Biochemistry Case Study: Deep Vein Thrombosis

Front 1

What does the process of Hemostasis become initiated by?

Back 1

Endothelial Cell injury

Front 2

What is the end result of Hemostasis?

Back 2

To effectively stop bleeding

Front 3

What does the entire process of Hemostasis involve?

Back 3

Platelet Adhesion, Activation and Degranulation, activation of blood clotting pathways, Thrombosis, and ultimately clot Dissolution.

Front 4

In healthy individuals, what does the blood clotting process represent?

Back 4

A delicate balance between clot formation and dissolution, that functions to prevent excessive Thrombosis or bleeding.

Front 5

If the Endothelial cells remain intact (undamaged), what does the equilibrium of the blood clotting process favor?

Back 5

Blood flow through the Endothelium lined vasculature

Front 6

If the Endothelial cells remain intact (undamaged), what does the equilibrium of the blood clotting process oppose?

Back 6

Clot formation

Front 7

What are the other names of the two coagulation pathways?

Back 7

Intrinsic Pathway - Contact Activation Pathway
Extrinsic Pathway - Tissue Factor Pathway

Front 8

What do both coagulation pathways converge to activate?

Back 8

Activate Thrombin
Activate Factor XIII

Front 9

What does the activation of Factor XIII and Thrombin form?

Back 9

A cross-linked hard Fibrin clot

Front 10

Aside from the two (enzymatic) coagulation pathways, what else does the blood clotting process entail that is a mutually reinforcing component that is ongoing concurrently?

Back 10

Platelet-mediated cellular component

Front 11

Since it is known that several of the clotting reactions take place on the Platelet surface at the site of trauma, what does this tell us about Hemostasis and Platelets?

Back 11

Hemostasis requires adequate numbers of Platelets and Platelet functionality needs to be up to par.

Front 12

Where do the activated "sticky" Platelets adhere to?

Back 12

Activated Platelets adhere to the Subendothelial Collagen that was recently exposed by Endothelial Cell damage.

Front 13

What is needed to adhere the activated "sticky" Platelets to the Subendothelial Collagen?

Back 13

Von Willebrand Factor

Front 14

What is the function of Von Willbrand Factor?

Back 14

It adheres the activated Platelets to the Subendothelial Collagen

Front 15

As soon as the activated Platelets adhere to the Subendothelial Collagen, what happens to the Platelets?

Back 15

Calcium-mediated changes in Platelet structure facilitate Platelet Plug formation at the site of blood vessel injury.

Front 16

What must occur just prior to Platelet Plug formation at the site of blood vessel injury?

Back 16

Activated sticky Platelets must adhere to the Subendothelial Collagen by a Von Willebrand Factor. This is what causes the Calcium-mediated changes to Platelet structure which in turn facilitates Platelet Plug formation.

Front 17

What becomes stimulated as soon as the Platelets adhere to the Subendothelial Collagen?

Back 17

Platelet Degranulation

Front 18

The process of Platelet Degranulation stimulates the release of?

Back 18

Degranulation liberates Chemical signals from the Cytoplasmic granules contained in the Platelets.

Front 19

When can the clot be dissolved?

Back 19

As soon as the damaged Endothelial cells have healed.

Front 20

What is the general process of clot dissolution?

Back 20

Plasmin dissolves the clot in the Fibrinolytic system.

Front 21

How can we clinically measure the accumulation of Fibrin degradation fragments in pathological conditions?

Back 21

D-dimer assay

Front 22

What are the two major effects of the Fibrin degradation fragments?

Back 22

Reduce Thrombin activity.
Inhibit further Fibrin Polymerization.

Front 23

What does the initiation of Fibrinolysis consequentially terminate?

Back 23

Blood clotting cascade

Front 24

What is the main reason why it's easy for Plasminogen to be incorporated into the blood clot?

Back 24

Plasminogen has a high affinity for Fibrin

Front 25

What are two common activators for Plasminogen?

Back 25

Tissue Plasminogen Activator (tPA)
Urokinase-type Plasminogen Activator (uPA)

Front 26

What is the main function of Tissue Plasminogen Activator (tPA) and Urokinase-type Plasminogen Activator (uPA)?

