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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	Subcategory	Disease		History	Clinical manifestation						Laboratory testing					Comments
					Mucosal bleeding	Petechia	Ecchymoses	Menorrhagia	Hematoma	Hemarthrosis	Plt	BT	PT	PTT	TT
Platelet disorders	Thrombocytopenia	Infection-Induced thrombocytopenia		History of prior infection	+	+	+	+	+	+	↓	↑	Nl	Nl	Nl	−
		Medications-Induced thrombocytopenia		History of medications such as: Furosemide Nonsteroidal anti-inflammatory drugs (NSAIDs) Penicillin Quinidine Quinine Ranitidine Sulfonamides Linezolid	+	+	+	+	+	+	↓	↑	Nl	Nl	Nl	Most important part of treatment is discontinuing of the medication.
		Heparin-Induced thrombocytopenia		Thrombosis Unexplained thrombocytopenia up to 3 weeks after the end of heparin therapy	+	+	+	+	+	+	↓	↑	Nl	Nl	↑	For more information click here: Heparin-induced thrombocytopenia.
		Immune Thrombocytopenic Purpura (ITP)		History of prior infection or no history	+	+	+	+	+	+	↓	↑	Nl	Nl	Nl	−
		Inherited Thrombocytopenia		Positive family history	+	+	+	+	+	+	↓	↑	Nl	Nl	Nl	−
		Thrombotic Thrombocytopenic Purpura (TTP)		History of: Cancer Bone marrow transplantation Pregnancy Medication Platelet aggregation inhibitors (ticlopidine and clopidogrel) Immunosuppressants (cyclosporine, mitomycin, tacrolimus/FK506, interferon-α) HIV-1 infection	+	+	+	+	+	+	↓	↑	Nl	Nl	Nl	−
		Hemolytic Uremic Syndrome		History of: Infections Malignancy, chemotherapy, and ionizing radiation Calcineurin inhibitors and transplantation Pregnancy, HELLP syndrome, and oral contraceptive pill Systemic lupus erythematosis Antiphospholipid antibody syndrome Glomerulopathy	+	+	+	+	+	+	↓	↑	Nl	Nl	Nl	−
	Subcategory	Disease		History	Mucosal bleeding	Petechia	Ecchymoses	Menorrhagia	Hematoma	Hemarthrosis	Plt	BT	PT	PTT	TT	Comments
	Thromobcytosis	Iron deficiency anemia Inflammatory diseases Splenectomy Essential thrombocytosis		Digital pain Gangrene Erythromelalgia Headache Paresthesias Transient ischemic attacks	−	−	−	−	±	±	↑	Nl or ↑	Nl	Nl	Nl	−
	Qualitative Disorders of Platelet Function	Inherited Disorders of Platelet Function	Glanzmann’s thrombasthenia	Positive family history	+	+	+	+	−	Rare	Nl or ↓	↑	Nl	Nl	Nl	AR inheritance Absence of the platelet Gp IIb/IIIa receptor Diminished for GP 2B-3A on flow cytometry
			Bernard-Soulier syndrome	Positive family history	+	+	+	+	−	−	Nl or ↓	↑	Nl	Nl	Nl	AR inheritance Absence of the platelet Gp Ib-IX-V receptor On PBS: giant platelets Ristocetin - no aggregation
			Wiskott-Aldrich syndrome	Positive family history	+	+	+	+	−	−	Nl or ↓	↑	Nl	Nl	Nl	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: Hermansky-Pudlak syndrome Chediak-Higashi syndrome Gray platelet syndrome	Positive family history Hairy cell leukemia Cardiovascular bypass	+	+	+	+	−	−	Nl or ↓	↑	Nl	Nl	Nl	AD inheritance AbNlities of platelet granule formation
		Acquired Disorders of Platelet Function		Uremia Cardiopulmonary bypass Hematologic disorders such as: myeloproliferative and myelodysplastic syndromes	+	+	+	+	±	±	Nl or ↓	↑	Nl	Nl	Nl	−
		Von Willebrand Disease		Easy bruising Epistaxis Oral cavity bleeding Bleeding after dental extraction/surgery Menorrhagia Postpartum hemorrhage	+	+	+	+	±	±	↑	Nl	↑	↑	Nl	See the table below for the details about different types.
	Subcategory	Disease		History	Mucosal bleeding	Petechia	Ecchymoses	Menorrhagia	Hematoma	Hemarthrosis	Plt	BT	PT	PTT	TT	Comments
Vessel wall disorders	Metabolic and Inflammatory Disorders	Acute febrile illnesses Mixed cryoglobulinemia Monoclonal gammopathies Certain pathogens, such as the rickettsiae causing Rocky Mountain spotted fever Vitamin C deficiency Cushing’s syndrome Chronic glucocorticoid therapy Aging Vasculitis such as Henoch-Schönlein,		History of the underlying disease.	−	+	+	±	−	−	Nl	Nl or ↑	Nl	Nl	Nl	−
	Inherited Disorders of the Vessel Wall	Marfan’s syndrome Ehlers-Danlos syndrome Pseudoxanthoma elasticum Hereditary hemorrhagic telangiectasia (HHT, or Osler-Weber-Rendu disease)		Positive family history	−	+	+	±	−	−	Nl	Nl or ↑	Nl	Nl	Nl	−
