paroxysmal nocturnal hemoglobinuria paroxysmal means episodic or in the form of attacks nocturnal means at night hemoglobin aurilla hemoglobin in the urine the problem is a pie gene mutation this is médicos is perfection Ellis we continue our series on hematology okay P&H is an acquired chronic hemolytic anemia contrast that with thalassemia or sickle cell anemia those were inherited in an autosomal recessive fashion PNH is acquired it's not congenital it's not inherited it's acquired after you're born you acquire this disease due to the fact in the myeloid stem cells myeloid stem cells will give rise to red
blood cells neutrophils and platelets and others the mutation is in the PI gene on the short arm of the X chromosome position 22.2 the mutation occurs after birth hence acquired by the way pi guess stands for phosphatidyl inositol gleich and anchor biosynthesis class a holy guacamole pygar gene encodes an enzyme that synthesize something called membrane associated proteins these regulate the complement and they include GPI which stands for glyco cell phosphatidyl inositol who if there is no GPI there is no complement regulatory proteins which include cluster differentiation 55 also known as decay accelerating factor and cluster
differentiation 59 also known as membrane inhibitor of reactive lysis also known as homologous restriction factor did you understand the thing of course not but that's why meta kosis is here let's dissect everything so that you can understand all of these crazy words let's review some amine ology complement system why the name is complement because it complements the ability of antibodies to do their job three different pathways depending on who pulls the trigger who will store the Cascade if it's antigen-antibody complex this is the classical pathway if it's the bacterial and toxin this is the alternative
pathway if mannose binding lectin this is the election pathway in PNH the problem is usually in the alternative pathway so let's elaborate now alternative pathway of the complement what triggers the cascade is bacterial endotoxin which is a lipo polysaccharide in the outer membrane of gram-negative bacteria that was nice microbiology there we start with factor c3 hydrolysis in the presence of water into factor C 3 B it will bind with factor B and then factor D will convert factor B into B a and B B factor baby will combine with 3 3 B to form c3
convertase this is a big deal c3 convertase will convert c3 into c3a and c3b c3b will bind with c3 convertase to form c5 convertase c5 convertase will do what converts c5 into c 5a and c5 b c 5b together with c 6 7 8 and 9 will form something called the Mac this is not anti microsoft and this is not MacDonald's either this is the membrane attack complex it will form a pore in the cell membrane of the bacteria which will disrupt the ionic and osmotic environment of the cell and now the bacteria will die
go to hell Shakespeare time plays to attack or not to attack this is the question how does the compliment differentiate between self and non-self non-self bacteria are foreigners and we should destroy them but self are our own cells such as red blood cells we should never touch them how does the compliment no thanks to compliment regulatory proteins think of regulatory as inhibitory they inhibit the complement from attacking these include CD 55 and CD 59 so this is the cell membrane of your red blood cell or neutrophil or platelets these are the myeloid lineage there are
no lymphocytes here because these are the lymphoid stem cell origin now the PI gap gene will encode an enzyme that will give rise to GPI GPI is an anchor protein it will anchor CD 55 and CD 59 to the sole membrane CD 55 will prevent the formation of c3 convertase so the complement cannot attack CD 59 will block the binding of c9 so there is no Mac when there is no Mac there is no attack and everybody is happy and the complement can recognize the cell and not attack it this is normal let's see now
he will understand every single word in this page pH is an acquired chronic hemolytic anemia due to defect in the myeloid stem cells yes pygar gene mutation correct pi gain codes for GPI if there is no GPI there is no CD 55 or CD 59 so the complement will destroy the normal blood cells the self the complement x the red blood cell in an intravascular hemolysis most of the time pH is an intrinsic intravascular acquired hemolytic anemia what ascent him also throughout the day but when you go to bed you increase your urine concentration this
is true because the first morning urine sample is the highest concentration so you will see your urine darker and it has hemoglobin in it so that patient is shouting dr. help me there is blood in my urine complications of PNH include iron deficiency anemia why because you are losing hemoglobin in the urine as well as acute myeloid not lymphoid myeloid leukemia most common cause of death thrombosis especially venous what's the cause of thrombosis nobody knows a theory suggests that of the myeloid lineage our playlist when platelets are destroyed by the complement they produce some factors
which are Pro coagulant and lead to thrombosis okay venous thrombosis in the hepatic veins known as bud Kyary syndrome portal or cerebral and the second most common cause of death is infection now clinically a nice triad hemolytic anemia pancytopenia and venous thrombosis hemolytic anemia will have its symptoms as splenomegaly as we have discussed in our famous video intravascular versus extravascular hemolysis pancytopenia no neutrophils infections no platelets bleeding no red blood cells fatigue and anemia okay aplastic anemia can coexist with the pancytopenia of PNH venous thrombosis depending on the location in hepatic veins this is but
Kyary syndrome in absence of any lever disease so the patient lever is completely fine no cirrhosis no hepatitis no cancer but the veins are having thrombosis this is pH abdominal veins spell necrosis and severe abdominal pains revenge stroke veins of the skin skin nodules esophageal spasms may coincide with hemoglobinuria this is high-yield PNH can cause fever of unknown origin now let's go to the lamp CBC how about hemoglobin and hematocrit both are decreased because this is the definition of anemia how about reticulocytes are increased because this is a response from the bone marrow to hemolysis
except if there is a plastic anemia in that case reticulocytes will be low but most of the times they are high MCB is usually normal which means 80 to 100 but there are some tiny exceptions one of the complications of PNH is iron deficiency anemia which will lead to low MCV another exception if reticulocyte ptosis exists MCB will be high because as you know reticular cytosis are mature red blood cells and they are larger than the red blood cells raising the MCV in the serum LDH is high unconjugated bilirubin is high haptoglobin is low and
go back to my video on hemolysis direct Coombs test is negative because there is no antigen-antibody reaction there is no classical complement pathway contrast that with autoimmune hemolytic anemia where the Coombs test is positive because then there is antigen-antibody reaction sucrose him hemolysis test is very unreliable and it's a screening test acidified serum test or ham is very reliable used for confirmation flow cytometry is the gold standard it can detect the absence of CD 55 and CD 59 which is P&H how to treat pn h pn h is a hemolytic anemia give iron and folate
if severe RBC transfusion glucocorticoids can be used in hemolytic anemias but specifically in pn h they are contraindicated occlusion map is a new miraculous drug for pn mab means monoclonal antibody antibody against one antigen and one antigen only this one antigen is c5a Collegium ab will bind to c5 and prevents its cleavage into c 5a c5 b by the enzyme c5 convertase there is no c5 a c5 b so there is no mac and no attack it reduces mortality so patient can live longer if you are giving a collision map vaccinate against Neisseria meningitidis definitive
treatment of course is stem cell transplant if P and H coexists with aplastic anemia do a bone marrow transplant see in the next video a mnemonic on P and H
