Defects in Coagulation (Part 2) Flashcards
What is the most common inherited bleeding disorder?
Von Willebrand Disease (VWD)
Functions of vWF?
- Support platelet adhesion
* Serve as carrier for Factor VIII
Clinical symptoms of VWD?
mucosal bleeding (nose and menorrhagia common)
postop bleed
oral cavity bleed
GI bleed
How do you treat VWD?
Desmopressin (synthetic vasopressin releases VWF from storage) or transfusion with cryoprecipitate
What is hemophilia?
A factor deficiency state causes delayed/deficient thrombin formation -> friable clots with tendency to re-bleed
What are the three types of hemophilia?
A: factor 8
B: factor 9
Factor 11
all deficiencies
How are Hemophilia A and Hemophila B inherited?
X-linked inheritance
What is the hallmark of Hemophilia A and Hemophila B?
hemarthrosis & deep muscle bleeds
with prolonged PTT that corrects with 1:1 mix
Vitamin K deficiency causes decrease in what factors?
Factors II, VII, IX, & X, Protein C & S because vit K is needed for gammacarboxylation
What can cause Vit K deficiency?
– Drugs: Oral anticoagulant (warfarin) inhibit liver enzymes and Antibiotics: Decrease bowel flora (less vitamin K synthesis)
– Malabsorption or dietary deficiency
– Liver disease
– Newborns
Vit K deficiency treatment?
Replace vit K
Why is liver disease considered a re-balancing hemostasis?
Deficiency of multiple pro and anti coagulation factors as well as thrombocytopenia (decreased TPO and hypersplenism)
Procoagulants: Factors II, VII, IX, & X, and also V
Anticoagulants: Antithrombin, Protein C, Protein S
When do you treat liver disease related coagulation disease?
only when they are bleeding: replace vit K, plasma, platelets
How do PT and PTT react to liver disease?
Prolonged PT shows up before prolonged PTT because tests are most sensitive to defects at the top of the cascades for which they test
What is Virschow’s Triad?
endothelial injury
hypercoagulability
abnormal blood flow
What are Coagulation Control Mechanisms?
- Blood Flow: washes away activated factors
- Natural anticoagulant processing: TFPI, Antithrombin, Protein C system
- Fibrinolytic system: Digests Fibrin clot
What does Antithrombin do?
Inhibits serine proteases (mainly Xa, IIa)
complexes with heparan to be turned on
What does the protein C system do?
protein C binds protein S and they degrade factors 5 and 8
turned on by thrombomodulin complex and are vit k dependent
In general what can cause Primary Hypercoagulable States?
– Deficiency of Control Proteins: Antithrombin, Protein C or Protein S.
– Subtle changes causing control mechanisms: Factor V Leiden (Resistance to aPC)
– Increased coagulation factor levels: Prothrombin gene variation G20210A
Primary Hypercoagulable States are usually associated with clotting where?
Venous Thromboembolism
When do we see AT, Protein C & Protein S deficiencies?
- Account for 5-15% of familial thrombosis.
- Risk picks up after puberty
Almost always require acquired risks for thrombosis to actually have an event
What tests should you order if you suspect AT, Protein C & Protein S deficiencies?
Functional AT, PC or PS assay
Protein S free antigen
What is Factor V Leiden?
Resistance to activated Protein C due to genetic defect in factor 5 Arg 506 replaced with Gln
What test does Factor 5 Leiden usually show up in?
Failure of PTT to prolong in response to addition of activated protein C.
What type of bleeding does Factor 5 Leiden put people at risk for?
venous thrombotic risk factor
the heterozygote form is much weaker risk factor for clotting
but the disease is 10 times more frequent than deficiency of AT-III, Protein C or Protein S
What is Prothrombin gene variation?
G20210A in 3’untranslated region of RNA causes mRNA to be more stable = more prothrombin
Associated with venous events (DVT/PE)
How common is Prothrombin gene variation?
