Heme - Coagulopathies

Front 1

Von Willebrand Disease - Which multimers have the most activity?

Back 1

High MW ones.

Front 2

Von Willebrand Disease - General char.

Back 2

Most common hered bleeding disorder. Autosomal dom.

Lower levels of the prot normally in type O blood. So this isn't a true deficiency, but it may be associated with bleeding.

Front 3

vWD 1

Back 3

Low levels of vWF.Very very prevalent.

Front 4

vWD 2

Back 4

Normal levels of vWF. Reduced activity due to abnormal molecule or decresaed high MW multimers. 20-30% prevalence.

2A - No high MW multimers (which are the most effective)
2B - High MW multimers are preserved.

Front 5

vWD 3

Back 5

Absence of vWF and this affects factor VIII. Very Very rare.

Front 6

vWD acquired

Back 6

Usually an autoantibody against vWF. Very rare.

Front 7

vWD phenotype

Back 7

Mucocutaneous bleeding (epistaxis, oropharyng. bleeding, easily bruised).

Many women have menorrhagia.

Prolonged bleeding time.

No bleeding into joints (hemarthroses)

Aspirin exacerbates bleeding.

Front 8

Lab testing (for vWD)

Back 8

Coag screening tests - only aPTT has a chance of being prolonged if there are enough factor VIII issues).

Platelet function will be abnormal (bc poor adherence)- prolonged PFA-100, bleeding time.

Ristocetin

Front 9

Ristocetin

Back 9

Gold standard test for vWD

Antibiotic that aggregates platelets in the presence of vwf. Done via the GPIb receptor. Need to add agonists to the platelets as well.

If vWF is low, platelets will not adhere and cross-linking won't occur--solution will remain cloudy.

Types 1,2,3 will have impaired response.

Type 2b and platelet-type will have hyper-aggregation at low ristocetin levels (unusual--hallmark of vWF2b disease

Front 10

vWD2b

Back 10

Gain of func mutation in vWF. Overbinds platelets and clears the out of circulation (so there is also quantitative thrombocytopenia)

Caused by a mutation in vWF (contrast with platelet-type vWD.

Front 11

platelet-type ("pseudo") von Willebrand disease

Back 11

Hyper-agg of low ristocetin doses, gain of function mutation in GP1b receptor.

So same phenotype as vWD2b, and mutation is in the platelet receptor.

Front 12

Electrophoresis of vWF in a patient with thrombotic thrombocytopenic purpura

Back 12

Can't cleave the vWF multimers, so will see a ton of the high MW proteins.

Front 13

Tx of pt with vWD - Indications

Back 13

Not everyone needs to be treated.

Acute bleeding episodes, prophylaxis for hemostatic challenges, menorrhagia.

Front 14

Tx of pt with vWD

Back 14

DDAVP (desmopressin or synthetic vasopressin) - stimulates release of vWF and VIII from endothelial cells.
Works well for type 1 and some type 2 pts. Avoid in type 2b.

Factor replacement (give pt vWF and VIII) - Humate P, Alphanate, Cryoprecipitate. V. good for pts with Type 2b

Antifibrinolytic therapy - Great for women with menorrhagia. These stabilize a clot once it forms.

Contraceptives for menorrhagia - may require combo therapy with a hemostatic agent.

Medic alert bracelet

Avoid aspirin.

Front 15

X-linked recessive hemophilias:

Back 15

A (VIII def) - 80% prevalence among hemophiliacs
B (IX def) - AKA CHristmas disease.

Female carrier may or may not bleed. Menorrhagia is common.

May have combined disorders (e.g. vWD as well)

Severity depends on factor levels.

Front 16

Autosomal recessive hemophilias:

Back 16

Mainly bleeders in the homozygous state.
Only common bleeder in heterozygous state is C (XI deficiency)

C - XI def
Parahemophilia - V def

Front 17

Mild hemophilia

Back 17

Factor level: 5-40%
aPTT may be normal.
Bleeding occurs with trauma or surgery.

Front 18

Moderate hemophilia

Back 18

2-5% factor level
Prolonged aPTT
Bleeding may be spontaneous

Front 19

Severe hemophilia

Back 19

<1% factor levels
Prolonged aPTT
spontaneous bleeding is common.

Front 20

Bleeding pattern in hemophilia

Back 20

Bleeding will initially stop and then start again (because primarly platelet plug is fine)

Hemarthroses may develop a "target" joint. Muscle hematomas (e.g. psoas) is common too.

CNS, bleeding after minor trauma, hematuria.

Thrombin burst is affected in hemophilia.

Front 21

Lab eval in hemophilia A and B

Back 21

aPTT is the only thing could be prolonged. Should correct with a mixing study (unless acquired hemophilia)

Mild hemophilia (factor level >30%) may be associated with a normal aPTT

Front 22

Tx of hemophilia

Back 22

Coagulation factor concentrates are the best way.
Recombinant VIII and IX have replaced plasma derived (bc of contamination with diseases).
Mild VIII deficiency may respond to DDAVP (because vWF and factor VIII is stored in the vascular endothelium).

Prophylactic tx now to maintain factor levels >1%. - reduced joint morbidity

Front 23

Complications of hemophilia

Back 23

Chronic arthopathy due to hemarthroses (knees, ankles, elbows)

Infectious disease due to infected plasma products. (HIV, Hepatitis)

Inhibitors develop to the missing factor. Very common with factor VIII. This requires the use of bypassing agents to treat bleeding episodes. Get to the clot through a differnet pathway (e.g. recombinant factor VIIa)

Front 24

Acquired hemophilia

Back 24

Spontaneous ab to factor VIII.
Most are idiopathic--associated with lymphoproliferative disorders, cancer, medications, post-partum...

aPTT will be prolonbed BUT WILL NOT correct with a mixing study. (if low titers - there will first be a correction then a prolongation again)

Bethesda assay measures the amount of antibody.

