It may seem obvious, but what are the differences between intravascular and extravascular hemolysis?

Extravascular hemolysis:

results from increased phagocytosis of RBCs by mononuclear phagocytes in the spleen, liver, and Bone marrow. These phagocytes also known as the RES -- reticulo-endothelial system

Intravascular hemolysis:

results from RBCs lysed within the blood vessels by mechanical injury, complement fixation, infection, or toxins

Anemias may show signs of both depending on the pathology involved.

Hgb catabolism starts with Hgb break down into _______ and ______.

The second component is then broken down sequentially into _____, ______, ______. The next step conjugates biliruben with _______. The conjugated form is excreted into the feces and converted to ______, though the action of intestinal flora.

The final break down products are mostly excreted in feces and a small amount is resorbed.

Globin and Heme

Protoporphyrin, Biliverdin, Bilirubin

Glucuronic acid

Urobilinogen

Provide the key laboratory data that can demonstrate hemolysis. What would correlate with these finding clinically?

note: there are a few differences between IVH and EVH

elevation of indirect bilirubin -- correlates with jaundice

decreased haptoglobin levels -- bound up with hgb, not detected with laboratory assay in this form

Increased reticulocyte count as the bone marrow compensates.

Urobilinogen is increased in the urine; if Hgb exceeds haptoglobin levels -- hemoglobinuria directly

Positive Coombs test if hemolysis is antibody related

Also possible in IVH is hemosiderinuria - Bound iron in circulation overloading the kidneys

___________ represent a red cell disorder characterized by an imbalanced production of _____chains of Hgb___.

What are the two types of imbalances, represented by the name of the chain they affect?

Thalassemias

globin

A

Alpha and Beta Thalassemia

What are the "Thalassemmic indices"?

Think about how they relate to other microcytic anemias...jus for fun

RBC count is elevated (This seems a bit dubious since the abnormal hgb causes premature destruction of the cells in the bone marrow and spleen. I assume it depends on the severity of the disease and the robustness of the reticulocyte compensation.)

But, the prof notes this as opposite of ID anemia and ACD.

low Hgb -- finally, something that makes sense!!!!

Low MVC (microcytic)

Normal iron studies.

There are ____ Alpha globulin genes. ___ on each chromosome 16.

This means there can be multiples combinations of defective genes. Describe the disease briefly as more genes are being affected.

4, 2

1 deleted gene...a_/aa....silent carrier (mcv 78-80, MCH borderline low)

2 deleted genes..._ _/aa or a_/a_...minimal to no anemia, low MCV...trait

3 deleted genes..._ _/a_...HbH disease...moderately severe...Aggregated Beta globins...high O2 affinity, bad for exchange. Older RBCs removed by spleen (megaly). Mainly Asians

4 deleted genes (a⁰)..._ _/_ _...early death...hydrops fetalis...gamma-globin (fetal Hb) form tetramers, called Hb Bart's, with too high of an O2 affinity --> no O2 delivery

deletions

Point mutations (often creates stop codons, nonsense mutation)

Thalassemia minor -- asymptomatic with mild or absent anemia

Thalassemia Intermedia -- moderate, does not require blood transfusion

Thalassemia Major (Cooley's anemia)-- this will get it's own flash card!

What would the facies of someone with Thalassemia major look like?

Widening of the maxilla, nasal bridge, frontal bone, and parietal bone.

Also called the Chipmunk facies.

Due to hyperexpansion of the bone marrow in an attemp to produce enough functional RBCs. Recall, bone marrow in long and flat bones typically produce blood cells.

What are the major clinical findings in Thalassemia major?

Think about the mechanism and compensatory response...this is a severe disease necessitating regular blood transfusions.

Hepatsplenomegaly -- sequestration and removal of rbcs with heinz bodies.

Anemia

Expansion of bone marrow leading to bone disfigurement, including the chipmunk face and Hair-on-end as seen in radiographs.

Secondary hemochromatosis (iron overload) due to excessive iron absorption and accumulation from constant transfusions

Laboratory findings of the thalassemias (alpha and beta):

special indices,

Chemistry analytes,

Blood smear

high total rbc count, low MCV (microcytic), normal RDW

elevated reticulocyte count

serum is normal or increased (increased absorption/transfusions), ferritin is normal or increased (same as above).

Peripheral smear:

Target cells, microcytes, tear drop cells, Nucleated RBCs

All these things plus HgA₂ electrophoresis make the diagnosis!

Paroxysmal Noxturnal Hemoglobinuria is an x-linked, _____ disorder that affects the ___gene.

This gene is involved in synthesizing ______, which anchors proteins such as ____, ____, and ____ to the cell membrane.

Without these proteins the cell is lysed by components of the ____________.

acquired

PIG-A

GPI (Glycosylphosphatidylinositol)

CD55, CD59, DC8

Complement System

What could be the reason for the increased risk of thrombosis associated with PNH?

What are some major vessels, mentioned in our notes, that are susceptible?

Thrombocytes are derived from the same myeloid precursors as RBCs and granulocytes, so they are susceptible to damage by complement. This damage can release their inflammatory products and lead to thrombosis.

Important vessels to worry about are the hepatic veins, portal vein, and cerebral veins.

How would you diagnose PHN?

How would you treat PNH?

immunosupression -- prevent complement activation (C5a monoclonal antibody), also for marrow aplasia

Bone Marrow Transplant

Three types of immune-mediated hemolytic anemia.

What are they?

What antibodies are implicated?

