Case 10: Eva Foster

Coagulation Factor Generation

Hepatocytes:

• Fibrinogen

• Prothrombin

• Factors V, VII, IX, X, XI, XII

Endothelial Cells:

• FVIII

• vWF

Extravascular/Stromal Cells: TF

Megakaryocytes: vWF

Platelet Function

Form primary hemostatic plug (white thrombus)

Increase fibrin adhesion

Coagulation Factor Function

Form secondary hemostatic plug (red thrombus)

• Coagulation cascade

Increase thrombin and fibrin network formation

Fibronolysis

Hemostasis stage 5

1. Tissue injury = Release + activate plasminogen activators = Plasminogen → Plasmin

• Plasminogen Activators:

  • Tissue plasminogen activator (tPA)

  • Urokinase

• Inhibited by plasminogen activator inhibitors

2. Plasmin break down + deactivate fibrin and fibrinogen = Release fibrin degradation products (D-dimers)

• Inhibited by plasmin inhibitors

Natural Anticoagulants

Endothelial surface factors

Antithrombin III

Heparin

Natural Anticoagulant: Endothelial Surface Factors

Smooth surface prevent intrinsic pathway activation (no collagen exposure)

Glycocalyx layer repel clotting factors and platelets

Thrombomodulin

• Bind thrombin = Remove thrombus

• Activate plasma protein C = Inactivate FV + FVIII

Natural Anticoagulant: Antithrombin III

Bind thrombin = Inactivate + inhibit fibrinogen activation (decrease fibrin)

Natural Anticoagulant: Heparin

Combine with antithrombin III = Increase activity

Shock

Circulatory failure decreasing pressure/volume in blood vessels

Types:

• Cardiogenic

• Distributive

• Obstructive

• Hypovolemic

Cardiogenic Shock

Low CO = Hypotension

• Cardiac ischemia

• Arrhythmia

Treatment:

• Inotropic drugs

• Vasopressors

• IV fluids

Distributive Shock

Fluid extravasation = Decrease intravascular fluid = Hypotension

• Sepsis

• Anaphylaxis

• CNS injury (neurogenic)

Treatment:

• IV fluids

• Vasopressors

• Treat underlying cause

Obstructive Shock

Physical vessel blockage = Decrease CO = Hypotension

• Cardiac tamponade

• Tension pneumothorax

• Pulmonary embolism

Treatment:

• IV fluids

• Treat obstruction

Hypovolemic Shock

Intravascular volume loss = Hypotension

• Fluid loss (GI, skin, kidneys)

• Hemorrhage

Treatment:

• IV fluids

• Blood transfusion

Venous Thromboembolism (VTE): Description

Thrombus formation in venous system

• Recurrent: Recurring VTE after 2 weeks of treatment

• Provoked: VTE with ≥ 1 risk factors

• Unprovoked/Idiopathic: VTE without risk factor

Types:

• Deep Vein Thrombosis (DVT)

• Pulmonary Embolism (PE)

DVT: Description

Blood clot in deep vein

Usually in lower extremities

• Proximal: Above calf vein trifurcation (knee joint)

  • Femoral, profunda femoris, and popliteal veins

• Distal: Below calf vein trifurcation

PE: Description

Blood clot in pulmonary arteries

VTE: Epidemiology

Risk factors:

• Older age (≥ 65 years)

• Smoking

• Obesity

• Cancer

• Surgery

• DVT/PE history

VTE: Etiology

Thrombotic Embolisms: Virchow Triad

• Endothelial damage

• Venous stasis

• Hypercoagulability

Nonthrombotic Embolisms:

• Fat

• Air bubbles

• Amniotic fluid: Fetal cell + Debris from fluid → Maternal circulation

VTE Virchow Triad: Endothelial Damage

Inflammation

Trauma

VTE Virchow Triad: Venous Stasis

Slow blood flow

Varicosis

Immobilization

• Travel/flights

• Bed rest

VTE Virchow Triad: Hypercoagulability

Increased blood viscosity

Genetics

• Thrombophilia

• Increase platelet adhesion

Oral contraceptives

Pregnancy

Malignancy

DVT: Pathogenesis

1. Virchow triad induce thrombus formation (coagulation cascade) around lower extremity vein valves

• More common in lower extremities from…

  • Immobility

  • Gravity-dependent blood pooling in venous valves

  • Low blood flow

2. Thrombus occlude blood vessel

PE: Pathogenesis

1. DVT in legs/pelvis embolize

• IVC → Pulmonary arteries

2. Obstruct pulmonary arteries

• Lung/pleural infarction + inflammation

• Impair gas exchange + cardiac function

• Pulmonary vasoconstriction

  • Thromboxane, prostaglandin, adenosine, thrombin, and serotonin secretion from platelets + thrombus

