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

Table 1: 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	-	+	-	-	-	+/-	+/-
Tenderness in extremities	+	+	+	+	+	+	+
Edema in extremities	+	+	+	+	+	+	+
Warmth in extremities	+	+	+	+	+	+	+
PT	Normal	N/A	Normal	Normal	↑	↑	N/A
aPTT	Normal Reduces the Increase in PTT after administration of heparin	↑	Normal / ↑	Normal / ↑	N/A	↑	↑
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	Portal vein thrombosis is observed in patients with coexistent hepatitis B	Increased impedance of flow in uterine arteries at 12-20 weeks of gestation
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	Pulmonary embolism	Pulmonary embolism
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	N/A	Antiphospholipid antibody Anticardiolipin antibody Lupus anticoagulant Anti-β2GPI antibody
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	Elevated fibrin degradation products (D-dimers) Decreased fibrinogen Decreased factor V and VIII Shistocytes (helmet cells) on peripheral blood smear Portal vein thrombosis	Both, arterial and venous thrombosis can occur History of spontaneous abortions False positive VDRL Stroke and transient ischemic attack (TIA) are most common forms of presentation of arterial thrombosis