week 6.2 hem

autoimmune hem anemia AIHA

sensitization, agglu, hemolysis, WAIHA, CAIHA (CAD), mixed type

alloimmune HA

do not react with own rbcs, HDFN- mom makes abs against ags on fetus rbcs, transfusion rxn- abc to ags on transfused donor cells

extravascular hemolysis

rbc sensitized with ab or complement, sensitized cells pagocytized by macroph in spleen or liver

intravascular hemolysis

compliment cascade activated, C9 MAC causing rbc lysis

higher titer of abs

nore likely to cause increased hemolysis

thermal amplitude of the ab

warn ab can cause hemolysis but cold usually dont

IgG mediated hemolysis

Fc receptos (FcYR- I, II, III on spleen macrophage), bind ab Fc attached to rbc, pits complex damaging membrane, repairs, repeated splenic passage forms spherocyte

IgG ab sensitized rbcs engulfed by

macrophages and PMN with FcYR-I, III

NK cells

FcYR-III, aDCC

complement mediated hemolysis

sensitization activated and deposited on rbc membrane, lysis- entire activated and deposition on rbc membrane, 1 IgM or IgG1 and 3 or 2 needed to activate

IgM mediated hemolysis

intravasc comp activated through C9, extravasc incomplete activation C3b coats rbc, sensitized cells destroyes by CR1 and 3 receptors on macrophage, can also agglu cells

DAT

detects rbc coated in vivo, required to diff AIHA from other HA

neg DAT in AIHA

not enough IgG molecules on rbc, autoab of IgA or M, autoab with low affinity for rbc

pos DAT in norm individual

healthy= no shortened rbc survival, ineffective macro removal of sensitized cells, not enough ab on cell surface, subclass AB not rec by macrophage, thermal amplitude <37, complement on rbc, pt with hypergammaglobulinemia or high IVG dose with nonspec binding

IAT

detects ags in plasma or serum (vitro), indicated alloimmunization or autoabs in pt serum

AIHA (auto)

immune tolerance normally prevents formation of autoab, occurs from genetic predisposition, infec agent (molecular mimicry), defects in immune tolerance reg, warm or cold→ primary or 2ndary

WAIHA

70% of AIHA, usually IgG (IgG3 lower Hb), most react with Rh complex not null or deleted cells, can have single specif within Rh system, extravasc

idiopathic WAIHA

60% of cases of WAIHA, actue- severe anemia, developing over 2-3 days, self limited hemolysis, lasts several weeks to years, chronic- unabating hemolysis

2ndary WAIHA

lymphoprolif disease (CLL, HD), neoplastic disease, autoimmun disorder (SLE- thrombocytopenia, RA, Crohns), infec espec in infants/kids, vaccines

WAIHA presentation

higher incidence if 40+, anemia, 2ndary underlying disorder symp, mild-mod splenomegaly >50% pts, hepatomegaly 1/3 pts

immune mediated WAIHA

pos DAT, autoab in serum, spherocytes

WAIHA pb

mod-severe norm anemia, Hb indicates severity, high retics, reticpenia if rxn against erythro precursors, poly, nrbc, sphero, schisto

WAHA lab eval

bm erythro hyperplasia, erythophagocytosis, pos DAT polyspecific AHG (30% pos anti-C3)

WAIHA vs HS

pos DAT, autohemolysis not corrected by glucose, non homogeneous spherocytes

CAIHA

16-30% of AIHA, IgM with complement activation, react with I/i or Pr ags, severity based on thermal range of ab

idiopathic CAIHA CAS

chronic, after age 50, monoclonal IgM/kappa with autoanti-one specificity

2ndary CAS

associated with infec disease or lymphoproliferative disorders

infectious disease CAS

acute, self limiting, polyclonal autoab for Ii ags, anti-I M. pneumo HIV, anti-i infec mono, anti-Pr rubella or varicella

lymphoproliferative disorders CAS

chronic in older people, monocloonal IgMk ab

CAIHA presentation

chronic or episodic HA, rbc agglu, vascular changes, hemoglobinuria, splenomegaly

rbc agglu in CAIHA

in area of body that cools to the ab thermal range or sludging of blood flow in capillaries

vascular changes in CAIHA

acrocyanosis, raynauds phenomenon (pain with color change pattern in skin)

CAIHA lab

falsely low rbc and high mcv (warm or dilute reagents), mild-mod anemia (norm, poly, spher, rbc clumps, nrbc, erythophago), bm normoblastic hyperplasia

CAIHA differentail dx benign vs pathologic

pathologic polyspec and monospec anti-comp DAT pos, rbc agglu at 0-20 C in saline reversible at 37 C, titer > 1:1000 (ref 1:64)

