Thrombophilia resident survival guide

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Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Associate Editor(s)-in-Chief: Anahita Deylamsalehi, M.D.[2]"
To read the thrombophilia microchapter click here.
Synonyms and Keywords: Approach to thrombophilia, thrombophilia workup, thrombophilia diagnostic approach

Overview

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.

Causes

Known causes of thrombophilia include:[1][2][3][4][5][6]

Diagnosis

Shown below is an algorithm summarizing the diagnosis of thrombophilia.[7][8][9][10][11][12][13][14]

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

 
 
 
Suspected Thrombophilia
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Determine the necessity for thrombophilia evaluation:

Factors that favor a throughout evaluation:

 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Further evaluation for Antiphospholipid syndrome, in the presence of features such as:

AND

 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Investigate other common etiologies:
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Investigate less common etiologies:
 
 
 
Prolongation of at least one Phospholipid dependent test
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Does addition of a healthy plasma correct the prolonged phospholipid dependent test?
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Yes.

No LA is present.

Investigate possible factor deficiency
 
 
 
 
 
 
No.
Does escalation of phospholipid concentration correct the prolonged phospholipid dependent test?
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Yes, LA is present
  • Confirm positive results to R/O transient conditions.
 


The following is two algorithms summarizing the diagnosis of protein C and protein S deficiency.[7][12]
Abbreviations: R/O: rule out; DIC: Disseminated intravascular coagulation;


 
 
 
Suspicious of protein S deficiency
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Free protein S assay
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Normal: No further testing
 
 
 
Abnormal
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Check protein S activity
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Abnormal protein S activity

R/O acquired causes, such as:

Repeat free protein S and protein S activity after 4-6 weeks.
 
 



 
 
 
Suspicious of protein C deficiency
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Functional assay of protein C
 
 
 
Protein C antigen assay
  • Not able to distinguish two types of AT deficiency.
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
R/O acquired causes of low protein C activity, such as:
 
 
 


Shown below is an algorithm summarizing the diagnosis of Factor V Leiden.[13]


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
 
 
 
Abnormal
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Run DNA analysis for FVL genotyping to confirm the diagnosis

Treatment

Shown below is an algorithm summarizing the treatment of thrombophilia.[15][16][17]
Abbreviation: VTE: Venous thromboembolism; AT: Antithrombin; UFH: Unfractionated heparin; LMWH: Low molecular weight heparin; INR: International normalized ratio;

 
 
 
 
 
 
 
 
Acute VTE
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
UFH or LMWH
  • At least for 5 days or until 2<INR<3
 
 
 
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's

Don'ts

References

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  6. 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.
  7. 7.0 7.1 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.
  8. 8.0 8.1 8.2 8.3 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 |pmid= value (help).
  9. 9.0 9.1 9.2 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.
  10. 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.
  11. 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.
  12. 12.0 12.1 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.
  13. 13.0 13.1 13.2 Pruthi RK (2017). "Optimal utilization of thrombophilia testing". Int J Lab Hematol. 39 Suppl 1: 104–110. doi:10.1111/ijlh.12672. PMID 28447412.
  14. 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 |pmid= value (help).
  15. 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.
  16. 16.0 16.1 16.2 Bauer KA (2003). "Management of thrombophilia". J Thromb Haemost. 1 (7): 1429–34. doi:10.1046/j.1538-7836.2003.00274.x. PMID 12871277.
  17. 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.
  18. Ginsberg JS, Hirsh J (1989). "Anticoagulants during pregnancy". Annu Rev Med. 40: 79–86. doi:10.1146/annurev.me.40.020189.000455. PMID 2658763.


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