This is more frequent than deficiency of AT-III, Protein C or Protein S
What is Antiphospholipid Antibody Syndrome?
Clinical symptoms:
– Venous and/or arterial thrombosis
– Recurrent fetal wastage
– May have thrombocytopenia
What is Antiphospholipid Antibody and what does it do?
– Anti-cardiolipin, anti ß2GP1
– “Lupus” anticoagulant: Inhibits phospholipid dependant in-vitro coagulation
assays clot time corrects with high PL
What are some general acquired predispositions to thrombosis?
- Obstruction to flow: Pregnancy, Prior deep vein thrombosis, etc
- Activation of hemostatic mechanism: Sepsis, Neoplasm, Foreign body, etc
- Damaged endothelium: Inflammation, Athlerosclerosis, trauma, etc
What is DIC?
Disseminated Intravascular Coagulation: Widespread activation of thrombin and
plasmin mechanisms may present as bleeding or thrombosis
Syndromes Associated with DIC are what?
• Introduction of extrinsic clot promoting
material: malignancy, amniotic fluid, fat embolism, etc.
• Intravascular elaboration of procoagulants: acute hemolytic process and heparin associated thrombocyotpenia
• Vascular injury: sepsis
Is DIC a disease?
NO
DIC is a manifestation of another disease and may reflect that diseases severity usually cause is blatantly obvious
However, sometimes DIC prompts search for underlying cause like purpura fulminans from Meningococcal sepsis or Severe protein C deficiency in a newborn
What is the clinical presentation of DIC?
– Bruising and petechia
– Bleeding from venipunctures and other sites
– Purpura Fulminans (microthrombosis in skin, elsewhere)
– Large vessel thrombosis
How do you diagnose DIC?
Based largely on clinical suspicion and appropriate clinical setting and lab studies can be supportive
– PT/PTT are usually prolonged (~50-75% of cases)
– Fibrinogen usually reduced
– Platelets usually reduced (< 30 K in ~ 80-90% of cases)
– D-dimer elevated in 99% of cases (sensitive, but less specific)
What is the big picture consequence of DIC?
Microcirculatory failure leading to multiorgan dysfunction
What is the treatment for DIC?
treat underlying condition
restore tissue perfusion and acid/base balance
replacement therapy for bleeding
Why is a D-dimer not a great test to order if you have high suspicion of DVT?
D-dimer is very specific to clotting and if you are not sure if you’re clotting it can tell you one way or the other.
but if you think they have a clot it is best to just get the ultrasound to see if there truly is one
What are some risk factors for DVT?
Age
Estrogen use
Recent travel with lengthy immobilization
Elevated Body Mass Index (BMI)
What’s the best treatment for DVT?
Immediate anticoagulation with low molecular weight heparin (warfarin takes too long and would inhibit protein C and S too)
If a patient experiences a PE while already anticoagulated on warfarin what could be the cause?
Factor V Leiden
Anti-phospholipid antibody syndrome
Protein S deficiency
Anti-thrombin deficiency
What is the next test if we know a pt has thrombocytopenia?
peripheral blood smear to look at platelet morphology and other types of cells
What is the mechanism causes shistocytes?
Mechanical shearing of RBCs
If you have decreased ADAMTS-13 what is your diagnosis?
Thrombotic thrombocytopenic purpura (TTP)
What is the significance of the elevation in D-dimer?
Suggests recent activity of thrombosis and fibrinolysis causing fibrin degredation
What test would we use to confirm heparin-induced thrombocytopenia?
ELISA for an platelet factor-4 heparin antibody
How would you treat HIT?
Discontinuation of warfarin with initiation of a direct thrombin inhibitor such as argatroban
What are the characteristics of HIT?
Occurs 5-10 days after initial heparin exposure
Moderate thrombocytopenia (rarely < 20,000/ul)
Associated with thrombotic events: increases risk for thrombosis 20-40 fold with clots include both venous thrombosis (DVT, pulmonary emboli) and arterial
