Thrombophilia differential diagnosis

Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Associate Editor(s)-in-Chief: M. Khurram Afzal, MD [2], Sogand Goudarzi, MD [3], Asiri Ediriwickrema, M.D., M.H.S. [4], Jaspinder Kaur, MBBS[5]

Overview

Thrombophilias must be differentiated from other diseases that cause the following clinical presentations: family history of thrombosis, especially at an early age (< 45 years), unprovoked thrombosis at an early age (<40-55 for venous thrombosis and <50-55 for arterial thrombosis), recurrent thrombosis including deep venous thrombosis, pulmonary embolism, or superficial venous thrombosis.

Differential Diagnosis

Thrombophilias must be differentiated from other diseases that cause the following clinical presentations:

• Family history of thrombosis, especially at an early age (< 45 years)
• Unprovoked thrombosis at an early age (<40-55 for venous thrombosis and <50-55 for arterial thrombosis)
• Recurrent thrombosis including deep venous thrombosis, pulmonary embolism, or superficial venous thrombosis
• Thrombosis at multiple sites, or unusual locations including in cerebral, hepatic, portal, mesenteric, and renal veins
• Thrombosis in arteries with the abscence of arterial disease
• History of fetal loss
• History of warfarin skin necrosis

Differentiating different thrombophilias on the basis of symptoms, physical examination, and laboratory findings

Characteristics	Antithrombin III deficiency	Factor V Leiden mutation	Protein C deficiency	Protein S deficiency	Prothrombin gene mutation	Disseminated intravascular coagulation (DIC)	Antiphospholipid antibody syndrome
Symptoms of DVT	+	+	+	+	+	+	+
Symptoms of Pulmonary Embolism	+	+	+	+	+	+	+
Symptoms of Myocardial Infarction	-	+	-	-	-	Example	Example
Tenderness in extremities	+	+	+	+	+	Example	Example
Edema in extremities	+	+	+	+	+	Example	Example
Warmth in extremities	+	+	+	+	+	Example	Example
PT	Normal	N/A	Normal	Normal	↑	Example	Example
aPTT	Normal Reduces the Increase in PTT after administration of heparin	↑	Normal / ↑	Normal / ↑	N/A	Example	Example
Doppler ultrasound	Evidence of deep vein thrombosis (DVT) Should be used for diagnosis and follow up	Recommended to do weekly Proximal DVT is more commonly observed as compared to distal DVT	Hypercoagulation Recurrent venous thromboembolism	Hypercoagulation Recurrent venous thromboembolism	Proximal DVT is more commonly observed as compared to distal DVT	Example	Example
Chest CT scan	Occlusion of brachiocephalic vein Large thrombus in superior vena cava	Pulmonary embolism	Venous thromboembolism Pulmonary embolism	Pulmonary embolism Thrombosis of superior mesenteric vein	Pulmonary embolism	Example	Example
Gold standard	Decreased plasma antithrombin (AT III) activity	N/A	Protein C functional assay ELISA assay: may produce false positive result in cross reaction with rheumatoid factor	Protein S free antigen assay	Detection of mutation using restriction enzyme and PCR DNA testing for prothrombin G20210A mutation	Example	Example
Additional findings	Nephrotic syndrome Decreased inhibition of factor II and Xa Antithrombin is a natural anticoagulant that is lost in the urine	Inactivates factor Va and factor VIIIa	Factor VIII elevation in acute phase Functional assay should not be performed if patient is on warfarin Purpura fulminans (skin necrosis) could be a form of presentation Risk of thrombotic skin necrosis following warfarin administration	When performing the gold standard test, beware of interference from samples positive for Factor V mutation, protein C deficiency and oral anticoagulants (rivaroxaban) Risk of thrombotic skin necrosis following warfarin administration Suspected in patients with a strong family history of VTE Post phlebitic syndrome Fetal loss	Mutation causes increased production of prothrombin Increased blood levels of prothrombin lead to venous clots in the circulatory system Hormonal oral contraceptive pills can increase the risk of VTE	Example	Example