11 07 2014 Thrombotic Disorders Flashcards
What are the 3 things that can cause the formation of thrombus?
- endothelial injury
- Stasis or turbulent blood flow
- hyper coagulability of the blood
Factor V Leiden
Mutation To Gln at two sites in Factor V gene which makes it less sensitive to APC (activated Protein C) cleave
4x increase risk (heterozygous form) of Venous thromboembolism. 80x increase risk in homozygous form.
- found in greater than 90% of patients with APC resistance
7% of Caucasian population
Seen in compound states with other defects: Protein C, S, or ATIII deficiency
Prothrombin G20210A mutation
- mutation?
- What happens due to this mutation?
- how much is his risk increased of having a VT?
- Who has this the most?
- What are heterozygotes at risk for?
- Homozygotes?
Mutation from G –>A in 3’ untranslated region
Results in more stable mRNA = increase levels of prothrombin
- Also causes an increase in prothrombin transcription
3x the risk for venous thrombosis
Found in 20% of caucasian population with unprovoked VTE (venous thrombemboli)
Patients at risk for young age of 1st thrombosis.
Increased thrombin generation apparent.
Homozygotes: variability in thrombotic risk
-up to 40% may not experience event
Hyperhomocysteinemia
Atherosclorotic risk factor = turbulence of blood flow
- coronary atherosclerosis, peripheral vascular disease, venous thrombi
Protein C Deficiency
- describe protein
- activated by what?
- heterozygote increased risk for what?
- Homozyogte increase risk for what?
Protein C - glycoprotein made by the liver on Chr 2.
Activated by Thrombin/Thrombomodulin complex
Requires Protein S as a co-factor
Heterozygotes:
- increased risk for venous thrombosis
- occasional increased arterial thrombosis
- warfin induced skin necrosis
Homozygotes:
- neonatal purpura Fulminans
- Fibrinogenolysis
- Chronic “DIC”- disseminated intravascular coagulation
Accounts for 5% of all VTEs in USA
Antithrombin III Deficiency
- describe protein and its function
- Incidence of biochemical deficiency and what percent of carriers become symptomatic
- Arterial vs venous thrombus?
- Heterzygote
- Homozygote
glycoprotein synthesized by liver, encoded on chromosome 3.
Inactivates thrombin, factor 10a, 11a, 7a, and 12a.
75% of carriers becomes symptomatic
Incidence of biochemical deficiency 1/10,000
Manifest arterial as well as venous thrombosis
Accounts for 0.35 of unprovoked VTEs
Heterozygote:
- increased venous thrombosis
- heparin resistance if severe
- relatively uncommon cause of thrombosis
- recombinant factor therapy available
Homozygote:
- neonatal purpura fulminans
anti‐phospholipid antibody syndrome
- clinical apperance
- association with hypercoagulability and VTE risk
Clinical: recurrent thrombosis, repeated miscarriages, cardiac valve vegetation (clots)
Associated with antibodies directed against anionic phospholipids ( prothrombin)
- may induce epithelial injury by activating platelets/ complement directly
secondary (acquired) hyper coagulability
- environment and situational factors
Environmental:
obesisty, smoking, age, oral contraceptives or hyper-estrogenic state of pregnancy, vascular injury
oral contraceptives : 3x- 4x increased risk of developing DVT or PE
Woman with factor V leiden + BC pills = 35X chance of developing DVT or PE
Situational
- surgery
- atherosclerosis
- liver disease
- prolonged bed rest
- long flight
Contrast the clinical presentation of venous thrombus in the superficial vs. the deep
venous systems in the lower extremity and the associated risk of PE.
Superficial venous system of LE:
- palpable, “cord-like” subcutaneous venous segment
- rarely embolize but can be painful and case local coagulation
Deep Venous Thrombosis (DVT):
- leg pain and swelling may be absent due to collateral veins
- If present:
- calf pain or tenderness
- (+) human’s sign : pain on dorsiflexion
- 30% of patients with DVT are (+)
- might see superficial venous dilation
- Cyanosis (if blockage is bad that it is affecting arteries
- Prone to embolize = pulmonary embolism
- associated with static blood and congestive heart failure and bed rest and immobilization, trauma/ surgery
heparin‐induced thrombocytopenia
- prevelance
- What exactly happens
- Assesment ( the four T’s)
3-5% of patients treated with unfractionated heparin
- heparin + platelet factor 4 make a complex
- patient creates antibodies to complex that leads to:
- platelet activation, aggregation and consumption
- causes endothelial injury
- causes a pro-thrombotic state even in presence of heparin (blood thinner) and low platelet counts
Assesment: the 4 T’s
- Thrombocytopenia : platelet fall
- Timing of platelet count fall
- Thrombosis of other sequelae
- oTher causes from thrombocytopenia
awarded points: 6-8 is high, 4-5 intermediate, 0 to 3 is low
- call Heme consult
warfarin‐induced skin necrosis
condition in which skin and subcutaneous tissue necrosis (tissue death) occurs due to acquired protein C deficiency following treatment with anti-vitamin K anticoagulants (coumarins, such as warfarin)
Protein S deficiency
- describe protein
- activated by what?
- heterozygote increased risk for what?
- Homozyogte increase risk for what?
glycoprotein synthesized by the liver, encoded on Chr. 3.
Circulates in “free” and bound states
Only free Protein S is active as a cofactor for APC.
50% is bound in serum to C4b BP — which is usually increased in inflammation/ pregnancy
accounts for 3% of all VTEs in USA
Heterozygous
- increased venous thrombosis
- occational increased arterial thrombosis
- war fin induced skin necrosis
Homozygous
- neonatal purpura fulminans
- Fibrinogenolysis
- Chronic “DIC”- disseminated intravascular coagulation
Annexins
family of calcium- and phospholipid binding proteins that interact with acidic membrane phospholipds.
They are key players in hemostasis by coordinating fibrinolytic activity
- bind tPA
Description of makeup of venous thrombi vs. arterial thrombi?
Venous thrombi are composed predominantly of fibrin and red blood cells with a variable component of platelet and leukocyte component
Atrial thrombi: platelet rich since platelet activation leads to this type of clot formation