Back 26

They convert Plasminogen to its active form - Plasmin.
Thus, favoring clot dissolution.

Front 27

Where is tPA released from?

Back 27

tPA is liberated from damaged Endothelial cells as an inactive precursor.

Front 28

How does the inactive tPA become activated?

Back 28

Upon binding to Fibrin.

Front 29

What is tPA pharmacologically widely used for the treatment of?

Back 29

Myocardial Infarction

Front 30

Where does Prostacyclin and NO get released from?

Back 30

Endothelial Cells

Front 31

List as many anticoagulants as you can, that favor blood flow and clot dissolution/opposing thrombosis.

Back 31

Prostacyclin
Nitric Oxide
Antithrombin
Protein C&S

Front 32

What occurs during the binding of Thrombin to Thrombomodulin?

Back 32

Substrate specificity is altered, and this favors the activation of Protein C.

Front 33

What stimulates the release of Prostacyclin and tPA?

Back 33

Protein C&S

Front 34

What are all the things that are inactivated by Protein C&S?

Back 34

Factors VIIIa and Va
Inhibitors of tPA

Front 35

What does Heparin enhance?

Back 35

Antithrombin binding to:
Thrombin
Factors VIIIa, IXa, and Xa

Front 36

Where is Heparin present?

Back 36

Plasma membrane of undamaged Endothelial cells.

Front 37

Where is Thrombomodulin released from?

Back 37

Endothelial Cells

Front 38

What is the main function of Heparin?

Back 38

Increases the affinity of Antithrombin for Thrombin by 1000x.

Front 39

Where do the clots formed by Deep Vein Thrombosis most commonly occur in the body?

Back 39

In the deep veins of the lower legs, thighs, or pelvis.
Less commonly in the arms too.

Front 40

Which group of people are more susceptible to Deep Vein Thrombosis, and why?

Back 40

Older adults.
As a result of an imbalance between blood clotting and fibrinolytic mechanisms.

Front 41

If someone starts suffering from Deep Vein Thrombosis, why is medical intervention immediately required?

Back 41

The clots may dislodge and form emboli in the lungs.

Front 42

What are the three predisposing factors for Deep Vein Thrombosis? What is the term for the three together?

Back 42

1. Endothelial Cell injury
2. Venous Stasis
3. Hypercoagulability

All three: Virchow's Triad

Front 43

What 5 things increase the risk of Deep Vein Thrombosis?

Back 43

Cigarette Smoking
Advancing age (>60)
Diabetes Mellitus
Hypertension
Obesity

Front 44

What can Deep Vein Thrombosis be a secondary result of? (4)

Back 44

Secondary to:
1. Trauma
2. Oral Contraceptive use
3. Long periods of immobilization in bed-ridden patients/post surgery (notably hip/knee surgery)
4. Cases of Tibial fracture without prophylaxis.

Front 45

Can Deep Vein Thrombosis be Idiopathic? Do you know what Idiopathic even means?

Back 45

Yes.
It means arising spontaneously or from an obscure or unknown cause.

Front 46

What are the first things required for a diagnosis of Deep Vein Thrombosis?

Back 46

A comprehensive patient history and a Physical examination.

Front 47

How is Deep Vein Thrombosis often presented, as far as symptoms are concerned?

Back 47

It is actually quite often asymptomatic, but may be present with localized Edema in the leg with acute painful onset worsened by movement and relieved by rest.

Front 48

What is a common complaint by patients who have Deep Vein Thrombosis before diagnosis?

Back 48

Pain in the groin or buttocks, and experiencing Tachycardia.

Front 49

What are the 2 major combined assessment methods to measure a patients risk for Deep Vein Thrombosis?

Back 49

Hamilton and Wells scores with the sensitive Fibrin D-dimer assay.
These are required for effective management.

Front 50

What are the 3 methods to confirm the diagnosis of Deep Vein Thrombosis?

