Blood Disorders - Boards

Hemoglobinopathies

Different pathogenic variants in the HBB gene result in different types of hemoglobinopathies

The single alleles are listed as:

• HbS: Sickle Cell

  • ( a a / s s)

• HbC:

• HbD

• HbE

Hemoglobinopathy: CBC

Complete Blood count: measures the number and characteristics of blood cells

Measures

• Red Blood Cells (RBC)

• Hemoglobin (Hb)

• Mean Corpuscular Hemoglobin (MCH): amount of hemoglobin in each RBC

• ****Mean Corpuscular Volume (MCV)****: average size of red blood cells

A MCV BELOW 80% IS SUGGESTIVE OF A HEMOGLOBINTOPYH OR IORN DEFIENCEY

Test allows you to know something is abnormal: but not what → need Hemoglobin Electrophoresis

Hemoglobin

Hemoglobin is composed of 4 chains (a a / b b )

There are 4 types of chains:

• Alpha (a) Gene HBA1/HBA2 : Fetal + Adult

• Beta (b) - Gene HBB : Adult

• Gamma (g) - Gene HBG1/HBG2 : Fetal

• Delta (d) - Gene HBD : Adult (small amount)

Come together to form diffrent forms of HEMOGLOBIN PROTIen

• Adult Major Hemoglobin (HbA): (a a / b b)

  • 95-98% of adult hemoglobin

• Adult Minor hemoglobin (HbA₂): (a a / d d)

  • 2% of Adult hemoglbin (normally)

  • ****elevated in BETA-THAL****

• Fetal Hemoglobin (HbF): (a a / g g)

  • binds O2 better than HbA → ‘outcompete’ the maternal RBCs

At 6months, Gama-chain decreases and Beta-chain increases (where all the pathogenic blood issue variants come form)

Hemoglobinopathy: Hemoglobin Electrophoresis

Tells you WHICH HEMOGLOBINS are present in the RBCs → pull protines through the gel see how they seperate

• Normal Audlt:

  • HbA: 98%

  • HbA2: 3%

  • HbF: <1%

• Sickle Cell Trait (HbA/S): still a normal HBB allele to produce some normal ( b ) to make HbA

  • HbA: ~60%

  • HbS: ~40% (BELOW 50%)

  • HbA2: Low

  • HbF: Low

• “Classic” Sickle Cell DIEASE (HbS/S): Both HBB alleles only make abnormal ( b ) = all HbS

  • HbA: 0%*****

  • HbS: 95%

  • HbF: INCREASED (2-20%)***

  • HbA2: low

Sickle Cell Anemia: Etiology

Gene: HBB (codes for the Beta-globin chain)

• A Hemoglobinopathy

• Hemoglobin in red blood cells polymerizes in low o2→ causes RB cell to form sickle shape = clots

• Represented as HbS: can combine with other Hb_ alleles to cause different ‘levels’ of sickle cell disease

  • ex:HbS/S = ‘classic’ Sickle Cell vs. HbS/C = more mild

Inheritance

• Autosomal Recessive

• Classic variant: c20A>T (p.Glu6Val)

Pathophysiology

Onset 4-6 months: fetal hemoglobin (HbF) prevents HbS polymerization → decline after birth

• Chronic Hemolytic Anemia: RB cells las 10-20days (vs 120 for normal)

• Vaso-Occlusive Pain Crisises: sickle cell RB cells block small blood vessles (ischemia)

Sickle Cell Anemia: Clinical Features

Chronic Anemia Related

• Hemolytic Anemia (Hallmark)

  • Fatigue

  • Pallor/Jaundice

  • Dark Urine

Vaso-Occlusive related (usually triggered by infection, dehydration, stress etc.)

• Limbs

  • Dactylitis (Hand-Foot syndrome): painful swelling of feet/hands - -

    • Onset 6months-2years

• Lungs

  • Acute chest Syndrome (Medical Emergency): blocks in lungs triggered by infection

• Brain

  • Stroke: 10% risk - childhood

• Spleen:

  • Functional Asplenia: spleen fails to filter blood → infections increas (encapsualted bacteria)

    • Onset by 5yo

Sickle Cell Anemia: Screening

Both NBS and carrier screening are extremely important for sickle cell

CBC

Parent Carrier

• ******CBC NORMAL!*****

Affected Child

• Hemoglobin/Hematocrit: Decreased

• ****MCV: NORMAL!!!*****

• WBC/Platelets: often elevated

Hb Electrophoresis

Parent Carrier (sickle-cell TRAIT)

