Bleeding Disorders

This article was last reviewed on

25 January 2023.

This article waslast modified on 25 January 2023.

What is it?

A bleeding disorder is an acquired or inherited tendency to bleed excessively. Normally, blood remains in the circulatory system inside the blood vessels. However, if veins or arteries are injured, they will begin to leak blood, either externally or into body tissues. The body stops the blood loss through a complex clotting process called haemostasis. During haemostasis, the injured blood vessel constricts to reduce blood flow, platelets adhere to the injury site and clump together to form a loose platelet plug, and a process of clot formation called the coagulation cascade is initiated.

Once the coagulation cascade has been initiated, coagulation factors are activated one after the other in a sequential process. As the cascade nears completion, soluble fibrinogen (fibrinogen dissolved in fluid) is changed into insoluble fibrin threads. These threads crosslink together to form a fibrin net that then stabilises at the injury site. The fibrin net adheres to the site of injury along with aggregated cell fragments called platelets to form a stable blood clot. This barrier prevents additional blood loss and remains in place until the injured area has healed. Haemostasis is a dynamic process, though, so once a clot is formed, other factors are activated to slow the clotting process. They eventually begin to dissolve the clot in a process called fibrinolysis so that the clot is removed when the injury site is healed. In normal, healthy individuals, this balance between clot formation and dissolution ensures that bleeding does not become excessive and that clots are removed once they are no longer needed.

Bleeding disorders occur when something goes wrong with the clotting process. If a component is missing, deficient, or dysfunctional, excessive bleeding may occur. Such bleeding may be severe, with bleeding episodes beginning in early childhood, or mild, involving bleeding for an extended period of time following surgery, dental procedures, or trauma. Bleeding disorders can be congenital (present from birth) or acquired (occurring in later life due to a trigger such as infection). Bleeding disorders may cause symptoms that range from nosebleeds, bleeding gums, bruising, heavy menstrual periods, blood in the stool and/or urine to arthritic-type symptoms (damage from bleeding into joints), loss of vision, and chronic anaemia.

Abnormalities may involve: the structure of the blood vessels, the production or function of one or more of the coagulation factors, the development of antibodies against one or more of the factors, the production or function of the platelets, and/or the integrity and stability of the blood clot. Inherited bleeding disorders are rare and tend to be caused by a deficiency or dysfunction of a single coagulation factor or clotting component. The most common are Haemophilia A (factor VIII deficiency) and von Willebrand’s disease (von Willebrand factor is a protein that helps platelets adhere to the injury site). Acquired bleeding disorders are varied and occur more frequently than inherited disorders. Common ones include multiple factor deficiencies caused by liver disease or vitamin K deficiency (since many coagulation factors are produced in the liver and several are vitamin K dependent) and factor inhibitors (especially factor VIII inhibitor, an antibody against factor VIII).

About Bleeding Disorders

Structural problems with blood vessels

Inherited
Hemorrhagic Telangiectasia -- blood vessels are more fragile than usual leading to recurrent bleeding episodes

Ehlers-Danlos syndrome --collagen that supports blood vessels is unusually weak and elastic, making blood vessels less protected and more prone to injury

Acquired
Henoch-Schonlein purpura --small blood vessels are inflamed and prone to leakage, a condition thought to be an autoimmune response and may be acute or chronic
Platelet deficiency (thrombocytopenia) or dysfunction
Inherited

A variety of rare inherited conditions may cause platelet disorders. The most severe are called Glanzmann Thrombasthenia and Bernard Soulier Syndrome.

Acquired

Bone marrow not producing enough platelets (e.g. leukaemia, aplastic anaemia)

Immune thrombocytopenic purpura (ITP), autoimmune disease; may go away on its own.

Drugs such as quinine, sulfa antibiotics, and gold salts may decrease number of platelets.

Drugs such as aspirin and other non-steroidal anti-inflammatory drugs will affect platelets functions.

Disease-related: HIV, liver disease, kidney failure, cirrhosis of the liver, and systemic lupus erythematosus may all cause decreased platelet counts

Massive blood transfusion (platelet survival is limited in stored blood)

Cardiopulmonary bypass surgery (platelets are activated and become deficient and dysfunctional)
Coagulation Factor deficiency or dysfunction
Inherited

Haemophilia A (Factor VIII deficiency) - X-chromosome linked bleeding disorder that occurs in males and is carried in females. The first bleeding episode may be with circumcision or other procedures as an infant. The severity of the bleeding caused by a factor VIII deficiency depends on its activity level. If it is very low, it may cause spontaneous or severe life-threatening bleeding; if it is moderate, it may only cause mild to moderate bleeding, becoming an issue primarily when having surgery or dental procedures.

