What is thrombosis?
Thrombosis is the formation of a platelet or fibrin mass within a vessel
What are the 3 physiologic components responsible for thrombosis?
- Low velocity in vessel
- Activation of coagulation cascade
- Vessel damage
What are sources of emboli?
From areas of hardening (atherosclerosis causing plaque) in the aorta and other large blood vessels
What is the difference between white (arteries and arterioles) and red thrombus (veins)?
- Mechanism
- Main component
WHITE
Main mechanism/risk factors: Atherosclerosis
Main component: Fibrin
Consequence: Stroke
RED
Main mechanisms: Superficial and Deep vein thrombosis
Causes and risk factors:
Superficial
- Blood clot due to IV line or trauma to vein
Deep vein
- Damage to vein from surgery or injury
- Inflammation and damage due to infection/injury
Main component: Erythrocytes
What are the risk factors for arterial thrombosis?
Increasing age
Hypercholesterolemia
Hypertension
Smoking
Physical inactivity
Obesity
Diabetes
Chronic diseases and inflammation
- Chronic renal failure
- HIV infection
- Hyperhomocysteinemia
What are the risk factors for venous thrombosis?
Stasis
Wall damage
Factor V Leiden and activate protein C resistance (APCR)
Deficiency of protease inhibitor
- PrS, PrC, AntiThrombin, heparin cofactor
Elevated prothrombin level
- Factor II mutation
Antiphospholipid antibody
Decreased fibrinolysis
Hyperhomocysteinemia
Surgery
Malignancy
Hereditary thrombophilia increases the risk of thrombosis because:
- Increase in procoagulant factors
- Decrease in inhibitors of clotting
- Combination of inherited and/or environmental factors
*What are the clinical manifestations of herditary thrombophilia?
- Venous thromboembolism (VTE) < 50
- Recurrent VTE
- Strong family history
- Unusual sites
*What are the hereditary conditions associated with thrombosis? What are the lab investigations for these conditions?
Factor V Leiden
- PCR
Prothrombin G20210a
- PCR
PS deficiency
- ELISA for total PS Ag
- Immunoassay for free PS
- Clot based assay showing ability of PS as cofactor for aPC
PC deficiency
- Clot based assay using protein C activators
Antithrombin deficiency
- Chromogenic assay
- Clot based method based on clotting of fibrinogen
What are the secondary (acquired) disorders that can lead to thrombosis?
- Antiphospholipid syndrom (APLS) - most common of acquired thrombophilia
- Refers to grp of auto-Ab that includes lupus anticoagulant (LA) and anticardiolipin Ab (aCL) and several subgroups which recognize phopholipids and phospholipid binding protein - Heparin-induced Thrombocytopenia (Type 2)
- Usually with unfractionated heparin - Thrombotic microangiopathies (TMA)
- Clinical disease featured by presence of microangiopathic hemolytic anemia (MAHA)
- Presence of schistocytes > 1%
What is the mechanism of thrombosis in APLS?
APLS
Anticoagulants inhibition:
- Interference with PC activation
- Inhibition of heparan sulfate interaction with antithrombin
- Decreased TFPI
- Inhibition of prostacyclin
- Blocking tPA and plasminogen, increases PAI-1
What is the laboratory investigation for APLS?
- Diagnosis required demonstration of LA or relevant protein cofactor
- Positive result should be persistent
- Test for protein cofactors - ELISA
- Evaluation of LA - clot based factors
What is the mechanism of heparin-induced thrombocytopenia (type 2)?
- Platelet factor 4 (PF4) is released during platelet activation and binds to heparin
- Heparin/PF4 complex attaches to platelet surface
- Body view complex as foreign and Ab is formed against complex
- Ab binds to complex and platelets are destroyed
What are the laboratory investigations for heparin-induced thrombocytopenia?
- Functional platelet activation assay
- Immunoassay - ELISA for detecting anti PF4/heparin Ab
What are some examples of thrombotic microangiopathies (TMA)? What are they caused by?
- Disseminated intravascular coagulation
- Cancer, sepsis, shock, significant emboli - Thrombotic thrombocytopenic purpura (TTP)
- Cleaving factor missing: ADAMTS-13
What are the lab signs of disseminated intravascular coagulation (DIC)? [EXAM]
Increased INR
Prolonged PTT
Decreased fibrinogen
Low platelets
What are the types of heparin and what is their function?
Unfractionated heparin enhances the activity of antithrombin and inhibits factor Xa.
Low molecular weight heparin (LMWH) inhibits factor Xa only, which inhibits coagulation. LMWH is only given at hospitals.
What are the monitoring methods used for heparin?
For unfractionated heparin:
- aPTT and Anti-Xa activity
For LMWH:
- Anti-Xa activity
What are the possible complications of using heparin? What can we do to treat them?
Bleeding
- Reversible if stopped
- If critical, use protamine sulphate
Heparin induced Thrombocytopenia (HIT)
- Stop use immediately
What is the mechanism of Vitamin K antagonists? Give an example.
Warfarin is an example of a VKA.
- Prevents Vit K from participating in hepatic carboxylation
How to monitor the use of VKA? What are the adverse events that could happen and what can we do to treat it?
Monitor using prothrombin time (PT) however each lab is different, not standardized.
Adverse effects include:
1. Bleeding
2. Lack of efficacy due to a mutation in gene which makes a person resistant to Vit K antagonist
In case of bleeding, give patient prothrombin complex as an antidote.
What are the advantages of DOACs over warfarin?
- No monitoring
- No food and less drug interactions
- Fixed dosing
What are the disadvantages of DOACs compared to warfarin?
- Renal function effects
- Not in liver dysfunction
- No reversal agents
What are examples of anticoagulant medications? What does each drug inhibit?
Dabigatran
- Inhibits free and clot-bound thrombin
Rivaroxaban
- Inhibits Factor Xa