Front 25

Tx of acquired hemophilia

Back 25

If low titer - treat with hig doses of VIII

High titer - recombinant VIIa
or
FEIBA (factor VIII inhibitor bypassing activity) - plasma derived concentrations of factors II, VII, IX, X. (these are the vit k dependent ones)

Also eradication by immune suppression - not useful in congenital hemophilia.
(anti CD20 ab [rituximab] and prednisone)
(cyclophosphamide)

Front 26

Fibrinolytic bleeding - Features

Back 26

Delayed (12-24 hours ) after injury.

Front 27

Hereditary fibrinolytic bleeding

Back 27

Very Very rare

Autosomal recessive
Alpha-2-antiplasmin def.
Plasminogen activator inhibitor 1 deficiency
Factor XI deficiency (fac XI also has a role in fibrinolysis)

Overexpression of plasminogen activator
Quebec platelet disorder - lots of fibrinolytic activity.

Front 28

Acquired fibrinolytic bleeding

Back 28

Cancer, liver disease, DIC, local release of plasminogen, activators from prostate surgery.

Front 29

Labs of fibrinolytic bleeding

Back 29

PT and aPTT prolonged as long as fibrinogen is consumed.

Increased D-Dimers

Diff to distinguish from DIC

Front 30

Tx of fibrinolytic bleeding

Back 30

Interesting because system is depleting fibrinogen AND degrading fibrin clots.

Supportive with plasma infusions (because fibrinolytic inhibitors are present there)

Specific drugs -
epsilon aminocaproid acid (Amicar) - binds to fibrin and prevents plasmin from degrading it.
Tranexamic acid.

Front 31

Vit K deficiency

Back 31

Required for coagulation factors II, VII, IX, X.
Req for Prot S and C

Gamma-carboxylation to let them bind to phospholipid surface.

Most common cause is overanticoagulation. Also due to diet, medications, or coumarin anticoagulants (warfarin, superwarfarins)

Front 32

Warfarin

Back 32

Blocks a recycling step in the glutamic acid carboxylation cycle.

Front 33

Vit K def labs

Back 33

PT and aPTT prolonged. Will correct in mixing study.
Normal platelets.
II, VII, IX, X levels decreased.

V LEVELS WILL BE NORMAL!!!! (this is how you distinguish between liver failure)

Front 34

Tx of Vit K def

Back 34

Oral formulations are best (fat sol). But it takes a couple hours to be effective.

In acute setting, give fresh frozen plasma and you must give Vit K as well because of the short half life of factor VII

Front 35

Liver functions- affecting these can result in pt bleeding

Back 35

Makes pts bleed if disturbed....
Coagulation factors (but remember that VIII also made by endothelial cells), fibrinolytic factor inhibitors., can make an abnormal fibrinogen (dysfibrinogenemia)

Front 36

Liver functions- affecting these can result in pt clotting

Back 36

Anticoag and fibrinolytic factors (Prot C, S, antithrombin, plasminogen).

Clearing activated coag factors.

Front 37

With severe liver damage...

Back 37

pts will likely bleed

(BUT STILL AT RISK OF CLOTTING)

Front 38

Lab findings of liver disease

Back 38

Prolonged PT (INR) and aPTT

Low factor levels (all Vit K dep factors and factor V). But Facotr VIII is preserved!


Don't autoanticoagulate a pt despire the prolonged INR

Front 39

MELD score

Back 39

INR, creatinine, bilirubin

Front 40

Tx of liver disease

Back 40

Transplant.

Vit K and fresh plasma only effective until liver function improves.

Front 41

DIC - General

Back 41

Too much intravascular thrombin resulting in fibrin clots in the circulation. This in turn activates platelets too.

Front 42

Compensatory reactions of DIC

Back 42

Consumption of coag factors, prot C, increase in plasmin and fibrinolysis.

Activation of endothelium and kinin system (produces vasoactive proteins)

CAUSES BLEEDING!

Front 43

Clinical presentations of DIC

Back 43

Severe bleeding (at IV sites)

Purpura fulminans (seen in meningitis - skin/tissue necrosis leading to amputations)

Asymptomatic - seen in cancer and there is only lab evidence for it

Thrombosis - Large ones are rare, micro ones are common and lead to end-organ damage. Common in cancer, trauma, obstetrics.

Front 44

Clinical conditions associated with DIC

Back 44

Infections, tumors, leukemias, obstetic catastrophes, trauma, shock, brain injury, snake bites, burns, hepatic necrosis, vasc disorders, intravasc hemolysis, inflamm disorders.

First Aid: ***STOP Making New Thrombi

Sepsis (Gram -), trauma, obstetric, pancreatitis. Malignancy, nephrotic syndrome, transfusion.

Front 45

Dx of DIC

Back 45

Clinical ev of hemorrhage or thrombosis in an appropriate clinical setting

and

lab evidence of procoag activation, fibrinolytic activation, inhibitor consumption, or biochem evidence of end-organ damage.

Front 46

Lab dx of DIC

Back 46

Prolonged PT/aPTT
Elev- D-Dimers
Dicreased fibrinogen/platelets
Anemia
RBC SCHISTOCYTES (shear of RBCs going through clots)
Low levels of endogenous anticoagulants. (antithrombin and proteins C/S)

Front 47

Tx of DIC

Back 47

Reduce thrombosis, support coagulation and RBCs.

Treat the underlying cause.

Transfusion of plasma.

Heparin to stop the DIC (but it can cause excess bleeding)

Front 48

Organ tests for suspected bleeding disorder

Back 48

Liver, renal, thyroid function tests.