• Saddle Thrombus: Clot in pulmonary trunk bifurcation = Complete obstruction = Right heart strain + Death

VTE: Clinical Presentation

DVT:

• Asymptomatic

• Unilateral symptoms

  • Swelling

  • Erythema

  • Warmth

  • Dull pain

• Fever

PE:

• Dyspnea

• Tachypnea

• Tachycardia → Most sensitive

• Chest pain

• Dizziness and syncope

• Weakness

• Hemoptysis

VTE: Investigations

Wells Score: Risk assessment

Diagnostic:

• D-dimer

• Compression US

• ECG

• Echo

• CT pulmonary angiogram (CTPA)

VTE: Wells Score

Higher score = More likely

DVT Criteria:

• Medical history (cancer, previous DVT)

• Immobilization

• Clinical features

  • Tenderness

  • Leg + calf swelling (> 3cm)

  • Pitting edema

  • Distended superficial veins

PE Criteria:

• Medical history (malignancy, pervious PE/DVT)

• Immobilization

• Clinical features

  • Hemoptysis

  • Tachycardia

VTE: D-Dimer

General (DVT and PE)

Negative: < 500 ng/mL

• No DVT

Positive:  ≥ 500 ng/mL

• US

VTE: Compression US

DVT

Apply pressure on obstructed vein + Doppler

Positive:

• Noncompressible

• Hyperechoic mass

• No venous flow

VTE: ECG

PE

Sinus tachycardia

VTE: Echo

PE

Increased RA pressure

VTE: CTPA

PE

Obstruction in pulmonary arteries

Pulmonary infarction

VTE: Treatment/Management

Temporary parenteral anticoagulant + long-term oral anticoagulant

• Parenteral: Heparin

• Oral: DOACs, Vit K antagonists (VKAs)

Severe:

• PE: O2 therapy

• Thrombolytics

• Catheter-directed thrombolysis

• Thrombectomy/embolectomy

VTE Treatment: Heparin

Unfractionated (UFH): Inhibit FXa and thrombin = Increase antithrombin activity (indirect) = Decrease coagulation + fibrin formation

• Monitor: aPTT

Low Molecular Weight (LMWH): Bind antithrombin III = Inhibit FXa = Increase antithrombin activity (indirect) = Decrease coagulation + fibrin formation

• Monitor: Anti-factor Xa activity

VTE Treatment: DOACs

Direct Thrombin Inhibitors: Inhibit thrombin = Decrease fibrin formation

• Dabigatran

Direct FXa Inhibitors: Inhibit FXa = Decrease coagulation + fibrin formation

• Rivaroxaban, apixaban, edoxaban

Preferred over VKAs

• No monitoring

• Lower bleeding risk

VTE Treatment: VKAs

Warfarin

Decrease hepatic vit K synthesis = Inhibit FII (prothrombin), FVIII, FIX, and FX activation = Decrease coagulation + fibrin formation

Monitor: PT/INR

VTE Treatment: Thrombolytics

tPA (alteplase)

Increase plasminogen → Plasmin = Increase fibrin degradation

VTE Treatment: CDT

Increase enzymes catalyzing plasminogen → Plasmin to break down clot

• Streptokinase

• Urokinase

• rtPA

VTE Treatment: Thrombectomy/Embolectomy

If CDT contraindicated

VTE Complications

DVT:

• PE

• Recurrence

PE:

• Recurrence

• Poor oxygenation

  • Pulmonary artery obstruction = Increase V/Q ratio (normal ventilation + no blood flow) = Decrease O2 delivery from inspired air → Blood

• Cardiovascular failure

  • Obstruction increase pulmonary artery pressure = Increase RV pressure + Decrease blood into LA = Decrease CO = Hypotension