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, MD Tuesday, August 2, 2005

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Page 1: Hematology: Inherited blood disorders, case histories and review Michael R. Jeng, MD Tuesday, August 2, 2005

Hematology: Inherited blood disorders, case histories and review

Michael R. Jeng, MDTuesday, August 2, 2005

 

Page 2: Hematology: Inherited blood disorders, case histories and review Michael R. Jeng, MD Tuesday, 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

Page 3: Hematology: Inherited blood disorders, case histories and review Michael R. Jeng, MD Tuesday, August 2, 2005

• 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

Page 4: Hematology: Inherited blood disorders, case histories and review Michael R. Jeng, MD Tuesday, August 2, 2005

• 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

Page 5: Hematology: Inherited blood disorders, case histories and review Michael R. Jeng, MD Tuesday, August 2, 2005

Peripheral Blood Smear

Page 6: Hematology: Inherited blood disorders, case histories and review Michael R. Jeng, MD Tuesday, August 2, 2005

Normal Smear Sickle Smear

Page 7: Hematology: Inherited blood disorders, case histories and review Michael R. Jeng, MD Tuesday, August 2, 2005

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.

Page 8: Hematology: Inherited blood disorders, case histories and review Michael R. Jeng, MD Tuesday, August 2, 2005

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

Page 9: Hematology: Inherited blood disorders, case histories and review Michael R. Jeng, MD Tuesday, August 2, 2005

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

Page 10: Hematology: Inherited blood disorders, case histories and review Michael R. Jeng, MD Tuesday, August 2, 2005

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.

Page 11: Hematology: Inherited blood disorders, case histories and review Michael R. Jeng, MD Tuesday, August 2, 2005

• 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

Page 12: Hematology: Inherited blood disorders, case histories and review Michael R. Jeng, MD Tuesday, August 2, 2005

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

Page 13: Hematology: Inherited blood disorders, case histories and review Michael R. Jeng, MD Tuesday, August 2, 2005

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

rviv

al

Probability of Survival for Male and Female Patients with SS Compared with Black Males and Females

Females with SSMales with SSBlack femalesBlack males

Page 14: Hematology: Inherited blood disorders, case histories and review Michael R. Jeng, MD Tuesday, August 2, 2005

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

Page 15: Hematology: Inherited blood disorders, case histories and review Michael R. Jeng, MD Tuesday, August 2, 2005

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)

Page 17: Hematology: Inherited blood disorders, case histories and review Michael R. Jeng, MD Tuesday, August 2, 2005

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

Page 19: Hematology: Inherited blood disorders, case histories and review Michael R. Jeng, MD Tuesday, August 2, 2005

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

Page 20: Hematology: Inherited blood disorders, case histories and review Michael R. Jeng, MD Tuesday, August 2, 2005

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

Page 21: Hematology: Inherited blood disorders, case histories and review Michael R. Jeng, MD Tuesday, August 2, 2005

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

Page 23: Hematology: Inherited blood disorders, case histories and review Michael R. Jeng, MD Tuesday, August 2, 2005

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

Page 24: Hematology: Inherited blood disorders, case histories and review Michael R. Jeng, MD Tuesday, August 2, 2005

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.

Page 25: Hematology: Inherited blood disorders, case histories and review Michael R. Jeng, MD Tuesday, August 2, 2005

• Expected PE

• What other history?

• Family History?

• WHAT TO DO NOW?

Page 26: Hematology: Inherited blood disorders, case histories and review Michael R. Jeng, MD Tuesday, August 2, 2005

• 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

Page 27: Hematology: Inherited blood disorders, case histories and review Michael R. Jeng, MD Tuesday, August 2, 2005

• 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.

