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Differential Diagnosis

Different causes of the bleeding disorders can be differentiated based on their clinical manifestation and laboratory findings.

These features have discussed in the below table:

Category Sub-category Diseases History Clinical manifestation Laboratory testing Comments
Mucosal bleeding Petechia Ecchymoses Menorrhagia Hematoma Hemarthrosis Platelet count Bleeding time (BT) Prothrombin time (PT) Activated partial thromboplastin time (aPTT) Thrombin time (TT)
Platelet disorders Thrombocytopenia Infection-Induced thrombocytopenia[1][2][3]
  • History of prior infection
 + + + + + + ↓ ↑ Normal Normal Normal −
Medications-Induced thrombocytopenia [4][5] + + + + + + ↓ ↑ Normal Normal Normal Most important part of treatment is discontinuing of the medication.
Heparin-Induced thrombocytopenia[6] + + + + + + ↓ ↑ Normal Normal ↑ For more information click here: Heparin-induced thrombocytopenia.
Immune Thrombocytopenic Purpura (ITP)[7] + + + + + + ↓ ↑ Normal Normal Normal −
Inherited Thrombocytopenia[8][9]
  • Positive family history
 + + + + + + ↓ ↑ Normal Normal Normal −
Thrombotic Thrombocytopenic Purpura (TTP)[10][11] History of: + + + + + + ↓ ↑ Normal Normal Normal −
Hemolytic Uremic Syndrome[12][13] History of: + + + + + + ↓ ↑ Normal Normal Normal −
Thromobcytosis Iron deficiency anemia

Inflammatory diseases

Splenectomy

Essential thrombocytosis

− − − − +/- +/- ↑ Normal or ↑ Normal Normal Normal −
Qualitative Disorders of Platelet Function Inherited Disorders of Platelet Function Glanzmann’s thrombasthenia
  • Positive family history
 + + + + − Rare Normal or ↓ ↑ Normal Normal Normal
  • AR inheritance
  • Absence of the platelet Gp IIb/IIIa receptor
  • Diminished for GP 2B-3A on flow cytometry
Bernard-Soulier syndrome[14][15]
  • Positive family history
 + + + + − − Normal/↓ ↑ Normal Normal Normal
  • AR inheritance
  • Absence of the platelet Gp Ib-IX-V receptor
  • On PBS: giant platelets
  • Ristocetin - no aggregation
Wiskott-Aldrich syndrome[16][17][18][19]
  • Positive family history
 + + + + − − Normal or ↓ ↑ Normal Normal Normal
  • Anti-WASP antibody can be used to detect presence or absence of WAS protein
  • In Wiskott–Aldrich syndrome, the platelets are small and do not function properly. They are removed by the spleen, which leads to low platelet counts.
Platelet storage pool disorder (SPD): + + + + − − Normal or ↓ ↑ Normal Normal Normal
  • AD inheritance
  • Abnormalities of platelet granule formation
Acquired Disorders of Platelet Function + + + + +/- +/- Normal/↓ ↑ Normal Normal Normal −
Von Willebrand Disease [20][20][21][22][23] + + + + +/- +/- ↑ Normal ↑ ↑ Normal See the table below for the details about different types.
Vessel wall disorders Metabolic and Inflammatory Disorders
  • History of the underlying disease.
 − + + +/- - - Normal ↑/Normal Normal Normal Normal -
Inherited Disorders of the Vessel Wall
  • Positive family history
 - + + +/- - - Normal ↑/Normal Normal Normal Normal -
Coagulation factor disorders[24][25][26][26][27][28][29][30][31][32][33] Fibrinogen deficiency[34] Different types of the fibrinogen disorders: - - + + +/- + Normal ↑ ↑ ↑ ↑
  • Impaired fibrin cross linking or clot dissolution.
  • The severity of bleeding in patients with fibrinogen disorders can be mild or severe, with higher bleeding risk in those with afibrinogenemia or lower levels of functional fibrinogen. The age of onset is also variable, with earlier onset in those with more severe deficiency.
Prothrombin deficiency + + + + + Normal Normal ↑ ↑ ↑ -
Factor V deficiency _ + + + + Normal ↑ ↑ ↑ Normal The severity of bleeding is only partly related to the degree of factor V deficiency. Some patients with undetectable plasma levels of factor V experience only relatively mild bleeding.
Factor VII deficiency + + + Normal ↑ Normal Normal Thrombosis occurs in inherited factor VII deficiency most cases are associated with the administration of factor VII replacement therapy
Factor X deficiency
  • Prolonged bleeding following circumcision
 + + + + + Normal Normal ↑ ↑ Normal -
Factor XII deficiency
  • Majority,asymptomatic
  • Recurrent miscarriages
  • Painful leg ulcers
 _ _ _ _ _ Normal Normal Normal ↑ Normal
High molecular weight kininogen (HMWK) deficiency
  • Possibility of positive family history of bleeding
 _ _ _ _ _ Normal Normal Normal ↑ Normal
Prekallikrein deficiency
  • Possibility of positive family history of bleeding
 _ _ _ _ _ Normal Normal Normal ↑ Normal
Factor XIII deficiency Types:
  • Sub unit A mutation disease (more common)
  • Sub unit B mutation disease
  • Possibility of positive family history of bleeding
 -/+ -/+ -/+ -/+ -/+ -/+ Normal Normal Normal/↑ Normal Normal
  • Impaired fibrin cross linking or clot dissolution
  • The severity of factor XIII deficiency bleeds can be different in different patients
Hemophilia[35][36][37][38][39][40] Type A deficiency - - - + + + Normal Normal Normal ↑ Normal -
Type B deficiency - - - + + + Normal Normal Normal ↑ Normal -
Type C deficiency
  • Family history
  • Bleeding after surgery or injury
 - - - + Rare Rare Normal Normal Normal ↑ Normal -
Rare diseases Disseminated Intravascular Coagulation[41] + + + + + + ↓ ↑ ↑ ↑ Normal -
Vitamin K Deficiency[42] + - + + + + Normal ↑ ↑ Normal or mildly prolonged Normal -

