Thrombosis

Thrombosis

Thrombosis Part 1

Which hypercoagulable workup results are concerning for hypercoagulable states?

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Factor V Leyden homozygous, antithrombin 3 deficiency, protein C deficiency, protein S deficiency,
heterozygous compound factor V Leyden and prothrombin gene mutation, homozygous prothrombin
gene mutation, antiphospholipid syndrome

Thrombosis Part 1
Thrombosis

What are 4 criteria that can direct a thrombophilia work-up?

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DVT in patient younger than 50 years old, one or more primary relatives affected, DVT at unusual
locations, duration of therapy not clear

Thrombosis
Thrombosis

What estrogen-related phenomenon can cause DVT?

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Pregnancies, exogenous estrogen use, birth control

Thrombosis
Thrombosis

Why are liver disease patients at high risk for DVT?

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Low protein C, low protein S, low antithrombin

Thrombosis
thrombosis

How do you manage homozygous F5L mutations?

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Lifetime treatment required

thrombosis
Thrombosis

What recommendations are there for patients with a positive family history of homozygous factor V
Leyden?

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+ family history and considering use oral contraceptive use – consider genetic testing

Thrombosis
Thrombosis

What is the thrombosis risk for heterozygote and homozygous for factor V Leyden?

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3 fold versus 18 fold

Thrombosis
Thrombosis

What his inheritance of factor V Leyden?

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Autosomal dominant

Thrombosis
Thrombosis

What is the mechanism of factor V Leyden mediated thrombosis ?

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Mutation leads to resistance to protein C

Thrombosis
Thrombosis

Which mutation is common in factor V Leyden?
G1691A

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Thrombosis
Thrombosis

What makes an arterial thrombus even more hypercoagulable?

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Plaque rupture

Thrombosis
Thrombosis

What mediates venous versus arterial thrombus formation ?

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Venous – tissue damage
Arterial – atherosclerosis therefore platelet mediated

Thrombosis
Thrombosis

Should protein C deficient patients receive lifetime anti-coagulation ?

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Highly encouraged

Thrombosis
Thrombosis

What are some of the thrombotic risks associated with protein C deficiency ?

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Increased miscarriages after 28 weeks
High arterial thrombosis risk for patients younger than 55

Thrombosis
Thrombosis

Is there a first venous thromboembolism or recurrence risk with protein C deficiency?

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24 x fold increase the first events
37% at 5 year recurrence

Thrombosis
Thrombosis

What are 3 false positive test that can be seen when diagnosing protein C deficiency?

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Antiphospholipid syndrome, elevated factor VIII levels, Coumadin use

Thrombosis
Thrombosis

What are the 2 types of protein C deficiency?

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Type I low quantitative low antigenic
Type II low qualitative normal antigen there is no difference clinically between the 2 types

Thrombosis
Thrombosis

What is the inheritance of protein C deficiency?

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Autosomal dominant

Thrombosis
Thrombosis

What is the mechanism of the protein C and protein S complex ?

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Activated protein C binds with protein S forming a complex that inactivates factor V and factor VIII

Thrombosis
Thrombosis

which geographic location has the highest incidence of prothrombin G20210 mutation?

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Southern Europe

Thrombosis
Thrombosis

What is the duration of anti-coagulation for patients with prothrombin 20210 with the first deep venous
thrombosis?

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Recommendations are not any different

Thrombosis
Thrombosis

What is the incidence of homozygous prothrombin G20210A mutation?

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70 cases worldwide

Thrombosis
Thrombosis

What is a lifetime risk of venous thromboembolism with a prothrombin G20210A mutation?

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3-fold lifetime risk of venous thromboembolism

Thrombosis
Thrombosis

What his inheritance pattern of prothrombin G20210?

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Autosomal dominant

Thrombosis
Thrombosis

What is the second most common inherited thrombophilia?

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Prothrombin G20210A mutation

Thrombosis
Thrombosis

What are the 2 tests to confirm factor V Leyden?

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PCR activated protein C with factor V deficient plasma

Thrombosis
Thrombosis Part 2

What is the absolute increased risk for deep venous thrombosis for protein S deficiency?

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30X

Thrombosis Part 2
Thrombosis

What 2 tests need to be ordered to confirm protein S deficiency?

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Protein S Activity level and antigen level

Thrombosis
Thrombosis

What conditions can falsely lower protein S level?

