Bleeding diathesis

Bleeding diathesis main page
Overview
Classification
Differential Diagnosis Platelet disorders Immune Thrombocytopenic Purpura Thrombotic Thrombocytopenic Purpura Hemolytic Uremic Syndrome Thrombocytosis Von Willebrand Disease
Coagulation disorders Fibrinogen deficiency Prothrombin deficiency Factor V deficiency Factor VII deficiency Factor VIII deficiency Factor IX deficiency Factor X deficiency Factor XI deficiency Factor XII deficiency High-molecular-weight kininogen deficiency Prekallikrein deficiency Factor XIII deficiency Hemophilia
Rare diseases Disseminated Intravascular Coagulation Vitamin K Deficiency
Different types of Von-Willebrand diseases

Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Mehrian Jafarizade, M.D [2], Nazia Fuad M.D.

Overview

Bleeding diathesis is unusual susceptibility to bleed due to hypo-coagulopathies. These diseases can occur due to a disorder of homeostasis, localized process (tissue injury), or medications. Bleeding diathesis can be resulted from vessel wall injury, platelet disorders, and coagulation factor disorders. Clinical manifestation of bleeding disorders can have a wide range of symptoms from asymptomatic to symptomatic massive and life threatening bleeding. Platelet disorders mostly have skin manifestations such as petechiae, and ecchymoses. In order to find the cause of hypo-coagulopathy; there are established laboratory tests, such as peripheral blood smear, platelet count and platelet function analysis, coagulation factor deficiencies and inhibitors, fibrinolysis tests (eg. D-dimer level), bleeding time, prothrombin time, activated partial thromboplastin time, thrombin time and reptilase time.

Homostasis

Hemostasis is the process of blood clot formation at the site of bleeding. This process has 4 main phases as below:

Platelet plug formation

At the site of vascular injury platelets are activated and bound to the collagen with the surface collagen-specific glycoprotein Ia/IIa receptor. This bindings are provided by the linking of large multimeric circulating protein von Willebrand factor (vWF). Ultimately, the platelets makes a platelet clot to initially stop the bleeding.

Fibrinolysis

For more information click here, and here.

Classification

Disorders of hemostasis can be classified into two main categories: platelet disorders, and disorders of coagulation. Each category can be further classified as bellow:

Platelet disorders:

1. Thrombocytopenia: platelet count less than 150,000 per mm³
2. Thromobcytosis: platelet countcmore than 450,000 per mm³
3. Qualitative Disorders of Platelet function such as Von Willebrand Disease, inherited or acquired functional disorders.

Coagulation disorders

1. Vessel wall disorders: Endothelial cells are lining entire vessel walls all over the body. Endothelium is an active layer responsible for inflammatory responses, angiogenesis and blood cell interactions. Endothelial cells have a very important role in hemostasis and they are regulating blood fluidity by the balance of antithrombotic/prothrombotic and vasodilatory/vasoconstrictor effects.
   • Metabolic and Inflammatory Disorders
   • Inherited Disorders of the Vessel Wall
2. Coagulation factor disorders:
   • Fibrinogen deficiency
   • Prothrombin deficiency
   • Factor V deficiency
   • Factor VII deficiency
   • Factor X deficiency
   • Factor XII deficiency
   • HK deficiency
   • Prekallikrein deficiency
   • Factor XIII deficiency
   • Hemophilia
3. Disseminated Intravascular Coagulation
4. Vitamin K Deficiency
5. Coagulation Disorders Associated with Liver Failure
6. Acquired Inhibitors of Coagulation Factors

Differential Diagnosis

Differential diagnosis of "Bleeding disorders":