Page 28: Hematology: Inherited blood disorders, case histories and review Michael R. Jeng, MD Tuesday, August 2, 2005

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

Page 29: Hematology: Inherited blood disorders, case histories and review Michael R. Jeng, MD Tuesday, August 2, 2005

Malaria Belt

Page 30: Hematology: Inherited blood disorders, case histories and review Michael R. Jeng, MD Tuesday, August 2, 2005
Page 31: Hematology: Inherited blood disorders, case histories and review Michael R. Jeng, MD Tuesday, August 2, 2005

• 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

Page 32: Hematology: Inherited blood disorders, case histories and review Michael R. Jeng, MD Tuesday, August 2, 2005

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

Page 33: Hematology: Inherited blood disorders, case histories and review Michael R. Jeng, MD Tuesday, August 2, 2005

Beta Thalassemia

• Beta Thal Minor/ Beta Thal Trait

• Asymptomatic, carriers.

• Mild anemia, and microcytosis

Page 34: Hematology: Inherited blood disorders, case histories and review Michael R. Jeng, MD Tuesday, August 2, 2005

• 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

Page 35: Hematology: Inherited blood disorders, case histories and review Michael R. Jeng, MD Tuesday, August 2, 2005
Page 37: Hematology: Inherited blood disorders, case histories and review Michael R. Jeng, MD Tuesday, August 2, 2005

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.

Page 38: Hematology: Inherited blood disorders, case histories and review Michael R. Jeng, MD Tuesday, August 2, 2005

• What other history?

• Labs?

Page 39: Hematology: Inherited blood disorders, case histories and review Michael R. Jeng, MD Tuesday, August 2, 2005

• Review of labs:– Mother: Rh negative, Anti-Rh antibodies

present– CBC: WBC: 12 Hgb: 10, with spherocytes,

reticulocyte count: 16%, Platelets – 242

– Coombs positive

Page 40: Hematology: Inherited blood disorders, case histories and review Michael R. Jeng, MD Tuesday, August 2, 2005

• RH disease

Page 41: Hematology: Inherited blood disorders, case histories and review Michael R. Jeng, MD Tuesday, August 2, 2005

• 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

Page 42: Hematology: Inherited blood disorders, case histories and review Michael R. Jeng, MD Tuesday, August 2, 2005

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

Page 43: Hematology: Inherited blood disorders, case histories and review Michael R. Jeng, MD Tuesday, August 2, 2005

For Prenatal Care

• Test for Fetal-Maternal Hemorrhage

– Rosette Test

– Kleihauer-Betke Test

Page 44: Hematology: Inherited blood disorders, case histories and review Michael R. Jeng, MD Tuesday, August 2, 2005

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

Page 45: Hematology: Inherited blood disorders, case histories and review Michael R. Jeng, MD Tuesday, August 2, 2005

• 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.

Page 46: Hematology: Inherited blood disorders, case histories and review Michael R. Jeng, MD Tuesday, August 2, 2005

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.

Page 47: Hematology: Inherited blood disorders, case histories and review Michael R. Jeng, MD Tuesday, August 2, 2005

• 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.

Page 48: Hematology: Inherited blood disorders, case histories and review Michael R. Jeng, MD Tuesday, August 2, 2005

• 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.

Page 49: Hematology: Inherited blood disorders, case histories and review Michael R. Jeng, MD Tuesday, August 2, 2005

• 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 **

Page 50: Hematology: Inherited blood disorders, case histories and review Michael R. Jeng, MD Tuesday, August 2, 2005

• G6PD: 2.5 u/gm Hg (5.5 – 8.8)

• PK: 13.8 (3.2 – 6.5) **

• What other causes?

Page 51: Hematology: Inherited blood disorders, case histories and review Michael R. Jeng, MD Tuesday, August 2, 2005

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

Page 52: Hematology: Inherited blood disorders, case histories and review Michael R. Jeng, MD Tuesday, August 2, 2005

OXIDANT-INDUCED RBC INJURY

Page 53: Hematology: Inherited blood disorders, case histories and review Michael R. Jeng, MD Tuesday, August 2, 2005

HEINZ BODIES

Page 54: Hematology: Inherited blood disorders, case histories and review Michael R. Jeng, MD Tuesday, August 2, 2005

RBC METABOLISM - OVERALL

Page 55: Hematology: Inherited blood disorders, case histories and review Michael R. Jeng, MD Tuesday, August 2, 2005