Paroxysmal cold hemoglobinuria PCH

rare autoimmune, massive intermittent acute hemolysis and hemoglobinuria, rare in adults, 30-40%. of AIHA in kids under 5 (due to infec), transient, transfus if severe

infections associated with PCH in kids

epstein-barr, cytomegalovirus, measles, mumps, parvovirus 19, haemophilus influenzae, klebsiella pneumo

PCH pathophysiology

bi-phasic comp fixing IgG ab (donath-landsteiner, auto-anti-P specif), binds rbc <20 C activating comp, detaches and rbc lysed by comp MAC at 37 C

PCH presentation

hemoglobinuria, jaundice, pallor, hepatosplenomegaly, Raynauds, rarely acute renal failure with hemolysis

PCH lab

anemia, Hb sharp drop to 5, hempglobinemia, methemalbuminemia, hemoglobinuria, neutropenia (left shift), low retics, spherocytes, aniso, poik, fragments, high serum bili BUN LD, low serum comp and hapt, erythrophagocytosis

PCH DAT

usually neg for abs, weakly pos for complement, IAT pos if cold, low titers <1:32, verified by D-L test

mixed AIHA

high titer and thermal amplitude of IgG and M, 50% are idiopathic, rest are lymphoproliferative or autoimmune disease (SLE), intra M and extravasc G, treat with corticosteroids

drug induced HA DIHA

acquired, >135 drugs ID, causes immune response, piperacillin most common cause, must dif from nonimmune hemolysis and spontaneous autoimmune disorders

Drug induces HA mechanisms

drug adsorption, immune complex, autoab-like, membrane modification,

drug induced HA new “unifying“ hypothesis

drug binds to rbc membrane, abs produced to react with drug epitopes, combination of drug and rbc proteins, causes pt to develop more than one type

nonimmunological protein adsorption NIPA

pos DAT but rarely hemolysis

alloimmune HA

acute IgM occurs within 24 hrs intravasc, delayed IgG 2-14 days post transfuc extravasc

HDFN feto-maternal blood group incompatibility

mom IgG alloab cross placenta and destroy fetal rbcs in utero, Rh(D) by anti-D severe with anti-K, ABO by anti-A and/or B common, other

pathophysiology of HDFN

mom sensitized to rbc ag she lacks, fetus must possess this ag, mom produces abs to it, moms ab crosses placenta

HDFN lab eval

mom- ABO/Rh typing and IAT, baby- ABO/Rh typing and DAT (elution if needed to ID ab)

HDFN baby pb

macro/norm, high retics, leukocytosis left shift, high NRBC, Rh- poly, mild-no poik, fer sphero, high bili,+ DAT, ABO- nrbc, schiso, sphero, poly, sl high bili, weakly + DAT

HDFN Rh immune globulin RhIG

passive injection containing anti-D preventing maternal immunization, give at 28 weeks and following birth of Rh+ baby, dose based on # of fetal cells in maternal circulation

RhIG dose tests

Kleihauer-betke test quantitative, rosette test qualitative, flow cytometry

TMA thrombotic microangiopathic anemia also MAHA

microcirculatory lesions causing hemolysis, thrombocytopenia, ischemic damage to organs, endothelial lining of small vessels damage, plts and fibrin deposition in microvasculature

plts and fibrin deposition in microvasculature

thrombus formation within bv, rbcs forced through fibrin strand in thrombus, fragmented by force of flowing blood

TMA or MAHA pb

schisto, keratocytes, high retics, intra and or extravasc hemolysis, low plts

underlying disorders associated with TMA / MAHA

classic shiga toxin producing e coli hemolytic uremic syndrome STEC-HUS, atypical hemolytic uremic syndrom aHUS, thrombotic thrombocytopenic purpura TTP

conditions characterized by MAHA

disseminated cancer, malignant hypertension, autoimmune disorders, sepsis, preg complications

pregnancy complications causing MAHA

preeclampsia, eclampsia, HELLP (hemolyis, elevated liver enzymes and low plt count) syndrome

HUS hemolytic uremic syndrome

multisystem disorder, rbc fragmentation, thrombocytopenia, acute nephropathy (can include acute renal failure), D+ pr -, STEC-HUS, 2ndary, atypical

STEC-HUS

shiga-like toxin producing organism, 90% of cases, kids <5, GI infec- e. coli O157:H7, or shigella dysenteriae type 1

2ndary HUS

post infectious HUS not STEC, s. pneumo, epstein-barr, HIV, cytomegalovirus, or associated with lupis, cancer, diabetes, immunosuppressive therapt

