emesis, which they report as
being approximately five times, a yellow-greenish
color, no blood and no diarrhea.
• They also noticed that his eyes were yellow, and his
skin was yellow, and therefore, they brought him into
the emergency room.
• ROS: Dark-colored urine since yesterday
– History of ingesting fava beans (2 days prior to on Friday
presentation).
• PMH: full-term at birth, with neonatal
hypobilirubinemia with T-bili up to 24.3, for which he
required phototherapy for two days. H
• History of iron deficiency anemia in 1998 with a
hemoglobin down to 9.8 and an MCV down to 74.
• Other than this, he has had no hospitalizations or
surgeries and no prior instances of jaundice outside of
the neonatal period.
• MEDICATIONS: None.
• ALLERGIES: No known drug
allergies.
• FAMILY HISTORY: There are no bleeding
problems, no members with jaundice, no
• members with autoimmune diseases, such as
SLE or rheumatoid arthritis.
• There is no known family history of G6PD
deficiency.
• Physical Exam: Pallor, scleral icterus,
jaundice, 3/6 systolic heart murmur. No HSM.
No other findings.
• Initial lab studies:
– Hemoglobin = 6.8 gm/dL
– Total bilirubin = 6.1 mg/L
– Reticulocyte count of 1%.
• Repeat laboratory studies:
– Hemoglobin = 5.1 gm/dL LDH: 2429 u/L (900)
– Reticulocyte count = 18% TBili: 8.2 mg/L (<1.4)
– Coombs test = negative **
• G6PD: 2.5 u/gm Hg (5.5 – 8.8)
• PK: 13.8 (3.2 – 6.5) **
• What other causes?
G6PD DEFICIENCY - DIAGNOSIS
• Acute non-immune hemolysis in association with
infection, chemical or drug ingestion
• Characteristic RBC morphology
• Heinz bodies seen with BCB preps
• Enzyme screen or specifc assay for G6PD
activity.
• False negatives can occur due to removal of most
deficient cells – particularly a problem with Class
III (G6PD A-) males and affected females
OXIDANT-INDUCED RBC INJURY
HEINZ BODIES
RBC METABOLISM - OVERALL
RBC ENZYMOPATHIES ASSOCIATED
WITH HEMOLYTIC ANEMIA
G6PD DEFICIENCY MILLIONS
PYRUVATE KINASE (PK)
DEFICIENCY – THOUSANDS
OTHERS - VERY RARE
G6PD DEFICIENCY - DEMOGRAPHICS
• Occurs worldwide – most prevalent
in tropical areas -Africa 15-20%
• All mediteranean and mid-east
countries - 70% in Kurdish Jews
• Frequent in Southeast Asia (5-15%)
• Related to distribution of malaria
G6PD DEFICIENCY - GENETICS
• Gene for G6PD on X chromosome
• Enzyme deficiency expressed in males
• Heterozygous females usually are
asymptomatic – but not always!
• Study of G6PD deficiency in women
used to support Lyon hypothesis
WORLD HEALTH ORGANIZATION (WHO)
CLASSIFICATION OF G6PD VARRIANTS
% NORMAL
ACTIVITY
CLINICAL
FEATURES
EXAMPLE
CLASS I
10 – 20 %
Chronic
hemolysis
CLASS II
< 10 %
Intermittent
hemolysis
Mediterranean
CLASS III
10 – 60 %
Intermittent
hemolysis
A-, Canton
CLASS IV
100 %
None
B, A+
DECAY OF RBC G6PD ACTIVITY
G6PD DEFICIENCY: CLINICAL FEATURES
Acute hemolytic anemia
Favism
Congenital nonspherocytic hemolytic anemia
Neonatal hyperbilirubinemia
PRIMAQUINE-INDUCED HEMOLYSIS
G6PD DEFICIENCY - ACUTE HEMOLYSIS
• With most common G6PD variants (Class
II and III), there is no hemolysis in the
steady state - Hgb, Retics, and Bilirubin
are normal.
• Hemolytic anemia occurs only in presence
of certain drugs or infection.
• Infection is the most common clinical
cause of hemolysis.
