hematology: inherited blood disorders, case histories and review michael r. jeng, md tuesday, august...
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Hematology: Inherited blood disorders, case histories and review
Michael R. Jeng, MDTuesday, August 2, 2005
• 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.
Case A
• 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 HemoglobinNormal 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.
• 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.
Epidemiology
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
SSSC
1.00
.95
.90
.85
.80
.75
Pro
po
rtio
n S
urv
ivin
g
Age
2M 20Y10Y6Y3Y1Y
ALL
Age (Years)
1.0
0.9
0.8
0.7
0.6
0.5
0.4
0.3
0.2
0.1
0
0 10 706050403020
Pro
ba
bil
ity
of
Su
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al
Probability of Survival for Male and Female Patients with SS Compared with Black Males and Females
Females with SSMales with SSBlack femalesBlack males
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.
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)
Affected Populations
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/dLLDH: 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
Acute hemolytic anemia
Favism
Congenital nonspherocytic hemolytic anemia
Neonatal hyperbilirubinemia
G6PD DEFICIENCY: CLINICAL FEATURES
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 PrimaquineFurazolidone (Furoxone) SulfacetamideMethylene blue Sulfamethoxazole (gantanol)Nalidixic acid (Neg—Gram) SulfanilamideNaphthalene (Mothballs) SulfapyridineNitrofurantoin (Furadantin) ThiazolesulphonePhenazopyridine (Pyridium) Toluidine bluePhenylhydrazine Trinitrotoluene (TNT)
Safe in usual therapeutic doses (Class II and III G6PD variants *)
Acetaminoph ProbenecidAscorbic Acid ProcainamideAspirin PyrimethamineChloramphenicol QuinidineChloroquine QuinineColchicine StreptomycinDiphenhydramine SulfamethoxypyridazineIsoniazid SulfisoxazolePhenacetin TrimethoprimPhenylbutazone 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
Hoffman et al. Hoffman et al. Blood Coagul FibrinolysisBlood Coagul Fibrinolysis 1998;9(suppl 1):S61. 1998;9(suppl 1):S61.
TF-Bearing CellTF-Bearing Cell
Activated PlateletActivated Platelet
PlateletPlatelet
TFTF
VIIIaVIIIa VaVa
VIIIaVIIIa VaVa
VaVa
VIIaVIIa
TFTF VIIaVIIa XaXa
XX IIIIIIaIIa
IXIXVV VaVa
IIII
VIIIVIII/vWF/vWF
VIIIaVIIIa
IIII
IXaIXa
XXIXIX
XX
IXaIXa
IXaIXaVIIaVIIaXaXa
IIaIIa
IIaIIa
XaXa
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%
• Hemophilia A: 20.6 per 100,000 males
– Severe: 50-60%
• Hemophilia B: 5.3 per 100,000 males
– Severe: 44%
U. S. Incidence of Hemophilia
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.
Inhibitors• Definition
– 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