Thrombophilia resident survival guide
Editor-In-Chief: C. Michael Gibson, M.S., M.D. ; Associate Editor(s)-in-Chief: Anahita Deylamsalehi, M.D.
To read the thrombophilia microchapter click here.
Synonyms and Keywords: Approach to thrombophilia, thrombophilia workup, thrombophilia diagnostic approach
|Thrombophilia Resident Survival Guide Microchapters|
Thrombophilia is defined as a predilection for clot formation (thrombosis). It could be inherited/genetical or acquired, nevertheless most of the time thrombophilia is due to an interplay between both inherited and acquired factors. Protein C deficiency is the most common cause of inherited thrombophilia. This clot formation tendency can lead to venous or arterial thrombus formation and subsequent conditions such as pulmonary embolism, deep venous thrombosis, pregnancy loss, severe pre-eclampsia, myocardial infarction and stroke. Most of patients with thrombophilia may remain asymptomatic until another thrombophilic condition has been added and patients with more than one inherited/genetical defects carry higher chance of thrombus formation. Symptoms, if present, are generally depended on organ that is involved. There are numerous causes related to thrombophilia, such as protein C deficiency, prothrombin gene mutation, Factor V Leiden, protein S deficiency and antiphospholipid syndrome. Nevertheless it is recommended to first rule out acquired causes and look for necessity of further laboratory evaluations. In other words not every patient presented with thrombosis requires thrombophilia diagnostic evaluation. Acute thromboembolism management with anticoagulation therapy should be considered for at least 3-6 months, although they are specific cases which need indefinite anticoagulation therapy.
- Protein C deficiency (most common cause of inherited hypercoagulable state)
- Prothrombin gene mutation such as prothrombin G20210A, which is the second most common cause of inherited hypercoagulable state
- Factor V Leiden
- Protein S deficiency
- Antithrombin deficiency or antithrombin reduction due to liver disease and/or severe malnutrition
- Medications such as combined oral contraceptives, bevacizumab, lenalidomide, asparaginase, erythropoietin, raloxifene, tamoxifen, tranexamic acid, heparin, ethinylestradiol and hormone replacement therapy
- Elevation in some coagulation factors such as VII, VIII, IX and XI
- Hyperhomocysteinemia and Methylenetetrahydrofolate mutation
- Plasminogen deficiency
- Elevated Lipoprotein(a)
- Klinefelter syndrome
- Polycythemia vera
- Myeloproliferative neoplasm
- Paroxysmal nocturnal hemoglobinuria
- Sickle cell disease
- Chronic renal insufficiency
- Systemic lupus erythematosus
- Antiphospholipid syndrome
Abbreviations: CBC: complete blood count; VTE: Venous thromboembolism; R/O: Rule out; PT: Prothrombin time; PTT: Partial thromboplastin time; INR: international normalized ratio; ELISA: Enzyme-linked immunosorbent assay, AT: Antithrombin
1) History taking:
Determine the necessity for thrombophilia evaluation:
Factors that favor a throughout evaluation:
Investigate other common etiologies:
Prolongation of at least one Phospholipid dependent test
Does addition of a healthy plasma correct the prolonged phospholipid dependent test?
No LA is present.Investigate possible factor deficiency
Yes, LA is present
Suspicious of protein S deficiency
Free protein S assay
Normal: No further testing
Check protein S activity
Abnormal protein S activity
R/O acquired causes, such as:
Suspicious of protein C deficiency
Functional assay of protein C
Abbreviations: APCR: Activated Protein C resistance; FVL: Factor V Leiden; DNA: Deoxyribonucleic acid
Suspicious of Factor V Leiden
Check APCR with second generation (V-deficient) test
Normal: No further testing
Shown below is an algorithm summarizing the treatment of thrombophilia.
Abbreviation: VTE: Venous thromboembolism; AT: Antithrombin; UFH: Unfractionated heparin; LMWH: Low molecular weight heparin; INR: International normalized ratio;
|UFH or LMWH
||Resistant to heparin therapy?|
Does the patient require large doses of heparin to reach the ideal INR?
|Start Warfarin or other vitamin K antagonists||Yes. Check for possible AT deficiency.|
|Confirmed AT deficiency? |
Recurrent or severe thrombosis despite sufficient anticoagulation therapy?
|Yes. Administer AT concentrate|
Conditions that require indefinite anticoagulation therapy:
❑ History of two or more thrombosis
❑ History of one life threatening thrombosis, such as near fatal Pulmonary embolism, thrombosis of cerebral, mesentric or portal veins
❑ History of one thrombus formation due to genetical defects, antithrombin deficiency or antiphospholipid antibody syndrome
❑ Thrombus formation in unusual sites, such as cerebral and mesentric veins
- Do thrombophilia plasma tests at least 6 months after the acute thrombotic episode due to effect of acute thromboembolic event on these tests. Moreover, since oral anticoagulants given after acute thrombotic episode affect the results of testing for protein C, protein S, antithrombin deficiency and activated protein C resistance (APC resistance), it is recommended to do laboratory tests at least 2 weeks after oral anticoagulants discontinuation.
- Run factor VIII test at least 6 weeks postpartum if factor VIII elevation is suspected in a pregnant patient with thrombophilia.
- Consider anticoagulant prophylaxis with subcutaneous heparin or low molecular weight heparin for pregnant women with previous history of thrombosis, positive familial history for thrombosis and confirmed antithrombin deficiency.
- Consider anticoagulant prophylaxis with low molecular weight heparin for patients with inherited thrombophilia who are candidate for surgery. 
