The importance of laboratory testing to confirm hereditary thrombophilia and for prophylaxis of thrombotic episodes

Gabriela Jimborean, Paraschiva Postolache, Alpar Csipor, Edith Simona Ianoși


We present the case of a complicated pulmonary embolism in a young patient with factor V (factor V Leiden) (FVL) mutation - induced thrombophilia, aiming to emphasise the role of laboratory testing for thrombophilia in patients with deep vein thrombosis (DVT). A 22-year-old female (non-smoker, with chronic use of contraceptives) was admitted in the Pulmonary Clinic with a brutal episode of thoracic pain and fever. One month before, the patient was diagnosed with an extended femoral DVT. She was treated with anticoagulants and an arterial- venous shunt for vein patency preservation was placed. In our clinic, we found on CT scan a pulmonary infarction with pleural collection. The bacteriology of pleural fluid revealed Staphylococcus aureus. Targeted therapy was instituted (antibiotic guided by antibiogram, anticoagulants and anti-inflammatory drugs). We performed a large panel of tests to detect the etiology of thrombophilia. Factor V (FVL) mutation was found. The patient improved under treatment, and was discharged with recommendation for surgical reduction of the arterial-venous shunt, anticoagulants and contraceptives cessation. She was advised to permanently wear elastic stockings and avoid smoking and prolonged limbs immobilisation. A future pregnancy will need to be closely monitored, given the risk for pregnancy- associated thrombosis (repeated DVT, miscarriages, pre-eclampsia, foetal growth stop). Conclusion. Sudden thrombosis occurring in young patients benefit from an extended laboratory investigation for hereditary thrombophilia. In these patients, antepartum and postpartum anticoagulation therapy should be a long-term prophylaxis method against thromboembolism and pregnancy complications.

thrombophilia, pulmonary infarction, factor V Leiden, prophylaxis  


The three major causes of thrombosis, described by the german pathologist Rudolph Virchow (1821-1902), consist in Virchow’ triad: blood hypercoagulability, vas-cular endothelial injury, and stasis or turbulence of the blood flow.

Hypercoagulability (thrombophilia) may be fre-quently due to genetic or acquired factors(1-3). Among the genetic factors, there are: deficiency in anti-thrombin III, deficiency in protein C or S by gene mutations, factor V Leiden mutation(genetic mutation in F5 gene at 1691 position)(4), elevated clotting factor levels (Factors VIII, IX, XI), mutation of G20210A prothrombine gene (≥50% of hereditary thrombophilia)(5), mutation of metylen-tetra-hydro-folatreductase (MTHFR) and hyper-homo-cysteinemia. Alone or associated with the hereditary factors may act acquired factors(6-10) such as: smoking, myocardial infarction, obesity, infection, autoimmune diseases (collagen diseases and antiphospholipid syn-drome)(5,8,10), chronic use of contraceptives, malignant tumours(7), burns and polytrauma(11), pregnancy and labor, sickle-cell disease, essential thrombocytosis, poly-cytemia vera or leukaemia, abdominal or lower limb surgery.


Vascular injury can also be encountered in several conditions: long period of legs immobility (bed rest due to severe diseases or after surgery, orthopaedic diseases, fractures, stroke, devices for bones contention), inflam-mation, infection, burns, vessels trauma and implants(11,12).

Blood stasis may occur in common conditions: varicosi-ties of the veins and vein compression, venous insufficiency, long-distance travel, chronic heart failure, atrial fibrillation, mitral stenosis, cardiac tumours, obesity(12,13).

The majority of hereditary thrombophilia cases are mild and affected individuals never develop abnormal clots. Hereditary thrombophilia may be associated with acquired comorbidities (heart failure, pregnancy, leg injuries, surgery, infection, advanced age, contracep-tives, tumours or obesity) and the risk for thrombosis may consequently strongly increase. All the risk factors need to be identified and eliminated as soon as possible, and the patients benefit from anticoagulation preven-tion treatment.

The possible consequences of thrombophilia are: recurrent DVT, pregnancy complication (DVT in preg-nancy, recurrent abortions, preeclampsia, delay of intra-uterine growth, death of the foetus, premature birth)(14) and early coronary disease in patients under 50 years of age(12,13).

Factor V Leiden (FVL) represents an abnormal type of V factor which becomes resistant to the action of activated protein C - aPC (FVL cannot be easily degraded by aPC). FVL is a pro-coagulant that increases trombine blood levels. It is slowly inactivated (compared to the normal type) and it can contribute to the production of large quantities of trombine(15). FVL is the specific name of the V factor gene mutation (chromosome 1q23) which controls the synthesis(4,16). FVL is the most common genetic disor-der of the blood coagulation, accounting for about 50% from all hereditary thrombophilia cases. Its prevalence is 5-7% in the general Caucasian population(17).

The thrombosis risk in FVL is 10% for heterozygote and 40% for homozygote individuals(17). Sixty percent of pregnant women with DVT have FVL. The thrombotic risk increases with the association of other hereditary disorders or other pro-coagulants factors (from the “Virchow” triad).

Case report

pneA 22-year-old female patient (non-smoker) was admitted in the Pulmonology Clinic of Târgu-Mureș for high fever (38.5˚C), dry cough, weakness and sudden thoracic pain.

One month before, the patient had been admitted in another hospital for an extended DVT of the main left femoral vein confirmed by Doppler ultrasound. The patient started an anticoagulant treatment with low molecular weight heparin, followed by oral anticoagu-lants (acenocumarol 2 mg/day). An arterio-venous shunt was performed in the Vascular Surgery Unit to ensure vein patency and to prevent clinically significant pul-monary embolism (PE) (in the absence of the inferior vena cava filters). The patient was a non-smoker, but she chronically used oral contraceptives.