Haemophilia B (Factor IX deficiency) – similarly to Haemophilia A, Haemophilia B is an X-chromosome linked bleeding disorder, with bleeding severity correlating to levels of factor IX.

von Willebrand disease -resulting from defective or decreased von Willebrand factor. Symptoms include bruising, prolonged bleeding from cuts, nosebleeds, heavy periods and bleeding after tooth extration or surgery. Von Willebrand factor is a protein that attaches platelets to the site of a blood vessel injury.

Other factor deficiencies – fibrinogen, II, V, VII, X, IX, (Haemophilia B, also called Christmas disease), XI.

Acquired:

Liver dysfunction or disease

Vitamin K deficiency

Fat malabsorption

Some snake venoms

Therapy for malignancies

Factor inhibitors (antibodies that target a specific clotting factor, such as factor VIII, decreasing its activity and making factor replacement more of a challenge)

Anticoagulant drugs: such as coumadin (warfarin) or heparin; these drugs are used to treat clotting disorders but in excessive amounts may cause bleeding.

Some bacterial infections

Disseminated intravascular coagulation (DIC), may cause both bleeding and clotting. It is usually an acute condition, may be from a complicated childbirth, from an endotoxin produced during a severe infection, with massive tissue damage due to burns or trauma, or due to certain cancers such as leukaemia. DIC causes tiny clot formation throughout the body, using up clotting factors at an accelerated rate, leading to excessive bleeding.

Laboratory Tests

When performing laboratory tests to evaluate bleeding disorders, the coagulation cascade can be thought of as having two branches: the extrinsic pathway and the intrinsic pathway. Each of these pathways utilizes different coagulation factors, proteins that are carried in an inactive form in the blood. These factors are sequentially activated down one pathway or the other and come together to complete the clotting process in the common pathway.

Using this approach, bleeding disorder testing is a step-by-step investigative procedure. If someone presents with a bleeding episode, a doctor may order a Prothrombin Time (PT), which evaluates the extrinsic and common pathways, Partial Thromboplastin Time (PTT), which evaluates the intrinsic and common pathways, and a FBC to see whether or not the patient is anaemic and to evaluate the number of platelets present. If the PT is prolonged, further testing may be done to identify problems with factors involved in the extrinsic or common pathway. If the PTT is prolonged, then the doctor may follow-up with other testing to look for specific factor deficiencies in the intrinsic or common pathway and to see whether or not there may be factor inhibitors.

Some of the tests that may be ordered include:

Test	Measures	Ordered when/to	Abnormal results may indicate
FBC (Full Blood Count)	Counts and evaluates size and shape of platelets, red and white blood cells (WBCs), types of WBCs; measures haemoglobin and haematocrit	Ordered as a routine screen, to check for any abnormalities	Decreased platelet numbers increase bleeding tendency
Coagulation Factors, Activity	Individual tests to measure the function of specific coagulation factors	Evaluate bleeding episodes	Decreased activity of one or more factors may increase risk of bleeding
Coagulation Factors, Antigen	Measures the quantity of individual factors	When factor activity is consistently low	Decreased production or increased use of one or more factors, increased risk of bleeding
D-dimer	Measures a specific type of cross-linked fibrin degradation	Evaluate blood clot formation during bleeding and clotting episodes	If elevated, indicates recent clotting activity which may be due to acute or chronic condition, such as a thromboembolism or Disseminated intravascular coagulation (DIC)
Factor Inhibitors	Individual tests for coagulation factor antibodies	Evaluate excessive bleeding and prolonged PTT	If present, may cause specific factor deficiencies and excessive bleeding
Fibrinogen	Reflection of clotting ability and activity	Evaluate bleeding and clotting	If low, may indicate decreased production or increased use; may be elevated with infection and inflammation. It is an acute phase reactant.
International Normalised Ratio (INR)	Time to clot: a standardised version of the PT test, the results comparable between laboratories worldwide.	Used specifically to monitor warfarin or other coumarin anticoagulants.	The higher the ratio the less the patient is likely to clot but more to bleed.
Partial Thromboplastin Time (PTT)	Time to clot; evaluates the intrinsic and common pathways of coagulation cascade	-Investigate bleeding -Pre-surgical screen for risk of excessive bleeding -Monitor heparin anticoagulant therapy	Prolonged PTT suggests need for further tests. May indicate: -Coagulation factor deficiency -Specific inhibitor (such as Factor VIII antibody) - Nonspecific inhibitor (such as Lupus anticoagulant) -Patient on heparin and/or blood sample contaminated with heparin
Platelet aggregation (Platelet function test)	Evaluate platelets’ ability to be activated and stick to each other (agglutinate)	Evaluate bleeding, especially when platelet count normal	If abnormal, increases risk of excessive bleeding; may indicate presence of one of several disorders including von Willebrand disease
Platelet Function Analyzer PFA^¹⁰⁰	An automated method to measure platelet function (this is the most widely used; there are also other analyzers)	Sometimes used as a pre-surgical screen or to evaluate recurrent bleeding	Abnormal result may indicate acquired platelet disorder or von Willebrand disease. Indicates greater risk of excessive bleeding. This test has largely replaced the Bleeding time test.
Prothrombin Time (PT)	Time to clot test; evaluates the extrinsic and common pathways of coagulation cascade	Investigate bleeding or thrombotic episode Pre-surgical screen for risk of excessive bleeding	Prolonged PT may suggest need for further tests. May be elevated in inherited or acquired conditions.
Ristocetin Cofactor (VWF:RCo)	Indirect measure of von Willebrand factor (VWF) activity/function	Evaluate bleeding episodes	VWF activity and decreased ability for platelets to adhere to injuries; may be due to von Willebrand’s disease, increased risk of bleeding VWF: Collagen binding test is often requested as an additional measure of VWF function
Thrombin Time (TT)	Time to clot; thrombin activates fibrinogen to fibrin stands; TT detects presence of inhibitors to this process	Help evaluate bleeding episode; sometimes when PTT prolonged; when heparin contamination suspected	If elevated, heparin may be contaminating blood sample; also elevated with FDP, with very low levels of fibrinogen, and with abnormal fibrinogen
von Willebrand Factor (VWF) Antigen (VWF: Ag)	Quantitative measure of VWF	Done together with VWF activity test (e.g. as measured by Ristocetin Cofactor); evaluate bleeding episodes

Treatments

Most bleeding disorders are managed through a combination of risk reduction, medications, and replacement therapies to prevent excessive blood loss and to prevent complications that may arise from bleeding. The degree and frequency of treatment needed will depend on the severity of the deficiency or condition, whether or not there is a stimulus for bleeding – such as surgery or trauma, and whether or not the condition progresses or worsens over time.

Simply avoiding injury- limiting physical contact sports, for instance- and setting up the daily environment to avoid cuts, bruises, and trauma may be enough to minimize bleeding episodes in those with mild conditions, and under most circumstances, in those with moderate bleeding tendencies. Someone with severe deficiencies, such as Haemophilia A (factor VIII deficiency), and/or someone who is having an acute bleeding episode will need to have one or more of their coagulation factors replaced. Factor VIII and other individual factors are usually available in a concentrated form that is expensive but effective. Single and multiple factor deficiencies are sometimes treated with transfusions of fresh frozen plasma or plasma concentrates that contain multiple coagulation factors. These concentrates and replacements can be given during a bleeding episode and as a preventative measure before necessary surgeries and dental procedures to control excessive bleeding.

If the bleeding disorder is due to dysfunctional or deficient platelets, the person may also be transfused. If the disorder is due to von Willebrand disease or a mild form of Haemophilia A, a drug called desmopressin (DDAVP) may be given to improve clotting temporarily; this causes the release of stored factor VIII and VWF, and may temporarily raise levels high enough and long enough to allow procedures to be performed without transfusions.

If a bleeding disorder is due to an acquired condition, it may improve or worsen as the underlying condition is resolved or progresses. If, for instance, factor deficiencies are due to a lack of Vitamin K, they may return to normal with vitamin supplementation. If they are due to liver disease or to a cancer, they will likely follow the course of the disease. If a bleeding disorder is due to or exacerbated by the development of factor antibodies, such as antibodies to factors VIII or IX, alternative factor replacements may need to be given, and/or patients may need to take corticosteroids or other immune-suppressive drugs to reduce their antibody levels.

With an acute condition, such as DIC, immediate treatment may be crucial and complicated. Since DIC involves both clotting and bleeding throughout the body, treatment may involve platelet and clotting factor transfusions as well as heparin or other anticoagulant therapy.