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APL, F5L, elevated factor VIII, estrogen, pregnancy, liver disease, DIC, nephrotic syndrome, warfarin

Thrombosis
Thrombosis

What in vitro complication is seen with protein C or protein S deficiency?

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Neonatal purpura fulminans

Thrombosis
Thrombosis

What is the inheritance of protein S deficiency?

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Autosomal dominant

Thrombosis
Thrombosis

When can you use antiplatelet agents for antiphospholipid syndrome?

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No consensus

Thrombosis
Thrombosis

How can you monitor warfarin therapeutic efficacy in patients with antiphospholipid syndrome who
have elevated PTT or PT at baseline, secondary to an antibody ?

High PTT – Anti factor Xa

High PT – Factor II activity and chromogenic Factor X

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Thrombosis
Thrombosis

Why should positive antibody test for antiphospholipid syndrome be repeated?

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High percentage transient antibody therefore repeat in 12 weeks required for diagnosis

Thrombosis
Thrombosis

When should an INR target of of 3-4 be used for an antiphospholipid syndrome?

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There is no high level data to support the use of an INR of 3-4

Thrombosis
Thrombosis

What is the warfarin failure rate for antiphospholipid syndrome?

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15%

Thrombosis
Thrombosis

How can you increase the sensitivity of detecting antiphospholipid antibodies?

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Check all 3 tests, beta-2 glycoprotein, anticardiolipin, lupus anticoagulant

Thrombosis
Thrombosis

What is the mechanism of lupus anticoagulant antibodies?

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Antiphospholipid antibody reactive phospholipids needed for the ex vivo coagulation process therefore
increasing clotting times

Thrombosis
Thrombosis

Which tests can be performed if there is a high suspicion for antiphospholipid syndrome in a paitent already on warfarin ?

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Chromogenic factor X, clot-based factor II, factor Xa activity level

Thrombosis
Thrombosis

What coagulation tests can be misleading for antiphospholipid syndrome?

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INR because antiphospholipid antibody can interfere with a prothrombin read

Thrombosis
Thrombosis

What are the 3 different antibodies of antiphospholipid syndrome?

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IgG or IgM beta-2 glycoprotein
IgG or IgM anticardiolipin
Lupus anticoagulant

Thrombosis
Thrombosis

What are the Saporro criteria for antiphospholipid syndrome diagnosis?

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Presence of deep venous thrombosis or arterial thromboembolism, pregnancy loss, positive antibody
testing on 2 tests at least 12 weeks apart

Thrombosis
Thrombosis

Which 2 proteins does antiphospholipid antibody bind to?

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Beta-2 glycoprotein and prothrombin

Thrombosis
Thrombosis

What can be used instead of heparin for antithrombin III deficiency patients if no change in PTT with
heparin?

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Concentrated antithrombin

Thrombosis
Thrombosis

Which of the binding defect subtypes of antithrombin 3 deficiency is more thrombogenic?

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Thrombin binding defect is more thrombogenic

Thrombosis
Thrombosis

What percentage of new DVT are found in cancer patients?

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20% of all DVTs in cancer patients
6% of new DVTs are undiagnosed cancer
10% of new DVTs have a cancer diagnosis within one year

Thrombosis
Thrombosis

What other clotting cascade proteins are associated with elevated thrombosis?

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Factor IX, factor XI fibrinogen

Thrombosis
Thrombosis

What are high fibrinogen levels associated with?

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Increased arterial thrombosis

Thrombosis
Thrombosis

Which blood groups are at an elevated risk of DVT?

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Non-O

Thrombosis
Thrombosis

Which protein is related to atherosclerosis and causes elevated deep venous thrombosis risk?

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Lipoprotein A interferes with plasminogen

Thrombosis
Thrombosis

Which 4 fibrinolysis proteins may have a role in venous and arterial thromboembolism?

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Plasminogen, tPA, TAFI, PAI-1

Thrombosis
Thrombosis

Should PNH patients receive primary prophylaxis for deep venous thrombosis?

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Yes

Thrombosis
Thrombosis

Does eculizumab antibody therapy changed the VTE profile for PNH?

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Yes

Thrombosis
Thrombosis

Where are the uncommon sites of deep venous thrombosis in MPN patients?

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Hepatic vein, mesenteric vein, splenic vein, splenic vein

Thrombosis
Thrombosis

Which venous pool should make you very suspicious for a primary myeloproliferative neoplasm
diagnosis?

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Splanchnic vein thrombosis

Thrombosis
Thrombosis

Should primary prophylaxis be given to patients with myeloproliferative neoplasms ?

