Arterial and Venous Thrombosis¶
Chapter 122 | Part 4: Oncology and Hematology
KEY CLINICAL POINTS¶
- Thrombosis is hemostasis 'at the wrong place and at the wrong time' with significant morbidity/mortality in arterial and venous diseases.
- Arterial thrombosis is driven by vessel wall injury, platelet activation, and coagulation, while venous thrombosis is linked to stasis, hypercoagulability, and endothelial dysfunction.
- Key risk factors include age, obesity, immobility, cancer, hormonal therapies, and genetic variants (e.g., Factor V Leiden).
- Antiplatelet agents (aspirin, clopidogrel) and anticoagulants (heparin, DOACs) are central to management.
- Genetic polymorphisms (e.g., CYP2C19, MTHFR) influence drug response and thrombotic risk.
1. DEFINITION & OVERVIEW¶
Thrombosis is hemostasis 'at the wrong place and at the wrong time' (MacFarlane). It involves obstruction of blood flow by thrombi, leading to tissue ischemia and organ damage. Arterial thrombosis is characterized by platelet-rich clots, while venous thrombosis involves fibrin-rich clots. Platelets, coagulation factors, and endothelial dysfunction are central to pathogenesis.
Table 122-2: Genetic Variation and Pharmacogenetic Responses to Platelet Inhibitors¶
| POTENTIAL GENE ALTERED | TARGET CLASS | SPECIFIC DRUG |
|---|---|---|
| P2Y1 and P2Y12 | CYP2C19, CYP3A4, CYP3A5 | ADP receptor inhibitors (Clopidogrel, Prasugrel) |
| PlA1/A2 | Receptor inhibitors | Abciximab, Eptifibatide, Tirofiban |
| Glycoprotein IIb-IIIa | Receptor inhibitors | Receptor inhibitors |
1.1 Platelet Function¶
Platelets are anucleate cells (1–5 µ m) derived from megakaryocytes. They mediate hemostasis via adhesion (GPIb-IX-V), activation (GPIIb/IIIa), and aggregation. Platelet granules release ADP, serotonin, and thromboxane A2, which amplify clot formation.
1.2 Coagulation Cascade¶
The coagulation cascade involves sequential enzymatic reactions converting fibrinogen to fibrin. Tissue factor (TF) exposure initiates the extrinsic pathway, while endothelial damage triggers the intrinsic pathway. Thrombin activates fibrinogen and platelets, stabilizing the clot.
2. EPIDEMIOLOGY¶
In 2020, heart disease caused ~1/4 of U.S. deaths (655,000). Coronary disease killed 382,820, and stroke killed 160,743. DVT/PE occurred in 1–2/1000 annually, with 300,000–600,000 new cases. 60,000–80,000 deaths annually attributed to DVT/PE. Risk factors include age, obesity, immobility, cancer, and hormonal therapies.
2.1 Incidence/Prevalence¶
DVT/PE incidence: 5 per 10,000 person-years in general population; 20 per 10,000 in 70–79-year-olds. 5–8% of U.S. population has genetic risk for VTE.
2.2 Risk Factors¶
Genetic: Factor V Leiden, Prothrombin 20210G → A, MTHFR 677C → T. Acquired: Surgery, trauma, pregnancy, obesity, immobility, cancer, antiphospholipid syndrome, hormonal therapies.
3. ETIOLOGY & PATHOPHYSIOLOGY¶
Arterial thrombosis: Platelet activation, endothelial damage, and coagulation. Venous thrombosis: Stasis, hypercoagulability, and endothelial dysfunction. Platelet adhesion (GPIb-IX-V binding von Willebrand factor), activation (GPIIb/IIIa), and aggregation (ADP, thromboxane) drive clot formation. Inflammation and immune activation (e.g., platelet-leukocyte aggregates) exacerbate thrombosis.
Table 122-1: Heritable Causes of Arterial and Venous Thrombosis¶
| A. Arterial Thrombosis | B. Venous Thrombosis |
|---|---|
| Platelet Receptors (b3, a2 integrins, GPIb), Redox Enzymes, MTHFR | Procoagulant Proteins (Fibrinogen, Prothrombin), Anticoagulant Pathway (Factor V Leiden), Fibrinolytic Proteins (PAI-1) |
| Homocysteine (MTHFR 677CfiT), CYP2C19 variants | Homocysteine (MTHFR 677CfiT), Antiphospholipid Syndrome |
3.1 Platelet Activation¶
Platelet receptors (ADP, thrombin, collagen) trigger signaling via tyrosine kinase, phospholipase C, and calcium influx. GPIIb/IIIa binds fibrinogen, stabilizing aggregates. Platelet-derived cytokines and P-selectin mediate inflammation.
