Heme - Hypercoagulable States

Front 1

With age, a thrombus normally....

Back 1

Platelets swell and lyse

Fibrin solidifies

Leukocytes move into the area. Thrombolysis (via tPA, plasmin, leukocytes, elastases) occurs.

But it CAN embolize, fully lyse, organize, or recanalize (more frequent). Collateral blood flow around this area develops as well.

Front 2

Virchow's Triad

Back 2

Changes in vessel wall

Stasis/change in blood flow

Changes in coagulability of blood

Arterial is less reliable on stasis and interruption of endothelium is key.
Venous usually initiates with stasis or hypercoagulable state.

Front 3

Hypercoagulable state caused by what two broad things

Back 3

Increase in thrombogenic or decrease in anticoagulant factors

Pathogenesis of arterial and venous thrombosis differs

Front 4

Increase in Thrombogenic factors -

Back 4

Damage to endothelium, platelet activation, activ of coag cascade, inhibition of fibrinolysis, stagnation of blood flow.

Front 5

Decrease in Anticoagulant factors

Back 5

Anticoag activity of the endothelium, inhibitors of the coagulation cascade, clearance of active factors by liver/RES, fibrinolysis.

Front 6

Arterial thrombosis

Back 6

"True" arterial thrombosis is rare (e.g. DIC)

Mostly atherosclerosis

This can result in MI or stroke.

Occurs in high pressure and flow muscular arteries

Front 7

Atherosclerosis

Back 7

Disrupted endothelium
leukocytes adhere and initiate inflammation
cytokines released
stimulate SM proliferation
synth of ECM
accum of macrophages and lipids resulting in foam cells.

Front 8

Venous thrombosis complicatiosn

Back 8

Pulmonary embolism
post-phlebitic syndrome (pain at site of previous DVT)
risk of recurrent thrombosis due to abnormal vessel wall

Front 9

Venous thrombosis - what causes it?

Back 9

Stasis is very important. Causes hypoxic vascular endothelium which then becomes procoagulant and initiates coagulation reactions.

Hypercoagulability is also important.

Front 10

DVT

Back 10

Can cause distal edema, pain, swelling, redness.

Front 11

PE

Back 11

Can cause pain, SOB, tachycardia/pnea, feeling of doom, hypotension, hemoptysis.

(usually from a clot in the leg)

Front 12

Venous thromboembolism risk with age

Back 12

Doubles with every 10 year increase in age.

Front 13

Thrombophilia

Back 13

A hereditary or acquired predisposition to VENOUS thromboembolism.

An interplay of genetic and env factors, so it is more than a hypercoagulable state.

Front 14

Acquired thrombophilia

Back 14

Inflammation
Surgery
Obesity (increased factor VIII due to inflamm cytokines from adipose. Also more PAI-1-plasminogen activator inhibitor-1 produced by fat cells)
Cancer
Medications (estrogen)
Pregnancy (more VIII and vWF, less protein S
Hematologic disorders (myeloproliferative disorders [excess cells produced] and paroxysmal nocturnal hemoglobinuria [complement induced hemolytic anemia])

Heparin induced thrombocytopenia

Hyperhomocysteinemia (separate card for this)

Front 15

Hyperhomocysteinemia

Back 15

An acquired thrombophilia

Homocysteine from methionine metabolismm, and elevated levels of it cause higher arterial and venous thrombosis risk. It is probably toxic to vascular endothelium

Etiology: genetic (rare), nutritional deficiencies (folate, b12, b6 -- common) or renal dysfunction (especially end stage renal disease)

Vitamins will bring down homocysteins levels, but don't decrease thrombosis risk.

Front 16

Antiphospholipid antibodies (APA)

Back 16

Autoantibodies against protein component of phospholipids, and plasma proteins are usually bound to phospholipids.

Occurs with medications, infections, other autoimmune disorders, and as a primary autoimmune phenomenon.

Asymptomatic, but increased risk for v/a thrombosis and recurrent pregnancy loss.

So this includes two distincy syndromes: anticardiolipin and lupus anticoagulant.

Front 17

Subtypes of antiphospholipid antibody (4)

Back 17

Lupus anticoagulant
Anti Beta2-GP1
Anti-prothrombin
Anti-cardiolipin

Front 18

Lupus anticoagulant
(a complete misnomer)

Back 18

A subtype of antiphospholipid antibody

Prolongs aPTT (usually not PT) IN VITRO because interferes with binding of prothrombinase (Xa, Va and II) to phospholipid surface. Doesn't correct with mixing study.

In vivo effect is to trigger art and ven thrombosis.

Can't stress this enough. Although PTT is high, this is not a bleeding disorder! It is a clotting disorder!!! (Due to some sort of cross-reactivity)

In vivo, these abs result in hypercoag and thrombosis bc they attach to phospholipid in vasc endothelium and disrupt it to potentiate a thrombus.

Front 19

APA sydney conference consensus criteria

Back 19

Need a clinical event
a/v thrombosis or unexplained pregnancy complication

plus

persistently positive APA
lupus anticoag, ACA (anticardiolipin antibodies) at moderate titer or anti-beta-2GP1 in titer > 99th percentile

Need a positive test on two occasions twelve weeks apart.

Front 20

Anticardiolipin antibody (ACA)

Back 20

5 times more common the lupus anticoagulant.

Doesn't affect PT and aPTT

Measured by ELISA

Front 21

Elev coagulation factor levels

Back 21

>150% and persist over time - at risk for art and venous thrombosis.