In our clinic, a thoracic CT scan showed posterior left lobe pulmonary infarction with pleural collection, thick-ening of the pleura and a small pneumothorax (Figures 1, 2 and 3). The abdominal scan sections showed splenomegaly.

The thoracentesis revealed a sero-hematic, turbid fluid. The pleural fluid was an exudate, glucose 56 mg%, rich in neutrophils and mesothelial cells, without tumoral cells. The bacteriology exam of the pleural fluid revealed an infection with Staphylococcus aureus, and thus targeted antibiotic therapy was instituted accord-ing to the antibiogram. Acid fast bacilli in the pleural fluid were smear negative (Ziehl-Neelsen stain) and no growth on Löwenstein-Jensen medium for mycobacte-rium was present after two months.

We performed a large panel of laboratory tests to confirm the suspicion of hereditary thrombophilia and to diagnose the type of genetic disorder: test of resist-ance to activated protein C (aPC), DNA analysis for fac-tor V Leiden and for prothrombin mutation, deficit of C protein or S protein or anti-thrombin III, genetic analy-sis for mutation of protein C, S. A heterozygous factor V mutation was evidenced (factor V Leiden).

Blood culture, basic haematology tests and immunologic tests for collagen diseases (antinuclear antibodies, antiphos-pholipidic and anticardiolipin antibodies, anti-beta2 glyco-protein 1, lupus inhibitor) were negative. The International Normalized Ratio at the admission in our clinic was 2.80.

The treatment was complex: antibiotics (cephalo-sporin and aminoglycosides corresponding to the germs drug sensibility), low molecular weight heparins (enoxa-parin) followed by acenocumarol (anti-vitamin K; AVK) for long term, evacuation of the pleural collection and anti-inflammatory drugs. The patient was also under a close thoracic surgery surveillance, but given the com-plete resorbtion of the fluid by conservatory approach, she didn’t need a drain insertion.

After three weeks of favourable evolution, the patient was discharged with the recommendation for surgical reduction of the arterial venous shunt, oral anticoagu-lants and cessation of contraceptives. We also recom-mended permanently elastic stockings, avoidance of smoking and of prolonged limbs immobilization.

A future pregnancy will need to be closely monitored because of the pregnancy-associated thrombosis risks (DVT of the mother, miscarriages, preeclampsia and impaired foetal growth). During pregnancy, the patient will benefit of anticoagulant heparin therapy.


The sudden onset of DVT in our young patient deter-mined us to search for an hereditary thrombophilia. Screening for specific hereditary thrombophilia is recom-mended by several literature data in a large array of clinical conditions: DVT or arterial accidents (myocardial infarction or stroke) under age of 50 and especially in small children(4,18-21), family medical history of DVT or thrombophilia, DVT in other sites than “usual inferior members” (brain, liver and lungs, spleen)(2,16,21), recurrent

thrombosis (with no apparent cause), DVT or other preg-nancy complication (recurrent abortion, preeclampsia, placental abruption, delay of intrauterine growth, death of the foetus, premature birth), heavy smokers, female with DVT and contraceptive, use of tamoxifen(21) etc.

In our case, the pulmonary embolism was considered a delayed complication of the DVT in the context of the large extension of DVT, thrombophilia and contraceptives use.

We interpreted the small pneumothorax and the pleural collection like a complication of the lung infarc-tion. The ischemic process with necrosis increases vas-cular permeability and releases vasoactive cytokines(22). The staphylococcus found in the liquid was considered a subsequent infection in the long-lasting pleural effusion associated to the lung infarction (ischemic necrosis area with low immunity).

Contraceptive drugs use was an additional risk factor for clinical thrombosis, developing in female patients carrying a genetic disorder.

Several laboratory tests are now available to diag-nose hereditary thrombophilia. In our case, the lab investigation was crucial for the diagnosis of thrombo-philia. The right etiological diagnosis permitted the accurate treatment and lifestyle recommendation for future thrombosis prevention (mostly in special condi-tion – pregnancy, surgery, and immobilization). Complicated DVT with pulmonary embolism (DVT in a “high position” – main femoral vein in our case) has to be carefully and closely watched by clinic examination and by venous Doppler ultrasound examination.

We provided a targeted medical education (for the patient and family) with practical information for thrombosis prevention. Long-term anticoagulant treatment (3-6 months) will be recommended to reduce the risk for complications and clotting events.

After the complete restoration of vein patency, the surgical reduction of the A-V shunt under antithrom-botic treatment will be needed.

The patient has to abandon for good the contraceptives use, to avoid smoking and inform other physicians (sur-geon, gynaecologist, and anaesthetist) about the presence of the FVL disorder. Elastic stockings will be used espe-cially when standing for long periods of time. She will avoid prolonged limbs immobilization, weight gain, leg trauma and “contact sports”. Regular physical exercise could prevent vein stasis. Antepartum and postpartum anticoagulation (heparin) therapy will achieve prophy-laxis against thrombosis and pregnancy complication.


Any thrombosis occurring in young patients should trigger laboratory investigations for thrombophilia. Screening for specific hereditary thrombophilia is recom-mended in some clinical conditions, especially in compli-cated, repeated DVT in young people without other evident recent risk factors, heavy smoking or using oral contraceptives. Contraceptive drugs use is a frequent risk factor for clinical thrombosis in female patients with this genetic disorder. Complicated DVT with pulmonary embo-lism has to be carefully long-term followed-up (by clinical examination and venous Doppler investigation).

Targeted medical education (for patient and family) regarding lifestyle is important to avoid additional risk factors for thrombosis. Antepartum and postpartum antico-agulation therapy has to be included for prophylaxis against thromboembolism and pregnancy complication.


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