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D&T - E1 > Hemostasis and Thrombosis > Flashcards

Hemostasis and Thrombosis Flashcards

1
Q

Normal hemostasis relies on 2 functions

A
  1. Maintenance of blood in a fluid, clot-free state in normal vessels
  2. Induction of a rapid and localized hemostatic plug at a site of vascular injury
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2
Q

Hemostatsis is regulated by 3 general components

A
  1. Endothelium (vascular wall)
  2. Platelets
  3. Coagulation cascade
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3
Q

Sequence of events in hemostasis at the site of vascular injury

A
  1. VASOCONSTRICTION of arterioles due to reflex neurogenic mechanisms and secretion of endothelin (a vasoconstrictor) from endothelial cells
  2. PRIMARY HEMOSTASIS: platelet adhesion, platelet activation, platelet aggregation
  3. SECONDARY HEMOSTASIS: tissue factor, thrombin, cross-linked fibrin
  4. COUNTERREGULATORY MECHANISMS
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4
Q

Primary hemostasis

A

a. PLATELET ADHESION to exposed subendothelial extracellular matrix (ECM) (esp collagen), with the help of von Willebrand factor
b. PLATELET ACTIVATION: change shape and release secretory granules; secretory granules recruit more platelets
c. PLATELET AGGREGATION: recruited platelets form a hemostatic plug

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5
Q

Secondary hemostasis

A

a. TISSUE FACTOR: exposed at the site of injury activates the coagulation cascade which results in the activation of thrombin
b. THROMBIN converts circulating soluble fibrinogen to insoluble fibrin which is deposited; thrombin also induces further platelet recruitment and granule release

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6
Q

Role of platelets - Adhesion

A

von Willebrand Factor bridges platelet surface receptor glycoprotein Ib and exposed collagen

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7
Q

Role of platelets - Activation - Shape change

A

Increases surface area

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8
Q

Role of platelets - Activation - Secretion (release reaction)

A
  1. Degranulation occurs soon after adhesion and is initiated by agonists binding platelet surface receptors → alpha and gamma/dense granules
  2. Phospholipids appear on surface of activated platelets - bind Ca2+ and act as sites of for assembly of various coagulation factors
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9
Q

Role of platelets - Activation - Secretion (release reaction) - alpha granules

A
  • P-selectin: an adhesion molecule
  • Fibrinogen
  • Factors V and VIII
  • Platelet factor 4: heparin binding chemokine
  • Platelet derived growth factor (PDGF)
  • Transforming growth factor beta
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10
Q

Role of platelets - Activation - Secretion (release reaction) - gamma granules (dense granules)

A
  • ADP: activates platelet aggregation
  • ATP
  • Fibronectin
  • Ca2+: required in coagulation cascade
  • Histamine
  • Serotonin
  • Epinephrine
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11
Q

Role of platelets - Activation - Platelet aggregation

A
  • ADP and thromboxane A2 (TxA2: a prostaglandin produced by activated platelets) amplify aggregation forming primary hemostatic plug [cyclooxygenase (target for aspirin) is a platelet enzyme needed for thromboxane synthesis]
  • Thrombin binds to protease-activated receptor (PAR) on the platelet membrane and with ADP and TxA2 causes further aggregation (REVERSIBLE TO THIS POINT)
  • PLATELET CONTRACTION: a fused mass of paltelets occurs forming the secondary hemostatic plug
  • Thrombin converts fibrinogen to fibrin cementing the platelet plug in place
  • Fibrinogen binds GpIIIa/IIb receptors on activated platelets promoting aggregation
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12
Q

Role of the coagulation cascade

A
  1. Series of enzymatic conversions turning inactive proenzymes into activated enzymes, culminating in formation of fibrin
  2. Occurs on negatively charged surface of activated platelets
  3. Traditionally divided into extrinsic and intrinsic pathways converging where factor X is activated to a common pathway
  4. Extrinsic pathway is activated by TISSUE FACTOR which is exposed at the site of tissue injury
  5. Thrombin overview: converts fibrin to fibrinogen, induces platelet activation, pro-inflammatory via protease activate receptors (PARs), anticoagulant effects
  6. Size of the ultimate clot is moderated by a fibrinolytic cascade
    - PLASMIN breaks down fibrin into FIBRIN SPLIT PRODUCTS (fibrin split products can be measured to diagnose abnormal clotting such as DIC, dvt, pulmonary embolus)
    - Plasmin is formed from the conversion of plasminogen by factor XII-dependent pathway or by plasminogen activators (PAs) (tissue plasminogen activator, tPA, synthesized by endothelium is most active when bound to fibrin; most important PA)
    - To control plasmin endothelial cells also release plasminogen activator inhibitors (PAI)
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13
Q

