What are the three steps in clotting?
(1) Blood vessel constricts
- Blood loss decreases
- Platelets and factors meet
(2) Platelets form a plug
- Proteins are exposed
- Platelets adhere
- Granules release contents
- Platelets aggregate
- Phospholipids are exposed
(3) Fibrin seals up the plug
- Tissue factor is exposed
- Cascade begins
- Cascade makes fibrin
- Fibrin solidifies plug
What are the two mechanisms of anti-clotting?
(1) Cascade inhibition
- TFPI
- ATIII
- Proteins C, S
(2) Clot lysis
- t-PA
- Plasmin
What are the platelet membrane molecules we need to memorize?
Phospholipids (activate coag factors)
GP Ia (binds collagen)
GP Ib (binds vWF)
GP IIb-IIa (binds fibrinogen)
What is the end goals of the coagulation cascade?
Make fibrin!!!
Why are the two arms of the cascade named intrinsic and extrinsic?
Intrinsic- everything you need for the cascade is in the blood
Extrinsic- Need extrinsic factor for cascade to go
Where does tissue factor (TF) come from?
- “Hidden” cells exposed during injury
- Microparticles floating in blood
- Endothelial cells and monocytes (during inflammation)
What does thrombin do?
Thrombin converts:
VIII –> VIIIa (Intrinsic)
VII –> VIIa (Extrinsic)
V –> Va (Intrinsic)
These are cofactors in the cascade
What happens in the SEXtrinsic pathway?
Simple pathway….
- Exposed TF complexes with VIIa (which was converted from thrombin from VII)
- TF/VIIa complex converts X –> Xa
COMMON PATHWAY
-Xa converts prothrombin to thrombin
-Thrombin converts fibrinogen to fibrin –> CLOT!!!
What happens after a little bit of thrombin is produced via the Extrinsic pathway?
Xa has a negative feedback on the TF/VIIa complex essentially shutting down the extrinsic pathway……
But, you have some thrombin there to start the intrinsic pathway
What are the factors we need to remember on the Extrinsic side?
Exposed TF
TF/VIIa complex
TF, 7
Explain the SINtrinsic pathway…..
- Thrombin converts XI to XIa
- XIa converts IX –> IXa
- IXa complexes with VIIIa (thrombin converts VIII to VIIIa)
- IXa/VIIa complex converts X –> Xa
- V is converted to Va by thrombin
- Va complexes with Xa
COMMON PATHWAY
-Xa/Va converts prothrombin to thrombin
-Thrombin converts fibrinogen to fibrin –> CLOT!!!
What are the factors/cofactors we need to remember for the SINtrinsic pathway?
XI to XIa
VII to VIIa (cofactor)
V to Va (cofactor)
11, 9, 10, 5
What are the little chunks of broken up clot called?
Fibrin Degradation Products (FDP)
What converts clots to FDP’s?
Plasmin
How is plasmin formed?
Plasminogen is converted to plasmin using t-PA
What does Protein C do?
Blocks Va and VIIIa cofactors…..less clotting
What does ATIII do?
Blocks XIa, IXa, Xa, Thrombin, and VIIa….less clotting
What does TFPI do?
Tissue Factor Pathway Inhibitor
Blocks TF……less clotting
What are the two important platelet lab tests?
Count: 150-450 x10^9
Morphology: size and granulation
What is the dark center part of the platelet called? Outer light layer?
Granulomere
Hyalomere
What is the Template Bleeding Time (Bleeding Time)?
This evaluates patients response to vascular injury….this is the one you use a blood pressure cuff and slice the patient and time how long it takes them to clot…..lots of factors that effect this test.
What is an alternative to the Bleeding Time test? How does it work? Are there any advantages of this test?
Closure time:
Machine measures how quickly platelets occlude small holes in a membrane “in vitro” bleeding time
Better at detecting aspirin related bleeding and von Willenbrand disease
How and why do you do a platelet aggregation test?
How: add aggregating agents to patients sample and see if it aggregates, measure the decrease in sample turbidity…..always repeat an abnormal test
Why: To find platelet function abnormalities
How do coagulation tests work?
Draw blood into citrate tube
Spin tube, decant plasma
Add reagents to plasma
Watch for formation of fibrin
This test is either normal or prolonged
What pathway is being tested with Prothrombin Time?
Extrinsic Pathway
How does the PT test work? What factor is it basically testing?
You add thromboplastin to a patients plasma, thromboplastin acts like TF which stimulates the extrinsic pathway to go
Factor VII
How is PT essentially testing Factor VII?
Factor VII is the most dependent on K so when you throw Coumadin in the mix you run out of Factor VII which prolongs PT
Fun facts about FII?
- Made by liver
- Needs K
- Dec. by Coumadin
- Short half-life
How do you increase PT?
- Dec. VII, X, V, II, I
- Coumadin
- Heparin
- DIC
When should you order a PT?
Never!!! Order an INR which is just a corrected PT
When should you order an INR?
- To assess liver function
- To monitor Coumadin therapy
- To diagnose DIC
- To assess pre-op status
How do you do a Partial Thromboplastin Time? Which arm is this testing?
Take the patient’s plasma and add back in phospholipid
Measures the intrinsic pathway
When should you order a PTT?
- To investigate a history of abnormal bleeding
- To monitor heparin therapy
- To diagnose DIC
- To diagnose an antiphospholipid antibody
- To assess pre-op status
What is a Thrombin Time? What does it assess?
Patient’s plasma + thrombin
Assesses conversion of fibrinogen to fibrin (bypasses intrinsic and extrinsic pathways)
What causes PTT increase?
- Hemophilia A (VIII)
- Hemophilia B (IX)
- DIC
- Heparin
- Inhibitors
How do you get an increased Thrombin Time?
- Decreased fibrinogen
- Increased Fibrin Degredation Products (FDP)
When should you order a Thrombin Time?
When PTT is prolonged…..do this to rule out fibrinogen problem….this is really rare
What is a PTT Mixing study? When do you do it?
- Take pooled plasma + patient plasma + phospholipid….if PTT corects there’s something missing, if it doesn’t correct there’s an inhibitor.
- Do this test when: PTT is prolonged but TT is normal
What does Fibrin Degredation Product Assay measure? Why do you do the test?
Measures FDPs (including D-dimers) VERY SENSITIVE
Use it to to RULE OUT a clot….FDPs increase in thrombi and normal minor clotting
What causes a decrease in fibrinogen?
DIC
Massive bleeds