Different types of Von-Willebrand diseases can be differentiated from each other based on the following table:[43]

Type of VWD Type of factor deficiency Prevalence Inheritance pattern Clinical manifestations VWF activity RIPA Factor VIII
Type 1 Quantitative/ partial 60-70% AD
  • Bleeding severity mild to severe
 ↓ ↓ ↓
Type 2 2A[44] Qualitative 10% AD/AR ↓ ↓ N or ↓
2B Qualitative 5% AD ↓ ↑ N or ↓
2M Qualitative <1% AD/AR ↓ ↓ N or ↓
2N Qualitative <1% AR N N ↓
Type 3 Complete deficiency 1-2% AR Absent ↓ Low, 1-10%

For more information on Von Willebrand disease, click here.

  1. ↑ Neunert C, Lim W, Crowther M, Cohen A, Solberg L, Crowther MA (April 2011). "The American Society of Hematology 2011 evidence-based practice guideline for immune thrombocytopenia". Blood. 117 (16): 4190–207. doi:10.1182/blood-2010-08-302984. PMID 21325604.
  2. ↑ Karimi O, Goorhuis A, Schinkel J, Codrington J, Vreden S, Vermaat JS, Stijnis C, Grobusch MP (March 2016). "Thrombocytopenia and subcutaneous bleedings in a patient with Zika virus infection". Lancet. 387 (10022): 939–940. doi:10.1016/S0140-6736(16)00502-X. PMID 26906627. Vancouver style error: initials (help)
  3. ↑ Zammarchi L, Stella G, Mantella A, Bartolozzi D, Tappe D, Günther S, Oestereich L, Cadar D, Muñoz-Fontela C, Bartoloni A, Schmidt-Chanasit J (February 2015). "Zika virus infections imported to Italy: clinical, immunological and virological findings, and public health implications". J. Clin. Virol. 63: 32–5. doi:10.1016/j.jcv.2014.12.005. PMID 25600600.
  4. ↑ Kam T, Alexander M (October 2014). "Drug-induced immune thrombocytopenia". J Pharm Pract. 27 (5): 430–9. doi:10.1177/0897190014546099. PMID 25134884.
  5. ↑ Seco-Melantuche R, Delgado-Sánchez O, Álvarez-Arroyo L (2013). "[Incidence of drug-induced thrombocytopenia in hospitalized patients]". Farm Hosp (in Spanish; Castilian). 37 (1): 27–34. doi:10.7399/FH.2013.37.1.42. PMID 23461497.
  6. ↑ Warkentin TE, Safyan EL, Linkins LA (January 2015). "Heparin-induced thrombocytopenia presenting as bilateral adrenal hemorrhages". N. Engl. J. Med. 372 (5): 492–4. doi:10.1056/NEJMc1414161. PMID 25629757.
  7. ↑ Wright JF, Blanchette VS, Wang H, Arya N, Petric M, Semple JW, Chia WK, Freedman J (October 1996). "Characterization of platelet-reactive antibodies in children with varicella-associated acute immune thrombocytopenic purpura (ITP)". Br. J. Haematol. 95 (1): 145–52. PMID 8857953.
  8. ↑ Johnson B, Fletcher SJ, Morgan NV (September 2016). "Inherited thrombocytopenia: novel insights into megakaryocyte maturation, proplatelet formation and platelet lifespan". Platelets. 27 (6): 519–25. doi:10.3109/09537104.2016.1148806. PMC 5000870. PMID 27025194.
  9. ↑ Wang Q, Cao L, Sheng G, Shen H, Ling J, Xie J, Ma Z, Yin J, Wang Z, Yu Z, Chen S, Zhao Y, Ruan C, Xia L, Jiang M (August 2018). "Application of High-Throughput Sequencing in the Diagnosis of Inherited Thrombocytopenia". Clin. Appl. Thromb. Hemost.: 1076029618790696. doi:10.1177/1076029618790696. PMID 30103613.
