Thrombophilia causes

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Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1] Associate Editor(s)-in-Chief: Asiri Ediriwickrema, M.D., M.H.S. [2] Jaspinder Kaur, MBBS[3]

Overview

Thrombophilia may be caused by either acquired, inherited, or, more commonly, a combination of both conditions.

Causes

• Virchow's triad: The cause of thrombosis is multifactorial which causes an imbalance in endogenous anticoagulation and hemostasis through a complex pathophysiologic mechanism. Rudolf Virchow proposed Virchow's triad in 1856 and described the three common factors which predisposes to thrombosis as follows:
  • Damage to the endothelial lining of the vessel wall: It leads to the production of pro-inflammatory and prothrombotic cytokines, an increase in available tissue factor, the proliferation of adhesion molecules, and enhanced platelet activation. Cytokines initiate inflammation-promoting interaction between leukocytes and endothelial cells. Inflammation is a normal body reaction to unwanted stimuli such as foreign pathogens or infection and endothelial damage, whether acute (e.g., catheter placement, trauma or surgery) or chronic (underlying inflammatory disorders or peripheral vascular disease).
  • Hypercoagulable state: It is due to a variety of alterations in the coagulation and hemostatic system, which can result from inflammatory factors, variations in the viscosity of blood and blood components, increased cytokines, and prothrombotic proteins in circulation, or deficiencies of natural or endogenous anticoagulant factors.
  • Arterial or venous blood stasis: This third aspect could be due to immobility, pregnancy, or impaired blood flow resulting from previous thrombosis such as residual blood clot, remodeling or fibrosis of blood vessels, or atherosclerosis. Long trips with limited mobility in cases where concurrent additional risk factors are present can be considered as a relative risk factor for thrombosis.

• Hypercoagulable states: Hypercoagulability disorders are either acquired or inherited. However, actual thrombosis occurs due to the interplay of both genetic and environmental factors and follows the multiple hit hypothesis, thereby explaining the inter-individual differences observed in patients with inherited mutations.
  • Inherited forms can be identified in up to 30% of patients with venous thromboembolism and are mainly attributable to factor V Leiden and prothrombin G2021A mutation. These two thrombophilias implicate a weak thrombotic risk. However, other inherited thrombophilias are rare such as antithrombin III, protein C and protein S deficiency (around 1% in the general population) but pose a higher risk for thrombosis. Mutations influencing coagulation factors can present in heterozygous or homozygous genotype.
  • Acquired factors are far more common and influence the coagulation cascade by multitude of factors including medications (e.g., oral contraceptives, estrogen or other hormonal replacement), recent inflammatory conditions such as pregnancy, surgery, trauma, or infection, and chronic inflammatory conditions (e.g., morbid obesity, rheumatologic disease, ulcerative colitis, heavy smoking).
  • Malignancy (occult or diagnosed) can predispose to hypercoagulability as tumor cells can express a variety of procoagulant proteins including increased expression tissue factor. Some solid tumors such as pancreatic cancer are known to significantly increase the risk of thrombosis.
  • Typically, venous thrombosis is initiated by endothelial damage, while arterial thrombosis starts with atherosclerosis, and acquired hypercoagulable states leading to both venous and arterial thrombus include acquired antiphospholipid syndrome (APS) and heparin-induced thrombocytopenia & thrombosis (HITT).

• Venous thromboembolism (VTE): Stasis behind venous valves contributes to venous thrombosis and red thrombus formation. An anatomy of the deep veins of the extremities and the pulmonary system should be considered such as the deep veins of the lower extremity include the femoral, iliac, and popliteal veins; and the upper extremity veins include the subclavian, axillary, brachial veins. Other thrombosis sites include superior vena cava thrombosis, jugular vein thrombosis, cerebral venous sinus thrombosis, cavernous sinus thrombosis, and retinal vein occlusion. Thrombosis of superficial veins is possible with provoking factors such as intravenous catheterization or localized cellulitis; however, the treatment of superficial vein thrombosis does not typically require any anticoagulation.