Role of Endothelial Cells

A

ANTI-THROMBOTIC PROPERTIES: inhibit platelet adherence and blood clotting when intact and restrict coagulation to the site of vascular injury

  • Antiplatelet effects
  • Anticoagulant properties
  • Fibrinolytic effects

PRO-THROMBOTIC PROPERTIES: stimulated by injury or activation of endothelial cells to augment local clot formation

  • Platelet effects
  • Procoagulant effect
  • Antifibrinolytic effects
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14
Q

Role of Endothelial Cells - Anti-thrombic properties - Antiplatelet effects

A
  • Intact endothelium covers thrombogenic ECM
  • Nonactivated platelets do not adhere to intact endothelium
  • PROSTACYCLIN (PGI2) and NO: vasodilators, interfere with platelet adhesion and aggregation
  • ADENOSINE DIPHOSPHATASE: inhibits platelet aggregation by degrading ADP
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15
Q

Role of Endothelial Cells - Anti-thrombic properties - Anticoagulant properties

A
  • THROMBOMODULIN (on endothelial cell surface) binds thrombin and the compound activates PROTEIN C which with PROTEIN S inactivates factors Va and VIIIa
  • HEPARIN-LIKE MOLECULES (on endothelial cell surface) bind and activate ANTITHROMBIN III (a plasma protein) which inhibits thrombin and factors IXa, Xa, XIa, and XIIa; THIS IS THE SITE OF ACTION OF THE ANTICOAGULANT DRUG HEPARIN
  • TISSUE FACTOR PATHWAY INHIBITOR (TFPI) inhibits tissue factor VIIa and Xa
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16
Q

Role of Endothelial Cells - Anti-thrombic properties - Fibrinolytic effects

A

TISSUE TYPE PLASMINOGEN ACTIVATOR (synthesized by endothelial cells; tPA): cleaves plasminogen to plasmin which cleaves fibrin and degrades thrombi

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17
Q

Role of Endothelial Cells - Pro-thrombic properties - Platelet effects

A

VON WILLEBRAND FACTOR (vWF): cofactor in binding platelets to ECM exposed during endothelial injury

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18
Q

Role of Endothelial Cells - Pro-thrombic properties - Procoagulant effects

A
  • Endothelial cells activated by cytokines downregulate expression of THROMBOMODULIN
  • TISSUE FACTOR: activates extrinsic clotting cascade, synthesis stimulated by TNF, IL-1 bacterial endotoxins and others
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19
Q

Role of Endothelial Cells - Pro-thrombic properties - Procoagulant effects

A

Endothelial cells secrete plasminogen activator inhibitors (PAIs), limiting fibrinolysis

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20
Q

Thrombosis definition

A

A clot in the cardiovascular system formed during life

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21
Q

Thrombosis - Virchow Triad

A
  • Endothelial injury
  • Abnormal blood flow
  • Hypercoagulabilit
22
Q

Thrombosis - Virchow Triad - Endothelial injury

A

Loss of endothelium

  • Etiology: atherosclerosis, trauma, inflammation
  • Exposes ECM
  • Adhesion of platelets: platelet adherence and activation is necessary for thrombus formation under high shear stress such as in arteries; this is the reason platelet inhibitors are one of the treatments for CORONARY ARTERY DISEASE
  • Tissue factor release
  • Depletion of PGI2 and PAs

Dysfunction of endothelium

  • Etiology: hypertension, turbulent flow, bacterial endotoxins
  • Increased procoagulant factors, decreased anticoagulant effectors
23
Q

Thrombosis - Virchow Triad - Abnormal blood flow

A

Turbulence and stasis

  • Disrupt laminar flow, exposing platelets to endothelium
  • PREVENT DILUTION OF CLOTTING FACTORS
  • Slow inflow of clotting factor inhibitors, thrombi accumulate
  • Promote endothelial activation (thrombosis, leukocyte adhesion, etc.)

Clinical

  • Turbulence: atherosclerotic plaques
  • Stasis: aneurysms, noncontractile myocardium post MI, heart chamber dilation, atrial fibrillation, etc.
24
Q

Thrombosis - Virchow Triad - Hypercoagulability

A
  • Primary hypercoagulability states are GENETIC

- Secondary hypercoagulability states are ACQUIRED

25
Q

Primary Hypercoagulable States

A

Common Mutations

  • Factor V Leiden
  • Prothrombin gene
  • MTHFR gene

Rare Deficiencies

  • Antithrombin III
  • Protein C
  • Protein S
26
Q

Primary Hypercoagulable States - Factor V Leiden

A
  • Arg → Glu substitution at residue 506
  • 2-15% of Caucasians carry the mutation
  • FACTOR V IS RESISTANT TO CLEAVAGE BY PROTEIN C
  • Heterozygotes have a 5X relative risk of venous thrombosis
  • Homozygotes have a 50X relative risk of venous thrombosis
  • 60% of patients with recurrent DVTs have this mutation
27
Q