  10. ↑ Knöbl P (2018). "Thrombotic thrombocytopenic purpura". Memo. 11 (3): 220–226. doi:10.1007/s12254-018-0429-6. PMID 30220931.
  11. ↑ Mannucci PM, Cugno M (November 2015). "The complex differential diagnosis between thrombotic thrombocytopenic purpura and the atypical hemolytic uremic syndrome: Laboratory weapons and their impact on treatment choice and monitoring". Thromb. Res. 136 (5): 851–4. doi:10.1016/j.thromres.2015.09.007. PMID 26386489.
  12. ↑ Webster K, Schnitzler E (2014). "Hemolytic uremic syndrome". Handb Clin Neurol. 120: 1113–23. doi:10.1016/B978-0-7020-4087-0.00075-9. PMID 24365375.
  13. ↑ Picard C, Burtey S, Bornet C, Curti C, Montana M, Vanelle P (June 2015). "Pathophysiology and treatment of typical and atypical hemolytic uremic syndrome". Pathol. Biol. 63 (3): 136–43. doi:10.1016/j.patbio.2015.03.001. PMID 25845294.
  14. ↑ Dupuis A, Gachet C (September 2018). "Inherited platelet disorders : Management of the bleeding risk". Transfus Clin Biol. 25 (3): 228–235. doi:10.1016/j.tracli.2018.07.003. PMID 30077511.
  15. ↑ Andres O, Henning K, Strauß G, Pflug A, Manukjan G, Schulze H (June 2018). "Diagnosis of platelet function disorders: A standardized, rational, and modular flow cytometric approach". Platelets. 29 (4): 347–356. doi:10.1080/09537104.2017.1386297. PMID 29227167.
  16. ↑ Wang YQ, Cui YX, Feng J (January 2013). "[Clinical phenotype and gene diagnostic analysis of Omenn syndrome]". Zhonghua Er Ke Za Zhi (in Chinese). 51 (1): 64–8. PMID 23527934.
  17. ↑ Patil RB, Shanmukhaiah C, Jijina F, Bamborde S, Wasekar N, Toshniwal M, Mohite A, Patil V (2016). "Wiskott-Aldrich Syndrome Presenting with JMML-Like Blood Picture and Normal Sized Platelets". Case Rep Hematol. 2016: 8230786. doi:10.1155/2016/8230786. PMC 4906177. PMID 27340577.
  18. ↑ Kaneko R, Yamamoto S, Okamoto N, Akiyama K, Matsuno R, Toyama D, Hoshino A, Imai K, Isoyama K (2018). "Wiskott-Aldrich syndrome that was initially diagnosed as immune thrombocytopenic purpura secondary to a cytomegalovirus infection". SAGE Open Med Case Rep. 6: 2050313X17753788. doi:10.1177/2050313X17753788. PMC 5768273. PMID 29348920.
  19. ↑ Ozcan E, Notarangelo LD, Geha RS (December 2008). "Primary immune deficiencies with aberrant IgE production". J. Allergy Clin. Immunol. 122 (6): 1054–62, quiz 1063–4. doi:10.1016/j.jaci.2008.10.023. PMID 19084106.
  20. ↑ 20.0 20.1 Elbatarny M, Mollah S, Grabell J, Bae S, Deforest M, Tuttle A, Hopman W, Clark DS, Mauer AC, Bowman M, Riddel J, Christopherson PA, Montgomery RR, Rand ML, Coller B, James PD (November 2014). "Normal range of bleeding scores for the ISTH-BAT: adult and pediatric data from the merging project". Haemophilia. 20 (6): 831–5. doi:10.1111/hae.12503. PMC 4251588. PMID 25196510.
