chapter 24 – extrinsic defects leading to increased erythrocyte destruction – non immune causes
TRANSCRIPT
1 Chapter 24 – Extrinsic Defects Leading to
Increased Erythrocyte Destruction – Non-‐Immune Causes
GENERAL OVERVIEW:
Microangiopathic Hemolytic Anemia
-‐ Aka MAHA -‐ Group of disorders characterized by RBC
fragmentation, hemolysis -‐ The fragmentation occurs as the cells
pass by small vessels. The RBC membrane is sheared mechanically by microthrombi or damaged epithelium. Upon shearing the RBC membrane quickly reseals forming schistocytes.
-‐ These schistocytes are screen in the spleen and hemolyzed extravascularly
-‐ The presence of schistocytes on the peripheral blood smear is a characteristic feature of MAHA
-‐ Decreased HgB, haptoglobin. Hematocrit -‐ Increased Retic ct, serum unconjugated
bilirubin, urine urobilinogen
-‐ May also see Helmet cells and microspherocytes.
-‐ Under Microangiopathic, the condition is termed as Thrombotic microangiopathy to describe when the MAHA is due to formation of thrombi in the microvasculature
-‐ Thrombotic Microangiopathy includes.. 1. Thrombotic thrombocytopenic
purpura 2. Hemolytic uremic syndrome 3. Hemolysis, elevated liver enzymes,
low platelet count (HELLP) 4. Disseminated intravascular
coagulation
Thrombotic Thrombocytopenic Purpura -‐ Elevated serum LD, WBC Count (left shift
since WBCs are immature), severe thrombocytopenia (less than 20*109/L) HgB conc less than 10g/dl.
-‐ Appearance of polychromasia and nRBCs
-‐ Pathophysiology is the release of von Willebrand factor from vascular endolethial cells. The long VWF bind to platelets and clog small blood vessels leading to the formation of thrombi.
-‐ May be acquired or familial 1. Acquired
Extrinsic Hemolytic Anemia
non-‐immune
Microangiopathic Anemia
Macroangiopathic Anemia
Hemolytic Anemia caused by
Infectious Agents
immune
see chapter 25
Helmet cells
Microspherocytes
2 -‐ Divided into secondary or non
secondary -‐ Secondary is associated with stem cell
transplantation, pregnancy, systemic infections, disseminated cancer, drugs, autoimmune disorders
-‐ Non secondary is aka idiopathic TTp. Usually due to deficiency in VWF known as disentegrin-‐like and metalloprotease domain with thrombospodin type1 motifs 13 or aka ADAMTS 13
-‐ Under normal condition, ADAMTS 13 cleave the long VWF to smaller segements preventing excessive platelet aggregation and ultimately microthrombi formation.
-‐ To treat the deficiency, give fresh frozen plasma to patient. 2. Familial TTPs
-‐ Rare disorders due to mutation in the ADAMTS 13 gene
Hemolytic Uremic Syndrome (HUS) -‐ Two types D+ HUS and atypical HUS -‐ D+ HUS preceded bu an episode of
gastroenteritis often with bloody diarrhea
-‐ Atypical HUS have no antecedent diarrhea
1. D+ HUS -‐ Caused by E Coli 0157 H7 -‐ The E Coli release Shiga Toxins which
interact with endothelial cells and result to cell disruption and formation of fibrin clot.
2. Atypical -‐ Uncontrolled complement pathway due
to mutation in Factors H,I,B ; membrane cofactor protein, thrombomodulin
HELLP Syndrome -‐ Mostly develops in 3rd trimester -‐ Complication in pregnancy
-‐ Hemolysis, elevated liver enzymes (LD and AST), low platelet count
-‐ Exact pathogenesis is unknown -‐ If prothrombin time and the partial
thromboplastin time are within the reference range helps distinguish HELLP from DIC
-‐ Mortality to mom is 3-‐5% -‐ Mortality to fetus is 9 -‐24%
Disseminated Intravascular Coagulation -‐ Characterized by the widespread
activation of hemostatic system -‐ Prothrombin time and partial
thromboplastin time are prolonged. Level of D dimer is increased to distinguish DIC
Macroangiopathic Hemolytic Anemia 1. Traumatic Cardiac HA -‐ Can occur in patients with prosthetic
cardiac valve -‐ Platelet count is normal while LD,
indirect bili, LD and plasma HgB are increased.
-‐ Surgical repair or prosthesis replacement
-‐ Hemoglobinuria and Hemosiderunia 2. Exercise – Induce Hemoglobinuria -‐ Decreased level of serum haptoglobin -‐ Increased level of free plasma HgB -‐ Hemoglobinuria after exercise