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Depends on their risk stratification

Thrombosis
Thrombosis

What happens in Methylene DHF reductase enzyme deficiency?

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Elevated homocystine levels and hence elevated deep venous thrombosis and arterial thrombosis risk

Thrombosis
Thrombosis

What factor VIII level cut-off in acute deep venous thrombosis leads to a 5-fold increase in primary DVT
risk?

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More than 150%

Thrombosis
Thrombosis

What is the consensus on the use elevated factor VIII levels in the determining long term anti-coagulation in patients with DVT/PE ?

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There is lack of consensus to determine

Thrombosis
Thrombosis

What are the 3 approved phosphodiesterase inhibitors?

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Dipyridimole, cilostazole, pentoxyphylline

Thrombosis
Thrombosis

How many days are required off aspirin to recover platelet function?

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10 days

Thrombosis
Thrombosis

Which enzyme is inhibited with aspirin?

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TXA2

Thrombosis
Thrombosis

What are the natural endogenous anticoagulants and fibrinolytics?

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tPA, plasmin, AT3, Protein C, Protein S

Thrombosis
Thrombosis

What are the conditions when you would consider hypercoagulable workup in adults?

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If it changes management, unusual anatomic location, +DVT and a notable family history, no DVT but +
family history of DVT, recurrent DVT while on treatment, arterial embolism in a young patient, at least 3
miscarriages before 10 weeks or 1 greater than 10 weeks

Thrombosis
Thrombosis

Which inherited thrombophilia is an issue for pregnant women?

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Compound heterozygotes
AT3 deficiency, Protein C/S deficiency

Thrombosis
Thrombosis

When would you screen for JAK2, PNH or Lipoprotein(A) when a new DVT is diagnosed?

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Lipo(A)- pediatric cases
JAK2/PMH screen – Splanchnic vein thrombosis

Thrombosis
Thrombosis Part 3

What INR range do you always give vitamin K with?

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>9

Thrombosis Part 3
Thrombosis

What are the mechanisms of action of the hirudins ?

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thrombin inhibition

Thrombosis
Thrombosis

What is Fondaparunox’s mechanim?

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Pentasacharide that binds antithrombin

Thrombosis
Thrombosis

What is released by the granules to the cell surface from platelets?

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Serotonin, calcium, magnesium, ADP

Thrombosis
Thrombosis

What is released from the dense structure from platelets?

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Calcium

Thrombosis
Thrombosis

What are the inhibitors of fibrinolysis?

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PAI-1 blocks tPA and alpha-2-Antiplasmin blocks plasmin

Thrombosis
Thrombosis

How do protein C and protein S work?

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Protein C and protein S form a complex which inactivates factor Va and factor VIIIa hence lowering the
thrombin burst

Thrombosis
Thrombosis

What are the 3 regulatory proteins of the clotting Cascade?

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Protein C, Protein S, and TFPI

Thrombosis
Thrombosis

What is the purpose of anti-thrombin?

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Scavenges free thrombin

Thrombosis
Thrombosis

What are the breakdown products of Fibrinogen?

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D-dimer and epsilon fragment

Thrombosis
Thrombosis

Where is tPA released ?

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At the site of injury

Thrombosis
Thrombosis

Which 2 proteins form the clot stabilization?

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Factor XIII and TAFI

Thrombosis
Thrombosis

What is the purpose of the intrinsic and extrinsic pathways?

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Intrinsic pathway = tissue factor & factor VII is for the primary thrombin burst
Extrinsic pathway = secondary thrombin burst

Thrombosis
Thrombosis

What does tissue factor and factor VIIa complex form?

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Xa-ase complex

Thrombosis
Thrombosis

Which platelet surface protein binds to collagen?

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Gp1ba

Thrombosis
Thrombosis

What 2 things are released with endothelial damage?

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Tissue factor and collagen

Thrombosis
Thrombosis

What are the 3 phases of a thrombotic event?

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Vascular, platelet, and plasma phase

Thrombosis
Thrombosis

What is the purpose of protein S?

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Cofactor for protein C

Thrombosis
Thrombosis

What is the binding distribution of protein S in the serum?

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40% free
60% binding to C4b

Thrombosis
Thrombosis

What must be monitored clinically when anticoagulating with protein C deficiency?

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Skin necrosis

Thrombosis
Thrombosis

How can you confirm the diagnosis of Glanzman’s or Bernard Soulier?