• Arterial thrombosis:
  • Arterial thrombosis results from atherosclerotic plaque rupture around which a platelet-rich white thrombus forms. Arterial thrombosis and microthrombi formation typically initiates by the accumulation of lipid plaques in the arterial wall provoking chronic inflammatory cells and platelet activation.
  • Atherosclerosis: The initial lipid plaques evolve into fibrous plaques. Fibrous plaques could rupture, and the erosion of the surfaces of these plaques could lead to the release of additional pro-coagulating factors. This process is called atherosclerosis which further allows the activation of platelets, causing adhesion and aggregation, and the clot formation predisposing to the ischemic heart disease and myocardial infarction.
  • In the heart, microthrombi can develop as a result of blood stasis in the ventricles or atria due to underlying valvular heart disease, cardiomyopathies, or arrhythmias such as atrial fibrillation predisposing to ischemic emboli and CVA. Hence, an increased incidence of obesity, hypertension, diabetes, and hypercholesterolemia all can contribute to the risk of an arterial thrombosis. Other risk factors include underlying connective tissue or rheumatologic conditions such as SLE, vasculitis; HITT, antiphospholipid syndrome, myeloproliferative disorders, and PNH.
  • Thereby, it can present as an acute stroke, myocardial infarction, or acute on the chronic peripheral arterial disease. Other less common sites can include renal arteries, mesenteric arteries, and retinal arteries.
  • Antiplatelet agents: Platelets play a significant role in the development of arterial thrombosis compared to venous thrombosis; and hence, explains why antiplatelet agents form a cornerstone of the prevention and treatment of arterial thrombosis.

Table 1: System wise causative factors of thrombophilia

Systemic organ	Medical conditions
Cardiovascular	Cerebral vein thrombosis, Acute myocardial infarction, Deep vein thrombophlebitis, Portal vein thrombosis, Pelvic thrombophlebitis
Drugs Adverse Effects	Asparaginase, bevacizumab, combined oral contraceptive pill, certolizumab pegol, Ccproterone, diethylstilboestrol,drospirenone, eltrombopag, erythropoietin, ethinylestradiol, fosfestrol, granulocyte-macrophage colony stimulating factor, heparin, hormone replacement therapy, lenalidomide, peginesatide, polyestradiol, raloxifene, strontium ranelate, tamoxifen, tobacco smoking, tranexamic acid,vorinostat
Endocrine	Hyperosmolar non-ketotic diabetic coma
Gastroenterologic	Acute pancreatitis, Portal hypertension
Genetic	Congenital Dysfibrinogenemia, Factor II mutation, Hereditary thrombophlebitis, Antithrombin III deficiency, Factor V Leiden mutation, Protein C deficiency, Protein S deficiency, Klippel-Trenaunay syndrome, Klinefelter syndrome, Sickle cell disease, Carbohydrate-deficient glycoprotein syndrome type 1b, Factor XII deficiency, Haemoglobin SC disease, Hyperprothrombinemia 20210G-A, Plasminogen deficiency, Activated protein C resistance, CD59 antigen deficiency, Cystathionine beta-synthase deficiency
Hematologic	Polycythemia vera, Essential thrombocythemia, Myeloproliferative disease, Hyperviscosity syndrome, Paroxysmal Nocturnal Hemoglobinuria, Thrombocytosis, Raised homocysteine levels
Iatrogenic	Surgical complication
Infectious Disease	Intraperitoneal abscess, Acute peritonitis, Visceral abscess, Diverticulitis, Intravenous catheter infection
Musculoskeletal / Ortho	Orthopedic surgeries, Abdominal surgery
Nutritional / Metabolic	Cystathionuria, Homocystinuria, Methyltetrahydrofolate reductase deficiency, Metabolic Syndrome, Insulin resistance, Folic acid deficiency, Obesity
Obstetric/Gynecologic	Pregnancy, Puerperium period, Ovarian hyperstimulation syndrome
Oncologic	Malignancy, Peritoneal metastasis, Adenocarcinoma of cecum, Adenocarcinoma of colon, Occult malignancy, Leukemia, Pancreatic cancer, Glucagonoma
Renal / Electrolyte	Chronic renal failure, Paroxysmal Nocturnal Hemoglobinuria, Nephrotic syndrome
Rheum / Immune / Allergy	Antiphospholipid Syndrome, Circulating anticoagulant, Heparin induced thrombocytopenia, Inflammatory bowel disease, Crohn's disease, Behcet disease, Hughes-Stovin syndrome, Polyarteritis Nodosa, SLE
Trauma	Trauma, Abdominal trauma
Miscellaneous	Paraneoplastic syndrome, Hypereosinophilic syndrome, Immobility