DRUGS AND CHEMICAL ASSOCIATED WITH HEMOLYSIS IN G6PD DEFICIENCY
Unsafe (Class I, II and III G6PD variants)
Acentanilid
Furazolidone (Furoxone)
Methylene blue
Nalidixic acid (Neg—Gram)
Naphthalene (Mothballs)
Nitrofurantoin (Furadantin)
Phenazopyridine (Pyridium)
Phenylhydrazine
Primaquine
Sulfacetamide
Sulfamethoxazole (gantanol)
Sulfanilamide
Sulfapyridine
Thiazolesulphone
Toluidine blue
Trinitrotoluene (TNT)
Safe in usual therapeutic doses (Class II and III G6PD variants *)
Acetaminoph
Ascorbic Acid
Aspirin
Chloramphenicol
Chloroquine
Colchicine
Diphenhydramine
Isoniazid
Phenacetin
Phenylbutazone
Probenecid
Procainamide
Pyrimethamine
Quinidine
Quinine
Streptomycin
Sulfamethoxypyridazine
Sulfisoxazole
Trimethoprim
Phenytoin
Vitamin K
G6PD DEFICIENCY - FAVISM
• Symptoms of intravascular hemolysis - within 24
hours of ingesting fava beans.
• Occurs in some, but not all G6PD deficient
individuals. Seen primarily with G6PD deficiency
in the mediteranean, Mid East, and Asia
• Reactions to fava been are erratic in affected
G6PD deficient individuals
• Thought to be due to a second defect – altered
metabolism of fava bean oxidants
• Occurs with exposure to fava pollen and after
ingestion of fresh or cooked beans.
G6PD DEFICIENCY - TREATMENT
• Determined by clinical situation
• Avoid known oxidant drugs (exceptions
can be made)
• RBC transfusions as indicated
• Treatment for neonatal hyperbilirubinemia
as indicated
• With Class I G6PD – monitor as with any
chronic hemolytic disorder
Case E
• A previously healthy 4 year old boy comes in
with a large, swollen knee. He has stopped
walking for the last 2 days.
• He is on no medications.
• On ROS: The patient is noted to have a lot of
bruising and hematomas with his immunizations.
He is also always noted to be a “heavy bruiser”.
• PMH: He has not been circumsiced. Otherwise
a full term infant, without known medical
problems.
•
•
•
•
Laboratory evaluation:
CBC: WBC: 13.2, Hgb: 11.4, Plt 341
PT: 11.2sec (10.4-12.6)
PTT: >80 sec (25-40)
•
•
•
•
Factor 9: 145%
Factor 8: 4%
Vwf antigen: 151%
Ristocetin cofactor: 164%
What is hemophilia?
Hemostatic System
• Blood vessels
• Platelets
• Plasma coagulation system
• Proteolytic or Fibrinolytic system
How Bleeding Stops
• Vasoconstriction
• Platelet plug formation
• Clotting cascade activated to form
fibrin clot
Normal Hemostasis
II
X
VIII/vWF
TF VIIa
Xa
Va
IIa
VIIIa
TF-Bearing Cell
TF
VIIa
IXa
IX
VIIIa
Va
Platelet
II
X
IXa
VIIa
V
IX
Xa
Activated Platelet
IXa
VIIIa
Xa
X
IIa
Va
Va
II
IIa
Hoffman et al. Blood Coagul Fibrinolysis 1998;9(suppl 1):S61.
Types of Bleeding Disorders
• Hemophilia A (factor VIII deficiency)
• Hemophilia B (factor IX deficiency)
• von Willebrand Disease (vWD)
• Other
What is Hemophilia?
• Hemophilia is an inherited
bleeding disorder in which
there is a deficiency or lack of
factor VIII (hemophilia A) or
factor IX (hemophilia B)
How do you get hemophilia?