Back 50

1. Non-invasive compression Ultrasound
2. Computed Tomography
3. Magnetic Resonance Imaging (MRI)

Front 51

Which test specifically measures the presence of Fibrinolytic products in the blood? What is the problem associated with this test?

Back 51

D-dimer assay.
The problem is that false positives and false negatives may occur.

Front 52

What is the D-dimer assay often performed alongside? What does this test indicate?

Back 52

Often, D-dimer assays are performed alongside PT (Prothrombin Time) and PTT (Partial Thromboplastin Time).

This indicates the presence of Thrombotic disease.

Front 53

If a patient has low risk for DVT and the D-dimer assay comes back with low values, what does this show?

Back 53

This effectively rules out DVT and clotting problems as a cause of their symptoms.

Front 54

Aside for DVT, when might high D-dimer values occur?
What is the next step?

Back 54

High D-dimer values may occur following surgery/trauma, Cardiovascular disease, and Cancer.

In this scenario, Ultrasound tests will likely be indicated as the next step for the physician.

Front 55

Which test is generally preferred over a Venogram?

Back 55

Doppler Ultrasound

Front 56

What is an Ultrasound evaluating exactly?

Back 56

The blood flow in the legs and the presence of clots.

Front 57

How is an Ultrasound performed?

Back 57

Serially (in a few steps/installments)

Front 58

Which test may provide useful information regarding DVT, specifically in the Pelvis, and also allowing imaging of both legs?
What is the one downfall?

Back 58

MRI - Magnetic Resonance Imaging.

Problem: EXPENSIVE AS FUH

Front 59

Which test indicates if the patient is Anemic, also used to establish Platelet numbers?

Back 59

Complete Blood Count

Front 60

Which test provides information on the numbers of circulating Leukocytes, Erythrocytes, Hemoglobin concentration, and Hematocrit?

Back 60

Complete Blood Count

Front 61

What 4 conditions are known to extend the Bleeding Time?

Back 61

Thrombocytopenia
Platelet Dysfunction
Hypofibrinogenemia
Ehlers Danlos Syndrome

Front 62

Why is the Bleeding Time test no longer used in children?
Why has its use been limited?

Back 62

No longer used in children due to the risk of scarring.
Its use has been limited due to problems with standardization and wise intra- and inter- test variability.

Front 63

Which test was historically used to establish the risk of bleeding during surgery?

Back 63

The Bleeding Time test.

Front 64

How long does normal bleeding take to stop, and what is required?

Back 64

Normal bleeding stops in 7 minutes and requires Platelet activity.

Front 65

Which test measures the functionality of Prothrombin (Factor II), as well as Factors I, V, VII, and X?

Back 65

Prothrombin Time (PT)

Front 66

What does the Prothrombin Time (PT) test measure?

Back 66

Functionality of:
Factors I, II (Prothrombin), V, VII, and X.
Liver
Extrinsic and Common pathways

Presence of:
Vitamin K Deficiency
Bleeding disorders

Efficacy of:
Anticoagulant drugs (Warfarin)

Front 67

Which test may be used to evaluate Liver function? Which assay is this usually done alongside?

Back 67

Prothrombin Time, alongside AST/ALT assay.

Front 68

Which test is used to determine the presence of Vitamin K deficiency, and other bleeding disorders?

Back 68

Prothrombin Time

Front 69

What is an extended Prothrombin Time indicative of?

Back 69

A deficiency of any of the Clotting Factors it measures (I, II, V, VII, and X)

Front 70

Which test establishes the functionality of the Extrinsic and Common Pathways, and which test establishes the functionality of the Intrinsic and Common Pathways?

Back 70

Extrinsic and Common Pathways: PT
Intrinsic and Common Pathways: APTT

Front 71

What does an extended APTT indicate?

Back 71

A deficiency in Factors II, V, VII, IX, X, XI, or XII.

Front 72

Which test can be effectively used to establish appropriate dose-titration for Heparin treatment?

Back 72

APTT

Front 73

What is APTT often tested alongside? What is the purpose of this?

Back 73

Alongside PT.
This allows the Physician to determine the precise location of the clotting disorder.

