1 - Coagulation Disorders

thrombosis definition

formation of blood clots (partial or complete) within the blood vessels which limits natural blood flow

hemostasis definition

tightly regulated process where the body attempts to maintain normal blood flow in vessels despite damage/trauma

hemostasis process (steps)

1. constriction of the blood vessel

2. primary hemostasis: formation of a temporary platelet plug

3. secondary hemostasis: activation of the coagulation cascade

4. formation of a fibrin plug

primary hemostasis

• initiated due to damage to the endothelium of the blood vessel

• smaller vessel allows for less blood loss

• several biomarkers are released to promote vasoconstriction

• promotion of platelet adhesion and activation at the injured site

• formation of temporary platelet plug

biomarkers that support vasoconstriction

• endothelin-1

• collagen

• ATP

• von Willebrand factor (vWF)

platelet plug steps

• part of primary hemostasis

1. activation: platelet plug stabilizes to the vessel wall via vWF

2. granules of serotonin, ADP, and Ca2+ are released

3. glycoprotein IIb/IIIa receptors are activated

4. aggregation

5. platelet plug

aggregation definition

attracts other platelets to the site

platelet plug definition

a weak, temporary seal in primary hemostasis

secondary hemostasis

• AKA coagulation cascade

• clotting factors are activated

• prothrombin is converted to thrombin

• fibrinogen is converted to fibrin

• a strong plug is formed

intrinsic pathway AKA contact activation pathway - speed

slower than extrinsic pathway (takes minutes)

intrinsic pathway AKA contact activation pathway - activation & beginning

• begins when Factor XII comes into contact with foreign material from injury to vessel wall

• activated by calcium

vessel wall examples

endothelial cells

collage

extravascular material

intrinsic pathway AKA contact activation pathway steps

1. Hageman Factor (XII) → XIIa via collagen, kallikrein, HMWK

2. XI → Xla via XIIa

3. IX → IXa via Xla and calcium

4. VIII → VIIIa via thrombin

   

extrinsic pathway AKA tissue factor pathway - speed

very fast pathway (seconds)

extrinsic pathway AKA tissue factor pathway - what activates it?

TF (Factor III)

what forms activated complex in extrinsic pathway AKA tissue factor pathway?

TF and Factor VII form activated complex

extrinsic pathway AKA tissue factor pathway - steps

1. tissue factor (III) → IIIa via damage to endothelial tissue

2. VII → VIIa

   

common pathway - steps

1. X → Xa via:

   1. calcium, VIIa, IIIa

   2. or

   3. IXa, calcium, VIIIa

2. V → Va via thrombin

3. II → IIa (thrombin) via Xa, Va, and calcium

4. I → Ia (fibrin) via IIa (thrombin)

5. XIII (stabilizing factor) → XIIIa via thrombin

6. stable fibrin clot via Ia (fibrin), calcium, and XIIIa

natural anticoagulants in the clotting cascade

• Protein C

• Protein S

• Antithrombin (ATIII)

• TFPI: Tissue Factor Pathway Inhibitor (FVIIa)

Protein C

• a natural anticoagulant

• part of the clotting cascade

• inhibits FVIIIa and FVa (vitamin K dependent)

factors VIIIa and Va are ______ dependent

vitamin K dependent

Protein S

• a natural anticoagulant

• part of the clotting cascade

• cofactor for protein C

antithrombin (ATIII)

• a natural anticoagulant

• part of the clotting cascade

• inhibits factors Xa and IIa primarily

clotting cascade steps

another name for II and IIa

II = prothrombin

IIa = thrombin

another name for I and Ia

I = fibrinogen

Ia = fibrin

in the clotting cascade, what can inhibit the formation of VII → VIIa?

TFPI

in the clotting cascade, what can inhibit X → Xa?

antithrombin

in the clotting cascade, what can inhibit thrombin (IIa)?

antithrombin

in the clotting cascade, what can inhibit V → Va?

active protein C

in the clotting cascade, what inhibits VIII → VIIIa?

active protein C

how is protein C created in the clotting cascade?