Warm Autoantibody -- IgG fixes to RBCs at 37 degrees (body temp) --extravascular hemolysis

Cold agglutinin -- IgM fixes complement to RBCs in the cooler peripheral body parts and transiently agglutinates. When the cells return to the warm organs, the IgM releases but the complement C3b remains -- extravascular hemolysis

Cold Hemolysin -- IgG autoantibodies to P-antigen. Attach in cold areas, lyses in warmer areas. May be severe.  Intravascular Hemolysis

Paroxysmal COLD Hemolysis

How to treat the immunohemolytic anemias:

Warm Antibody?

Cold Agglutinin?

Cold Hemolysin?

Warm Antibody:

removal of initiating factor (usually autoimmune, drugs, lymphoid neoplasm)

Cold Agglutinin:

Very difficult to treat. Avoid the cold. Usually caused by infection or lymphoma.

Cold Hemolysin:

Usually self limiting, caused follwing viral infection

Mechanical RBC destruction comes in a few flavors.

On the macro level there can be cardia abnormalities such as   _____, _____, ______

On the micro level there is usually a narrowing or obstruction in the vasculature by ______ formation

examples include:

1.?

2.?

3.?

mechanical valve, aortic stenosis, aortic coarctation (Narrowing to increase turbulence)

Fibrin formation

1. Disseminated Intravascular Coagulation (DIC)

2. Thrombotic Thrombocytopenic Purpura (TTP)

3. Hemolytic Uremic Syndrom (HUS)

ITP

Idiopathic Thrombocytopenic Purpura

Primary (Idiopathic) or secondary (associated with a clinical condition

Autoimmune.

Acute or Chronic

Produces antiplatelet antibodies that coat platelets and mediate their removal in the spleen

Chronic ITP is usually seen in ______, under 40.

Associated with Autoimmunity disease but can be seen in AIDs, after viral infections, and drugs (meds?)

Since the disease is idiopathic it is a diagnosis of _________.

Ig_ antibodies often against platelet membrane receptors _____ or ______

women

exclusion

IgG, GP IIb/IIIa, Ib-IX

"that idiot Iggor, grabs platelets 2 or 3 at a time."

Idiopathic IgG GP II/III

What to look for with chronic ITP clinically:

thrombocytopenia, which causes disruption of primary hemostasis...

epistaxis (nose bleed)

mucus membrane bleeding

Petechiae (pinpoint bleeding <2mm)

ecchymoses

Laboratory findings of Chronic ITP:

Thrombocytopenia (as in the name)

Megathrombocytes (compensatory enlargement, perhaps from rapid pumping out)

Megakaryocyte hyperplasia in Bone Marrow

Normal RBC and WBC morphology

Normal PT/aPTT

Chronic ITP treatments:

Steroids

Splenectomy if steroids fail (to remove the destroyer...plus it probably gets pretty congested)

immunosuppresive therapy (to attack antibody production)

What is the difference in epidemiology of Acute vs chronic ITP?

Acute ITP typically affects children and men and women equally. Chronic ITP usually affects adult, predom. women under 40

Acute ITP had abrupt onset following a viral infection

Lab findings of Acute ITP:

Thrombocytopenia (don't forget this one)

antiplatelet antibodies

Normal RBCs and WBCs

You could use the "wait and see" approach because it is usually self-limiting

or, if it's severe you can try steroids.

BUT, despite your best efforts it may become chronic

TTP:

Thrombotic Thrombocytopenic Purpura

The name describes what's happening...

Platelets form a thrombus, that depleates the platelet store, leading to purpura through out the body.

As a bonus, the fibrotic thrombi cause mechanical destruction of RBCs, so be on the look out for shistocytes.

What is the molecular defect in TTP?

Deficiency in ADAM-TS 13 (inherited or enz. antibody)

A metalloprotease, whose deficiency leads to large vonWillebrand multimers to float around (otherwise they'd be degraded) and cause platelet activation due to endothelial injury

To remember:

There was an old show called ADAM 12.

This is ADAM 13, The Sequal (ADAM TS 13)

"The Thrombus Police" setting up a dragnet to capture rogue platelets.

Laboratory findings to diagnose TTP:

Thrombocytopenia + Microangiopathic hemolytic anemia

Shistocytes on smear

Normal PT and aPTT (coag. not excessively stimulated)

low ADAM 13 level

vWF multimers circulate between episodes

Symptoms of TTP:

A classic Pentad -- though they don't all have to be present

Fever

Thrombocytopenia

Microangiopathic Hemolytic Anemia (can lead to widespread organ disfunction)

Transient Neurologic Deficits

Renal Failure

Treatment of TTP:

Takes care of ADAM TS' job

Exchange transfusion

• replaces ADAM activity
• removes antibodies to ADAM TS 13

Hemolytic Urea Syndrom (HUS)

Pathogenesis:

Hint: Hus rhymes with Pus, which could be a symptom of what causes this.

Caused by E. coli 0157:H7 (the super virulent strain)

causes gastroenteritis with a Shiga-like toxin.

especially damaging to glomeruli.

plt activation leads to thrombi

How does HUS present:

Think of the causative organism

Bloody diarrhea followed by microangiopathic hemolytic anemia (secondary to the thrombi formed in the microvasculature)

Thrombocytopenia by using up the platelets in the thrombi

Renal failure

Laboratory findings in HUS:

Shistocytes on the blood smear

Normal ADAM TS 13

PT and aPTT normal.

Abnormal renal function tests (ex BUN, creat)

Supportive care in children...they'll bounce back.

In adults, be more careful. Can become a chronic condition.