Coagulation factor disorders	Fibrinogen deficiency	Different types of the fibrinogen disorders: Congenital afibrinogenemia Congenital hypofibrinogenemia Fibrinogen storage disease Congenital dysfibrinogenemia Hereditary fibrinogen Aα-Chain amyloidosis Acquired dysfibrinogenemia Congenital hypodysfibrinogenemiaCryofibrinogenemia Acquired hypofibrinogenemia		Epistaxis Easy bruising Menorrhagia Muscle bleeds Hemarthrosis Bleeding from the umbilical cord stump after birth Bleeding after dental surgery or tooth extraction AbNl bleeding during or after injury, surgery, or childbirth Gastrointestinal hemorrhage Cerebral hemorrhage Thrombosis	−	−	+	+	±	+	Nl	↑	↑	↑	↑	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.
	Subcategory	Disease		History	Mucosal bleeding	Petechia	Ecchymoses	Menorrhagia	Hematoma	Hemarthrosis	Plt	BT	PT	PTT	TT	Comments
	Prothrombin deficiency			Easy bruising Epistaxis Soft-tissue hemorrhage Excessive postoperative bleeding Menorrhagia Muscle hematomas Hemarthrosis Intracranial bleeding	−	+	+	+	+	+	Nl	Nl	↑	↑	↑	−
	Factor V deficiency			Excessive bruising with minor injuries Epistaxis Hemarthrosis Menorrhagia Intracerebral hemorrhages Pulmonary hemorrhage	−	_	+	+	+	+	Nl	↑	↑	↑	Nl	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			Easy bruising Mucosal bleeding Postoperative bleeding Menorrhagia Soft tissue hematomas Thrombosis				+	+	+	Nl		↑	Nl	Nl	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 Easy bruising Hematuria Menorrhagia Abortion Postpartum hemorrhage Epistaxis Pseudotumors Intracranial bleeding Hemarthroses		+	+	+	+	+	Nl	Nl	↑	↑	Nl	−
	Factor XII deficiency			Majority,asymptomatic Recurrent miscarriages Painful leg ulcers		_	_	_	_	_	Nl	Nl	Nl	↑	Nl
	Subcategory	Disease		History	Mucosal bleeding	Petechia	Ecchymoses	Menorrhagia	Hematoma	Hemarthrosis	Plt	BT	PT	PTT	TT	Comments
	High molecular weight kininogen (HMWK) deficiency			Possibility of positive family history of bleeding		_	_	_	_	_	Nl	Nl	Nl	↑	Nl
	Prekallikrein deficiency			Possibility of positive family history of bleeding		_	_	_	_	_	Nl	Nl	Nl	↑	Nl
	Factor XIII deficiency	Sub unit A mutation disease (more common) Sub unit B mutation disease		Possibility of positive family history of bleeding	±	±	±	±	±	±	Nl	Nl	Nl or ↑	Nl	Nl	Impaired fibrin cross linking or clot dissolution The severity of factor XIII deficiency bleeds can be different in different patients
	Hemophilia	Type A deficiency		Eeasy bruising Inadequate clotting in trauma or mild injury Spontaneous hemorrhage Hemarthrosis Epistaxis Gingival bleeding	−	−	−	+	+	+	Nl	Nl	Nl	↑	Nl	−
		Type B deficiency		Neonatal bleeding Trauma-related soft-tissue hemorrhage Hemarthrosis Hematomas	−	−	−	+	+	+	Nl	Nl	Nl	↑	Nl	−
		Type C deficiency		Family history Bleeding after surgery or injury	−	−	−	+	Rare	Rare	Nl	Nl	Nl	↑	Nl	−
	Subcategory	Disease		History	Mucosal bleeding	Petechia	Ecchymoses	Menorrhagia	Hematoma	Hemarthrosis	Plt	BT	PT	PTT	TT	Comments
Rare diseases	Disseminated Intravascular Coagulation			Trauma Burn Crush injury Sepsis Malignancy Obstetric complication: abruption, amniotic fluid embolism Hemolytic anemia	+	+	+	+	+	+	↓	↑	↑	↑	Nl	−
	Vitamin K Deficiency			Bleeding after trauma Epistaxis Hematoma Gastrointestinal bleeding Menorrhagia Hematuria Gum bleeding Oozing from venipuncture sites Easy bruisability	+	−	+	+	+	+	Nl	↑	↑	Nl or mildly prolonged	Nl	−

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

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	Qualitative	10%	AD/AR	Moderate to severe bleeding	↓	↓	N or ↓
	2B	Qualitative	5%	AD	Thrombocytopenia Moderate to severe bleeding	↓	↑	N or ↓
	2M	Qualitative	<1%	AD/AR	Moderate to severe bleeding	↓	↓	N or ↓
	2N	Qualitative	<1%	AR	Clinically similar to hemophilia A with joint, soft tissue, urinary bleeding	N	N	↓
Type 3		Complete deficiency	1-2%	AR	Clinically similar to hemophilia A with joint and soft tissue bleeding Severe mucosal bleeding	Absent	↓	Low, 1-10%

For more information on Von Willebrand disease, click here.