Hematology: Inherited blood disorders, case histories and review Michael R. Jeng, MD Tuesday,

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Hematology Inherited blood disorders, case
histories and reviewMichael R. Jeng,
MDTuesday, August 2, 2005 
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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.

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• 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

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• 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

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Peripheral Blood Smear
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Normal Smear Sickle Smear
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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.

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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 lt 20 days

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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

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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.

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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.

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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 lt20 years of age
1.00
.95
.90
Proportion Surviving
.85
SS
SC
.80
ALL
.75
2M
20Y
10Y
6Y
3Y
1Y
Age
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Probability of Survival for Male and Female
Patients with SS Compared with Black Males and
Females
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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

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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)

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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

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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

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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

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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

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Other Clinical IssuesFEVER/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

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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.

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• Expected PE
• What other history?
• Family History?
• WHAT TO DO NOW?

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• 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

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• 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.
  

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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)
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Malaria Belt
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• Two main types alpha or beta thalassemia
• Alpha Thalassemia
• 4 copies of the alpha globin genes on Chromosome
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• Thus, there are 4 genotypes possible

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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

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Beta Thalassemia

• Beta Thal Minor/ Beta Thal Trait
• Asymptomatic, carriers.
• Mild anemia, and microcytosis

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• Beta Thal Major/Beta Thalassemia (Cooleys
  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

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Case C

• A 1 day old newborn is noted to be icteric and
  jaundiced.
• Maternal history Born to a 32 year old G3P1 gt 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.

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• What other history?
• Labs?

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• Review of labs
• Mother Rh negative, Anti-Rh antibodies present
• CBC WBC 12 Hgb 10, with spherocytes,
  reticulocyte count 16, Platelets 242
• Coombs positive

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• RH disease

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• 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

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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

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For Prenatal Care

• Test for Fetal-Maternal Hemorrhage
• Rosette Test
• Kleihauer-Betke Test

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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

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• 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.

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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.

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• 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.

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• 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.

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• 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
  (lt1.4)
• Coombs test negative

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• G6PD 2.5 u/gm Hg (5.5 8.8)
• PK 13.8 (3.2 6.5)
• What other causes?

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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

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OXIDANT-INDUCED RBC INJURY
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HEINZ BODIES
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RBC METABOLISM - OVERALL
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RBC ENZYMOPATHIES ASSOCIATED WITH HEMOLYTIC
ANEMIA
G6PD DEFICIENCY - MILLIONS PYRUVATE KINASE
(PK) DEFICIENCY THOUSANDS OTHERS - VERY RARE
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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

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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

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WORLD HEALTH ORGANIZATION (WHO) CLASSIFICATION OF
G6PD VARRIANTS
NORMAL ACTIVITY CLINICAL FEATURES EXAMPLE
CLASS I 10 20 Chronic hemolysis
CLASS II lt 10 Intermittent hemolysis Mediterranean
CLASS III 10 60 Intermittent hemolysis A-, Canton
CLASS IV 100 None B, A

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DECAY OF RBC G6PD ACTIVITY
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G6PD DEFICIENCY CLINICAL FEATURES
Acute hemolytic anemia Favism Congenital
nonspherocytic hemolytic anemia Neonatal
hyperbilirubinemia
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PRIMAQUINE-INDUCED HEMOLYSIS
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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.

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DRUGS AND CHEMICAL ASSOCIATED WITH HEMOLYSIS IN
G6PD DEFICIENCY Unsafe (Class I, II and III
G6PD variants) Acentanilid
Primaquine Furazolidone (Furoxone)
Sulfacetamide Methylene blue
Sulfamethoxazole (gantanol) Nalidixic acid
(NegGram) Sulfanilamide Naphthalene
(Mothballs) Sulfapyridine Nitrofurantoin
(Furadantin) Thiazolesulphone Phenazopyridin
e (Pyridium) Toluidine blue Phenylhydrazine
Trinitrotoluene (TNT)
Safe in usual therapeutic doses (Class II and III
G6PD variants ) Acetaminoph
Probenecid Ascorbic Acid Procainamide Aspirin
Pyrimethamine Chloramphenicol
Quinidine Chloroquine Quinine Colchicine
Streptomycin Diphenhydramine
Sulfamethoxypyridazine Isoniazid
Sulfisoxazole Phenacetin Trimethoprim Phenylb
utazone Phenytoin Vitamin K
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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.

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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

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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.

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• Laboratory evaluation
• CBC WBC 13.2, Hgb 11.4, Plt 341
• PT 11.2sec (10.4-12.6)
• PTT gt80 sec (25-40)

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• Factor 9 145
• Factor 8 4
• Vwf antigen 151
• Ristocetin cofactor 164

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What is hemophilia?Hemostatic System

• Blood vessels
• Platelets
• Plasma coagulation system
• Proteolytic or Fibrinolytic system

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How Bleeding Stops

• Vasoconstriction
• Platelet plug formation
• Clotting cascade activated to form fibrin clot

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Normal Hemostasis
II
X
VIII/vWF
TF
VIIa
Xa
IIa
Va
VIIIa
TF-Bearing Cell
TF
V
Va
VIIa
IX
Platelet
II
IXa
X
IIa
Xa
VIIIa
IXa
Va
Activated Platelet
VIIa
IXa
Va
IIa
Xa
VIIIa
II
IX
X
Hoffman et al. Blood Coagul Fibrinolysis
19989(suppl 1)S61.
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Types of Bleeding Disorders

• Hemophilia A (factor VIII deficiency)
• Hemophilia B (factor IX deficiency)
• von Willebrand Disease (vWD)
• Other

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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)

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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

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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

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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 lt1

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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

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Types of Bleeds

• Joint bleeding - hemarthrosis
• Muscle hemorrhage
• Soft tissue
• Life threatening-bleeding
• Other

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Joint or Muscle Bleeding

• Symptoms
• Tingling or bubbling sensation
• Stiffness
• Warmth
• Pain
• Unusual limb position

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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

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Other Bleeding Episodes

• Mouth bleeding
• Nose bleeding
• Scrapes and/or minor cuts
• Menorrhagia

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Complications of Bleeding

• Flexion contractures
• Joint arthritis / arthropathy
• Chronic pain
• Muscle atrophy
• Compartment syndrome
• Neurologic impairment

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How do you treat hemophilia?

• Replacement of missing clotting protein
• On demand
• Prophylaxis
• DDAVP / Stimate
• Antifibrinolytic Agents
• Amicar
• Supportive measures
• Icing
• Immobilization
• Rest

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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

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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

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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
• lt50 kg. body weight - 1 spray (150 mcg.)
• gt50 kg. body weight - 2 sprays (300 mcg.)

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Amicar(epsilon amino caproic acid)

• Antifibrinolytic
• Uses
• Mucocutaneous bleeding
• Dosing 50 - 100 mg./kg. q. 6 hours
• Side effects
• Contraindications
• Hematuria

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Target Joints

• Steroids
• NSAIDS

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Complications of Treatment

• Inhibitors/Antibody development
• Hepatitis A
• Hepatitis B
• Hepatitis C
• HIV

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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

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Special Issues Continued

• Dentistry
• Elective Surgery
• HIV/Hepatitis CDC/UCD STUDY
• Cost of factor/Insurance

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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

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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