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Arterial and VenousThrombosis

Chapter 122 | Part 4: Oncology and Hematology · Part 4 – Hematologic Disorders & Hemostasis · Chapter 122

Key Clinical Points

  1. Thrombosis is defined as hemostasis 'at the wrong place and at the wrong time' (MacFarlane).
  2. Arterial thrombosis depends on vessel wall state, platelet function, and blood flow factors.
  3. Venous thrombosis is driven by hypercoagulable states (genetic/acquired), stasis, or vascular dysfunction.
  4. Platelets are anucleate, disc-shaped cells (1–5 μm) with a life span of 7–10 days; they are essential for primary hemostasis.
  5. Tissue factor (TF) exposure initiates the coagulation cascade via Factor VIIa activation.
  6. Cancer patients have a fourfold increased risk of venous thromboembolism (VTE).
  7. Up to 30% of new VTE cases die within 30 days; pulmonary embolism (PE) in cancer has a 25% fatality rate.
  8. Clopidogrel metabolism is influenced by CYP2C19; loss-of-function alleles (CYP2C19*2) lead to increased platelet activity (reduced drug efficacy).
  9. Major heritable causes of venous thrombosis include Factor V Leiden (1691G → A) and Prothrombin (20210G → A).
  10. Aspirin resistance is heterogeneous; there is no clinical indication for genotyping to optimize aspirin efficiency.
  11. Platelet activation involves the release of Thromboxane A_2 (TxA_2), serotonin (5-HT), and adenosine diphosphate (ADP).

1. DEFINITION & OVERVIEW

• Definition: Thrombosis is defined as hemostasis 'at the wrong place and at the wrong time' (MacFarlane). • Pathophysiology: Obstruction of blood flow due to thrombus formation may result in tissue anoxia and damage, a major cause of morbidity and mortality. • Mechanism: Hemostasis and thrombosis involve interplay among vessel wall, coagulation/fibrinolytic proteins, and platelets.

1.1 Arterial vs. Venous Thrombosis

• Arterial thrombosis: ◦ Factors: Dependent on vessel wall state, platelet function, and blood flow factors. ◦ Mechanism: Platelet adhesion → recruitment → thrombin activation. • Venous thrombosis: ◦ Factors: Driven by hypercoagulable states (genetic/acquired), stasis, or vascular dysfunction. ◦ Primary forms: Deep-vein thrombosis (DVT) and pulmonary embolism (PE), collectively termed venous thromboembolic disease (VTE).

2. EPIDEMIOLOGY

• Global Impact: Arterial and venous thrombosis are major causes of morbidity/mortality globally. • Heart Disease Statistics: ◦ In the US, heart disease caused ~1/4 deaths in 2020 (382,820 coronary deaths; 160,747 stroke deaths). ◦ Annual estimates: 600,000 new coronary events; 200,000 myocardial infarctions in prior patients. • Stroke Statistics: ◦ ~795,000 annual ischemic stroke cases; 1/6 cardiovascular deaths in 2018. • VTE Statistics: ◦ Annual estimates: 600,000 VTE events (DVT/PE); 60,000–80,000 VTE-related deaths. ◦ Incidence: ~5 per 10,000 person-years for first DVT; increases to 20 per 10,000 in 70–79-year-olds. • Mortality Rates: ◦ ARIC study: 9% 28-day DVT mortality; 15% PE mortality. ◦ Cancer-associated PE: 25% fatality rate.

3. ETIOLOGY & PATHOPHYSIOLOGY

Pathophysiologic processes share similarities but differ in triggers. Thrombosis occurs when hemostatic mechanisms are dysregulated.

3.1 The Platelet

• Structure: Anucleate, disc-shaped (1–5 μm), 200–400,000/μL. ◦ Life span: 7–10 days. ◦ Origin: Derived from megakaryocytes; regulated by thrombopoietin (TPO). ◦ Granules: Alpha-granules (coagulation proteins, growth factors); dense-granules (ADP, serotonin). ◦ Key Receptors: P2Y12, PAR1–4, GPIb-IX-V, GPIIb/IIIa.

3.2 Platelet Adhesion and Activation Mechanisms

• Adhesion: Initiated by exposure of subendothelial collagen and von Willebrand factor (vWF). ◦ Mechanism: GPIb-IX-V binds vWF, triggering platelet adhesion. • Activation: ◦ Process: Signal transduction → release of TxA_2, 5-HT, and ADP → conformational change in GP IIb/IIIa receptor. ◦ Result: Enables fibrinogen binding, promoting aggregation. ◦ Regulation: Calcium-dependent processes amplify signaling.