Hemolytic Infections Caused by Infectious Agents
1. Malaria -‐ Genus Plasmodium Species ! Falciparum ! Vivax ! Ovale ! Malariae ! Knowlesi -‐ Common in Africa, SEA
3 Life Cycle 1. Bite of an infected female Anopheles
misquito 2. Sporozoites invade hepatic parenchymal
cells to begin exoerythrocytic schizogony
3. After 5-‐16 days, cells rupture releasing merozoites
4. Merozoites invade RBCs in circulation thus beginning erythrocytic schizogony
5. Merozoite grows into a ring form which
6. then grows to an mature schizont with
merozoites. Parasitic cycles recur at regular interval
7. Some merozoites enter RBCs to form gametocytes which is the ingested by an uninfected female anopheles
8. The gametocytes eventually develop into oocyst in salivary gland ang secrete sporozoites.
Pathogenesis
-‐ No infection –May immunity ie. sickle cell anemia*
-‐ Asymptomatic anemia – no symptoms but malaria is present in blood
-‐ Uncomplicated malaria – has symptoms and parasite but no organ dysfunction
-‐ Severe malaria – has symptoms, parasite(hyperparasitemia) and organ dysfunction
-‐ Clinical outcome is dependent on different factors such as parasitic (specie, number, multiplication rate, virulence, drug resistance) and host (age, immunity, pregnancy, genes, social factors)
-‐ Cause of anemia in malaria 1. Direct lysis of infected RBC
during schizogony 2. Immune destruction of RBC (both
infected and non ineffective) in spleen
3. Inhibition & ineffective erythropoesis
*both infected and non infected RBCs are destroyed kasi the parasite shed non self proteins to blood and the proteins bind to the RBC membrane of healthy cells.
-‐ Malarial parasites metabolize hemoglobin forming hemozoin. When cell lysis occurs and hemozoin is released, it triggers an inflammatory response
-‐ IR includes TNF a (promote inflammation) and Interferon gamma (increased MHC expression).
-‐ Increased amounts of TNF α and INF γ results to inhibition of erythropoesis.
-‐ IL 6 is also increased and stimulates hepcidin production which decreases iron available to RBC. ( Note: Hepcidin is also an Acute Phase Reactant and with haptoglobin deny bacteria of Fe)
-‐ P falciparum adheres to endothelial cells of in the microvasculature of organs which obstructs the blood vessel and protects the parasite from the spleen.
Malarial Pathogenesis
no infection
asymptomatic parasitemia
uncomplicated malaria
severe malaria
Clinical outcome of infected mosquito
4 Pathogenesis of some species of Plasmodium -‐ Vivax and Ovale -‐> reticulocytes -‐ Malariae -‐> older RBCs -‐ Falcimparum and knowlesi -‐> all RBCs -‐ P vivax need Duffy antigens in RBC so
Duffy negative people are immune to vivax
Diagnosis -‐ Use Wright Giemsa stain -‐ Should make 2 thin and 2 thick smears -‐ Thick smears concentrate the parasites
initial screening and stained with Wrights Giemsa without methanol fixation
-‐ Thin smears are used for specie differentiation and det. of parasitemia. Stained after methanol fixation
-‐ A negative result for a single set does not confirm absence of parasite.
-‐ Fluorescent Des may be used to detect parasite infection
-‐ Molecular based test to differentiate specie
-‐ Dipstick type rapid antigen test • Based on the detection of P
falciparum and Plasmodium aldolase
Treatment -‐ Choloroquine or hydroxychloroquine
except for vivax and falciparum -‐ Use instead atovaquone-‐proguanil -‐ Primaquine may eradicate hypnozoites
in liver
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2. Babesiosis -‐ Tick transmitted disease -‐ B microti is most common -‐ Originally caused Nantucket fever -‐ Other species include Duncani,
Divergens, Venatorum -‐ Mortality rate is less than 10% -‐ Symptoms include fever and respiratory
flu like symptoms
Diagnosis -‐ Use Wright Giemsa thin smear -‐ Dec hemoglobin, haptoglobin -‐ Inc retic ct -‐ Bilirubinemia, Leukemia, -‐ Thrombocytopenia, hemoglobinemia -‐ Appear as tetrads inside RBC -‐ Ring form may be round, ovoid,
amoeboid with dark purple cytoplasm, minimal amt of cytoplasm surrounding a blue cytoplasm
-‐ PCR methods for speciation -‐ Distinguished from p falciparum due to
pleomorphism of their ring forms
Treatment -‐ Combination therapy with
azithromycin/atovaquone/ clindamycin/quinine
3. Clostridial Sepsis -‐ Caused by Clostridium perfringes -‐ C. perfringes produce α toxin with
phospholipase C and sphyngomyelinase which hydrolase RBC membranes
-‐ May trigger DIC and renal failure 4. Bartonellosis -‐ Transmitted by female sandfly -‐ Caused by Bartonella bacilliformis -‐ 2 stages
" Stage 1 – acute hemolytic anemia
" Stage 2 – chronic verruga stage characterized by skin lesions and warts
Diagnosis -‐ Made by blood culture -‐ Wright Giemsa stained peripheral blood
smear -‐ Inidirect immunofluorescent antibody
Hemolytic Anemia caused by other RBC Injury 1. Drugs -‐ Cause oxidative denaturation of
Hemoglobin and formation of Methemoglobin and Heinz bodies
2. Venom -‐ Disrupt or alteration of RBC membrane -‐ From contact with snakes, spiders, bees
and wasps 3. Extensive burns -‐ Warming to 49oC in vitro induces RBC
fragmentation and budding -‐ Schistocytes, spherocytes and
microspherocytesare also observed -‐ Clear within 24 hrs