Similar conditions involving minor trauma or spontaneous bleeds may present as differential diagnoses to hemophilia. It is important to exclude them before confirming a diagnosis of hemophilia. Some of these conditions include platelet dysfunction, Fabry disease, disseminated intravascular coagulation (DIC), Ehlers-Danlos syndrome, and deficiencies of fibrinogen or factors V, VII, or X. Patients with von Willebrand disease (vWD) have bleeding similar to mild hemophilia, however, they have more mucosal bleeding than musculoskeletal bleeding. Patients with hemophilia have musculoskeletal bleeding unlike Ehlers-Danlos syndrome, scurvy, or Fabry disease, where the bleeding is usually mucosal. Unlike patients with factor deficiency in hemophilia, patients with Ehlers-Danlos syndrome have hyperextensible skin and hypermobile joints. Patients with scurvy suffer from vitamin C deficiency. The diagnosis of patients with Fabry disease involves tissue biopsy, genetic testing, and clinical features. Patients experiencing other ailments involving platelet dysfunction disorders may show similarities in terms of mucocutaneous bleeding.¹

Disseminated Intravascular Coagulation

DIC has symptoms similar to hemophilia that involve easy bruising over various areas in small dots or larger patches. It involves bleeding at injection sites or surgical sites. Patients with DIC suffer from widespread bleeding. This can occur in the nose, gums, or mouth, and patients with DIC may witness bleeding after brushing their teeth. Stools may have a tar-like appearance or a dark red color due to bleeding in the intestines or stomach. Blood in the urine is also a common phenomenon. Patients may experience difficulty breathing, chest pain, and shortness of breath. Other symptoms include seizures, dizziness, swelling in the lower leg, and unusually heavy periods. DIC is a rare condition with abnormal blood clotting throughout the body’s blood vessels. It can make the body’s normal clotting process overactive, and it can be caused by injury or infection. It can develop quickly over hours or days or it can develop slowly, and it usually requires emergency treatment in the hospital. DIC can be treated using blood products that can stop bleeding and prevent blood clots. The differentiation of DIC from hemophilia is based on medical history, examination, and various laboratory tests.²

Hemophilia A Differential Diagnosis

Factor assays can help clinicians to differentiate between hemophilia A and B, as clinical differentiation is quite difficult. The diagnosis of hemophilia A can get obscured by certain factors that influence factor VIII levels such as stress, exercise, age, and ABO blood type. Differential diagnosis should involve the consideration of certain factor deficiencies and vitamin K deficiency.

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Various congenital disorders must be excluded as well, such as Glanzmann thrombasthenia, vWD, deficiency of coagulation factors II, V, VII, X, or XI, or fibrinogen deficiency. The following differential diagnoses may be considered for hemophilia A: Ehlers-Danlos Syndrome, factor XI deficiency, Glanzmann thrombasthenia, acquired hemophilia, hemophilia B, and hemophilia C.³

Hemophilia B Differential Diagnosis

The differential diagnoses for hemophilia B include Ehlers-Danlos Syndrome, factor V, VII, and XI deficiencies, hemophilia A, hemophilia C, platelet disorders, vWD, and dermatofibrosis lenticularis or Buschke Ollendorff syndrome.

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The diagnosis of hemophilia B can be delayed due to low levels of vitamin K-dependent coagulation factors. A factor IX Leyden gene should also be considered as part of a hemophilia B diagnosis.⁴

Von Willebrand Disease

Von Willebrand disease acts as a differential diagnosis for hemophilia, as women suffering from vWD experience menorrhagia as one of the most common bleeding symptoms. Bleeding disorders in women can cause heavy menstrual periods lasting for more than 7 days. They can limit daily activities like work, social activities, and exercise. Prolonged bleeding can lead to anemia or iron deficiency.

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Bleeding disorders like factor deficiency (hemophilia) or vWD in women can lead to menorrhagia, irregular cycles at menarche, and other bleeding symptoms. The diagnosis of women with type 1 vWD may get delayed after initial bleeding and can lead to preventable postoperative bleeding. It is important to distinguish between hemophilia A and vWD. Menorrhagia in women can also be due to endometriosis, pregnancy, pelvic masses, or menopause.⁵ Unlike hemophilia, vWD can be diagnosed with quantitative tests that check for factor VIII clotting activity and vWD factor antigen levels, as well as qualitative tests like vWD multimers, which measure how vWD factor works, and ristocetin cofactor.¹

Platelet Disorders

Platelet disorders can lead to a decrease in the platelet count (thrombocytopenia), platelet dysfunction, or abnormal increase in platelet number (reactive thrombocytosis and thrombocythemia). They can lead to bleeding similar to hemophilia due to the defective formation of a hemostatic plug. Platelet disorders are a differential diagnosis for hemophilia. The risk of bleeding is inversely proportional to platelet function and platelet count in platelet disorders. Thrombocythemia is a myeloproliferative disorder that can lead to the overproduction of platelets and cause clonal abnormality of hematopoietic stem cells. 

Glanzmann’s thrombasthenia is an inherited platelet disorder that involves the failure of platelet aggregation when stimulated with adenine diphosphate or other agonists. Patients with this disorder are not able to form a thrombus and platelet spreading is abnormal. The GPIb-mediated attachment of the platelets remains normal and the blood passes through in vitro, stimulating normal blood flow in the microvasculature. Congenital or acquired platelet disorders can lead to a heightened risk for bleeding as platelets play a critical role in hemostasis. Platelets adhere to the subendothelium and secrete granule components. Failure to form a platelet aggregate can lead to bleeding similar to hemophilia.⁶

Hemophilia C

Hemophilia C, also known as factor XI deficiency or Rosenthal syndrome, can cause severe bleeding similar to hemophilia A and B. A wide variation of bleeding risk is associated with factor XI deficiency. Most patients are diagnosed with increased bleeding during or after procedures, as the bleeding risk does not necessarily correlate with clotting studies or factor XI levels.

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Spontaneous bleeding is rare, but epistaxis and menorrhagia are reported in patients with hemophilia C.⁷

References

  1. Mehta P, Reddivari AKR. Hemophilia. In: StatPearls [Internet]. Treasure Island, FL: StatPearls Publishing; 2021.
  2. Disseminated intravascular coagulation. NIH: National Heart, Lung, and Blood Institute. Updated October 8, 2019. Accessed August 3, 2021.
  3. Drelich DA. Hemophilia A differential diagnoses. Medscape. Updated June 5, 2020. Accessed July 30, 2021
  4. Zaiden RA. Hemophilia B differential diagnoses. Medscape. Updated October 2, 2020. Accessed August 3, 2021.
  5. Ragni MV, Bontempo FA, Hassett AC. von Willebrand disease and bleeding in women. Haemophilia. 1999;5(5):313-317. doi:10.1046/j.1365-2516.1999.00342.x
  6. Krishnegowda M, Rajashekaraiah V. Platelet disorders: an overview. Blood Coagul Fibrinolysis. 2015;26(5):479-491. doi:10.1097/01.mbc.0000469521.23628.2d
  7. Jayakrishnan T, Shah D, Mewawalla P. Hemophilia C: a case report with updates on diagnosis and management of a rare bleeding disorder. J Hematol. 2019;8(3):144-147. doi:10.14740/jh522

Reviewed by Harshi Dhingra, MD, on 8/11/2021.

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