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Flow cytometry

Thrombosis
Thrombosis

What are the 4 patterns of platelet aggregometry?

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All abnormal except ristocetin = Glanzman’s
All normal except Ristocetin = Bernard Soulier
If ADP causes disaggregation = secretion defect
If no light burst with ATP = dense granule defect

Thrombosis
Thrombosis

What CBC change will make a PFA-100 obsolete?

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Platelet count less than 100 and hemoglobin less than 10

Thrombosis
Thrombosis

What are the 4 types of genetic platelet defect disorders?

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GpIb – functional defect = Bernard Soulier
GpIb – gain of function mutation – platelet type von Willebrand disease
Granular defect – Delta1 gray platelet syndrome
Alpha IIb- Beta-3 = Glanzman’s

Thrombosis
Thrombosis

What is another name for the Alpha-2b-Beta-3 platelet surface receptor?

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Fibrinogen receptor

Thrombosis
Thrombosis

What does the inside-out to outside-in signaling eventually lead to?

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Platelet Granule release

Thrombosis
Thrombosis

Which platelet surface protein is a converting point for aggregation?

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Alpha-2b-Beta-3

Thrombosis
Thrombosis

What is the screening test for suspected platelets or von Willebrand factor bleeding disorders?

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PFA-100 and platelet aggregation study

Thrombosis
Thrombosis

What is the first test performed after a PT/PTT screen for a bleeding diathesis?

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50:50 mixing study

Thrombosis
Thrombosis

What bleeding disorders are missed with PT and PTT screening?

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Factor XI, von Willebrand factor deficiency, factor XIII, PAI-1 and alpha-2-AP

Thrombosis
Thrombosis

What are the 2 types of signaling in platelets?

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Inside out and outside in
Inside out–von Willebrand factor and collagen binding leads to elevated alpha 2B Beta 3 which increases
fibrinogen binding
Outside in–increased fibrinogen binding leads to increased platelet granule release

Thrombosis
Thrombosis

Which antithrombin 3 deficiency is more thrombogenic?

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Type1

Thrombosis
Thrombosis

What are the causes of acquired antithrombin deficiency?

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Sepsis, DIC, liver disease, nephrotic syndrome, L-asparaginase, chemotherapy

Thrombosis
Thrombosis

What is the mechanism of type II antithrombin 3 deficiency?

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Sepsis, DIC, liver disease, nephrotic syndrome, L-asparaginase, Chemotherapy

Thrombosis
Thrombosis

Which antithrombin 3 deficiency subtype is the most common?

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Type II

Thrombosis
Thrombosis

What is the inheritance pattern of anti-thrombin 3 deficiency?

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Autosomal dominant

Thrombosis
Thrombosis

What is the difference between the 2 types of antithrombin deficiency?

Type

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1 low concentration
Type 2 qualitative defect

Thrombosis
Thrombosis

What is the target of antithrombin?

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Factor XI, factor IX, thrombin

Thrombosis
Thrombosis

How can you treat purpura fulminans in newborn with protein S deficiency?

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FFP or Protein S concentrate

Thrombosis
Thrombosis

How can you treat protein S deficiency?

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Warfarin or protein S concentrate

Thrombosis
Thrombosis Part 4

What is the incidence of DVT/PE in patients using CDK4/6 inhibitors such as palbociclib?

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5%

Thrombosis Part 4
Thrombosis

What is the saccharide length of unfractionated heparin versus low molecular weight heparin?

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Unfractionated heparin approximately 40 units while LMWH is 15

Thrombosis
Thrombosis

Where are unfractionated heparin extractions taken from?

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pig intestine and cow lung

Thrombosis
Thrombosis

What types of drugs are eptifibatide, abciximab, and tirofiban?

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Peptide, Fc portion of antibody, and small molecule respectively

Thrombosis
Thrombosis

What is the target of eptifibatide?

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RGD binding site, 3aa sequence

Thrombosis
Thrombosis

Why does abciximab cause thrombocytopenia?

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Pseudothrombocytopenia secondary to platelet clumping in EDTA tube

Thrombosis
Thrombosis

What are the 3 different anti-GP2b3a inhibitors?

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Eptifibatide, abciximab, tirofiban

Thrombosis
Thrombosis

What is the mechanism behind blocking glycoprotein 2b3a on platelets?

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Blocks fibrinogen binding

Thrombosis
Thrombosis

Which enzyme mutation leads to low clopidogrel activity?

