Thrombosis Flashcards
Thrombosis
- Definition
- Virchow’s Triad (Factors predisposing thrombosis)
- Thrombosis –> Pathological process of blood clotting in uninjured vessel or an exaggerated blood clotting response
-
Virchow’s Triad (factors predisposing thrombosis)
- Endothelial injury
- Blood stasis or turbulence of blood flow
- Blood hypercoagulability
Where do arterial thrombi grow? Venous thrombi?
Arterial –> back to the heart
Venous –> toward the heart
Anti-Thrombic Properties of Endothelium
- Anti-platelet effects (2)
- Anticoagulant properties (2)
- Fibrinolytic properties (1)
- PGI2 and NO (prevent platelet adhesion)
- Heparin-like molecule (activates ATIII) and Thrombomodulin
- tPA
Prothrombotic Properties
3 of them
vWF
Tissue Factor
Plaminogen Activator Inhibitors (PAI)
-Key regulators of the fibrinolytic system
What does aspirin (ASA) inhibit?
Activation and release of contents from platelets
What makes the platlet plug irreversible (secondary hemostatic plug)?
Action of Thrombin
Arterial Thrombosis
- Key factors
-
Endothelial injury
- Loss of endothelium will expose ECM and hence activation of platelets and thrombosis
So any factors that damage endothelium will predispose you to thrombosis
How does vWF react to bloodflow?
Unfolds under shear stress
***Faster the blood flows, the stickier it gets***
What is the job of Thrombin?
Converts Fibrinogen to Fibrin (irreversible plug)
Hypercoagulability
- Primary (Genetic) Disorders
Factor V Leiden mutation
ATIII deficiency
Protein C deficiency
Protein S deficiency
Prothrombin G20210A gene mutation
Hypercoagulability
- Secondary Disorders
Anti-phospholipid Syndrome
Lupus anticoagulant
Prolonged immobilization
Cancer
Nephrotic Syndrome
Contraceptive pills
Smoking
Heparin-Induced Thrombocytopenia (HIT Syndrome)
***A Hypercoagulable state***
Occurs during heparin therapy
Antibodies bind to platelets and active them continually
Antiphospholipid Syndrome (Lupus Anticoagulant)
***A Hypercoagulable state***
Antibodies to phospholipid (e.g. Cardiolipin)
In vitro –> inhibits coagulation
In-vivo (in life) –> induces coagulation
Disseminated Intravascular Coagulation
- What is it?
- Occurs in
- Leads to
- Symptoms
- Sudden widespread fibrin thrombi in the microcirculation
- Occurs in shock, infection, pregnancy, and malignancy (cancer)
- Leads to circulatory insufficiency (Brain, lung, heart, kidneys)
Also leads to cosumption of platelets and clotting factors
***So you have clots everywhere and are at increased risk of bleeding all at the time same***
Fate of Thrombus
4 of them
- Propagation (progression)
- Embolization
- Lysis
- Organization and recanalization (chronic inflammation and fibrosis - Prothrombotic Syndrome)
- Requires direct lysis (e.g. tPA); Coumadin will just prevent further clot formation, not lyse the clot already there
What is the most common cause of preventable hospital death?
PE (Pulmonary Embolism)
Pulmonary Thromboembolism
- Small
- Medium
- Large
- Massive
Small –> Silent or organization with cumulative damage (idiopathic pulmonary hypertension)
Medium –> pulmonary infarct w/ acute cardiorespiratory symptoms
Large –> right heart failure and collapse (>60% pulmonary circulation)
Massive –> sudden DEATH (e.g. saddle embolus)
- Saddle Embolus
- Paradoxical Embolus
- Occludes main pulmonary artery
- Cardiac embolus passing to the right side of the heart through a septal defect
What causes 99% of infarction?
Thrombosis (mostly arterial)
-Venous infarct occurs in organs with single venous outflow (e.g. Testis or Ovary)
Factors Influencing Development of Infarct
4 things
- Vulnerability to Hypoxia
Neuron - 3-4 mins
Heart - 20-30 mins
Fibrous tissue - hours
- Oxygen content of the blood (e.g. heart failure pt with low oxygen content)
- Nature of Blood Supply (Dual: lung, liver, hands; End-arterial: spleen, kidneys)
- Rate of Occlusion (atherosclerosis of coronary arteries is SLOW)
Inherited Thrombophilias
- Compare Number of Genotypes, Prevalence of Thrombophilia, and RR of thrombosis between AT deficiency, Protein C deficiency, Protein S deficiency, Factor V Leiden, Prothrombin G20120A
Antithrombin (AT), Protein C, and Protein S deficiencies all have many genotypes, 5% or less prevalence of thrombophilia, and up to 10 RR of thrombosis
Factor V Leiden –> One Genotype –> 40-50% prevalence of thrombophilia –> 3-7 RR of thrombosis
Prothrombin G20120A –> One Genotype –> 5-10% prevalence of thrombophilia –> 2-3 RR of thrombosis
Relative Risk of Venous Thrombosis
- Oral Contraceptives
- Factor V Leiden (carrier)
- Factor V Leidein (carrier) + Oral Contraceptives
- 7
- 9
34.7
When in the presence of clot, what will the measurements of Protein C and Protein S be?
Low (so does not necessarily indicate a deficiency if clot is present)
When to “further evaluate”
Young patients
Family history
Thrombosis in absence of known risks
Recurrent miscarriages (Factor V Leidin or Protein C/S deficiency)
Warfarin-induced skin necrosis
Neonatal purpura fulminans
Further Evaluation
- Lab Tests (7)
Factor V Leiden
Prothrombin 20210
Lipoprotein a
Factor VIII and vWF levels
PAI-1
Heparin cofactor 2
Plasminogen
What is a commmon inherited thrombophilia that is due to increased production of pro-coagulant?
Prothrombin G20120A gene mutation
Characteristics of ATIII Deficiency
Autosomal dominant inheritance
Quantiative and qualitative defects
Thrombotic phenomena in adolescence or even earlier
Frequently Pulmonary Embolism as first clinical manifestation
***YOUNG CHILDREN***
Characteristics of Protein C deficiency
Autosomal dominant and recessive inheritance
Quantitative and qualitative defects
Homozygotes is incompatible with life
Thrombotic phenomena in adolescence
***Skin necrosis when WARFARIN THERAPY introduced***
Characteristics of Protein S deficiency
Autosomal dominant inheritance
Quantitative and qualitative defects
Homozygotes is incompatible with life
Thrombotic phenomena in adolescence
***Skin necrosis when WARFARIN THERAPY introduced***
Factor V Leiden
- Mutation
- Effects
- Prevalence
- Missense muation changes amino acid 506 of factor V from arginine to glycine
- Mutation is at preferred protein C cleavage site, slows inactivation of factor Va by protein C
***factor Va procoagulant activity is not affected
- VERY COMMON (5% of population is heterozygous and accounts for 50% of inherited thrombophilia)
Prothrombin G20210A Mutation
- Mutation
- Effects
- Diagnosis
- Mutation in 3’ non-coding part of prothrombin gene
***NO EFFECT ON STRUCTURE OR FUNCTION
- Heterozygotes have 5-10% higher plasma prothrombin and 2-3 fold risk of venous thrombosis
- Diagnosed –> DNA testing
Overall Risk
- Thrombosis is….
MULTI-FACTORIAL
You need at least 2 risk factors if not 3 or 4
(One prothrombotic condition increases the risk of thrombosis by a factor of 5-8)
