FETAL HEMATOPOIESIS

YOLK SAC

Erythropoiesis is established soon after implantation of the blastocyst, with primitive erythroid cells appearing in yolk sac blood islands by day 18 of gestation. Ie the first blood island appear in mesoderm at around 3 weeks of development.

How does yolk sac erythroblasts differ from their later definitive counterparts ?

[1] Primitive erythroblasts differentiate within the vascular network rather than in the extravascular space and remain nucleated as they circulate.

[2] Primitive erythroblasts are characterized by more rapid maturation, increased sensitivity to erythropoietin, and a shortened life span compared to fetal and adult erythroblasts.

[3] Yolk sac erythroblasts are extremely large red cells c/a megaloblasts

After 7 weeks gestation, hematopoietic progenitors are no longer detected in the yolk sac but yolk sac derived primitive erythroblasts continue to circulate until approximately 12 weeks of gestation.

SO HEMATOPOIESIS IN YOLK SAC = 3rd to 7th WEEK

Note that blood islands in yolk sac have HEMANGIOBLASTS arising from MESODERM. Hemangioblasts in centre of island form bood cells and are callled as HEMATOPOIETIC STEM CELLS and those in perifery differentiate into ANGIOBLASTS which form blood vessels.

LIVER :

Blood cells arising in blood islands of yolk sac is a transitory phenomena as the definitive hematopoietic cells arise from mesoderm surrounding aorta called as AORTA-GONAD-MESONEPHROS REGION (AGM Region). These cells will first colonise the liver which becomes major hematopoietic organ of liver  and later on these stem cells from liver will colonise the bone marrow.

BFU-E appear in the fetal liver as early as 5 weeks of gestation, and CFU-E are evident soon thereafter. The liver serves as the primary source of red cells from the 9th to the 24th weeks of gestation.

 

In contrast to the yolk sac, where hematopoiesis is restricted to erythroid and macrophage cells, hematopoiesis in the fetal liver also includes other myeloid as well as lymphoid lineages. So some “may be asked- NOT so important points” ( DNB oneliners)

[1] First RBC’S = 3rd week( yolk sac)

[2] Megakaryocytes are present in the liver by 6 weeks of gestation and Platelets are first evident in the circulation at 8–9 weeks gestation.

IMPORTANT NOTE POINT : The liver remains the primary site of erythropoietin transcription throughout fetal life as compared to kidney in adults.

BONE MARROW

Hematopoietic cells are first seen in the marrow of the 10- to 11- week embryo and they remain confined to the diaphyseal regions of long bones until 15 weeks gestation.The marrow becomes the major site of hematopoiesis after the 24th week of gestation.

 

NOTE : Lymphopoiesis is present in the lymph plexuses and the thymus beginning at 9 weeks gestation.

 

EMBRYONIC HEMOGLOBINs
[1] Hb PORTLAND = Zeta & gamma chains**
[2] Hb GOWER 1 = Zeta & epsilon chains **
[3] Hb GOWER 2 = Alpha & Epsilon chains**
FETAL Hb = HbF = Alpha & Gamma chains**

EMBRYONIC HEMOGLOBINS

Hb Gower 1 is the major hemoglobin in embryos less than 5 weeks of gestation****Q

Hb Gower 2 has been found in embryos with a gestational age 4-13 weeks.

Hb Portland is found in young embryos but persists in infants with homozygous  thalassemia.

At 10 -11 weeks fetal Hb becomes predominant Hb****Q

Adult Hb appears as early as 16- 20 weeks but synthesised in a nearly exclusive manner after 38 weeks.

Ref : [1] Langman’s medical embryology/10ed /pg 77

         [2] Williams Hematology, 8e , Chapter 6: Hematology of the Fetus and Newborn.


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COPPER : MENKES DS : WILSON DS

Why is copper  required in body ?

What if there is deficiency of copper ?

what if there is excess of copper ?

1. Copper acts as cofacter for various enzymes = TYROSINASE , LYSYL OXIDASE , SUPEROXIDE DISMUTASE, CYTOCHROME C OXIDASE, DOPAMINE BETA HYDROXYLASE. [Q]

2. If there is deficiency of copper these enzymes will not work properly as for eg in copper deficient state lysyl oxidase will not work and there will be ineffectual cross linking in collagen and elastin leading to weakened vascular wall and fragile skin.

MENKES DISEASE IS A X-LINKED RECESSIVE DISORDER DUE TO DEFICIENCY OF COPPER

PATHOGENESIS : Defect in ATP7A gene[Q] so that copper is absorbed in the intestinal eptithelial cells but cant be transported out of intestinal epithelial cells into blood stream so that the intestinal epithelial cells are loaded with copper but there is deficiency of copper in body.