RBC ENZYMOPATHIES ASSOCIATED WITH HEMOLYTIC ANEMIA

G6PD DEFICIENCY - MILLIONS

PYRUVATE KINASE (PK) DEFICIENCY – THOUSANDS

OTHERS - VERY RARE

Page 56: Hematology: Inherited blood disorders, case histories and review Michael R. Jeng, MD Tuesday, August 2, 2005

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

Page 57: Hematology: Inherited blood disorders, case histories and review Michael R. Jeng, MD Tuesday, August 2, 2005

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

Page 58: Hematology: Inherited blood disorders, case histories and review Michael R. Jeng, MD Tuesday, August 2, 2005

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+

Page 59: Hematology: Inherited blood disorders, case histories and review Michael R. Jeng, MD Tuesday, August 2, 2005

DECAY OF RBC G6PD ACTIVITY

Page 60: Hematology: Inherited blood disorders, case histories and review Michael R. Jeng, MD Tuesday, August 2, 2005

Acute hemolytic anemia

Favism

Congenital nonspherocytic hemolytic anemia

Neonatal hyperbilirubinemia

G6PD DEFICIENCY: CLINICAL FEATURES

Page 61: Hematology: Inherited blood disorders, case histories and review Michael R. Jeng, MD Tuesday, August 2, 2005

PRIMAQUINE-INDUCED HEMOLYSIS

Page 62: Hematology: Inherited blood disorders, case histories and review Michael R. Jeng, MD Tuesday, August 2, 2005

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.

Page 63: Hematology: Inherited blood disorders, case histories and review Michael R. Jeng, MD Tuesday, August 2, 2005

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

Page 64: Hematology: Inherited blood disorders, case histories and review Michael R. Jeng, MD Tuesday, August 2, 2005

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.

Page 65: Hematology: Inherited blood disorders, case histories and review Michael R. Jeng, MD Tuesday, August 2, 2005
Page 66: Hematology: Inherited blood disorders, case histories and review Michael R. Jeng, MD Tuesday, August 2, 2005
Page 67: Hematology: Inherited blood disorders, case histories and review Michael R. Jeng, MD Tuesday, August 2, 2005
Page 68: Hematology: Inherited blood disorders, case histories and review Michael R. Jeng, MD Tuesday, August 2, 2005

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

Page 69: Hematology: Inherited blood disorders, case histories and review Michael R. Jeng, MD Tuesday, August 2, 2005

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.

Page 71: Hematology: Inherited blood disorders, case histories and review Michael R. Jeng, MD Tuesday, August 2, 2005

• Laboratory evaluation:

• CBC: WBC: 13.2, Hgb: 11.4, Plt 341

• PT: 11.2sec (10.4-12.6)

• PTT: >80 sec (25-40)

Page 72: Hematology: Inherited blood disorders, case histories and review Michael R. Jeng, MD Tuesday, August 2, 2005

• Factor 9: 145%

• Factor 8: 4%

• Vwf antigen: 151%

• Ristocetin cofactor: 164%

Page 73: Hematology: Inherited blood disorders, case histories and review Michael R. Jeng, MD Tuesday, August 2, 2005

What is hemophilia?Hemostatic System

• Blood vessels

• Platelets

• Plasma coagulation system

• Proteolytic or Fibrinolytic system

Page 74: Hematology: Inherited blood disorders, case histories and review Michael R. Jeng, MD Tuesday, August 2, 2005

How Bleeding Stops

• Vasoconstriction

• Platelet plug formation

• Clotting cascade activated to form

fibrin clot

Page 75: Hematology: Inherited blood disorders, case histories and review Michael R. Jeng, MD Tuesday, August 2, 2005

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

Page 76: Hematology: Inherited blood disorders, case histories and review Michael R. Jeng, MD Tuesday, August 2, 2005

Types of Bleeding Disorders

• Hemophilia A (factor VIII deficiency)

• Hemophilia B (factor IX deficiency)

• von Willebrand Disease (vWD)

• Other

Page 77: Hematology: Inherited blood disorders, case histories and review Michael R. Jeng, MD Tuesday, August 2, 2005

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)