• HbA: 60%

• HbS: 35%

• HbA2: 3%

Affected Child (sickle-cell DIEASE)

• ****HbA: 0%****

• HbS: 95%

Sickle Cell Disease: All Hb variants

• HbSS: Classic sickle Cell Anemia

• HbSC: Milder form (Proliferative retinopathy common) 2nd most common form

  • HbS 50%

  • HbC 50%

• HbS/β⁰: Similar to HbSS in severity

  • HbS Domiant

  • HbA₂ increased

  • HbF increased

• HbSD-Punjab: Similar to HbSS in severity

  • HbD by itself is benign

  • But HbD + Hbs : promotes polymerization → sickle cell RBCs

• HbS/β⁺: Mild to moderate

  • HbA PRESENT but REDUCED

  • HbS Dominant

  • Normal HbF/HbA2

• HbSE: Less severe than HbSS

  • More frequent in South-East Asian populations

Common Hemoglobin Alleles

• HbA - Normal Hemoglobin

• HbS - Causes sickling when

  • Homozygote

  • combined iwth certain variants

• HbC: Causes ***mild hemolytic anemia*** as homozygote

  • BUT does not cause sickle by itself

• HbD: Usually clincially silent

  • UNLESS combined with HbS : will promote sickling of HbS and cause SSD

• HbE: Mild B-Thalassemia-like phenotype

Beta-Thalessemia: Overview

Gene: HBB (beta chain globin that makes up part of hemoglobin in RBCs)

• A QUANATATIVE hemoglobinopathy: not abnormal structure but lack of proper amount causes disease

• Either complete absent or reduced B-globin production

  • β⁰ : No production

  • β⁺ : Reduced production

Inheritance

• Autosomal Recessive

  • ****POINT MUTATIONS****

Two forms:

• B-Thalassemia Major

  • β⁰/β⁰ or severe β⁺/β⁰

  • Small RBCs + Marrow expansion + Transfusions

• B-Thalassemia Intermedia

  • β⁺/β⁺ or mild Mild β⁺/β⁰

  • Less severe: occasional transfusion

• B-Thalassemia Trait

  • β/β⁰ or β/β⁺

  • Asymptomatic or very mild Anemia

Beta-Thalassemia Major: Clinical features

Age of onset 4-6 months

Chronic infusions + increased intestinal iorn absorption (body’s response to anemia) = Iron Overload

Skeletal

• Bone Marrow Expansion

  • Frontal Bossing + Prominent Cheek bones+ Maxillary over growth (“Chipmunk facies”)

  • Osteopenia

  • Fractures

  • Long bone deformities

Liver/Spleen

• Hepatosplenomegaly (RBC breakdown)

• Liver cirrhosis (transfusion Iron overload)

Heart

• ***Cardiomyopathy (transfusion Iron overload)***

  • *** Leading cause of death ***

B-Thal Intermdia:

• similar but less sever

• Varialbe age of presenation

B-thal Minor (trait)

• asymptomatic or mild anemia

Beta-Thalassemia: Screening

B-Thalassemia Major

• CBC

  • MCV: very low

  • RBC: Low

• Electro

  • HbA: ****ABSENT***

  • HbF: **** 98% ***

  • HbA2: 2-5%

β-Thalassemia Intermedia

• CBC

  • MCV: very low

  • RBC: variable

• Electro

  • HbA: 40% (SOME HbA still being made)

  • HbF: **** 40% Elevated ****

  • HbA2: 4-8%

B-Thalassemia Minor (Trait)

• CBC

  • Hemoglobin: lower

  • **** MCV: Very Low ****

  • RBC: NORMAL

• Electro

  • HbA: 95%

  • ****HbA2: 4-8% ELEVATED****

Beta-Thalassemia: Management

B-Thal Major

• Blood Transfusions

  • Every 3-5 weeks

• Iron Chelation

  • Prevent iron buildup (Cardiomyopathy, chrisosis)

• Hematopoietic Stem Cell Transplantation (HSCT)

  • Only curative option

  • Best for

    • young patients,

    • matched siblings,

    • before severe iron overload

B-Thal-Intermedia

• Avoid chronic transfusions if possible

  • Only do them occasionally when needed

    • infection

    • pregnancy

    • surgery

Alpha-Thalassemia: overview

Gene: HBA1, HBA2 (codes for the a-globin chain that is a part of all hemoglobin forms - ex. HbA ( a a / b b)

• Because there are two genes for a- globin, normal people have 4 WORKING COPIES of a-globin producing genes