3.2 Coagulation Cascade¶
Tissue factor initiates extrinsic pathway (FVIIa-TF complex activates FX). Intrinsic pathway (contact activation) and common pathway (thrombin generation) converge. FXa and thrombin convert fibrinogen to fibrin, stabilized by FXIII.
4. CLINICAL FEATURES¶
Arterial: Chest pain (MI), stroke, limb ischemia. Venous: Leg swelling, pain, DVT symptoms. Complications: PE (sudden death), recurrent VTE, post-thrombotic syndrome. Inflammation: Platelet-leukocyte aggregates, immune activation (CD40L, TLRs).
4.1 Arterial Thrombosis¶
Myocardial infarction (chest pain), ischemic stroke (neurological deficits), peripheral artery occlusion (claudication, gangrene).
4.2 Venous Thrombosis¶
Deep vein thrombosis (leg swelling, pain), pulmonary embolism (sudden dyspnea, hemoptysis), post-thrombotic syndrome (chronic edema, ulcers).
5. DIFFERENTIAL DIAGNOSIS¶
Arterial: Aortic dissection, coronary artery spasm, embolism. Venous: DVT mimics (muscle strain, lymphedema), PE mimics (pulmonary infection, tumor). Inflammatory conditions: SLE, vasculitis.
5.1 Arterial Mimics¶
Aortic dissection (chest pain, hypertension), coronary artery spasm (angina), embolic events (acute stroke).
5.2 Venous Mimics¶
Muscle strain, lymphatic obstruction, pelvic congestion, tumor thrombosis.
6. INVESTIGATIONS & DIAGNOSIS¶
D-dimer (rule out PE/DVT), ultrasound (venous duplex), CT pulmonary angiography (PE). Wells score for DVT, Geneva score for PE. Genetic testing (Factor V Leiden, MTHFR).
Table 122-3: Acquired Causes of Venous Thrombosis¶
| Surgery | Trauma | Antiphosp holipid Syndrome | Pregnancy | Long-Dista nce Travel | Obesity | Oral Contr aceptives/ HRT | Myeloprolif erative Disorders |
|---|---|---|---|---|---|---|---|
| Neurosurge ry, Major Abdominal Surgery | Trauma | Antiphosph olipid Syndrome | Pregnancy | Long-Dista nce Travel | Obesity | Oral Contra ceptives/Ho rmone Repl acement | Polycythem ia Vera |
6.1 Diagnostic Tests¶
D-dimer, venous ultrasound, CT pulmonary angiography, ECG (for MI), cardiac enzymes (troponin).
6.2 Criteria¶
Wells score for DVT ( ≥ 3 points: high probability), Geneva score for PE ( ≥ 4 points: high suspicion).
7. MANAGEMENT & TREATMENT¶
Acute: Anticoagulation (heparin, LMWH, DOACs). Chronic: Warfarin, DOACs. Antiplatelet (aspirin, clopidogrel). Thrombolytics (alteplase) for massive PE. Compression stockings for post-thrombotic syndrome. Risk stratification (CHA2DS2-VASc score).
7.1 Anticoagulation¶
Heparin (IV), LMWH (subQ), DOACs (rivaroxaban, apixaban). Warfarin (INR 2–3). Monitor for bleeding, drug interactions.
7.2 Antiplatelet Therapy¶
Aspirin (81–325 mg), clopidogrel (75 mg), prasugrel, ticagrelor. Avoid in active bleeding, recent surgery.
8. PROGNOSIS & COMPLICATIONS¶
PE mortality: 25% in cancer patients, 15% in general population. Recurrent VTE: 30% within 10 years. Long-term risks: Post-thrombotic syndrome, chronic venous insufficiency, pulmonary hypertension. Genetic risk: 5–8% of U.S. population.
9. SPECIAL CONSIDERATIONS¶
Pregnancy: Low-dose aspirin, LMWH. Elderly: Monitor for bleeding, adjust anticoagulation. Cancer: Thromboprophylaxis, consider DOACs. Immunosuppressed: Monitor for infections, bleeding.
9.1 Pregnancy¶
Low-dose aspirin, LMWH (avoid heparin in late pregnancy). Monitor for placental abruption. Adjust anticoagulation doses, monitor renal function, avoid NSAIDs for bleeding risk.
10. KEY POINTS & CLINICAL PEARLS¶
- Thrombosis is a leading cause of mortality in cardiovascular disease. 2. Arterial thrombosis is platelet-driven; venous is fibrin-driven. 3. Genetic variants (Factor V Leiden, MTHFR) increase VTE risk. 4. Anticoagulation is first-line for DVT/PE. 5. Monitor for bleeding in anticoagulant therapy.