Page 78: Hematology: Inherited blood disorders, case histories and review Michael R. Jeng, MD Tuesday, August 2, 2005

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

Page 79: Hematology: Inherited blood disorders, case histories and review Michael R. Jeng, MD Tuesday, August 2, 2005

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

Page 80: Hematology: Inherited blood disorders, case histories and review Michael R. Jeng, MD Tuesday, August 2, 2005

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%

Page 81: Hematology: Inherited blood disorders, case histories and review Michael R. Jeng, MD Tuesday, August 2, 2005

• 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

Page 82: Hematology: Inherited blood disorders, case histories and review Michael R. Jeng, MD Tuesday, August 2, 2005

Types of Bleeds

• Joint bleeding - hemarthrosis

• Muscle hemorrhage

• Soft tissue

• Life threatening-bleeding

• Other

Page 83: Hematology: Inherited blood disorders, case histories and review Michael R. Jeng, MD Tuesday, August 2, 2005

Joint or Muscle Bleeding

• Symptoms– Tingling or bubbling sensation

– Stiffness

– Warmth

– Pain

– Unusual limb position

Page 84: Hematology: Inherited blood disorders, case histories and review Michael R. Jeng, MD Tuesday, August 2, 2005

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

Page 85: Hematology: Inherited blood disorders, case histories and review Michael R. Jeng, MD Tuesday, August 2, 2005

Other Bleeding Episodes

• Mouth bleeding

• Nose bleeding

• Scrapes and/or minor cuts

• Menorrhagia

Page 86: Hematology: Inherited blood disorders, case histories and review Michael R. Jeng, MD Tuesday, August 2, 2005

Complications of Bleeding

• Flexion contractures

• Joint arthritis / arthropathy

• Chronic pain

• Muscle atrophy

• Compartment syndrome

• Neurologic impairment

Page 87: Hematology: Inherited blood disorders, case histories and review Michael R. Jeng, MD Tuesday, August 2, 2005

How do you treat hemophilia?

• Replacement of missing clotting protein– On demand– Prophylaxis

• DDAVP / Stimate• Antifibrinolytic Agents

– Amicar

• Supportive measures– Icing– Immobilization– Rest

Page 88: Hematology: Inherited blood disorders, case histories and review Michael R. Jeng, MD Tuesday, August 2, 2005

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

Page 89: Hematology: Inherited blood disorders, case histories and review Michael R. Jeng, MD Tuesday, August 2, 2005

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

Page 90: Hematology: Inherited blood disorders, case histories and review Michael R. Jeng, MD Tuesday, August 2, 2005

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.)

Page 91: Hematology: Inherited blood disorders, case histories and review Michael R. Jeng, MD Tuesday, August 2, 2005

Amicar(epsilon amino caproic acid)

• Antifibrinolytic

• Uses– Mucocutaneous bleeding

• Dosing: 50 - 100 mg./kg. q. 6 hours

• Side effects

• Contraindications– Hematuria

Page 92: Hematology: Inherited blood disorders, case histories and review Michael R. Jeng, MD Tuesday, August 2, 2005

Target Joints

• Steroids

• NSAIDS

Page 93: Hematology: Inherited blood disorders, case histories and review Michael R. Jeng, MD Tuesday, August 2, 2005

Complications of Treatment

• Inhibitors/Antibody development

• Hepatitis A

• Hepatitis B

• Hepatitis C

• HIV

Page 94: Hematology: Inherited blood disorders, case histories and review Michael R. Jeng, MD Tuesday, August 2, 2005

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

Page 95: Hematology: Inherited blood disorders, case histories and review Michael R. Jeng, MD Tuesday, August 2, 2005

Special Issues Continued

• Dentistry

• Elective Surgery

• HIV/Hepatitis – CDC/UCD STUDY

• Cost of factor/Insurance

Page 96: Hematology: Inherited blood disorders, case histories and review Michael R. Jeng, MD Tuesday, August 2, 2005

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

Page 97: Hematology: Inherited blood disorders, case histories and review Michael R. Jeng, MD Tuesday, August 2, 2005

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