Pulmonary embolism is defined as an obstruction of the pulmonary artery by an embolus, i.e. blood clot, that originates in deep veins of the lower limbs or pelvis, and then a part of it is detached and lodged in one of the pulmonary arteries. When it is big enough, it may obstruct the main pulmonary artery, causing a critical condition known as massive pulmonary embolism that leads to hemodynamic compromise. Clearly, the condition always starts with deep vein thrombosis (DVT), and then complicates with pulmonary embolization.
In susceptible persons with several risk factors, platelet adhesion and aggregation take place forming a platelet nidus in the veins of the lower limbs or pelvis. This may also happen to a lesser extent in the upper limb. This event precedes thrombosis, increasing platelet aggregation and recruiting a fibrin network that filters more platelets from the blood, leading to a progressive stagnation and more thrombosis. Ultimately, a whole thrombus is formed. Blood fibrinolytic substances interacts with the thrombus, and then leads to partial dissolution. Detached particles of this thrombus will form the embolizing pulmonary thrombi that obstruct the pulmonary vessels.
So, why does venous thromboembolism take place?
The most important pathogenesis mechanism, which has been well-established by evidence-based medicine, is the so called “Virchow triad”, which consists of:
- Endothelial wall injury
- Stasis i.e. prolonged recumbency
- Blood hypercoagulability
Many acquired and congenitally inherited risk factors influence blood coagulability. For instance, thrombophilia is defined as hypercoagulable conditions that predispose people to an increased risk of venous thrombosis. These conditions are classified into acquired and inherited.
The most common inherited risk factors that are incorporated in venous thromboembolism are as follows:
- Factor V Leiden
- Prothrombin gene mutation G20210A
- Protein C and S, i.e. natural anticoagulants, deficiency
- Increased blood homocysteine
- Elevated factor VIII levels
On the other hand, the most common acquired risk factors are:
- Prolonged immobilization, long travel trips more than 3 hours in susceptible individuals
- Oral contraceptive pills
- Hormonal replacement therapy
- Antiphospholipid syndrome (Lupus anticoagulant/ anticardiolipin)
- Heparin induced thrombocytopenia
- Inflammatory bowel disorders
- Central venous catheters
- Nephrotic syndrome
- Dehydration and increased blood viscosity
- Disseminated intravascular thrombosis
Hypercoagulability screening should be considered in patients with:
- Idiopathic Venous thromboembolism,
- Positive family history of venous thromboembolism,
- Early adulthood venous thromboembolism, i.e. first thrombotic event before the age of 50 years,
- thrombosis at unusual locations,
- Resistance to anticoagulation i.e. patients who experience thrombotic attacks while being properly anticoagulated medically,
- Recurrent thrombotic attacks.
Factor V Leiden
Activated C Protein inactivates factors Va and VIIIa through this and other mechanisms to keep the blood in balance between clotting and bleeding. The autosomal dominant acquisition of a single-point mutation (FVL) in the factor V gene makes factor V resistant to inactivation by the activated C Protein. Both homozygous and heterozygous forms are present, and both result in an increased risk of venous thrombosis. The homozygous form is at much more risk, with a 50-fold to 100-fold increase versus a 3-fold to 7-fold increase in the heterozygous form.
Prothrombin gene mutation
Another autosomal dominant mutation is the prothrombin gene mutation G20210A (PT G20210A) which may lead to a higher plasma level of prothrombin.
Factor V Leiden mutation can be identified by testing for activated C Protein resistance in plasma or by gene analysis using polymerase chain reaction (PCR). The prothrombin gene mutation can also be identified by genetic screening. There are no clear evidence-based criteria for treating patients with thrombosis in the setting of factor V Leiden and prothrombin mutation. In general, acute thrombosis should always be treated by standard procedures, but with more aggressive strategy, and the long-term anticoagulation issue must be considered for secondary prophylaxis specially in the homozygous pattern.
Defects in the natural anticoagulants
Protein C, Protein S and Antithrombin are also known as natural anticoagulants. Deficiency of any of the three of them will be associated with an increased risk of venous thrombosis. All of the three forms are inherited as autosomal dominant defects. Based on their level of reduction, they are then subclassified to many degrees of malfunctioning. Levels of Protein S and Protein C are always expected to be lower in conditions such as disseminated intravascular coagulation (DIC), inflammatory disorders, nephrotic syndrome, acute thrombosis, and liver failure due to hypo-synthesis. Pregnancy and Oral Contraceptive Pills usage decrease the levels of Protein S in blood. Both Protein C and S levels are lowered by warfarin medication, and, therefore, testing their levels should not be assayed in patients who are receiving this medication. Similarly, initiation of warfarin therapy in long term anticoagulation plan without concomitant parenteral anticoagulation bridging in the setting of acute venous thromboembolism may lead to micro-thrombi deposited in small vessels of skin known as warfarin-induced skin necrosis (i.e. painful necrosis in skin with discoloration).