• Lack of a-globin + normal b-globin = excess b-globin forms abnormal tetramers (HbH-β₄) → poor 02 delivery

Inheritance

• Autosomal Recessive

  • ****GENE DELETIONS****

4 Clinical Forms

• Silent Carrier

  • - a / a a

  • 3 working copies

  • Asymptomatic

• α-Thalassemia Trait

  • - a / - a (trans) or - - / a a (cis)

    • Cis deletion common in SE Asian populations

  • 2 working copies

  • Mild microcytic anemia

• Hemoglobin H Disease

  • - - / a -

  • 1 working copy

  • Moderate hemolytic anemia

• Hb Bart Hydrops Fetalis

  • - - / - -

  • No working copies

    • No (a) = No (b) produced

    • Only (g) produced → forms Hb Bart’s : o2 binding EXTRMELY tight

  • Severe Anemia, Hydrops Fetalis, Edema, Heart Failure (FATAL if untreated)

Alpha-Thalassemia: Screening

Silent Carrier (- a / a a)

• CBC: normal

• Electro: normal

A-Thal Trait: Trans ( - a / a a) or Cis ( - - / a a)

• CBC: low MCV, normal RBC

• Electro: ***NORMAL***

*****DNA TESTING THE ONLY WAY TO DIAGONSIS SILENT AND A-THAL TRAIT*****

HbH Disease: ( - - / - a)

• CBC: very low MCV, low RBC

• Electro: HbH present (β₄), HbA low

Hb Bart Hydrops Fatalis: (- - / - -)

• CBC: ****ALL VALUES LOW: Hemoglbin, Hemocrit, MCV****

• Electro: ONLY Hb Bart’s (γ₄) PRESENT ***

Alpha Thalassemia: Clinical Features

Silent Carrier: Asymptomatic

A-Thal Trait: Asymptomatic → may be mis diagnosed with iron deficiency

Hemoglobin H Disease:

• Chronic Hemolytic Anemia

  • Fatigue, pallor, weakness, exercise intolerance

• Splenomegaly

• Infusions only when needed (infection, surgery, pregancy)

Hb Bart Hydrops Fetalis

• Severe Fetal Anemia

• Hydrops Fetalis

• Heart Failure

• Intrauterine transfusions + Chronic infusions after birth

  • ****MOTHER AT RISK FOR COMPLICAITONS****

• Fetus cannot surive without treatment

jaundice + splenomegaly + chronic hemolytic anemia + No dramatic skeletal changes = HbH Deiase

Gluclose-6-Phosphate Dehydrogenase (G6PD) Deficiency

Gene: G6PD (with out RBC cannot neutralize oxidative stress)

Inheritance

• ****X-Linked Recessive****

Clinical Features

• Acute Hemolytic Episodes

  • ****TRIGGERED by Oxidative Stress***

    • Infections

    • Medications: Sulfa-drugs

    • Food: ***FLAVA BEANS***

Diagnosis

• G6PD Enzyme Assay of RBCs

  • DONT test during acute hemolytic crisis

Diamond-Blackfan Anemia (DBA)

Gene: RPS19 (Most common) (ribosomal protein)

• Defective ribosomes lead to apoptosis of RBC -precursor cells → severe anemia

• Failure to make RBC, but WBC and Platelets normal

  • Pure red cell aplasia

Inheritance

• Autosomal Dominant

  • DE NOVO 70%

Clinical Features

Onset before 1yo

Blood

• Severe Anemia: very LOW RBCs produce

• Macrocytic Anemia; RBCs that re produced, are way to big

  • MCV: very high

  • Hemoglobin/Hemocrit: LOW

  • Reticulocyte: VERY LOW

Congenital Anomalies

• Upper Limbs

  • ****ABSENT THUMB****

• Craniofacial

  • Cleft Palate

• Cardiac

• Renal

Management

• Steroids: first line treatment

• Chronic transfusions: if steroids fail

• Iron Chelation

• Stem Cell Transplant

Hemophilia A

Gene: F8 (coagulation factor VIII)

• More common than Hemophilia B

• Hemophilia A + B are essentially indistinguishable

• DEEP TISSUE BLEEDING

Inheritance

• ****X-Linked Recessive*****

  • Inherited 70%

  • DE NOVO 30%

• Intron 22 Inversion: most severe

• Females protected

Clinical Features

Severe and Moderate forms

Severe:

• Presents in Infancy

  • Spontaneous + prolonged bleeding

  • Recurrent hemarthroses (joint bleeding)