Inheritance of Hemophilia
• Hemophilia A and B are X-linked recessive
disorders
• Hemophilia is typically expressed in males
and carried by females
• Severity level is consistent between family
members
• ~30 % of cases of hemophilia are new
mutations
Detection of Hemophilia
• Family history
• Symptoms
– Bruising
– Bleeding with circumcision
– Muscle, joint, or soft tissue bleeding
• Hemostatic challenges
– Surgery
– Dental work
– Trauma, accidents
• Laboratory testing
Degrees of Severity of
Hemophilia
• Normal factor VIII or IX level = 50-150%
• Mild hemophilia
– factor VIII or IX level = 6-50%
• Moderate hemophilia
– factor VIII or IX level = 1-5%
• Severe hemophilia
– factor VIII or IX level = <1%
U. S. Incidence of Hemophilia
• Hemophilia A: 20.6 per 100,000 males
– Severe: 50-60%
• Hemophilia B: 5.3 per 100,000 males
– Severe: 44%
Types of Bleeds
• Joint bleeding - hemarthrosis
• Muscle hemorrhage
• Soft tissue
• Life threatening-bleeding
• Other
Joint or Muscle Bleeding
• Symptoms
– Tingling or bubbling sensation
– Stiffness
– Warmth
– Pain
– Unusual limb position
Life-Threatening Bleeding
• Head / Intracranial
– Nausea, vomiting, headache, drowsiness, confusion, visual
changes, loss of consciousness
• Neck and Throat
– Pain, swelling, difficulty breathing/swallowing
• Abdominal / GI
– Pain, tenderness, swelling, blood in the stools
• Iliopsoas Muscle
– Back pain, abdominal pain, thigh tingling/numbness,
decreased hip range of motion
Other Bleeding Episodes
• Mouth bleeding
• Nose bleeding
• Scrapes and/or minor cuts
• Menorrhagia
Complications of Bleeding
• Flexion contractures
• Joint arthritis / arthropathy
• Chronic pain
• Muscle atrophy
• Compartment syndrome
• Neurologic impairment
How do you treat
hemophilia?
• Replacement of missing clotting protein
– On demand
– Prophylaxis
• DDAVP / Stimate
• Antifibrinolytic Agents
– Amicar
• Supportive measures
– Icing
– Immobilization
– Rest
Prophylaxis
• Scheduled infusions of factor
concentrates to prevent most bleeding
• Frequency: 2 to 3 times weekly to keep
trough factor VIII or IX levels at 2-3%
• Types
– primary prophylaxis
– secondary prophylaxis
• Use of IVAD necessary in some patients
DDAVP (Desmopressin acetate)
• Synthetic vasopressin
• Method of action – release of stores from endothelial cells raising
factor VIII and vWD serum levels
• Administration – Intravenous
– Subcutaneously
– Nasally (Stimate)
• Side effects
Stimate
• How supplied
– 1.5 mg./ ml (NOT to be confused with DDAVP
nasal spray for nocturnal enuresis)
– 2.5 ml bottle - delivers 25 doses of 150 mcg.
• Dosing
– Every 24-48 hours prn
– <50 kg. body weight - 1 spray (150 mcg.)
– >50 kg. body weight - 2 sprays (300 mcg.)
Amicar
(epsilon amino caproic acid)
• Antifibrinolytic
• Uses
– Mucocutaneous bleeding
• Dosing: 50 - 100 mg./kg. q. 6 hours
• Side effects
• Contraindications
– Hematuria
Target Joints
• Steroids
• NSAIDS
Complications of Treatment
• Inhibitors/Antibody development
• Hepatitis A
• Hepatitis B
• Hepatitis C
• HIV
Special issues for patients
with hemophilia.
• Definition
Inhibitors
– IgG antibody to infused factor VIII or IX
concentrates, which occurs after exposure
to the extraneous VIII or IX protein.
• Prevalence
– 20-30% of patients with severe hemophilia A
– 1-4% of patients with severe hemophilia B
Special Issues Continued
•
•
•
•
Dentistry
Elective Surgery
HIV/Hepatitis – CDC/UCD STUDY
Cost of factor/Insurance
Hepatitis
• Hepatitis A- small risk of transmission
– Vaccination recommended
• Hepatitis B - no transmissions since
1985
– Vaccination recommended
• Hepatitis C - no transmissions since
1990
– ~90% of patients receiving factor concentrates
prior to 1985 are HCV antibody positive
Human Immunodeficiency Virus
• No transmissions of HIV through factor
concentrates since 1985 due to viral
inactivation procedures
• HIV seropositive rate – 69.6% of patients with severe hemophilia A
receiving factor concentrates prior to 1985
– 48.6% of patients with severe hemophilia B
receiving factor concentrates prior to 1985