Thrombophilias

Question 1

___ is the leading cause of mortality from arterial thrombosis, whereas ___ accounts for most deaths due to venous thrombosis.

Answer 1

Myocardial infarction is the leading cause of mortality from arterial thrombosis, whereas pulmonary embolus accounts for most deaths due to venous thrombosis.

Question 2

History of patients with clinically significant thrombotic disease

Answer 2

Will often reveal factors that predispose to stasis, such as immobilization of a limb, pregnancy, or prolonged inactivity.

Question 3

Risk factors for thrombosis

Answer 3

• History of venous thrombosis
• Factors predisposing to immobilization (extended bed rest, long plane flights, truck driving)
• Male sex
• Obesity
• Increasing age
• Malignancy
• Estrogen level

Question 4

Proteins that regulate thrombosis

Answer 4

Question 5

Factor V Leiden

Answer 5

genetic variant that increases the activity of factor V

Delays inactivation of factor V by protein C

Question 6

Prothrombin G20210A

Answer 6

Base substitution in the 3′ UTR of the prothrombin gene that increases production of prothrombin

Question 7

Both factor V Leiden and prothrombin G20210A mutations are surprisingly common in ___ populations

Answer 7

Both factor V Leiden and prothrombin G20210A mutations are surprisingly common in white populations,

with prevalences of about 5% and 2%, respectively.

Question 8

Inherited defects in inhibitors that increase the risk of deep venous thrombosis

Answer 8

Include deficiencies of protein C, protein S, and antithrombin.

These are loss-of-function mutations that are much less common and much more heterogeneous than factor V Leiden and Prothrombin G20210A

Question 9

A functional antithrombin level of less than 10% of normal is . . .

Answer 9

A functional antithrombin level of less than 10% of normal is incompatible with life.

Question 10

Phenotype of homozygous protein S and protein C deficiency

Answer 10

Characterized by thrombosis in childhood, adolescence, or even infancy (neonatal purpura fulminans)

Question 11

Phenotype of heterozygous protein S and protein C deficiency

Answer 11

Increased risk of developing thrombosis in adulthood, albeit at low penetrance.

Question 12

Type I and type II protein S/C mutations

Answer 12

Type I: Decrease expression

Type II: Decrease functional activity

Question 13

How are inherited thrombophilias diagnosed?

Answer 13

Since Factor V Leiden and Prothrombin G20210A are common variants, they may be diagnosed by genetic analysis.

Since protein C, protein S, and antithrombin are much more heterogeneous, measurement of plasma levels and functional assays are used to diagnose these.

Question 14

In order to make a convincing diagnosis of an inherited deficiency of antithrombin, protein S, or protein C, . . .

Answer 14

In order to make a convincing diagnosis of an inherited deficiency of antithrombin, protein S, or protein C, measurements should be made after the patient has recovered from the thrombotic episode and is no longer receiving anticoagulants.

Question 15

Protein S and C function diagram

Answer 15

Question 16

Thrombomodulin

Answer 16

Transmembrane protein expressed on endothelial cells that has on its extracellular domain a binding site for thrombin.

Upon docking onto thrombomodulin, thrombin’s substrate specificity becomes restricted to protein C. Protein C binds to a receptor termed the endothelial protein C receptor on the endothelial cell surface and is then activated by the thrombin–thrombomodulin complex.

Activated protein C cleaves and degrades factors Va and VIIIa, with help from protein S.

Question 17

Protein S and C

Answer 17

Evolutionarily related to the enzymes of the coagulation cascade and also require vitamin K-mediated production in the liver. Protein C is a zymogen, protein S is just a cofactor.

Question 18

Warfarin-induced skin necrosis

Answer 18

Complication that individuals with protein C deficiency are at risk for on the first day of new warfarin therapy.

These patients occasionally develop painful ecchymoses in fat-containing areas of the body such as the breasts or buttocks if put on warfarin. Microscopically, these lesions contain fibrin thrombi within venules, accompanied by hemorrhagic necrosis.

This is because of the differential half-lives of vitamin-K-dependent proteins. Warfarin will wipe out any remaining protein C in the blood before levels of coagulation cascade factors begin to fall, resulting in a transient hypercoagulative state.

Question 19

Ecchymosis

Answer 19

A discoloration of the skin resulting from bleeding underneath, typically caused by bruising.

Question 20

Half-lives of vitamin K-dependent blood factors

Answer 20

Factor VII and protein C have the shortest half-lives (6 and 14 hours, respectively)

the other vitamin K–dependent proteins have half-lives of 24 to 60 hours.

Hence, when you hit someone with warfarin, protein C is one of the first to go. In patients with a full complement of protein C with sufficient reserve, this is not clinically significant, but in heterozygotes or homozygous mutants, this may result in warfarin-induced skin necrosis.

Question 21

Antithrombin requires ___ to function effectively.

Answer 21

Antithrombin requires heparin to function effectively.

Binding of the heparin polysaccharide to antithrombin markedly enhances its affinity for thrombin as well as for factors IXa, Xa, XIa, and XIIa

Question 22

Thrombosis Threshold diagram

Answer 22

Question 23

Risk factors for thrombosis tend to be ___.

