Thrombophilia Flashcards
White clots
Arterial clots
More likely to be composed predominantly of platelets and fibrin
Clue to a thrombotic process primarily reflecting platelet activation (i.e. thrombosis w/ heparin-induced thrombocytopenia)
Red clots
Venous clots
Composed predominantly of RBCs and fibrin
What type of coagulation factors does antithrombin inhibit?
Serine protease coagulation factors (most important being Xa)
Most of the activated versions of the factors in the intrinsic pathway above factor X are also serine proteases and are also inhibited to some degree by
antithrombin
Inheritance pattern of antithrombin deficiency
Autosomal dominant disorder
Inherited antithrombin deficiency increases risk for?
Venous thromboembolic events (VTEs)
Patients with inherited antithrombin deficiency are relatively resistant to anticoagulation by heparin.
Acquired antithrombin deficiency
Can occur in nephrotic syndrome (proteinuria) and in situations of activated coagulation (i.e. DIC, preeclampsia, sometimes liver disease, pregnancy, and oral hormonal contraceptives)
Protein C is vit-K-dependent protein that participates in a feedback relationship w/ what complex?
Thrombomodulin complex
What activates protein C
When the thrombin-thrombomodulin complex is formed - it activates protein C
What factors does protein C inactivate?
Factors Va and VIIIa
Inheritance pattern of protein C deficiency
Autosomal recessive
First thrombotic event typically occurs before age 40. Protein C deficiency is seen in approximately 3% of patients with their first VTE and in 6-8% of families with thrombophilia
Heterozygous for protein C deficiency
These individuals are born with DIC and have extensive venous and or arterial thrombosis with extremely low levels of protein C (less than 5%)
Children homozygous for protein C deficiency
What adverse event can occur when Tx’ing a Pt who is heterozygous for protein C deficiency w/ warfarin
Warfarin-induced skin necrosis - tend to be at “end-vessels” like the fingertips and the areolae of the breasts
Main cause of protein C resistance
Factor V Leiden mutation
Protein S
Vit-k-dependent factor
Cofactor for protein C
What can cause acquired protein S deficiency
Warfarin therapy or other vitamin K deficiency
Also protein S decreases during pregnancy and typically do not lead to VTE
Inheritance pattern of protein S deficiency
Autosomal dominant
Factor V Leiden is a mutation in factor V that affects the site at which ______ bind ______
Factor V Leiden is a mutation in factor V that affects the site at which protein C binds Va
Prevents protein C from inactivating Va
Most common inherited thrombophilic condition
When do homozygous factor V Leiden Pt’s typically experience their first VTE event?
Prior to the age of 40 y/o
What demographic is factor V Leiden most common?
European ancestry
Least common is persons of Asian/African ancestry
Second-most common inherited thrombophilic defect
Prothrombin mutation (aka Factor II mutation)
G20210A GOF mutation
Prothrombin mutation - increases prothrombin levels
Cerebral venous sinus thrombosis
Particularly associated w/ prothrombin mutation (factor II mutation)
Elevated factor VIII is a risk factor for?
Both VTE and arterial thrombosis
Two primary mutations in MTHFR that cause hyperhomocysteinemia
C677T and A1298C
Homozygous C677T mutations can cause elevated homocysteine but primarily in Pt’s who are deficient in folate
Heterozygous and homozygous A1298C mutations do not cause elevated homocysteine
Antiphospholipid syndrome
Elevated levels of antiphospholipid (APA) antibodies or anticardiolipin antibodies (aCL; an alternate methodology for the same phenomenon) in association with a qualifying clinical event.