Category	Sub-category	Diseases		History	Clinical manifestation					Laboratory testing					Comments
					Petechiae	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		History of prior infection	+	+	+	+	+	↓	↑	N	N	N	-
		Medications-Induced thrombocytopenia		History of medications such as: Furosemide Nonsteroidal anti-inflammatory drugs (NSAIDs) Penicillin Quinidine Quinine Ranitidine Sulfonamides Linezolid	+	+	+	+	+	↓	↑	N	N	N	Most important par of treatment is discontinuing of the medication.
		Heparin-Induced thrombocytopenia		Thrombosis Unexplained thrombocytopenia up to 3 weeks after the end of heparin therapy	+	+	+	+	+	↓	↑	N	N	↑	For more information click here: Heparin-induced thrombocytopenia.
		Immune Thrombocytopenic Purpura (ITP)		History of prior infection or no history	+	+	+	+	+	↓	↑	N	N	N	-
		Inherited Thrombocytopenia		Family history	+	+	+	+	+	↓	↑	N	N	N	-
		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	+	+	+	+	+	↓	↑	N	N	N	-
		Hemolytic Uremic Syndrome		History of: Infections Malignancy, cancer chemotherapy and ionizing radiation Calcineurin inhibitors and transplantation Pregnancy, HELLP syndrome and oral contraceptive pill Systemic lupus erythematosis and antiphospholipid antibody syndrome Glomerulopathy Familial, not included in part 1	+	+	+	+	+	↓	↑	N	N	N	-
	Thromobcytosis			Digital pain Gangrene Erythromelalgia Headache Paresthesias Transient ischemic attacks	−	−	−	+/-	+/-	↑	Ν/↑	ɴ	ɴ	N	-
	Qualitative Disorders of Platelet Function	Inherited Disorders of Platelet Function	Glanzmann’s thrombasthenia	Positive family history	+	+	+	-	Rare	N/↓	↑	ɴ	ɴ	N	AR inheritance Absence of the platelet Gp IIb/IIIa receptor/ Diminished for GP 2B-3A on flow cytometry
			Bernard-Soulier syndrome	Positive family history	+	+	+	-	-	N/↓	↑	N	N	N	AR inheritance Absence of the platelet Gp Ib-IX-V receptor On PBS: giant platelets Ristocetin - no aggregation
			Platelet storage pool disorder (SPD): Hermansky-Pudlak syndrome Chediak-Higashi syndrome Gray platelet syndrome	Positive family history Hairy-cell leukemia Cardiovascular bypass	+	+	+	-	-	N/↓	↑	N	N	N	AD inheritance Abnormalities of platelet granule formation
		Acquired Disorders of Platelet Function		Uremia Cardiopulmonary bypass Hematologic disorders such as: myeloproliferative and myelodysplastic syndromes	+	+	+	+/-	+/-	N/↓	↑	N	N	N	-
		Von Willebrand Disease		Easy bruising Epistaxis Oral cavity bleeding Bleeding after dental extraction/surgery Menorrhagia Postpartum hemorrhage	+	+	+	+/-	+/-	↑	Ν	↑	↑	N	See the table below for the details about types.
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.	+	+	+/-	-	-	N	↑/N	N	N	N	-
	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	+	+	+/-	-	-	N	↑/N	N	N	N	-
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 Abnormal bleeding during or after injury, surgery, or childbirth Gastrointestinal hemorrhage Cerebral hemorrhage Thrombosis	_	+	+	+/-	+	N	↑	↑	↑	↑	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			Easy bruising Epistaxis Soft-tissue hemorrhage Excessive postoperative bleeding Menorrhagia Muscle hematomas Hemarthrosis Intracranial bleeding	+	+	+	+	+	N	N	↑	↑	↑	-
	Factor V deficiency			Excessive bruising with minor injuries Epistaxis Hemarthrosis Menorrhagia Intracerebral hemorrhages Pulmonary hemorrhage	_	+	+	+	+	N	↑	↑	↑	N	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			+	+	+	N		↑	N	N	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	+	+	+	+	+	N	N	↑	↑	N	-
	Factor XII deficiency			Majority,asymptomatic Recurrent miscarriages Painful leg ulcers	_	_	_	_	_	N	N	N	↑	N
	High molecular weight kininogen (HMWK) deficiency			Possibility of positive family history of bleeding	_	_	_	_	_	N	N	N	↑	N
	Prekallikrein deficiency			Possibility of positive family history of bleeding	_	_	_	_	_	N	N	N	↑	N
	Factor XIII deficiency		Types: Sub unit A mutation disease (more common) Sub unit B mutation disease	Possibility of positive family history of bleeding	-/+	-/+	-/+	-/+	-/+	N	N/	N/↑	N	N	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	_	_	+	+	+	N	N	N	↑	N	-
		Type B deficiency		Neonatal bleeding Trauma-related soft-tissue hemorrhage Hemarthrosis Hematomas	_	_	+	+	+	N	N	N	↑	N	-
		Type C deficiency		Family history Bleeding after surgery or injury	_	_	+	Rare	Rare	N	N	N	↑	N	-
Rare diseases	Disseminated Intravascular Coagulation			Trauma Burn Crush injury Sepsis Malignancy Obstetric complication: abruption, amniotic fluid embolism Hemolytic anemia	+	+	_	+	+	↓	↑	↑	↑	N	-
	Vitamin K Deficiency			Bleeding after trauma Epistaxis Hematoma Gastrointestinal bleeding Menorrhagia Hematuria Gum bleeding Oozing from venipuncture sites Easy bruisability	+	+	+	+	+	N	↑	↑	Normal or mildly prolonged	N	-

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

References

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