1. 1
    • Venous thromboembolism (VTE) results from clot formation in the venous circulation and is manifested as deep vein thrombosis (DVT) and pulmonary embolism (PE).
  2. 2
    • Risk factors for VTE include increasing age, history of VTE, and aspects related to Virchow’s triad: (1) blood stasis (e.g., immobility and obesity); (2)vascular injury (e.g., surgery, trauma, and venous catheters); and (3) hypercoagulability (e.g., malignancy, coagulation factor abnormalities, antiphospholipid antibodies, and certain drugs).
    • The most common inherited hypercoagulability disorder is activated protein C (APC) resistance (Caucasian prevalence 2%–7%), which increases the risk of VTE threefold. Most APC resistance results from a factor V gene mutation (known as factor V Leiden) that renders it resistant to degradation by APC.
    • The prothrombin G20210A mutation is the second most frequent inherited hypercoagulability disorder (Caucasian prevalence 2%–4%) and imparts a threefold increased risk of VTE. The mutation increases circulating prothrombin and may enhance thrombin generation.
    • Inherited deficiencies of protein C, protein S, and antithrombin occur in less than 1% of the population and may increase the lifetime VTE risk by as much as sevenfold.
    • Normal hemostasis maintains the integrity of the circulatory system after blood vessel damage. Disruption of the endothelial cell lining with injury results in platelet activation and tissue-factor–mediated initiation of the clotting factor cascade, culminating in the formation of thrombin and ultimately a fibrin clot. In contrast to physiologic hemostasis, pathologic VTE occurs in the absence of gross vessel wall damage and may be triggered by tissue factor (TF) brought to the clot formation site by circulating microparticles. Clots are causing VTE to impair blood flow and often cause complete vessel occlusion.
    • Exposure of blood to damaged vessel endothelium causes platelets to become activated after binding to adhesion proteins (e.g., von Willebrand factor and collagen). Activated platelets recruit additional platelets, causing the formation of a platelet thrombus. Activated platelets change shape and release components that sustain further thrombus formation at the site. Activated platelets accumulating in the thrombus express the adhesion molecule P-selectin, which facilitates capture of blood-borne microparticles bearing tissue-factor, thereby triggering fibrin clot formation via the coagulation cascade.
    • The conceptual model for the coagulation cascade involves reactions that occur on cell surfaces in three overlapping phases (Fig. 1–1):

    FIGURE 1–1. Model of pathologic thrombus formation: (A) activated platelets adhere to vascular endothelium; (B) activated platelets express P-selectin; (C ) pathologic microparticles express active tissue factor and are present at a high concentration in the circulation—these microparticles accumulate, perhaps by binding to activated platelets expressing P-selectin; and (D) tissue factor can lead to thrombin generation, and thrombin generation leads to platelet thrombus formation and fibrin generation.

      • Initiation: A TF/VIIa complex (known as extrinsic tenase or X-case) on cells bearing TF that have been exposed after vessel injury or captured via P-selectin activates limited amounts of factors IX and X. The resulting factor Xa then associates with factor Va to form the prothrombinase complex, which cleaves prothrombin (factor II) to generate a small amount of thrombin (factor IIa). Factor IXa moves to the surface of activated platelets in the growing platelet thrombus. Tissue factor pathway inhibitor (TFPI) regulates TF/VIIa-induced coagulation rapidly terminating the initiation phase.
      • Amplification: Thrombin produced during initiation activates factors V and VIII, which bind to platelet surfaces and support the large-scale thrombin generation occurring during the propagation phase. Platelet-bound factor XI is also activated by thrombin during amplification.
      • Propagation: Factor VIIa/IXa (known as intrinsic tenase) and prothrombinase complexes assemble on the surface of activated platelets and accelerate the generation of factor Xa and thrombin, respectively, causing a burst of thrombin production. Thrombin generation is further supported by factor XIa bound to platelet surfaces, which activates factor IX to form additional intrinsic tenase.
      • Thrombin then converts fibrinogen to fibrin monomers that precipitate and polymerise to form fibrin strands. Factor XIIIa (also activated by the action of thrombin) covalently bonds these strands to form an extensive meshwork that encases the aggregated platelet thrombus and red cells to form a stabilised fibrin clot.
      • Hemostasis is controlled by antithrombotic substances secreted by intact endothelium adjacent to damaged tissue. Thrombomodulin modulates thrombin activity by converting protein C to its activated form (aPC), which joins with protein S to inactivate factors Va and VIIIa. This prevents coagulation reactions from spreading to uninjured vessel walls. Also, circulating antithrombin inhibits thrombin and factor  Xa. Heparan sulfate is secreted by endothelial cells and accelerates antithrombin activity. These self-regulatory mechanisms limit fibrin clot formation to the zone of vessel injury.
      • The fibrinolytic system dissolves formed blood clots; inactive plasminogen is converted to plasmin by tissue plasminogen activator (tPA). Plasmin is an enzyme that degrades the fibrin mesh into soluble end products (known as fibrin degradation products including d-dimer).
      • Thrombi can form in any part of the venous circulation but usually begin in the leg(s). Isolated calf vein thrombi seldom embolize; those involving the popliteal and larger veins above it are more likely to embolize and lodge in the pulmonary artery or one of its branches, occluding blood flow to the lung and impairing gas exchange. Without treatment, the affected lung area becomes necrotic, and oxygen delivery to other vital organs may decrease, potentially resulting in fatal circulatory collapse.
  3. 3
    • Many patients never develop symptoms from an acute event.
    • Symptoms of DVT may include unilateral leg swelling, pain, tenderness, erythema, and warmth. Physical signs may include a palpable cord and a positive Homan sign.
    • Symptoms of PE may include cough, chest pain or tightness, shortness of breath, palpitations, hemoptysis, dizziness, or lightheadedness. Signs of PE include tachypnea, tachycardia, diaphoresis, cyanosis, hypotension, shock, and cardiovascular collapse.
    • The postthrombotic syndrome may produce chronic lower extremity swelling, pain, tenderness, skin discolouration, and ulceration.
About Genomic Medicine UK

Genomic Medicine UK is the home of comprehensive genomic testing in London. Our consultant medical doctors work tirelessly to provide the highest standards of medical laboratory testing for personalised medical treatments, genomic risk assessments for common diseases and genomic risk assessment for cancers at an affordable cost for everybody. We use state-of-the-art modern technologies of next-generation sequencing and DNA chip microarray to provide all of our patients and partner doctors with a reliable, evidence-based, thorough and valuable medical service.