  21. ↑ Goodeve A, Eikenboom J, Castaman G, Rodeghiero F, Federici AB, Batlle J, Meyer D, Mazurier C, Goudemand J, Schneppenheim R, Budde U, Ingerslev J, Habart D, Vorlova Z, Holmberg L, Lethagen S, Pasi J, Hill F, Hashemi Soteh M, Baronciani L, Hallden C, Guilliatt A, Lester W, Peake I (January 2007). "Phenotype and genotype of a cohort of families historically diagnosed with type 1 von Willebrand disease in the European study, Molecular and Clinical Markers for the Diagnosis and Management of Type 1 von Willebrand Disease (MCMDM-1VWD)". Blood. 109 (1): 112–21. doi:10.1182/blood-2006-05-020784. PMID 16985174.
  22. ↑ Mammen EF, Comp PC, Gosselin R, Greenberg C, Hoots WK, Kessler CM, Larkin EC, Liles D, Nugent DJ (1998). "PFA-100 system: a new method for assessment of platelet dysfunction". Semin. Thromb. Hemost. 24 (2): 195–202. doi:10.1055/s-2007-995840. PMID 9579642.
  23. ↑ Bodó I, Eikenboom J, Montgomery R, Patzke J, Schneppenheim R, Di Paola J (July 2015). "Platelet-dependent von Willebrand factor activity. Nomenclature and methodology: communication from the SSC of the ISTH". J. Thromb. Haemost. 13 (7): 1345–50. doi:10.1111/jth.12964. PMC 5576173. PMID 25858564.
  24. ↑ Karimi M, Peyvandi F, Naderi M, Shapiro A (February 2018). "Factor XIII deficiency diagnosis: Challenges and tools". Int J Lab Hematol. 40 (1): 3–11. doi:10.1111/ijlh.12756. PMID 29027765.
  25. ↑ Peyvandi F, Garagiola I, Biguzzi E (November 2016). "Advances in the treatment of bleeding disorders". J. Thromb. Haemost. 14 (11): 2095–2106. doi:10.1111/jth.13491. PMID 27590165.
  26. ↑ 26.0 26.1 Bender L, Weidmann H, Rose-John S, Renné T, Long AT (2017). "Factor XII-Driven Inflammatory Reactions with Implications for Anaphylaxis". Front Immunol. 8: 1115. doi:10.3389/fimmu.2017.01115. PMC 5605561. PMID 28966616.
  27. ↑ Schmaier AH (September 2016). "Antithrombotic potential of the contact activation pathway". Curr. Opin. Hematol. 23 (5): 445–52. doi:10.1097/MOH.0000000000000271. PMC 5148823. PMID 27380557.
  28. ↑ Schmaier AH (January 2016). "The contact activation and kallikrein/kinin systems: pathophysiologic and physiologic activities". J. Thromb. Haemost. 14 (1): 28–39. doi:10.1111/jth.13194. PMID 26565070.
  29. ↑ Kaplan AP, Ghebrehiwet B (August 2010). "The plasma bradykinin-forming pathways and its interrelationships with complement". Mol. Immunol. 47 (13): 2161–9. doi:10.1016/j.molimm.2010.05.010. PMID 20580091.
  30. ↑ Zuraw BL, Christiansen SC (2011). "Pathophysiology of hereditary angioedema". Am J Rhinol Allergy. 25 (6): 373–8. doi:10.2500/ajra.2011.25.3661. PMID 22185738.
  31. ↑ Quail MT (2013). "Prekallikrein deficiency". J Pediatr Oncol Nurs. 30 (4): 198–204. doi:10.1177/1043454213487436. PMID 23629422.
  32. ↑ Dorgalaleh A, Alavi SE, Tabibian S, Soori S, Moradi E, Bamedi T, Asadi M, Jalalvand M, Shamsizadeh M (May 2017). "Diagnosis, clinical manifestations and management of rare bleeding disorders in Iran". Hematology. 22 (4): 224–230. doi:10.1080/10245332.2016.1263007. PMID 27894217.
  33. ↑ Maas C, Renné T (April 2018). "Coagulation factor XII in thrombosis and inflammation". Blood. 131 (17): 1903–1909. doi:10.1182/blood-2017-04-569111. PMID 29483100.