HUS pathophysiology

E. coli, S. dysenteriae type I, intestinal infec, damage to intestinal mucosa, shiga toxin absorbed into circulation

HUS shiga toxin absorbed into circulation

affects endothelial cells of microvasculature glomerulus, cytotoxic damage, release of prothrombotic vasoactive and plt aggregating subs, formation of plt-fibrin thrombi

STEC-HUS presentation

mostly 0-1 yr olds, acute- sudden pallor, abdominal pain, vomit, fever, bloody diarrhea, macro hematuria, serious- acute renal failure and chronic renal insufficiency, CNS symp, lethargic, minor seizures

HUS cbc

mod-severe norm anemia, Hb 7-9, schisto, helmet, sphero, burr, poly, maybe nrbc, leuko left shift, low plt

HUS lab eval

hemoglobinemia, high bili LD BUN creatinine, low hapt and GFR, renal damage, hypokalemia, hyponatremia, metabolic acidosis

HUS pee

proteinuria, hematuria, pyuria, casts

HUS plts

High D-dimer

TTP thrombotic Thrombocytopenic Purpura

acute, plt aggregation on microvasc endothelium, 20-50 yr olds, f more than m, congenital or acquired, 40% infec, 10-25% preg

TTP microthrombi

plts and ultra large forms of VWF multimers ULVWF, occlude capillaries and arterioles in organs (kidneys, heart, brain, pancreas), ADA MTS13 def

ADA MTS13 def causing TTP

protease that cleaves ultra large multimers of VWF, induces plt aggregation and plt thrombi, rbc fragment as pass trhough microthrombi

familial form TTP

mutations in ADAMTS13 gene resulting in def/dysfun enzyme

acquired form TTP

autoab against ADAMTS13 blocking its activity

TTP presentation

similar to HUS, more in young adults involving more organ systems, prominant neuro sym, renal dysfun less severe, mortality rate higher than HUS, fever

TTP cbc

Hb 8-9, norm anemia, mcv variable, poly, nrbc, high schisto, leuko > 20 left shift, severe thrombocytopenia

TTP lab eval

hemoglobinemia, hemoglbinuria, high bili and LD, low hapt

DIC disseminated intravasc coag

complex thrombohemorrhagic, normal coag altered (bacterial sepsis, neoplasms, immunologic disorders, trauma, obstetrical comp), damage endothelial lining vessels

DIC damage of endothelial lining vessels

release of thromboplastic subs, activate coag mech, plt activation and aggregation, deposition of fibrin, microthrombi forms in microvasc, rbc fragment to schisto, occlusions of vessles, bleeding, organ failure

DIC consumptive coagulopathy

severe thrombocytopenia and low coag factors, serious bleeding complications

DIC coag results

prolonges PT, APTT, TT, high D-dimer and FDPs, low fibrinogen <150 and antithrombin AT

traumatic cardiac HA

prosthetic heart valves, rarely massive hemolysis, many schito due to excessive turbulence of blood flow around valve (shear stress), low rbc fragmentation in new designs

thermal injury

HA in first 24-48 hrs after extensive burns, hemolysis based on % body area burned, denaturation of spectrin in rbc membranes

thermal injury pb smear

budding, schisti, sphero, hemoglobinuria, hemoglobinemia, after 48 hrs

exercise induced hemoglobinuria

march (runners) hemoglobinuria, strenuous exercise, transient intravas hemolysis, no anemia, hemoglobinemia and uria, can cause IDA

infect agents- malaria parasites

mild norm anemia, severe- thrombocytopenia, extravas, blackwater fever (P. falciparum complications intravas hemoglobinemia uria and hyperbilirubinemia),

infec agents- babesiosis

protozoan infec of rodents and cattle transmit to humans via tick, ring struct, extravas hemolysis, mild-mod anemia, high retics liver enzymes and bili, low plt, b. microti, divergensa, duncani

infec agents- bartonellosis

zoonotic, pleomorphic, GNCB, infects rbcs and endothelial cells, sandfly, bacilliformis (biphasic disease, fatal, myalgia, high fever, acute, severe HA), other spp not HA

infec agents- clostridium perfringens

norm flora in GI tract, transient bacteremia or deadly, potent exotoxins affecting rbc membrane (phospholipase C, streptolysin O, perdringolysin), rapid, massive intravas, fever, lysis causing DIC

infec agents- clostridium perfringens lab eval

hemoglobinemia, uria, throbocytopenia, neutroplilia, many microsphero, fer fragments

animal venoms

bees, wasps, spiders, scorpions, most common is brown recluse, localized lesions, systemic symp in 15%, change glycophorin on rbc membrane, comp lysis

chemicals and drugs

rbc hemolysis (dose dependent), hemmoglobinemia uria, methemoglobinemia, cyanosis, bm aplasia, lead poisoning inhib heme syn