Thrombophilia resident survival guide

Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Associate Editor(s)-in-Chief: Anahita Deylamsalehi, M.D.[2]

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 are generally depended on organ that is involved.

Causes

Known causes of thrombophilia include:

• 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
• Dysfibrinogenemia
• 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
• Pregnancy
• Antiphospholipid Syndrome
• Malignancy

Diagnosis

Shown below is an algorithm summarizing the diagnosis of thrombophilia.

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

Suspected Thrombophilia

1) History taking: Personal history of: VTE Pregnancy and postpartum stage Immobility and surgery Trauma Nephrotic syndrome Inflammatory disorders Medication history Family history 2) Physical examination 3) Laboratory investigations: CBC (important to R/O myeloproliferative disorders PT, PTT and INR

Determine the necessity for thrombophilia evaluation: Factors that favor a throughout evaluation: Recurrent or unprovoked thrombosis Young age Atypical thrombosis locations, such as cerebral vein Positive Family history for thrombotic events, specially in young (<45 years) first degree relatives History of purpura fulminans in neonates and children History of skin necrosis due to vitamin K antagonists use

R/O acquired etiologies of thrombophilia, such as: Antiphospholipid syndrome Medications Hyperhomocysteinemia due to vitamin deficiency Vitamin K deficiency Liver disease Trauma Pregnancy and postpartum stage

In the present of features such as: Venous/arterial thromboembolic diseases and adverse pregnancy outcomes such as unexplained miscarriage and/or preterm birth due to pre-eclampsia or placental insufficiency AND Elevated PTT

Further evaluation for Antiphospholipid syndrome with: Phospholipid dependent tests to detect lupus anticoagulant, such as activated partial thromboplastin time (aPTT), Kaolin clotting time (KCT), diluted russel viper venom test (dRVVT) and diluted prothrombin time Antiphospholipid antibodies with solid-phase ELISA tests to detect anticardiolipin (aCL) antibodies

Investigate other common etiologies: Defect or reduction in natural anticoagulant system such as protein C and protein S Factor V Leiden

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Treatment

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Do's

• 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'ts

• Don't run genetical or antigen detecting tests as screening for thrombophilia.
• 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.

References

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