- Test first degree relatives of a patient with confirmed genetical etiology of thrombophilia.
- Don't run genetical or antigen detecting tests as screening for thrombophilia.
- Don't run thrombophilia related tests for a patient with one venous thromboembolism due to a known temporary risk factor.
- Don't prescribe anticoagulant prophylaxis for asymptomatic patients who have risk factors for thrombophilia. Except for Factor V Leiden which is recommended to receive prophylaxis when exposed to hemostatic stressors such as surgery, prolonged immobilization and pregnancy even in the absence of any clinical manifestations.
- Khan S, Dickerman JD (2006). "Hereditary thrombophilia". Thromb J. 4: 15. doi:10.1186/1477-9560-4-15. PMC 1592479. PMID 16968541.
- Femi-Akinlosotu OM, Shokunbi MT (2020). "Changes in Neuronal Density of the Sensorimotor Cortex and Neurodevelopmental Behaviour in Neonatal Mice with Kaolin-Induced Hydrocephalus". Pediatr Neurosurg: 1–10. doi:10.1159/000510603. PMID 33108787 Check
- Rey E, Kahn SR, David M, Shrier I (2003). "Thrombophilic disorders and fetal loss: a meta-analysis". Lancet. 361 (9361): 901–8. doi:10.1016/S0140-6736(03)12771-7. PMID 12648968.
- Wun T, Brunson A (2016). "Sickle cell disease: an inherited thrombophilia". Hematology Am Soc Hematol Educ Program. 2016 (1): 640–647. doi:10.1182/asheducation-2016.1.640. PMC 6142455. PMID 27913540.
- Parker C, Omine M, Richards S, Nishimura J, Bessler M, Ware R; et al. (2005). "Diagnosis and management of paroxysmal nocturnal hemoglobinuria". Blood. 106 (12): 3699–709. doi:10.1182/blood-2005-04-1717. PMC 1895106. PMID 16051736.
- McMahon C, Abu-Elmagd K, Bontempo FA, Kant JA, Swerdlow SH (2007). "JAK2 V617F mutation in patients with catastrophic intra-abdominal thromboses". Am J Clin Pathol. 127 (5): 736–43. doi:10.1309/JA1WD8JNVLGYNQYE. PMID 17439832.
- Marlar RA, Gausman JN (2011). "Protein S abnormalities: a diagnostic nightmare". Am J Hematol. 86 (5): 418–21. doi:10.1002/ajh.21992. PMID 21523802.
- Lybeck A, Friberg H, Nielsen N, Rundgren M, Ullén S, Zetterberg H; et al. (2020). "Postanoxic electrographic status epilepticus and serum biomarkers of brain injury". Resuscitation. doi:10.1016/j.resuscitation.2020.10.027. PMID 33127439 Check
- Ballard RB, Marques MB, Education Committee of the Academy of Clinical Laboratory Physicians and Scientists (2012). "Pathology consultation on the laboratory evaluation of thrombophilia: when, how, and why". Am J Clin Pathol. 137 (4): 553–60. doi:10.1309/AJCP5SQT3ZKYQFBM. PMID 22431530.
- Cattaneo M, Chantarangkul V, Taioli E, Santos JH, Tagliabue L (1999). "The G20210A mutation of the prothrombin gene in patients with previous first episodes of deep-vein thrombosis: prevalence and association with factor V G1691A, methylenetetrahydrofolate reductase C677T and plasma prothrombin levels". Thromb Res. 93 (1): 1–8. doi:10.1016/s0049-3848(98)00136-4. PMID 10065893.
- Baglin T, Gray E, Greaves M, Hunt BJ, Keeling D, Machin S; et al. (2010). "Clinical guidelines for testing for heritable thrombophilia". Br J Haematol. 149 (2): 209–20. doi:10.1111/j.1365-2141.2009.08022.x. PMID 20128794.
- Haemostasis and Thrombosis Task Force, British Committee for Standards in Haematology (2001). "Investigation and management of heritable thrombophilia". Br J Haematol. 114 (3): 512–28. doi:10.1046/j.1365-2141.2001.02981.x. PMID 11552975.
- Pruthi RK (2017). "Optimal utilization of thrombophilia testing". Int J Lab Hematol. 39 Suppl 1: 104–110. doi:10.1111/ijlh.12672. PMID 28447412.
- Schmoldt A, Benthe HF, Haberland G (1975). "Digitoxin metabolism by rat liver microsomes". Biochem Pharmacol. 24 (17): 1639–41. PMID doi.org/10.1111/jth.13284 Check
- Khamashta MA, Cuadrado MJ, Mujic F, Taub NA, Hunt BJ, Hughes GR (1995). "The management of thrombosis in the antiphospholipid-antibody syndrome". N Engl J Med. 332 (15): 993–7. doi:10.1056/NEJM199504133321504. PMID 7885428.
- Bauer KA (2003). "Management of thrombophilia". J Thromb Haemost. 1 (7): 1429–34. doi:10.1046/j.1538-7836.2003.00274.x. PMID 12871277.
- Cumming AM, Shiach CR (1999). "The investigation and management of inherited thrombophilia". Clin Lab Haematol. 21 (2): 77–92. doi:10.1046/j.1365-2257.1999.00210.x. PMID 10342066.
- Ginsberg JS, Hirsh J (1989). "Anticoagulants during pregnancy". Annu Rev Med. 40: 79–86. doi:10.1146/annurev.me.40.020189.000455. PMID 2658763.