• protein C + thrombomodulin → active protein C

• catalyzed by Protein S

Protein C half life

medium-long

Protein S half life

medium-long

Factor II half life

long

factor VII half life

short

Factor IX half life

long

Factor X half life

very long

fibrinolysis

• blood clot = temporary patch

• once the vessel has healed, fibrin is lysed (fibrinolysis)

what activates the conversion of plasminogen to plasmin

Factor XII

what breaks down fibrin in the fibrinolytic cascade

activated plasmin

practice question: Daisy is in the kitchen chopping veggies. She cuts herself with a knife. She applies pressure and the bleeding stops.

1. What is the process called where the bleeding is stopped?

2. What pathway is triggered?

1. hemostasis

2. extrinsic pathway

   1. rationale: something external is causing blood loss

practice question: If a pt has a deficiency in Factor VIII, would they clot or bleed?

bleed

practice question: If a pt has a deficiency in Protein C, would they clot or bleed?

clot

practice question: If a pt has a deficiency in antithrombin, would they clot or bleed?

clot

arterial thrombosis - activation

• platelets

• injury to vessel wall

arterial thrombosis - common causes

• inflammation

  • high LDL level

  • infection

  • HTN

composition of arterial thrombosis

antiplatelet

examples of arterial thrombosis

• ischemic stroke due to atherosclerosis

• acute coronary syndrome

venous thrombosis - activation

clotting cascade

venous thrombosis - common cause/s

• stasis

• state of hypercoagulability

venous thrombosis - composition

fibrin rich

venous thrombosis - tx

anticoagulant

venous thrombosis - example/s

• DVT

• PE

• cardioembolic stroke due to AFib

Virchow’s Triad

• 3 components that can contribute to the development of a thrombus

• hypercoagulability

• (circulatory) stasis

• vascular damage AKA endothelial injury

hypercoagulability

• part of Virchow’s triad

• blood

• increased blood coagulation/hyperviscosity due to genetic defects, certain disease states, medications

• examples:

  • major surgery/trauma

  • malignancy

  • pregnancy

  • infection

  • thrombophilias

  • medications

    • estrogen

    • tamoxifen

    • raloxifene

    • cancer drugs

    • heparin products

  • autoimmune disease

  • dehydration

  • factor deficiencies/mutations

  • nephrotic syndrome

• VTE etiology

(circulatory) stasis

• part of Virchow’s Triad

• flow

• interrupted blood flow

• examples:

  • immobility

  • obesity

  • tumors

  • pregnancy

  • surgery

  • acute illness

  • paralysis

  • older age

• etiology of VTE

vascular damage AKA endothelial injury

• part of Virchow’s triad

• vessel

• irritation and inflammation of vessel wall leading to injury/trauma

• examples:

  • cellulitis

  • thrombophlebitis

  • atherosclerosis

  • heart valve

  • physical trauma or injury

• etiology of VTE

  • due to surgery, trauma, indwelling catheters, damage to valves leads to venous stasis

What component of triad is… cancer?

hypercoagulability

What component of triad is… mechanical heart valve?

vascular damage AKA endothelial injury

What component of triad is… obesity?

(circulatory) stasis

practice case:

What risk factors does this pt have for a clot?

67 yo F with PMH of depression, osteoarthritis, and post menopausal vasomotor sx.