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CYP2C19 polymorphism

Thrombosis
Thrombosis

What is the only disease where clopidogrel has better efficacy than aspirin?

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Peripheral arterial disease

Thrombosis
Thrombosis

Which drugs are approved as ADP receptor antagonist?

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Clopidogrel, ticlodipine, prasugrel, cangrelor, ticagrelor

Thrombosis
Thrombosis

What is another name for the ADP receptor on platelets?

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P2Y12

Thrombosis
Thrombosis

What is the mechanism of action of cilostazole?

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Blocks PDE3 and hence blocks granule/TXA2 release

Thrombosis
Thrombosis

What is the formal approval for dipyridamole?

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Secondary CVA prophylaxis in combination with aspirin

Thrombosis
Thrombosis

What is the mechanism of action of Dipyridamole?

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Elevated cyclic AMP and hence low platelet aggregation

Thrombosis
Thrombosis

How can you reverse fondaparunox related bleeding?

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Recombinant factor VIIa

Thrombosis
Thrombosis

What anti-Xa level corresponds to therapeutic aPTT level?

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0.3-0.7u/mL

Thrombosis
Thrombosis

How is low molecular rate heparin monitored in chronic kidney disease?

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Anti-10 A

Thrombosis
Thrombosis

What metabolizes heparin?

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Reticuloendothelial system in the spleen predominantly, with some clearance from the kidney

Thrombosis
Thrombosis

What can be used instead of the aPTT for heparin monitoring?

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Anti-Xa

Thrombosis
Thrombosis

What is the standard heparin bolus/Infusion dose?

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80 units/kg bolus +18 units/kg/hr infusion

Thrombosis
Thrombosis

How many hours off heparin infusion is required to return to baseline PTT?

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4 hours

Thrombosis
Thrombosis

What are 3 causes of heparin resistance?

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Antithrombin III deficiency, elevated heparin clearance, decreased baseline PTT 2/2 increased factor VIII
and increased fibrinogen

Thrombosis
Thrombosis

What protein is a serum ELISA assay targeting in heparin-induced thrombocytopenia?

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Platelet factor IV

Thrombosis
Thrombosis

What are the CBC criteria for starting warfarin in patients with confirmed heparin-induced
thrombocytopenia?

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Platelet count greater than 50,000

Thrombosis
Thrombosis

What 2 agents can be used if heparin-induced thrombocytopenia suspected?

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Bivalidurin, argatroban, desrudin, danaproid

Thrombosis
Thrombosis

What is the time frame for heparin exposure for type II heparin-induced thrombocytopenia?

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Heparin exposure during the last 100 days

Thrombosis
Thrombosis

What are the 2 targets of antithrombin?

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Prothrombin and factor Xa

Thrombosis
Thrombosis

What is the mechanism of heparin?

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5 saccharide units binding antithrombin and increasing its efficacy

Thrombosis
Thrombosis

Which patient should start at a lower dose of warfarin?

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Old patients, patients with small intestine resection, liver disease, recent antibiotic use

Thrombosis
Thrombosis

What is standard starting dose for warfarin?

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5 mg daily for 2 days and then check INR

Thrombosis
Thrombosis

Which factor half-lives explains the need for warfarin bridging for heparin-induced thrombocytopenia?

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Factor II = 50 hours (the longest)
Protein C = 8 hours (second shortest) therefore elevated thrombin and low protein C leads to a
hypercoagulable state

Thrombosis
Thrombosis

Which of the coagulation factors has the shortest half-life?

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Factor VII

Thrombosis
Thrombosis

What are desirudin and bivalidrudin approved for?

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Desirudin – DVT PPx
Bivalidrudin – PRCA

Thrombosis
Thrombosis

What are the 3 families of thrombin inhibitors?

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Argatroban, dabigatran, hirudins

Thrombosis
Thrombosis

Where are the hirudins derived from?

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Saliva of leech Heruda species

Thrombosis
Thrombosis

How do you manage low versus intermediate/high risk deep venous thrombosis patients pre-and post-
op with respect to warfarin dosing?

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Low risk preop discontinue warfarin for 5 days before surgery with no bridging required
Low risk postoperative restart 24 hours post with LMWH bridge
Intermediate and high-risk preoperative discontinue warfarin for 5 days and use low molecular weight
heparin bridge

Intermediate and high-risk postoperative restart warfarin 24 hours post surgery and bridge with low
molecular weight heparin

Thrombosis
Thrombosis

What are the advantages to the new oral anticoagulants?