Front 74

To what level of functionality does the APTT test measure?

Back 74

APTT is sufficiently sensitive to detect factors functioning at 70% of usual activity.

Front 75

What kind of blood can the APTT test be performed on?

Back 75

Fresh or citrated (circulating in the organs/tissues) whole blood samples.

Front 76

What is the APTT test unaffected by?

Back 76

Platelet numbers.

Front 77

Which test is often performed alongside PT or as a pre-surgery screening to detect the presence of bleeding disorders?

Back 77

Partial Thromboplastin Time (PTT)

Front 78

Which two tests are normally performed alongside PT?
What is the reason for these to be performed together?

Back 78

APTT with PT: To accurately locate the area of the clotting disorder.

PTT with PT: To detect the presence of bleeding disorders.

Front 79

Which test is used exclusively to measure clotting in patients undergoing bypass surgery who are taking unfractioned Heparin?

Back 79

Activated Clotting Time (ACT)

Front 80

What kind of blood can the ACT test be performed on?
What kind of blood can the APTT test be performed on?

Back 80

ACT: Fresh whole blood only.
APTT: Fresh or citrated (circulating in the organs/tissues) whole blood samples.

Front 81

Why would the ACT test be used over the APTT test?

Back 81

The ACT is less accurate than the APTT, but it is useful when high doses of Heparin are required.

Front 82

What does an extended ACT indicate?

Back 82

Thrombocytopenia
Deficiency in Factors VIII, IX, X, XI, and XII

Front 83

Compare: What is indicated by...
Elevated D-dimer assay:
Extended PT:
Extended APTT:
Extended ACT:

Back 83

Elevated D-dimer assay: May occur following surgery/trauma, Cardiovascular disease, or Cancer.

Extended PT: Deficiency in Factors I, II, V, VII, or X.

Extended APTT: Deficiency in Factors II, V, VII, IX, X, XI, or XII.

Extended ACT: Deficiency in Factors VIII, IX, X, XI, or XII.

Front 84

Since DVT is a potentially fatal complication following surgery, what must patients be educated on?

Back 84

Symptoms of DVT
Importance of adhering to post-surgery prophylactic measures (compression stockings, intermittent pneumatic compression devices to promote circulation and reduce swelling).

Front 85

What is the mainstay treatment post-surgery?

Back 85

Anticoagulation, especially for high risk patients.

Front 86

What kind of anticoagulation treatments are recommended initially, post-surgery?
What about for maintenance?
What about further treatment options?

Back 86

Initially:
Low Molecular Weight Heparins (LMWH)
Compression treatments with unfractioned Heparin.

Maintenance:
Slow, long acting Warfarin (Vit. K Antagonist) along with Fondaparinux.

Further options:
Direct Thrombin inhibitors such as Pradaxa.

Front 87

How does the synthetic pentasaccharide medication, Fondaparinux, work to maintain anticoagulation?

What is the one problem with any medications that inhibit Xa?

Back 87

It inhibits Factor Xa by promoting binding to Antithrombin.

Problem: Oral inhibitors of Xa are associated with severe bleeding complications.

Front 88

How long must anticoagulant treatment be maintained for, following surgery?

Back 88

Usually around 3 months OR as long as the benefits outweigh the risks.

Front 89

Following surgery, when are patients at the greatest risk for DVT?

Back 89

2-3 days post-surgery, and at 10 days post-surgery.

Front 90

Following surgery, if the patient is unresponsive what is the protocol?

Back 90

Surgical Thrombectomy or Catheter-directed Thrombolysis.

Front 91

Why would Pradaxa be favored over Warfarin?

Back 91

Warfarin is a Vitamin K Antagonist, and Pradaxa is a direct inhibitor of Thrombin.

Direct inhibitors of Thrombin have advantages over Vitamin K Antagonists because their predictable anti-clotting effects simplify anticoagulation therapy.

Front 92

What is the problem associated with Pradaxa? Fondaparinux?

Back 92

Pradaxa: Bronchioalveolar bleeding.
Fondaparinux: Severe bleeding complications.