3.3 Inflammation and Thrombosis

• Platelet-leukocyte aggregates: Increased in acute infections/coronary syndromes. ◦ P-selectin (CD62P): Mediates interactions with leukocytes via PSGL-1. ◦ CD40L: Links thrombosis and inflammation; activates endothelial cells and platelets. ◦ TLRs: Platelet TLR2/3/4 activation by pathogens (e.g., SARS-CoV-2, HIV) enhances proinflammatory responses.

3.4 Genetics of Arterial Thrombosis

• Heritable variants: GWAS identified loci associated with platelet count/volume and coronary artery disease (e.g., 12q24). ◦ Platelet Receptors: β3 and α2 integrins; P A2 polymorphism; Fc(gamma)RIIA; GPIV T13254C polymorphism; GPIb; Thrombin receptor PAR1-5061 → D. ◦ Redox Enzymes: Plasma glutathione peroxidase, GPx3, promoter haplotype H2; Endothelial nitric oxide synthase (–786T/C, –922A/G, –1468T/A); Paraoxonase (–107T allele, 192R allele). ◦ Homocysteine: Cystathionine β-synthase 833T → C; 5,10-MTHFR 677C → T. ◦ Pharmacogenetics: CYP2C19 polymorphisms affect clopidogrel metabolism (e.g., *2 allele reduces efficacy). ◦ Aspirin resistance: No clinical indication for genotyping to optimize antiplatelet effects.

3.5 Overview of the Coagulation Cascade and its Role in Venous Thrombosis

• Mechanism: Converts prothrombin to thrombin, which cleaves fibrinogen to form fibrin. ◦ Initiation: Tissue factor (TF) binds FVIIa → activates FX/FIX. ◦ Common pathway: FXa + FVa converts prothrombin to thrombin. ◦ Stabilization: Thrombin activates FXIII for clot stabilization. ◦ Regulation: Anticoagulants (antithrombin, TFPI) limit thrombin production.

4. CLINICAL FEATURES

• Arterial thrombosis: Causes myocardial infarction, stroke, and ischemia due to vessel occlusion. • Venous thrombosis: Primarily DVT (lower extremities) → PE; 10% occur in non-traditional sites. • Risk Factors: ◦ Arterial: Hypertension, LDL, smoking, diabetes, pregnancy, chemotherapy, SLE, antiphospholipid syndrome. ◦ Venous: Hypercoagulability (genetic/acquired), stasis, surgery, trauma, obesity, OCPs, malignancy.

4.1 Acquired Causes of Venous Thrombosis

• Surgery: Neurosurgery; Major abdominal surgery. ◦ Trauma: Physical injury. ◦ Medical conditions: Antiphospholipid syndrome, myeloproliferative disorders (polycythemia vera). ◦ Physiologic states: Pregnancy, long-distance travel, obesity. ◦ Medications: Oral contraceptives/hormone replacement.

5. DIAGNOSTIC APPROACH

  1. Risk Factor Assessment: Identify high-risk states including malignancy (4x VTE risk), hypercoagulable mutations (Factor V Leiden, Prothrombin 20210G → A), and clinical triggers (surgery, trauma).
  2. Pharmacogenetic Testing: CYP2C19 genotyping for patients on clopidogrel to assess metabolism; no indication for aspirin genotyping.

6. MANAGEMENT & TREATMENT

  1. Antiplatelet Therapy: ◦ Aspirin: Inhibits COX1, COX2. ◦ ADP receptor inhibitors: Clopidogrel, prasugrel (influenced by CYP2C19, CYP3A4, CYP3A5). ◦ GP IIb-IIIa receptor inhibitors: Abciximab, eptifibatide, tirofiban.
  2. Anticoagulant Therapy: ◦ Antithrombin and TFPI to limit thrombin production.

7. KEY PEARLS & HIGH-YIELD POINTS

• Arterial vs. Venous: Arterial = Platelet/Wall; Venous = Coagulation/Stasis. • Key Mutations: Factor V Leiden (1691G → A) and Prothrombin (20210G → A) are primary heritable venous risks. • Cancer Risk: 4x increased risk of VTE; 25% mortality for cancer-associated PE. • Platelet Activation: Triggered by vWF/collagen; leads to release of TxA_2, 5-HT, and ADP. • Coagulation Initiation: Tissue Factor (TF) is the primary initiator of the cascade via FVIIa.