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No bridging required, no dietary changes and no laboratory monitoring required

Thrombosis
Thrombosis

What is the limitation of 3 factor blood product PCC in the event of a serious bleed?

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No factor VII, must give recombinant VIIa

Thrombosis
Thrombosis

What are the 2 available protein C concentrates?

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USA – 3 factor -2,9,10
Europe/USA-4 factor – 2,7,9,10

Thrombosis
Thrombosis Part 5

Thrombosis Part 5

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Thrombosis Part 5

Thrombosis Part 5
Thrombosis

What is the structure of protein C?

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2 chains linked by disulfamide bridge

Thrombosis
Thrombosis

What is the active form of protein C?

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Activated protein C (aPC)

Thrombosis
Thrombosis

What type of enzyme is activated protein C?

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serine protease

Thrombosis
Thrombosis

What is required for the activation of protein C?

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Thrombin binding to thrombomodulin

Thrombosis
Thrombosis

Which electrolyte is required for proper activation of protein C?

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Calcium which enables phospholipid binding

Thrombosis
Thrombosis

What is the primary purpose of activated protein C?

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Inactivation of factor Va and factor VIIIa

Thrombosis
Thrombosis

Does protein C enhance protein S activity or vice versa?

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Protein S enhances protein C activity

Thrombosis
Thrombosis

What are the effect of protein C on inflammation?

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Reduced inflammation

Thrombosis
Thrombosis

Which gene codes for protein C?

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PROC

Thrombosis
Thrombosis

What is the difference between type I and type II protein C deficiency?

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Type I deficiency is a quantitative deficiency while type II is a qualitative deficiency

Thrombosis
Thrombosis

What type of mutations lead to type I protein C deficiencies?

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Missense or nonsense mutations

Thrombosis
Thrombosis

What defines severe protein C deficiency?

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Less than 1% activity

Thrombosis
Thrombosis

What can result from severe protein C deficiency in neonates at birth?

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Neonatal purpura fulminans

Thrombosis
Thrombosis

What are the 2 protein C complications of protein C defects in neonates?

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Neonatal purpura fulminans as well as intracranial thromboembolism

Thrombosis
Thrombosis

What are some acquired causes of protein C deficiency?

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DIC /severe liver disease/hepatic congestion

Thrombosis
Thrombosis

Which infection is known to cause significant protein C suppression?

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Meningococcemia

Thrombosis
Thrombosis

What are the effects of uremia on protein C levels?

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Experience drop but no change in actual activity

Thrombosis
Thrombosis

Which anticancer agent has been known to lower protein C levels?

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Asparaginase

Thrombosis
Thrombosis

How common is protein C deficiency in the general population?

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Up to 0.5%

Thrombosis
Thrombosis

How common is protein C deficiency in patients with venous thromboembolism?

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Up to 5%

Thrombosis
Thrombosis

How is the overall relative risk of thrombosis increased in patients who are heterozygous for protein C deficiency?

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7X

Thrombosis
Thrombosis

When should protein C deficiency be suspected?

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Thrombosis in uncommon vascular beds/thrombosis before the age of 50/strong family history of VTE/warfarin induced skin necrosis

Thrombosis
Thrombosis

What substrate is used to activate protein C with commonly used functional assays?

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Venom of the copperhead snake

Thrombosis
Thrombosis

What are the 2 types of functional assays commonly used for protein C deficiency detection?

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Clotting assays (aPTT and factor Xa) as well as amidolytic assays

Thrombosis
Thrombosis

How is warfarin induced skin necrosis managed?

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Discontinuation of warfarin followed by administration of vitamin K/unfractionated heparin and protein C concentrate as replacement

Thrombosis
Thrombosis

Besides protein C concentrate what is another source of protein C?

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Fresh frozen plasma

Thrombosis
Thrombosis

Which anticoagulants are the best option for patients with protein C deficiency?

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DOACs

Thrombosis
Thrombosis

What does the S stand for in protein S?

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The city of Seattle where it was first discovered

Thrombosis
Thrombosis

What is one major difference between protein S compared to protein C?

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Protein S is not a serine protease

Thrombosis
Thrombosis

What is the primary purpose of protein S?

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Cofactor for protein C

Thrombosis
Thrombosis

Which cells synthesize protein S?

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Predominantly hepatocytes but also megakaryocytes and endothelial cells

Thrombosis
Thrombosis

Which protein predominantly binds protein S in the serum?