Primary Hypercoagulable States - Prothrombin gene

A
  • 1-2% of population carry the mutation
  • Mutation causes elevated prothrombin levels
  • 3x relative risk of venous thrombosis
28
Q

Primary Hypercoagulable States - MTHRFR gene

A
  • Increases homocysteniemia
  • 5-15% of white and East Asians carry the mutation
  • Variant of 5,10-methylenetetrahydrofolate reductase
  • Causes a modest elevation in homocysteine
  • Homocysteine may inhibit antithrombin III and endothelial thrombomodulin
29
Q

Secondary Hypercoagulable States - High Risk

A
  • Prolonged immobilization (eg bedrest, travel ‘coach class syndrome’)
  • Myocardial infarction, a-fib, prosthetic cardiac valves
  • Tissue damage
  • Cancer: release of procoagulant tumor products
  • DIC: thrombohemorrhagic, covered with bleeding d/o
  • Heparin-Induced thrombocytopenia (HIT) - thrombohermorrhagic, covered in bleeding disorders
  • Antiphospholipid antibody syndrome (formerly known as lupus anticoagulant syndome)
30
Q

Secondary Hypercoagulable States - High Risk - Antiphospholipid Antibody Syndrome

A

Antiphospholipid antibody syndrome (formerly known as lupus anticoagulant syndrome)

  • Antibodies bind to protein complexes unveiled by phospholipid
  • Mechanism by which hyper coagulable state is induced is unknown
  • 2 categories of patients: 1. Patients with autoimmune disease (e.g. systemic lupus erythematosus (SLE)) - secondary antiphospholipid syndrome); 2. Points without h/o autoimmune disease - primary antiphospholipid syndrome
  • Clinical correlation: recurrent venous or arterial thrombi, repeated miscarriages, cardiac valvular vegetations, thrombocytopenia
  • Treatment: anticoagulation, immunosuppression for refractory cases
31
Q

Secondary Hypercoagulable States - Lower Risk

A
  • Cardiomyopathy
  • Nephrotic syndrome
  • Hyperestrogenic states (pregnancy)
  • Oral contraceptive use
  • Sickle cell anemia
  • Advancing age (decreases endothelial PGI2 production)
  • Smoking
  • Obesity
32
Q

Secondary Hypercoagulable States - Combined States

A
  • Greatly increases risk for venous thrombosis
  • Homozygotes for mutations
  • Concurrent inheritance of different mutations (compound heterzygosity)
  • Mutations + acquired risk factors
  • Standard of care: patients under the age of 50 who present with venous thrombosis should be checked for inherited causes of hyper coagulability even when acquired risk factors are present
33
Q

Thrombosis Morphology

A

Can occur anywhere in the circulatory system including cardiac chambers and cardiac valve cusps

Grossly and microscopically have laminations (lines of Zahn)

  • PALE LAYERS: platelets
  • DARKER LAYERS: fibrin and RBCs
  • Laminations indicate that thrombus is formed in flowing blood

Attach to underlying heart wall or vessel in heart known as MURAL THROMBUS

34
Q

Thrombosis - Morphology - Types

A
  • Arterial thrombi
  • Venous thrombi
  • Post-mortem clots
35
Q

Arterial Thrombi

A
  • Usually occlusive
  • SITES: coronary, cerebral, femoral
  • Usually overlies atherosclerotic plaque
  • Gray-white, friable mesh of platelets, fibrin, RBCs, WBCs
  • Grows retrograde to blood flow (toward heart)
36
Q

Venous Thrombi

A
  • Essentially always occlusive
  • Lower extremities (90% of cases), upper extremities, ovarian, uterine, prostatic, portal or hepatic vein, dural sinuses
  • Red, containing more RBCs than arterial because of stasis environment
  • Grow in direction of blood flow (toward hard), propagating tail not well attached, prone to embolism
37
Q

Post-mortem Clots

A
  • Usually not attached to wall
  • Dark red dependent portion
  • Yellow ‘chicken fat’ supernatant
38
Q

Fate of Thrombus

A
  • Propagation
  • Embolism
  • Dissolution: recent thrombi most susceptible to fibrinolysis
  • Organization and recanalization: ingrowth of endothelial cells, fibroblasts, smooth muscle cells; small channels for blood flow may develop through clot; may be incorporated into vessel wall resulting in narrowing of vessel
39
Q

