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]
To read the thrombophilia microchapter click here.
Synonyms and keywords: Approach to thrombophilia, thrombophilia workup, thrombophilia diagnostic approach

Thrombophilia Resident Survival Guide Microchapters
Overview
Causes
Diagnosis
Treatment
Do's
Don'ts

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:

• 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, AT: Antithrombin

Suspected Thrombophilia

1) History taking: Personal history: VTE Pregnancy and postpartum stage Immobility and surgery Malignancy 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 and splanchnic vein Positive Family history for thrombotic events, especially in young (<45 years) first degree relatives History of purpura fulminans in neonates and children (suggests protein C and protein S deficiency) History of skin necrosis due to vitamin K antagonists (suggests protein C and protein S deficiency)

R/O acquired etiologies of thrombophilia, such as: Antiphospholipid syndrome Medications Hyperhomocysteinemia due to vitamin deficiency (Vitamin B9 and vitamin B12 deficiency) Vitamin K deficiency Liver disease Trauma Pregnancy and postpartum stage

Further evaluation for Antiphospholipid syndrome, in the presence 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

Investigate other common etiologies: Defect or reduction in natural anticoagulant system such as protein C and protein S (For evaluation of protein C and protein S deficiencies, see below) Factor V Leiden (For evaluation of Factor V Leiden, see below) Prothrombin gene mutation such as Prothrombin G20210A

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 less common etiologies: Antithrombin deficiency Check functional assays of heparin cofactor activity to evaluate both types of AT deficiency. Dysfibrinogenemia Elevation in some coagulation factors such as VII, VIII, IX and XI

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.
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: Consumption of protein S: Thrombosis Surgery DIC decreased protein S synthesis: Liver disease Vitamin K deficiency Warfarin therapy Infants Nephrotic syndrome Redistribution of protein S: Chronic inflmmation and acute phase proteins Pregnancy Oral contraceptives Estrogen replacement therapy 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: Liver disease DIC

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

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.
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

• 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 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.