CLINICS : Mental retardation , seizures , hypothermia , twisted and hypopigmented hair (pili torti) , loose skin , arterial rupture and death in early childhood.

TREATMENT : To give copper by any other route than oral becoz intestinal absorption is impaired. Subcutaneous route copper is given and show some clinical improvement in disease state.

WILSON DISEASE IS DUE TO EXCESS DEPOSITION OF COPPER IN VARIOUS PARTS OF BODY:

PATHOGENESIS : Defect in ATP7B gene( CHROMOSOME 13)[Q] leads to defective excretion of copper from hepatocytes into billiary tree leading to copper excess in body . Two most commonly effected organ is liver and brain so also known as HEPATOLENTICULAR DEGENERATION.

CLINICS : It usually presents with acute or chronic liver disease in childhood . Liver disease is progressive if left untreated. Adults develop neurological symptoms as dysarthria and diminished cordination. Copper accumulation can also lead to arthropathy , cardiomyopathy, kidney damage and hypoparathyroidism , decemets membrane formation.

TREATMENT : Chelating agents as penicillamine and ammonium tetrathiomolybdate.

so to compile

MENKES = COPPER DEFICIENCY = ATP7A GENE = X-LINKED RECESSIVE = DEFECTIVE COPPER ABSORPTION

WILSON = COPER EXCESS = ATP7B GENE = CHROMOSOME 13 = AUTOSOMAL RECESIVE = DEFECTIVE COPPER EXCRETION

RHABDOMYOSARCOMA [AIIMS MAY 2013]

Q] Marker used for identification of Rhabdomyosarcoma…[AIIMS MAY 2013]
[A] DESMIN
[B] VIMENTIN
[C] CYTOKERATIN
[D] S-100

OR which of the following is superior to other markers for identification of Rhabdomyosarcoma?

Ans = [A] DESMIN

Desmin is a intermediate filament and is a sensitive marker for tumors of both smooth and skeltal muscle origin. More than 90 % of Rhabdomyosarcomas are positive , including those that are very poorly differentiatedDesmin has been proven to be superior to other muscle markers for identification of Rhabdomyosarcoma. In smooth muscle tumors desmin reactivity is variable. Note that MYOGLOBIN is found exclusively in skeltal muscle lesions and so it is specific for Rhabdomyosarcoma but its sensitivity is far less than that of desmin.[Ref : Strernbergs diagonostic surgical pathology 5ed/ vol 1/ page 134]

VIMENTIN : It is known as intermediate filament of mesenchymal tissues however vimentin positivity is not that informative from a diagonostic point of view because many tumors including carcinomas and melanomas contain vimentin.

CYTOKERATIN (CK) : Cytokeratins are specific for tumors of epithelial origin. The two sarcomas that characteristically displays epithelial markers are = Synovial sarcoma & Epitheloid sarcoma .

POMPES DISEASE : AN EXTRAORDINARY STORY OF DEVELOPMENT OF MYOZYME

POMPES DISEASE :it is a glycogen storage disease due to deficiency of lysosomal enzyme acid maltase or acid alpha glucosidase. it is TYPE II GLYCOGENOSES which is classified as muscle glycogenoses (AI1997). it is a unique glycogenoses in which glycogen accumulation is lysosomal rather then in cytoplasm. MUSCLE BIOPSY SHOWS VACOULAR MYOPATHY which denotes lysosomal glycogen accumulation.

INFANTILE FORM of the disease is fatal  and the neonate present as floppy infant(hypotonia) + hepatosplenomegaly  +  cardiomegaly ( high voltage QRS & short PR interval) + coarse facies ( AIIMS 2001). Note thal macroglossia is also present.

JUVENILE OAND ADULT FORM OF DISEASE usually present as slowly progressive myopathy without cardiac involvement.

Recombinant enzyme has been developed and approved by FDA for its treatment.it is a ORPHAN DRUG named ALGLUCOSIDASE ALPHA ( MYOZYME for infantile form andLUMIZYME for older patient without cardiac involvement.

 

EXTRAORDINARY MEASURES: is a 2010 movie based on true story when parents set up a biotechnology company to develop a drug to treat their children suffering from pompes disease which ultimately led to development of recombinant enzyme myozyme.This movie was adapted from non fiction book of journalist Geeta Anand” The cure : how a  father raised $ 100 million and bucked the medical establishment in a quest to save his children”Image