Thrombosis - Clinical Correlations

A

Obstruction and embolization

Venous thrombosis (phlebothrombosis)

  • Superficial venous thrombosis
  • Deep venous thrombosis

Arterial and Cardiac Thrombosis

40
Q

Venous Thrombosis (Phlebothrombosis) - Superficial Venous Thrombosis

A
  • Rarely embolize
  • Cause edema distal to obstruction
  • Predispose overlying skin to infections and ulceration
41
Q

Venous Thrombosis (Phlebothrombosis) - Deep Venous Thrombosis

A
  • AT OR ABOVE THE KNEE MAY EMBOLIZE
  • Symptoms of pain and edema may be relieved rapidly by collateral circulation, 50% asymptomatic
  • DIAGNOSIS: ultrasound or angiogram
  • TREATMENT: anticoagulation
  • BELOW THE KNEE: monitor for 1-2 weeks for propagation above the knee (25%)
42
Q

Arterial and Cardiac Thrombosis

A
  • CORONARY ARTERY THROMBOSIS: myocardial infarction
  • CEREBRAL ARTERY THROMBOSIS: stroke, TIA
  • FEMORAL ARTERY THROMBOSIS: gangrene
  • ATRIAL MURAL THROMBUS: secondary to a-fib or mitral valve stenosis, can embolize to brain, kidneys, spleen
  • VENTRICULAR MURAL THROMBUS: secondary to MI, cardiomyopathy, etc. can embolize
43
Q

Embolism Definition

A

A detached intravascular solid, liquid, or gaseous mass that is carried by the blood to a site distant from its point of origin

44
Q

Pulmonary Thromboembolism

A
  • 200,000 deaths annually
  • Source is DVT from lower extremity in 95% of cases
  • Often occur as multiple, sequentially or as a ‘shower’
45
Q

Pulmonary Thromboembolism - Clinical Correlation

A
  • Most pulmonary emboli (60-80%) are clinically silent because they are small
  • Multiple over time can cause pulmonary hypertension and right heart failure
  • Sudden death, right heart failure (cor pulmonale), or cardiovascular collapse when >/= 60% of pulmonary circulation is obstructed
  • Obstruction of medium-sized arteries may cause hemorrhage but not infarction because of DUAL CIRCULATION of lung
  • Obstruction of end-arteriolar branches usually results in infarction
46
Q

Systemic Thromboembolism

A
  • Travel in arterial circulation
  • 80% from intracardiac mural thrombi (left ventricle secondary to MI, left atrium secondary dilation and fibrillation)
  • Some from aortic aneurysm, atherosclerosis, valvular vegetations
  • Few are due to PARADOXICAL EMBOLISM (from right side, usually DVT, bypasses pulmonary circulation to systemic circulation through interatrial or interventricular septal defect)
47
Q

Systemic Thromboembolism - Clinical Correlation

A
  • Lodge at various sites, lower extremities (75%), brain (10%), intestines, kidneys, spleen, upper extremities
  • Ischemia or infarction of tissue distal to embolism depends on extent of collateral or dual circulation
48
Q

Fat Embolism

A

Microscopic fat globules may be found in circulation after fracture of long bones

90% of patients with severe skeletal injury have fat emboli, 10% have clinical findings

FAT EMBOLISM SYNDROME: 1-3 days post injury (timing is important)

  • PULMONARY INSUFFICIENCY: tachypnea, dyspnea, tachycardia
  • NEURO: irritability, restlessness progressing to delirium and coma
  • ANEMIA and THROMBOCYTOPENIA
  • ETIOLOGY: obstruction of pulmonary and cerebral microvasculature with toxic injury from release of free fatty acids
49
Q

Air Embolism

A

Obstruction of circulation by large or coalesced gas bubbles (>100 cc) is similar to thromboembolic obstruction

Sources of air emboli

  • Introduction of air into venous circulation via: neck and chest injuries, obstetric procedure, thoracentesis, hemodialysis
  • Decompression sickness: air breathed at high pressure results in increased amounts of air (mostly nitrogen) dissolving in the blood; rapid depressurization results in nitrogen coming out of solution, forming gas emboli; gas bubbles in skeletal muscle and tissue surrounding the joints is very painful, known as the ‘bends’; TREATMENT: compression chamber, gradual depressurization
50
Q

Aminiotic Fluid Embolism

A
  • Infusion of amniotic fluid or fetal tissue into maternal circulation peripartum
  • INITIAL SYMPTOMS: sudden severe dyspnea, cyanosis, hypotensive shock, then seizures and coma
  • LATER SYMPTOMS (in surviving patients): pulmonary edema, DIC
  • Rare but mortality is 20-40%

D&T - E1 (11 decks)

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