Catastrophic antiphosphollillpid syndrome
Multisystem small vessel ischemic occlusions that present as multisystem disease - lungs, kidneys, CNS, heart, and or skin
Requires immunosuppression and frequently plasmapheresis, in addition to anticoagulation
Tx of APA/aCL levels
Tx w/ hydroxychloroquine may decreases APA/aCL levels
Does not work in patients without SLE or in triple-positive Pt’s
Impaired primary fibrinolysis disorders
- Dysfibrinogenemia: congenital or acquired (liver disease)
- Increased plasminogen activator inhibitor
- Plasminogen deficiency
- Tissue plasminogen activator deficiency
- Thrombomodulin deficiency (decreases protein C activation)
- Tissue factor pathway inhibitor deficiency
- Increased lipoprotein a (Lp(a) stimulates PAI activity)
Major predictor of thrombosis in polycythemia vera
Elevated Hg/Hct (contributing to blood viscosity)
Thrombotic locations associated w/ myeloproliferative disorders
- Cerebral vein
- Intra-abdominal
- Renal vein
- Portal vein
- Mesenteric vein
- Hepatic vein
Also characteristic thrombotic locations of paroxysmal nocturnal hemoglobinuria
Cerebral vein thrombosis is specifically characteristic of what?
Prothrombin mutation
Antiphospholipid syndrome
Recurrent fetal loss is specifically characteristic of?
Antiphospholipid syndrome
Factor V Leiden mutation
Migratory superficial thrombophlebitis (Trousseau syndrome) is characteristic of?
Adenocarcinomas, particularly of the G.I. tract and pancreas
Neonatal purpura fulminas is specifically characteristic for?
Homozygous protein C or homozygous protein S deficiencies
Thrombophilia disorders that have a definite association w/ arterial thrombosis:
- Antiphospholipid antibody syndrome
- Hyperhomocysteinemia
- Myeloproliferative disorders (mostly polycythemia vera, essential thrombocythemia less so)
When to order D-dimer
Transient risk factors associated w/ venous thrombosis
- Surgery
- Trauma
- Prolonged immobilization
Do not require testing for thrombophilia and should receive a three month course of anticoagulation.
Duration of Tx for thrombotic events
When to screen asymptomatic relative of Pt’s with VTE
What is the predominant cause of activated protein C deficiency?
Factor V Leiden mutation
Which of the following is associated w/ resistance to heparin therapy?
A. Factor V Leiden
B. G20210A mutation
C. MTHFR mutation
D. Antithrombin deficiency
D. AT-III deficiency
What is the Dx criteria for antiphospholipid Ab syndrome?
Antibody against phospholipid/cardiolipin, β2 glycoprotein 1, or a lupus anticoagulant on two occasions three months apart.
Which of the following clinical thrombotic syndromes is most strongly associated with antiphospholipid antibodies?
A. Neonatal purpura fulminans
B. Migratory superficial thrombophlebitis
C. Cerebral venous sinus thrombosis
C. Cerebral venous sinus thrombosis
Current guidelines for thrombosis management recommend three months antigocagulation w/ no testing for specific thrombophilic disorders in what DVT occurrences?
Transient causes of DVT:
Surgery
Trauma
Immobility
A. Decreased factor Xa
Having a prolonged prothrombin time and INR is same as having decreased factor VII
What concludes a Dx of thrombophilia
Pt with two unprovoked DVT on separate instances
What is the most common cause of arterial thrombosis?
Athersclerosis
Purely arterial events typically don’t affect PT/PTT and can be managed by platelet inhibition
B. Neonatal purpura fulminans
When would ATIII be decreased?
ATIII may be excreted curing nephrotic syndrome (associated w/ VTE)
Also may be acutely decreased in VTE, DIC, and sometimes in liver disease
D. All of the above
C. It is associated w/ phospholipid-dependent prolongation of clotting times
Anticoagulant Tx in triple+ antiphospholipid Ab syndrome
Warfarin and DOACs contraindicated
Levito reticularis
C. Homozygous MTHFR C677T mutation
In what disease is CD55/CD59 expression decreased?
Paroxysmal nocturnal hemobloginuria
Tx’d w/ anticomplement therapy (Decay accelerating factor and MAC inhibitor)
B. Polycythemia vera
Thrombosis of mesenteric blood vessels is characteristic of myeloproliferative disorders
B. DVT w/ not identifiable provoking agent
Rest are transient risk factors
C. Normal D dimer after six months of anticoagulant Tx
Factor V Leiden inheritance pattern
Factor V Leiden thrombophilia is inherited in an autosomal dominant manner.
Individuals who are heterozygous for the factor V Leiden variant have a slightly increased risk for VTE; individuals who are homozygous for the factor V Leiden variant have a much greater thrombotic risk.