Medication List: estradiol 0.5mg once daily, sertraline 50mg once daily, acetaminophen PRN

Social sx: 1 PPD smoker x 30 yrs, occasional alcohol use (1-2 drinks per day)

Pt is s/p TKA (Total Knee Arthroplasty) this morning. She has just been moved to a room from the PACU (Post-Anesthesia Care Unit)

• estradiol

• osteoarthritis (decreased movement)

• TKA (decreased movement)

• age (decreased age could possibly mean decreased movement/mobility)

• smoking (vascular damage/endothelial injury)

• alcohol use (vascular damage/endothelial injury)

VTE pathophysiology (steps)

1. healthy vein in valve

2. blood pools in vein

3. blood clot forms in vein

4. embolus forms, causing thrombosis

DVT presentation

• unilateral leg pain and swelling

• Homan’s sign

• tenderness

• skin discoloration

• ulceration

• warmth

• asymptomatic

Homan’s sign

pain in back of knee when dorsiflexing the foot

PE clinical presentation

• chest pain/tightness

• shortness of breath

• tachypnea

• tachycardia

• syncope, dizziness, light-headedness

• cardiogenic shock

• hemoptysis

• signs of DVT first (occasionally)

ischemic stroke etiology

stasis in the atria

ischemic stroke pathophysiology

emboli from heart circulates to brain causing blood vessel occlusion

ischemic stroke presentation

• numbness/weakness in face, arm, or leg

• confusion

• trouble speaking

• vision changes

• trouble walking

• severe headache

Factor V Leiden (FVL) - etiology

point mutation in the F5 gene

Factor V Leiden (FVL) - pathophysiology

insensitive to activated protein C, 20-fold slower degradation of FVL

Factor V Leiden (FVL) - clinical presentation

• VTE

• asymptomatic

prothrombin 20210 - etiology

point mutation of the G20210A gene

prothrombin 20210 - pathophysiology

increased concentration of prothrombin in circulation

prothrombin 20210 - clinical presentation

• VTE

• asymptomatic

Protein C&S deficiency - etiology

Protein C: genetic mutation of PROC gene

Protein S: genetic mutation of PROS1 gene

Protein C&S deficiency - pathophysiology

increased factors V & VIII → increased thrombotic production → prothrombotic state

Protein C&S deficiency - clinical presentation

• VTE

• stroke

• miscarriage

• warfarin induced skin necrosis

antithrombin III deficiency - etiology

• hereditary

  • autosomal dominant trait → heterozygous for variant SERPINC1 gene

• acquired

  • disseminated intravascular coagulation (DIC)

  • liver disease

  • trauma

  • critical illness (sepsis)

  • medications

    • heparin

    • estrogen products

antithrombin III deficiency - pathophysiology

reduced levels of AT lead to uncontrolled thrombin generation and fibrin deposition

antithrombin III deficiency - clinical presentation

• VTE

• heparin resistance

• stroke

antiphospholipid syndrome (APS) - etiology

• autoimmune disorder creating antiphospholipid antibodies (APLA)

• triple positive has highest risk of thrombosis

antiphospholipid antibodies (APLA)

• anticardiolipin antibodies

• anti-beta-2-glyocprotein-I antibodies

• lupus anticoagulants

antiphospholipid syndrome (APS) - pathophysiology

• upregulation of tissue factor

• decreased nitric oxide

• increased endothelial injury

antiphospholipid syndrome (APS) - clinical presentation

• DVT (more common)/PE

• stroke

• catastrophic APS

• miscarriage

hyperhomocysteinemia - etiology

variation in the methylene tetrahydrofolate reductase (MTHFR) gene

hyperhomocysteinemia - pathophysiology

• exact mechanism unknown

• thought to cause endothelial injury and inflammation

hyperhomocysteinemia - clinical presentation

• VTE

• cardiovascular disease

Which of the following clotting disorders leads to upregulation of FV and FVIII?

a. FVL

b. Protein C deficiency

c. 20210 mutation

d. antiphospholipid syndrome

Which of the following clotting disorders leads to upregulation of FV and FVIII?

a. FVL

b. Protein C deficiency

c. 20210 mutation

d. antiphospholipid syndrome

In a patient with hyperhomocysteinemia, which of the following are they at an increased risk for? Select ALL that apply.

a. PE

b. hypotension

c. bleeding

d. MI

e. DVT

In a patient with hyperhomocysteinemia, which of the following are they at an increased risk for? Select ALL that apply.

a. PE

b. hypotension

c. bleeding

d. MI

e. DVT