Thrombophilias Flashcards Preview

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Flashcards in Thrombophilias Deck (50)
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1
Q

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

A

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

2
Q

History of patients with clinically significant thrombotic disease

A

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

3
Q

Risk factors for thrombosis

A
  • History of venous thrombosis
  • Factors predisposing to immobilization (extended bed rest, long plane flights, truck driving)
  • Male sex
  • Obesity
  • Increasing age
  • Malignancy
  • Estrogen level
4
Q

Proteins that regulate thrombosis

A
5
Q

Factor V Leiden

A

genetic variant that increases the activity of factor V

Delays inactivation of factor V by protein C

6
Q

Prothrombin G20210A

A

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

7
Q

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

A

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

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

8
Q

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

A

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

9
Q

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

A

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

10
Q

Phenotype of homozygous protein S and protein C deficiency

A

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

11
Q

Phenotype of heterozygous protein S and protein C deficiency

A

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

12
Q

Type I and type II protein S/C mutations

A

Type I: Decrease expression

Type II: Decrease functional activity

13
Q

How are inherited thrombophilias diagnosed?

A

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.

14
Q

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

A

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.

15
Q

Protein S and C function diagram

A
16
Q

Thrombomodulin

A

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.

17
Q

Protein S and C

A

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.

18
Q

Warfarin-induced skin necrosis

A

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.

19
Q

Ecchymosis

A

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

20
Q

Half-lives of vitamin K-dependent blood factors

A

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.

21
Q

Antithrombin requires ___ to function effectively.

A

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

22
Q

Thrombosis Threshold diagram

A
23
Q

Risk factors for thrombosis tend to be ___.

A

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

24
Q

Antiphospholipid syndrome

A

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.

25
Q

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

A

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

26
Q

Heparin-induced thrombocytopenia

A

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.

27
Q

Malignancy as a hypercoagulable state

A

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.

28
Q

Thrombosis risk in disorders of hematologic clonality

A

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.

29
Q

αIIbβ3

A

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.

30
Q

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?

A

Immune destruction

31
Q

Hemostasis is ___.

Thrombosis is ___.

A

Hemostasis is homeostatic.

Thrombosis is pathological.

32
Q

Thrombin positive feedback loop

A
33
Q

Virchow’s Triad

A
34
Q

TFPI mechanism

A
35
Q

APLS venn diagram

A
36
Q

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

A

Low molecular weight heparin is preferred over warfarin

recent data supports use of Direct Oral Anticoagulants

37
Q

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

A

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

38
Q

Antiplatelet agents

A
39
Q

Antiplatelets are mostly used and effective in treating ___.

A

Antiplatelets are mostly used and effective in treating arterial thrombosis.

They are not so effective in preventing venous thrombosis.

40
Q

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

A

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

41
Q

Pharmacologic heparins

A
42
Q

Protamine sulfate

A

Enables neutralization of unfractionated heparin, but less so LMW heparin

43
Q

Hirudin

A

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

Cleared from the body by renal excretion.

44
Q

Argatroban

A

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

45
Q

1972

A

2 7 9 and 10

The vitamin-K dependent clotting factors

46
Q

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

A

it’s an Xa inhibitor

47
Q

Dabigatran etexilate

A

Oral thrombin inhibitor

48
Q

Direct oral anticoagulants should never be used in. . .

A

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

49
Q

Idarucizumab

A

Purified Fab fragment that sequesters dabigatran, reversing its effects.

50
Q

Adexanet

A

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