Best data for factor VIII. But has also been seen with VII, IX, X, XI, XII and fibrinogen.

Possibly due to primary hypercoag state or marker for chronin inflammation.

Can be familial or acquired.

Front 22

Activated protein C - what does it inhibit?

Back 22

Factor Va (so Prothrombin can't be conv to thrombin)

Vit K dependent, produced by liver.

Normally activated by thrombin very slowly. But when thrombin is bound to thrombomodulin, protein C is 20,000 times quicker.

Along with factor S, it can inhibit V and VIII

Front 23

Activated protein C resistance diseases

Back 23

Factor V leiden (by far most common)
FV Hong Kong
FV Cambridge

Acquired
Pregnancy, cancer, thalidomide (for multiple myeloma), oral contraceptives, lupus anticoagulants.

Front 24

Factor V Leiden

Back 24

Most common inherited thrombophilia
5-8% Caucasians are heterozygotes. Very rare in africa and asia.

Probably asymptomatic, mild risk for venous thromboembolism. Almost no risk for arterial thrombosis

Lab testing - screen with test for APC resistance (keep adding APC to aPTT test), conform with PCR for mutation, genetic testing (need informed consent)

There is resistance of factor V to inactivation by activated protein C.

Front 25

Prothrombin G20210A

Back 25

Increased levels of prothrombin
2-3% Caucasians are hetero.


Lab testing - PCR and genetic test (need informed consent)

Majority are asymptomatic.

Almost no risk for arterial thrombosis.

Front 26

Families with strong thrombophilic background often have...

Back 26

Both FV Leiden and Prothrombin mutation.

Front 27

Hereditary Protein C Deficiency

Back 27

Autosomal dominant (homozygous is lethal)

Screening test - get false positives with warfarin use, Vit K deficiency and consumption due to acute clotting process

Higher risk mainly of venous thrombosis.

Remember, Vit K dependent and prod by liver.

Can inact V and VIII with S. Only V alone. short half life (6 hours). Risk for warfarin-induced skin necrosis (a thrombotic problem).

Can be hereditary or acquired.

Front 28

Classification of Protein C Deficiency

Back 28

Lab testing - screen with activity level and if low, measure antigen.

Hereditary - Type I (activity and antigen is low -- you can't synthesize the protein) and type II (activity is low but antigen is normal -- so the protein just doesn't work)

Acquired - Consumption (DIC, acute thrombosis, pregnancy catastrophe, sepsis/medical illness), liver disease, warfarin, vit K def.

Most prot C def is acquired (due to consumption).

Front 29

Hereditary protein S deficiency

Back 29

Autosomal dominant.

Increased risk of venous thromb, minimal role in arterial.

Vit k dep and synth by liver.
Longer half life than protein C (1.5 days)
Risk for warfarin-induced skin necrosis.

Front 30

Protein S equilibrium

Back 30

C4B binding protein sucks up lots of protein S and make it unavailable to work with protein C to inhibit factor VIII.

More C4b binding protein during inflammation so this can result in less protein S (functional loss)

Front 31

Classification of protein s deficiency

Back 31

Type 1 - usually acquired - low activity and antigen (low synthesis. e.g. due to pregnancy. vit k def, warfarin, etc.)

Type 2 - usually congenital - function is low but antigen is normal (making crappy protein)

Type 3 - Functional activ is low, free antigen is low, total antigen is normal. Due to increased C4b binding protein (acute phase rxn, chronic inflamm, etc.)

Front 32

Tx of protein C/S deficiency

Back 32

Use heparin first. Never warfarin alone as the initial anticoagulant.
This is bc prot c has very short half life, so the deficiency is worsened with warfarin originally. (prot c levels decrease before vit k dependent clotting factors decrease)

Using heparin before warfarin will prev temporary hypercoag state and possible skin necrosis.

Front 33

Hereditary antithrombin deficiency

Back 33

Autosomal dominant (homozygous usually lethal)

Increased risk of venous thromb, no real risk to arterial.

More severe thrombophilia than the others.

Labs - activity level first, and if that is low check the antigen level.

Front 34

Classification of antithrombin deficiency

Back 34

Type I - functional activity and antigen is low

Type II - functional activity is low but antigen is high.


Acquired - due to liver disease, consumption (e.g. acute clot, DIC, pregnancy catastrophe, heparin), proteinuria, I-asparaginase

Front 35

Antithrombin function

Back 35

Inactivates thrombin and factor X.

Note that pts with AT def may be resistant to heparin bc AT acts as a heparin cofactor and increases its ability to inactivate II and X.

Front 36

5, 10-methyltetrahydrofolate reductase gene polymorphisms

Back 36

enzyme for conversion of homocytseine to methionine.

polymorphisms lead to elev of homocyteine. but most almost all heterozygotes (almost 50% of population) are fine--no evidence of more risk of thrombosis.

Front 37

Relative Risk of first VTE highest with...

Back 37

Factor V leiden homozygote

but the highest percentage of women having VTE is with antithrombin deficiency.

Front 38

Tx of acute VTE

Back 38

5-10 day acute heparin. AT LEAST 5 days

3 month warfarin (long term secondary prophylaxis)

at least 24 hour hep and warfarin overlap after INR gets good enough.

Front 39

Clues to hereditary thrombophilia

Back 39

idiopathic

VTE at young age

weird locations

family history

recurrent obstetric complications

Front 40

Type O blood

Back 40

less likely to be in hypercoagulable state.

Front 41

Estrogen containing contraceptives

Back 41

higher risk for thrombosis.