Antithrombin is a protein synthesized by the liver, and its function is to inactivate thrombin and factors Xa, IXa, XIa, and XIIa. The Homozygous forms of its deficiency are incompatible with life. Levels are also low in the following: patients with disseminated intravascular coagulation (DIC), severe sepsis, liver failure, nephrotic syndrome; patients using oral contraceptives, and during pregnancy. As with proteins C and S deficiency, patients with Antithrombin deficiency may show resistance to heparin because it exerts its anticoagulant effect through Antithrombin. Antithrombin concentrates are available and can be used temporarily to correct this deficiency.
Increased homocysteine is a risk factor for intravascular thrombosis. It may be inherited in many genetic defect forms. For example, a deficiency of cystathionine β-synthase or a mutation in methylenetetrahydrofolate reductase. Acquired causes include prolonged deficiencies in vitamin B12, B6, or folate, smoking; and liver or renal failure. Treatment with folate supplementations in doses between 0.5 and 5 mg daily will effectively reduce the levels of homocysteine. However, this is not enough for susceptible patients to reduce their risk of major cardiovascular events when they are still prone for venous thromboembolism.
Heparin-induced thrombocytopenia is a condition in which the body become antigenic for heparin and starts to produce antibodies against this drug. Heparin-induced thrombocytopenia should be suspected in patients who develop thrombocytopenia (typically < 50% decline in platelet count) while receiving heparin or LMWH; or patients who develop new thrombosis or unexpected worsening of an existing thrombosis while receiving either of these agents. It is a common but unfortunately underrecognized, sometimes potentially life-threatening condition in patients who receive heparin or LMWH. The pathogenesis of Heparin-induced thrombocytopenia involves the formation of antibodies (usually immunoglobulin G [IgG]) against the heparin–platelet factor 4 (PF4) complex. These antibodies then trigger procoagulant effects through platelet and endothelial cell activation, as well as increasing thrombin leading to both microvascular and macrovascular thrombosis.
The clinical spectrum of Heparin-induced thrombocytopenia ranges from isolated thrombocytopenia i.e. without associated thrombosis to Thrombotic Heparin-induced thrombocytopenia, which is associated to both arterial and venous thromboses. Other manifestations may include hypotension from adrenal hemorrhage secondary to adrenal vein thrombosis, skin necrosis, or wet gangrene (i.e. venous limb gangrene).
Heparin-induced thrombocytopenia after de novo exposure to heparin (i.e. first exposure to heparin) thrombocytopenia usually occurs between the 5th to 14th day (day of heparin exposure is considered day 0). In patients with a history of previous recent exposure heparin or LMWH (within the last 100 days), Heparin-induced thrombocytopenia may develop earlier and is referred to as rapid onset Heparin-induced thrombocytopenia or develop from 9 to 40 days after heparin or LMWH discontinuation, and is referred to as delayed-onset Heparin-induced thrombocytopenia. The diagnosis of Heparin-induced thrombocytopenia is confirmed by laboratory tests which include detect IgG, IgM, or IgA antibodies that bind UFH to PF4.
The first step in the treatment of Heparin-induced thrombocytopenia is a rapid discontinuation of heparin or LMWH, including heparin flushes, heparin-coated catheters, and intermittent use of heparin during dialysis. However, approximately 20% to 53% of patients with Heparin-induced thrombocytopenia are at a high risk of developing thrombosis after discontinuation of heparin or LWMH alone. Therefore, the addition of an alternative anticoagulant to the treatment plan is recommended. These anticoagulants include Lepirudin and Argatroban (both approved by the FDA), which may be used initially. Then, after platelet counts increase more than 100,000 mm3, warfarin may be started at a low dose 2 to 5 mg, followed by an gradual increase to reach an INR >2 and <3. This range is sufficient in most of cases to avoid thrombosis without inducing hemorrhagic events.
They are a group of autoantibodies that are developed by the body immunity against healthy tissues. They induce thrombosis in a condition that is referred to as “Antiphospholipid syndrome”.
Antiphospholipid antibodies are divided into three groups:
- Anticardiolipin antibodies
- Lupus anticoagulants
- β2 glycoproteins.
They are often associated with recurrent abortions, usually secondary to placental, and arterial or venous thrombosis. Anticardiolipin antibodies are detected and quantified using an enzyme-linked immunosorbent assay, and may be IgG, IgM, or IgA. IgG titers have been correlated more often with thrombosis.
Lupus anticoagulants are accused that they can prolong phospholipid-dependent blood clotting times, and about fivefold increased risk of thrombosis in patients with this finding. Long-term therapy with warfarin must be considered in these cases.
Female patients with recurrent miscarriages and abortions should receive Aspirin and LMWH when planning for pregnancy and during pregnancy.
Malignancy by itself is known to be a hypercoagulable condition, and patients with malignancies are always prone to deep vein thrombosis and pulmonary embolism. Thus, in patients with idiopathic or recurrent Venous thromboembolic events or in unusual sites, a full workup for age and gender-specific malignancies should be done. LMWH as monotherapy for the first 3 months before bridging to warfarin has been shown to decrease the risk of venous thrombosis recurrence or anticoagulation failure.
- Elevated factor VIII levels and the dysfibrinogenemia.
- Plasminogen abnormalities.
- Tissue plasminogen activator abnormalities
- factor XIII polymorphisms
All of the above are considered as emerging risk factors for hypercoagulability.