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Complement C4b binding protein

Thrombosis
Thrombosis

What percentage of protein S is free-form / non-protein bound ?

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Up to 40%

Thrombosis
Thrombosis

What is the inheritance pattern of protein S deficiency?

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Autosomal dominant

Thrombosis
Thrombosis

Mutations in which gene are responsible for protein S deficiency?

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PROS1

Thrombosis
Thrombosis

Which type of protein S deficiency is the result of a qualitative defect?

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Type II

Thrombosis
Thrombosis

What is the main difference between type I and type III protein S deficiency?

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Type I is a reduction in total protein S including free protein S and protein S function wild-type while type III is selectively reduced protein S

Thrombosis
Thrombosis

What are some acquired causes of protein S deficiency?

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Pregnancy/DIC/acute thrombosis/birth control pill use/nephrotic syndrome

Thrombosis
Thrombosis

Does L-asparaginase therapy reduce protein C or protein S levels?

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Both

Thrombosis
Thrombosis

Are arterial or venous thromboses more common with protein S deficiency?

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Venous

Thrombosis
Thrombosis

Does protein S deficiency lead to an increased risk of stroke?

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No

Thrombosis
Thrombosis

When should protein S deficiency be suspected?

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Notable family history of VTE or known protein S deficiency/VTE before the age of 50/recurrent VTE/unusual anatomic sites for VTE

Thrombosis
Thrombosis

What type of assays are used to measure free protein S?

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Immunoassay

Thrombosis
Thrombosis

What type of assays are used to measure total protein S?

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Immunoassay

Thrombosis
Thrombosis

What type of assay is used to measure protein S functionality?

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Coagulation-based assay with time to clot formation measurement

Thrombosis
Thrombosis

Can NOACs affect protein S functional assays?

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Yes

Thrombosis
Thrombosis

Does heparin interfere with functional assays for protein S?

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No

Thrombosis
Thrombosis

Does acute illness lower or increase protein S levels?

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Lowers

Thrombosis
Thrombosis

What dosing adjustments to anticoagulation are needed for patients with protein S deficiency in the acute setting for VTE?

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None

Thrombosis
Thrombosis

Is primary prophylaxis required in patients with no history of VTE but confirmed protein S deficiency?

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No

Thrombosis
Thrombosis

Should oral contraceptive pills be avoided in patients with known inherited protein S deficiency?

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Yes

Thrombosis
Thrombosis

Is the prothrombin G20210A mutation in the coding or noncoding region?

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Noncoding region

Thrombosis
Thrombosis

How common is homozygosity with the prothrombin gene mutation?

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Exceedingly rare

Thrombosis
Thrombosis

Is the inheritance of the prothrombin gene mutation sex-linked or autosomal?

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Autosomal

Thrombosis
Thrombosis

Is the inheritance of prothrombin gene mutation recessive or dominant?

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Dominant

Thrombosis
Thrombosis

Do patients with inherited prothrombin gene mutations have elevated plasma prothrombin levels?

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Yes by at least 30%

Thrombosis
Thrombosis

What type of mutation is the prothrombin gene G20210A mutation considered?

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A gain of function mutation

Thrombosis
Thrombosis

What is the estimated prevalence of the prothrombin G20210A variant in Caucasians?

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2%

Thrombosis
Thrombosis

Which parts of Europe is the prothrombin G20210A variant more common?

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Southern Europe

Thrombosis
Thrombosis

What is the most common clinical manifestation of the prothrombin gene mutation?

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Venous thromboembolism

Thrombosis
Thrombosis

What is the risk of venous thromboembolism in patients who are heterozygous for the prothrombin gene mutation?

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Up to 4 fold higher

Thrombosis
Thrombosis

What is the most common compound thrombophilia seen in patients who have an underlying prothrombin gene mutation?

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Factor V Leiden

Thrombosis
Thrombosis

What is the odds ratio for VTE for patients to have a compound prothrombin G20210A and factor V Leyden mutation?

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20 fold

Thrombosis
Thrombosis

Should asymptomatic family members of patients with prothrombin gene mutations be tested?

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No

Thrombosis
Thrombosis

Can serum plasma prothrombin level to be used to screen for the prothrombin gene mutation?

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No

Thrombosis
Thrombosis

Can NOACs be used to manage VTE in patients with prothrombin gene mutations?