  34. ↑ Tiscia GL, Margaglione M (May 2018). "Human Fibrinogen: Molecular and Genetic Aspects of Congenital Disorders". Int J Mol Sci. 19 (6). doi:10.3390/ijms19061597. PMC 6032319. PMID 29844251.
  35. ↑ Aviña-Zubieta JA, Galindo-Rodriguez G, Lavalle C (January 1998). "Rheumatic manifestations of hematologic disorders". Curr Opin Rheumatol. 10 (1): 86–90. PMID 9448995.
  36. ↑ Plug I, Mauser-Bunschoten EP, Bröcker-Vriends AH, van Amstel HK, van der Bom JG, van Diemen-Homan JE, Willemse J, Rosendaal FR (July 2006). "Bleeding in carriers of hemophilia". Blood. 108 (1): 52–6. doi:10.1182/blood-2005-09-3879. PMID 16551972.
  37. ↑ Blanchette VS, Key NS, Ljung LR, Manco-Johnson MJ, van den Berg HM, Srivastava A (November 2014). "Definitions in hemophilia: communication from the SSC of the ISTH". J. Thromb. Haemost. 12 (11): 1935–9. doi:10.1111/jth.12672. PMID 25059285.
  38. ↑ White GC, Rosendaal F, Aledort LM, Lusher JM, Rothschild C, Ingerslev J (March 2001). "Definitions in hemophilia. Recommendation of the scientific subcommittee on factor VIII and factor IX of the scientific and standardization committee of the International Society on Thrombosis and Haemostasis". Thromb. Haemost. 85 (3): 560. PMID 11307831.
  39. ↑ Favaloro EJ, Meijer P, Jennings I, Sioufi J, Bonar RA, Kitchen DP, Kershaw G, Lippi G (October 2013). "Problems and solutions in laboratory testing for hemophilia". Semin. Thromb. Hemost. 39 (7): 816–33. doi:10.1055/s-0033-1356573. PMID 24026910.
  40. ↑ Blanchette VS, Key NS, Ljung LR, Manco-Johnson MJ, van den Berg HM, Srivastava A (November 2014). "Definitions in hemophilia: communication from the SSC of the ISTH". J. Thromb. Haemost. 12 (11): 1935–9. doi:10.1111/jth.12672. PMID 25059285.
  41. ↑ Wada H, Matsumoto T, Suzuki K, Imai H, Katayama N, Iba T, Matsumoto M (2018). "Differences and similarities between disseminated intravascular coagulation and thrombotic microangiopathy". Thromb J. 16: 14. doi:10.1186/s12959-018-0168-2. PMC 6040080. PMID 30008620.
  42. ↑ Shiraishi E, Iijima H, Shinzaki S, Nakajima S, Inoue T, Hiyama S, Kawai S, Araki M, Yamaguchi T, Hayashi Y, Fujii H, Nishida T, Tsujii M, Takehara T (April 2016). "Vitamin K deficiency leads to exacerbation of murine dextran sulfate sodium-induced colitis". J. Gastroenterol. 51 (4): 346–56. doi:10.1007/s00535-015-1112-x. PMID 26314836.
  43. ↑ Bodó I, Eikenboom J, Montgomery R, Patzke J, Schneppenheim R, Di Paola J (July 2015). "Platelet-dependent von Willebrand factor activity. Nomenclature and methodology: communication from the SSC of the ISTH". J. Thromb. Haemost. 13 (7): 1345–50. doi:10.1111/jth.12964. PMC 5576173. PMID 25858564.
  44. ↑ Lyons SE, Bruck ME, Bowie EJ, Ginsburg D (March 1992). "Impaired intracellular transport produced by a subset of type IIA von Willebrand disease mutations". J. Biol. Chem. 267 (7): 4424–30. PMID 1537829.
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