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]

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

Diseases	Clinical manifestations						Para-clinical findings				Gold standard	Additional findings
	Symptoms			Physical examination
							Lab Findings		Imaging
	Symptoms of DVT	Symptoms of Pulmonary Embolism	Symptoms of Myocardial Infarction	Tenderness in extremities	Edema in extremities	Warmth in extremities	PT	aPTT	Doppler ultrasound	Chest CT scan
Antithrombin III deficiency	+	+	-	+	+	+	Normal	Normal Reduces the Increase in PTT after administration of heparin	Evidence of deep vein thrombosis (DVT) Should be used for diagnosis and follow up	Occlusion of brachiocephalic vein Large thrombus in superior vena cava	Decreased plasma antithrombin (AT III) activity	Nephrotic syndrome Decreased inhibition of factor II and Xa Antithrombin is a natural anticoagulant that is lost in the urine
Factor V Leiden mutation	+	+	+	+	+	+	N/A	↑	Recommended to do weekly Proximal DVT is more commonly observed as compared to distal DVT	Pulmonary embolism	N/A	Inactivates factor Va and factor VIIIa
Protein C deficiency	+	+	-	+	+	+	Normal	Normal / ↑	Hypercoagulation Recurrent venous thromboembolism	Venous thromboembolism Pulmonary embolism	Protein C functional assay ELISA assay: may produce false positive result in cross reaction with rheumatoid factor	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
Protein S deficiency	+	+	-	+	+	+	Normal	Normal / ↑	Hypercoagulation Recurrent venous thromboembolism	Pulmonary embolism Thrombosis of superior mesenteric vein	Protein S free antigen assay	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
Prothrombin gene mutation	+	+	-	+	+	+	↑	N/A	Proximal DVT is more commonly observed as compared to distal DVT	Pulmonary embolism	Detection of mutation using restriction enzyme and PCR DNA testing for prothrombin G20210A mutation	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
Disseminated intravascular coagulation (DIC)	+	+	+/-	+	+	+	↑	↑	Portal vein thrombosis is observed in patients with coexistent hepatitis B	Pulmonary embolism	N/A	Elevated fibrin degradation products (D-dimers) Decreased fibrinogen Decreased factor V and VIII Shistocytes (helmet cells) on peripheral blood smear Portal vein thrombosis
Antiphospholipid antibody syndrome	+	+	+/-	+	+	+	N/A	↑	Increased impedance of flow in uterine arteries at 12-20 weeks of gestation	Pulmonary embolism	Antiphospholipid antibody Anticardiolipin antibody Lupus anticoagulant Anti-β2GPI antibody	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

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	Example	Example	Example
Tenderness in extremities	+	+	Example	Example	Example	Example	Example
Edema in extremities	+	+	Example	Example	Example	Example	Example
Warmth in extremities	+	+	Example	Example	Example	Example	Example
PT	Normal	N/A	Ex	Example	Example	Example	Example
aPTT	Normal Reduces the Increase in PTT after administration of heparin	↑	Example	Example	Example	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	Example	Example	Example	Example	Example
Chest CT scan	Occlusion of brachiocephalic vein Large thrombus in superior vena cava	Pulmonary embolism	Example	Example	Example	Example	Example
Gold standard	Decreased plasma antithrombin (AT III) activity	N/A	Example	Example	Example	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	Example	Example	Example	Example	Example