Answer 23

Risk factors for thrombosis tend to be multiplicative rather than additive.

Question 24

Antiphospholipid syndrome

Answer 24

Acquired inhibitor directed against proteins bound to membrane phospholipids and/or persistently antibodies against cardiolipin or β2-glycoprotein I.

Prolonged PTT, sometimes prolonged PT. Mixing studies will reveal that PTT is not corrected with standard plasma. Despite this, patients are at increased risk of thrombosis rather than bleeding.

Other manifestations include immune thrombocytopenia and recurrent fetal loss.

Question 25

Generally speaking, all heritable thrombophilias are associated with ___. All acquired thrombophilias are associated with ___.

Answer 25

Generally speaking, all heritable thrombophilias are associated with venous thrombosis, not arterial thrombosis. All acquired thrombophilias are associated with both venous and arterial thrombosis.

Question 26

Heparin-induced thrombocytopenia

Answer 26

Serious complication developed by ~1-5% of individuals given unfractionated heparin due to development of an autoantibody against a complex of the drug and platelet factor 4 released from platelet alpha granules.

This commonly results in mild or moderate thrombocytopenia, but more importantly, in about 20% to 50% of patients, it causes both venous and arterial thrombosis.

Question 27

Malignancy as a hypercoagulable state

Answer 27

There is a high incidence of venous thrombosis in cancer patients. Some evince migratory superficial thrombophlebitis (Trousseau syndrome), often in unusual sites such as the arms. Those who are terminally ill may develop nonbacterial thrombotic (marantic) endocarditis.

The pathogenesis of these thrombotic complications is unclear but probably involves release of thrombogenic agonists from malignant cells, such as microparticles containing tissue factor. Disseminated cancer also is associated with systemic chronic inflammation, which drives genes that favor coagulation in endothelial cells.

Question 28

Thrombosis risk in disorders of hematologic clonality

Answer 28

Patients with two types of clonal hematologic disorders, the myeloproliferative neoplasms and paroxysmal nocturnal hemoglobinuria, also are at a high risk for developing venous and arterial thrombosis.

Question 29

αIIbβ3

Answer 29

Platelet surface molecule which, when activated by platelet activation events, binds to fibrin by either end. Binding of the other end of the fibrin to another receptor enables platelet aggregation.

Question 30

A 24 year old chef developed joint pains, menorrhagia, and easy bruising. On physical examination, she has petechiae on her legs.

Laboratory test values:

Hemoglobin 13 g/dL; mean cell volume 84 fL; reticulocyte count 0.5%

White blood cell count 11 x 109/L with a normal differential

Platelet count 12 x 109/L

Blood smear shows normal red cell morphology and large platelets.

Normal PT and PTT

Normal iron and ferritin

What best characterizes the cause of the patient’s thrombocytopenia?

Answer 30

Immune destruction

Question 31

Hemostasis is ___.

Thrombosis is ___.

Answer 31

Hemostasis is homeostatic.

Thrombosis is pathological.

Question 32

Thrombin positive feedback loop

Answer 32

Question 33

Virchow’s Triad

Answer 33

Question 34

TFPI mechanism

Answer 34

Question 35

APLS venn diagram

Answer 35

Question 36

For hypercoagulability due to cancer, what is the treatment of choice?

Answer 36

Low molecular weight heparin is preferred over warfarin

recent data supports use of Direct Oral Anticoagulants

Question 37

For heparin-induced thombocytopenia, what is the treatment of choice?

Answer 37

Stop heparin and switch to IV argatroban or an oral direct clotting factor inhibitor.

Question 38

Antiplatelet agents

Answer 38

Question 39

Antiplatelets are mostly used and effective in treating ___.

Answer 39

Antiplatelets are mostly used and effective in treating arterial thrombosis.

They are not so effective in preventing venous thrombosis.

Question 40

Few anti-clotting drugs can be taken orally, with the notable exceptions of ___.

Answer 40

Few anti-clotting drugs can be taken orally, with the notable exceptions of aspirin/NSAIDs and oral thrombin inhibitors.

Question 41

Pharmacologic heparins

Answer 41

Question 42

Protamine sulfate

Answer 42

Enables neutralization of unfractionated heparin, but less so LMW heparin

Question 43

Hirudin

Answer 43

Derived from leeches. Binds irreversibly to thrombin directly and block its catalytic site. Given intravenously.

Cleared from the body by renal excretion.

Question 44

Argatroban

Answer 44

Selective thrombin inhibitor. Inhibits active site directly. Reversible inhibitor. Given intravenously. Biliary excretion.

Question 45

1972

Answer 45

2 7 9 and 10

The vitamin-K dependent clotting factors

Question 46

If an oral anticoagulant has “xa” in the name,

Answer 46

it’s an Xa inhibitor

Question 47

Dabigatran etexilate

Answer 47

Oral thrombin inhibitor

Question 48

Direct oral anticoagulants should never be used in. . .

Answer 48

. . . patients with APLS or patients with prosthetic heart valves

Question 49

Idarucizumab

Answer 49

Purified Fab fragment that sequesters dabigatran, reversing its effects.

Question 50

Adexanet

Answer 50

Factor Xa inhibitor sink. Sequesters factor Xa inhibitors and rescues factor Xa activity.