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

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.


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


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:


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?

No LA is present.

Investigate possible factor deficiency
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
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
Run DNA analysis for FVL genotyping to confirm the diagnosis


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
  • 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




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