Thrombosis

Question 1

Thrombosis

1. Definition
2. Virchow’s Triad (Factors predisposing thrombosis)

Answer 1

1. Thrombosis –> Pathological process of blood clotting in uninjured vessel or an exaggerated blood clotting response
2. Virchow’s Triad (factors predisposing thrombosis)
   - Endothelial injury
   - Blood stasis or turbulence of blood flow
   - Blood hypercoagulability

Question 2

Where do arterial thrombi grow? Venous thrombi?

Answer 2

Arterial –> back to the heart

Venous –> toward the heart

Question 3

Anti-Thrombic Properties of Endothelium

1. Anti-platelet effects (2)
2. Anticoagulant properties (2)
3. Fibrinolytic properties (1)

Answer 3

1. PGI2 and NO (prevent platelet adhesion)
2. Heparin-like molecule (activates ATIII) and Thrombomodulin
3. tPA

Question 4

Prothrombotic Properties

3 of them

Answer 4

vWF

Tissue Factor

Plaminogen Activator Inhibitors (PAI)

-Key regulators of the fibrinolytic system

Question 5

What does aspirin (ASA) inhibit?

Answer 5

Activation and release of contents from platelets

Question 6

What makes the platlet plug irreversible (secondary hemostatic plug)?

Answer 6

Action of Thrombin

Question 7

Arterial Thrombosis

1. Key factors

Answer 7

1. 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

Question 8

How does vWF react to bloodflow?

Answer 8

Unfolds under shear stress

***Faster the blood flows, the stickier it gets***

Question 9

What is the job of Thrombin?

Answer 9

Converts Fibrinogen to Fibrin (irreversible plug)

Question 10

Hypercoagulability

1. Primary (Genetic) Disorders

Answer 10

Factor V Leiden mutation

ATIII deficiency

Protein C deficiency

Protein S deficiency

Prothrombin G20210A gene mutation

Question 11

Hypercoagulability

1. Secondary Disorders

Answer 11

Anti-phospholipid Syndrome

Lupus anticoagulant

Prolonged immobilization

Cancer

Nephrotic Syndrome

Contraceptive pills

Smoking

Question 12

Heparin-Induced Thrombocytopenia (HIT Syndrome)

Answer 12

***A Hypercoagulable state***

Occurs during heparin therapy

Antibodies bind to platelets and active them continually

Question 13

Antiphospholipid Syndrome (Lupus Anticoagulant)

Answer 13

***A Hypercoagulable state​***

Antibodies to phospholipid (e.g. Cardiolipin)

In vitro –> inhibits coagulation

In-vivo (in life) –> induces coagulation

Question 14

Disseminated Intravascular Coagulation

1. What is it?
2. Occurs in
3. Leads to
4. Symptoms

Answer 14

1. Sudden widespread fibrin thrombi in the microcirculation
2. Occurs in shock, infection, pregnancy, and malignancy (cancer)
3. 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***

Question 15

Fate of Thrombus

4 of them

Answer 15

1. Propagation (progression)
2. Embolization
3. Lysis
4. 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

Question 16

What is the most common cause of preventable hospital death?

Answer 16

PE (Pulmonary Embolism)

Question 17

Pulmonary Thromboembolism

1. Small
2. Medium
3. Large
4. Massive

Answer 17

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)

Question 18

1. Saddle Embolus
2. Paradoxical Embolus

Answer 18

1. Occludes main pulmonary artery
2. Cardiac embolus passing to the right side of the heart through a septal defect

Question 19

What causes 99% of infarction?

Answer 19

Thrombosis (mostly arterial)

-Venous infarct occurs in organs with single venous outflow (e.g. Testis or Ovary)

Question 20

Factors Influencing Development of Infarct

4 things

Answer 20

1. Vulnerability to Hypoxia

Neuron - 3-4 mins

Heart - 20-30 mins

Fibrous tissue - hours

2. Oxygen content of the blood (e.g. heart failure pt with low oxygen content)
3. Nature of Blood Supply (Dual: lung, liver, hands; End-arterial: spleen, kidneys)
4. Rate of Occlusion (atherosclerosis of coronary arteries is SLOW)

Question 21

Inherited Thrombophilias

1. 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

Answer 21

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

Question 22

Relative Risk of Venous Thrombosis

1. Oral Contraceptives
2. Factor V Leiden (carrier)
3. Factor V Leidein (carrier) + Oral Contraceptives

Answer 22

3. 7
4. 9

34.7

Question 23

When in the presence of clot, what will the measurements of Protein C and Protein S be?

Answer 23

Low (so does not necessarily indicate a deficiency if clot is present)

Question 24

When to “further evaluate”

Answer 24

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

Question 25

**Further Evaluation** 1. Lab Tests (7)

Answer 25

Factor V Leiden Prothrombin 20210 Lipoprotein a Factor VIII and vWF levels PAI-1 Heparin cofactor 2 Plasminogen

Question 26

What is a commmon inherited thrombophilia that is due to **increased production of pro-coagulant**?

Answer 26

Prothrombin G20120A gene mutation

Question 27

**Characteristics of _ATIII Deficiency_**

Answer 27

**Autosomal dominant** inheritance Quantiative and qualitative defects Thrombotic phenomena in adolescence or even earlier Frequently **Pulmonary Embolism** as **first clinical manifestation** \*\*\***YOUNG CHILDREN**\*\*\*

Question 28

**Characteristics of _Protein C deficiency_**

Answer 28

**Autosomal dominant** and **recessive** inheritance Quantitative and qualitative defects Homozygotes is incompatible with life Thrombotic phenomena in adolescence **\*\*\*Skin necrosis** when **_WARFARIN THERAPY_** introduced\*\*\*

Question 29

**Characteristics of _Protein S deficiency_**

Answer 29

**Autosomal dominant** inheritance Quantitative and qualitative defects Homozygotes is incompatible with life Thrombotic phenomena in adolescence \*\*\***Skin necrosis** when **_WARFARIN THERAPY_** introduced\*\*\*

Question 30

**Factor V Leiden** 1. Mutation 2. Effects 3. Prevalence

Answer 30

1. Missense muation changes amino acid **506** of factor V from **arginine** to **glycine** 2. Mutation is at preferred **protein C cleavage site**, **slows inactivation** of factor **Va** by protein C \*\*\*factor Va procoagulant activity is not affected 3. **VERY COMMON** (5% of population is heterozygous and accounts for 50% of inherited thrombophilia)

Question 31

**Prothrombin G20210A Mutation** 1. Mutation 2. Effects 3. Diagnosis

Answer 31

1. Mutation in 3' non-coding part of **prothrombin gene** \*\*\*NO EFFECT ON STRUCTURE OR FUNCTION 2. Heterozygotes have 5-10% **higher plasma prothrombin** and **2-3 fold** risk of venous thrombosis 3. Diagnosed --\> **DNA testing**

Question 32

**Overall Risk** 1. Thrombosis is....

Answer 32

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**)