  • Easy Bruising

Moderate

• bleeding after minor trauma

Mild

• Bleeding after surgery and major trauma

Hemophilia B

Gene: F9 (coagulation factor IXa)

• Hemophilia A + B are essentially indistinguishable

• DEEP TISSUE BLEEDING

Inheritance

• ****X-Linked Recessive*****

  • Inherited 70%

  • DE NOVO 30%

• Intron 22 Inversion: most severe

• Females protected

Clinical Features

Severe and Moderate forms

Severe:

• Presents in Infancy

  • Spontaneous + prolonged bleeding

  • Recurrent hemarthroses (joint bleeding)

  • Easy Bruising

Moderate

• bleeding after minor trauma

Mild

• Bleeding after surgery and major trauma

von Willebrand disease

Gene: VWF

• Platlets affected

• MUSCOSAL BLEEDING

Inheritance

• Autosomal Dominant or Recessive

Clinical Features

• Prolonged bleeding (especially after dental work - mucosal bleeding)

• Easy Bruising

• Heavy mensuration

Unlike Hemophilia

• NO JOINT BLEEING

• Mucosal Bleeding is primary bleeding

Thrombocytopenia-Absent Radius (TAR) Syndrome

Gene: RBM8A

• Abnormal development of platelet precursors and upper limbs

• Weird feature: cow milk intolerance

Inheritance

• Autosomal Recessive

Clinical Features

Presents by 2yo

• Thrombocytopenia: low platelets (but get better with age)

  • ***Intracranial Hemorrhage in INFANCY****

• Limb Abnormalities

  • Bilateral Absent Radius

  • ****BUT THUMBS ARE PRESENT**** (unliked Fanconi anemia, Holt-Oram, VACTERL)

Factor V Leiden Thrombophilia

Gene: F5 (coagulation factor V)

• A BLOOD CLOTTING disorder → NOT a bleeding disorder

• too much CLOTTING

Inheritance

• Autosomal Dominant

• INCOMEPLTLE PENETRANCE

• Homozygotes have higher risk than Heterozygotes

Clinical Features

• Deep Vein Thrombosis: a blood clot

  • Usually forms in Calf or Femoral Artery

• Pulmonary Embolism: when clot breaks off and gets sucked into the lungs

  • can be life threatening

****Many Heterozygotes never develop a clot***

• ESTROGEN increased Embolism Risk

Severe combined immunodeficiency (SCID)

• SCID presents in early infancy with recurrent severe and opportunistic infections.

• Persistent thrush + failure to thrive + absent tonsils = think SCID.

• Newborn screening detects SCID using TRECs.

• The most common cause is X-linked IL2RG deficiency (T− B+ NK−).

• Early hematopoietic stem cell transplantation is the standard curative treatment and has the best outcomes when performed before serious infections occur.

Chronic Granulomatous Disease (CGD)

Gene: CYBB (important for neutrophils to kill pathogens once they eat them) but many genes

• Unable to effectively kill bacteria/pathogens = RECURRENT INFECTIONS

Inheritance

• X-Linked Recessive

Clinical Features

Onset in infancy or early childhood

Recurrent infections including

• Recurrent Pneumonia

• Skin Abscesses (from Staph. infections)

• Liver Abscesses (from Staphylococcus aureus)

  • Aspergillus especially

Wiskott-Aldrich Syndrome (WAS)

Gene: WAS (important for functioning in hematopoietic cells)

• Immune cells and Platelets cannot function properly

Inheritance

• ****X-Linked Recessive****

  • 1/3 DE NOVO

Clinical Features

Presents in infancy

• Thrombocytopenia (low Platelets)

• Eczema

• Recurrent infections

  • Otitis media (ear)

  • Sinusitis

  • Pneumonia

Chediak-Higashi Syndrome (CHS)

Gene: LYST (important for lysosome formation)

• s

Inheritance

• Autosomal Recessive

Clinical Features

Onset infancy or early childhood

• Partial Oculocutaneous Albinism: pigment reduced but NOT ABSENT

  • Light skin w Silver/light-colored hair

  • Vision issues

• Recurrent Infections: speciallystaphylococcal

  • Skin infections

  • Pneumonia

  • Otisis media

• *****Hemophagocytic lymphohistiocytosis (HLH)-like phase*****:

  • Immune system become hyperactivated → massive inflammation

  • = bone marrow failure + organ failure

• Progressive Neurologic Disease

Diagnosis

• Peripheral smear showing giant cytoplasmic granules in neutrophils