8. TABLES & FIGURES

• Table 122-1: Heritable Causes of Arterial and Venous Thrombosis ◦ Arterial: ◦ Platelet Receptors: β3/α2 integrins, P A2, Fc(gamma)RIIA, GPIV T13254C, GPIb, PAR1-5061 → D. ◦ Redox Enzymes: GPx3, NOS (–786T/C, –922A/G, –1468T/A), Paraoxonase (–107T, 192R). ◦ Homocysteine: CBS 833T → C; MTHFR 677C → T. ◦ Venous: ◦ Procoagulant Proteins: Fibrinogen (–455G/A, –854G/A), Prothrombin (20210G → A). ◦ Protein C Pathway: Factor V Leiden (1691G → A), Thrombomodulin (1481C → T). ◦ Fibrinolytic Proteins: tPA (7351C/T, 20,099T/C, 27,445T/A), PAI-1 (–675 position). ◦ Homocysteine: CBS 833T → C; MTHFR 677C → T. • Table 122-2: Genetic Variation and Pharmacogenetic Responses to Platelet Inhibitors ◦ ADP receptor inhibitors (Clopidogrel, prasugrel) → CYP2C19, CYP3A4, CYP3A5. ◦ Cyclooxygenase inhibitors (Aspirin) → COX1, COX2. ◦ Receptor inhibitors (Abciximab, eptifibatide, tirofiban) → PlA1/A2, INTB3, GPIbA. • Table 122-3: Acquired Causes of Venous Thrombosis ◦ Surgery: Neurosurgery, Major abdominal surgery. ◦ Trauma: Physical trauma. ◦ Medical Conditions: Antiphospholipid syndrome, Myeloproliferative disorders (Polycythemia vera). ◦ Physiology: Pregnancy, Long-distance travel, Obesity. ◦ Medications: Oral contraceptives/hormone replacement.

Reference Tables

TABLE 122-2 Genetic Variation and Pharmacogenetic Responses to Platelet Inhibitors

Harrison's 22e, p.939

POTENTIAL GENE
ALTERED		 TARGET THERAPEUTIC
CLASS		 SPECIFIC DRUG
P2Y1 and P2Y12 CYP2C19,
CYP3A4, CYP3A5		 ADP receptor inhibitors Clopidogrel, prasugrel
Cyclooxygenase
inhibitors
PlA1/A2 Receptor inhibitors Abciximab, eptifibatide,
tirofiban
Glycoprotein IIb-IIIa
receptor inhibitors

TABLE 122-1 Heritable Causes of Arterial and Venous Thrombosis A. Arterial Thrombosis Platelet Receptors

Harrison's 22e, p.939

  • A. Arterial Thrombosis
  • Platelet Receptors
  • β3 and α2 integrins
  • P A2 polymorphism
    l
  • Fc(gamma)RIIA
  • GPIV T13254C polymorphism
  • GPIb
  • Thrombin receptor PAR1-5061 → D
  • Redox Enzymes
  • Plasma glutathione peroxidase, GPx3, promoter haplotype H2
  • H2 promoter haplotype
  • Endothelial nitric oxide synthase
  • –786T/C, –922A/G, –1468T/A
  • Paraoxonase
  • –107T allele, 192R allele
  • Homocysteine
  • Cystathionine β-synthase 833T → C
  • 5,10-Methylene tetrahydrofolate reductase (MTHFR) 677C → T
  • B. Venous Thrombosis
  • Procoagulant Proteins
  • Fibrinogen
  • –455G/A, –854G/A
  • Prothrombin (20210G → A)
  • Protein C Anticoagulant Pathway
  • Factor V Leiden: 1691G → A (Arg506Gln)
  • Thrombomodulin 1481C →T (Ala455Val)
  • Fibrinolytic Proteins with Known Polymorphisms
  • Tissue plasminogen activator (tPA)
  • 7351C/T, 20 099T/C in exon 6, 27 445T/A in intron 10
  • Plasminogen activator inhibitor (PAI-1)
  • 4G/5G insertion/deletion polymorphism at position –675
  • Homocysteine
  • Cystathionine β-synthase 833T → C
  • 5,10-MTHFR 677C → T

TABLE 122-3 Acquired Causes of Venous Thrombosis Surgery Neurosurgery Major abdominal surgery Other Trauma…

Harrison's 22e, p.940

  • Surgery
  • Neurosurgery
  • Major abdominal surgery
  • Other
  • Trauma
    Antiphospholipid syndrome
  • Pregnancy
  • Long-distance travel
  • Obesity
  • Oral contraceptives/hormone replacement
  • Myeloproliferative disorders
  • Polycythemia vera