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Yes

Thrombosis
Thrombosis

When should indefinite anticoagulation be considered in patients with prothrombin gene mutations?

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Those with unprovoked VTE

Thrombosis
Thrombosis

Is primary prophylaxis with anticoagulation recommended in asymptomatic carriers of the prothrombin gene mutation?

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No

Thrombosis
Thrombosis

What are common triggers for prophylactic anticoagulation in patients with known prothrombin gene mutations?

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Pregnancy/acute illness as well as surgery

Thrombosis
Thrombosis

What is another name for Antithrombin III?

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Heparin cofactor 1

Thrombosis
Thrombosis

What are the targets of Antithrombin?

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Thrombin/factor Xa

Thrombosis
Thrombosis

What does the administration of heparin do to Antithrombin?

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Leads to a confirmational change exposing the reactive center leading to a 1000 fold increase in thrombin and activation

Thrombosis
Thrombosis

Where is antithrombin synthesized?

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In the liver

Thrombosis
Thrombosis

What are the 2 modes of antithrombin deficiency?

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Inherited and acquired

Thrombosis
Thrombosis

What is the inheritance of antithrombin deficiency?

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Autosomal Dominant

Thrombosis
Thrombosis

What is the difference between type I and type II Antithrombin deficiency?

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Type I is a quantitative defect while type II is a qualitative defect

Thrombosis
Thrombosis

What are the 3 types of type II defects for antithrombin deficiency?

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Reactive site defect / heparin binding site defect / pleiotropic effect mutations

Thrombosis
Thrombosis

What are some acquired causes of antithrombin deficiency?

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DIC/liver disease/nephrotic syndrome/asparaginase therapy/heparin therapy

Thrombosis
Thrombosis

What are the 2 major clinical complications of antithrombin deficiency?

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Elevated thrombotic risk as well as heparin insensitivity

Thrombosis
Thrombosis

How characteristic is arterial thrombosis with antithrombin deficiency?

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Very rare

Thrombosis
Thrombosis

What is the odds ratio of developing a venous thromboembolism in patients with antithrombin deficiency compared to the general population?

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16x

Thrombosis
Thrombosis

What are common acquired risk factors that can promote VTE in patients with known antithrombin deficiency?

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cral contraceptive pill use/surgery/trauma/pregnancy

Thrombosis
Thrombosis

How concerning is of VTE in patients with known Antithrombin deficiency who become pregnant?

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Odds ratio of 6 with a peripartum prevalence of up to 35%

Thrombosis
Thrombosis

Under what scenarios is screening for antithrombin deficiency appropriate in asymptomatic individuals?

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Known family history of hereditary AT deficiency/asparaginase therapy/heparin resistance

Thrombosis
Thrombosis

What type of assay is used to screen for plasma antithrombin deficiency?

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antithrombin–heparin cofactor assay

Thrombosis
Thrombosis

Which coagulation factors can be used in antithrombin–heparin cofactor assays?

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Thrombin and Factor Xa

Thrombosis
Thrombosis

When is the most appropriate time to test for antithrombin deficiency?

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After the acute event expires when patients are off anticoagulation

Thrombosis
Thrombosis

When should primary prophylaxis be considered in patients with known antithrombin deficiency?

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Pregnancy and surgery

Thrombosis
Thrombosis

When is antithrombin replacement appropriate?

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L-Asparaginase therapy and in certain cases surgery in the peripartum period

Thrombosis
Thrombosis

What are the 2 types of antithrombin products?

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Plasma derived antithrombin concentrate and recombinant antithrombin

Thrombosis
Thrombosis

What can serve as a substitute to recombinant or plasma derived antithrombin?

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Fresh Frozen Plasma

Thrombosis
Thrombosis

Is there any head-to-head comparison of recombinant antithrombin and plasma derived antithrombin concentrate?

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No

Thrombosis
Thrombosis

Is indefinite anticoagulation recommended in patients with antithrombin deficiency after a first unprovoked VTE?

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Yes

Thrombosis
Thrombosis

Is primary prophylaxis recommended in patients planning pregnancy with known antithrombin deficiency?

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Yes

Thrombosis
Thrombosis

When can antithrombin replacement be considered in patients treated with L-asparginase protocols for ALL ?

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When ATIII activity levels drop below 50U/mL or fibrinogen less than 100 mg/dL

Thrombosis
Thrombosis Part 5

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Thrombosis Part 5

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Thrombosis Part 5

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Thrombosis Part 5

Thrombosis Part 5
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