Clotting Factor Deficiencies

How clotting factors work

When a blood vessel is damaged, platelets plug the hole first. Then a chain of clotting proteins, called factors and numbered I to XIII, activate one another in a cascade. The end result turns fibrinogen (factor I) into fibrin strands that reinforce the platelet plug into a stable clot. If any link in the chain is weak, clots form slowly or are fragile, and bleeding lasts longer.

Types of factor deficiency

Inherited deficiencies

Hemophilia A and B together affect roughly 1 in 5,000 male births. The other rare inherited deficiencies affect between about 1 in 500,000 and 1 in 2 million people each, and are more common where marriage between relatives is common.

Factor XII deficiency prolongs the aPTT test but does not cause bleeding.

Acquired deficiencies

• Liver disease: the liver makes most clotting factors, so cirrhosis lowers several at once.
• Vitamin K deficiency: factors II, VII, IX and X need vitamin K. Causes include newborns not given vitamin K at birth, malabsorption, long antibiotic courses and poor diet.
• Blood thinners: warfarin blocks vitamin K-dependent factors. Newer anticoagulants block factor Xa or thrombin.
• Disseminated intravascular coagulation (DIC): factors are used up in widespread clotting during sepsis, trauma, cancer or obstetric emergencies.
• Acquired hemophilia: the immune system makes antibodies against factor VIII, usually in older adults or after childbirth. It causes sudden large bruises and muscle bleeds.
• Amyloidosis can bind and remove factor X.

Symptoms

• Easy bruising, including large raised bruises
• Frequent or long nosebleeds
• Bleeding gums and long bleeding after dental extraction
• Heavy menstrual bleeding and heavy bleeding after childbirth
• Prolonged bleeding from cuts, injections or surgery, sometimes starting again hours or days later
• Bleeding into joints (knees, ankles, elbows), causing pain, warmth and swelling
• Bleeding into muscles
• Blood in urine or stool
• In newborns, bleeding from the umbilical cord stump, after heel pricks or circumcision, or into the brain

Mild deficiencies may go unnoticed until surgery, dental work or childbirth.

Diagnosis

1. Bleeding history and family history, often scored with a standardized questionnaire.
2. Screening tests: - Prothrombin time (PT/INR): prolonged in deficiencies of factor VII, and of X, V, II or fibrinogen. - Activated partial thromboplastin time (aPTT): prolonged in deficiencies of factors VIII, IX, XI and XII, and of X, V, II or fibrinogen. - Fibrinogen level. - Platelet count and von Willebrand tests.
3. Mixing study: mixing the patient's plasma with normal plasma. If the time corrects, a factor is missing. If not, an inhibitor (antibody) is present.
4. Specific factor assays: measure the activity of each factor as a percentage of normal.
5. Factor XIII assay: needed separately, because PT and aPTT are normal in factor XIII deficiency.
6. Genetic testing for inherited forms and family planning.

Treatment

Treatment is usually led by a hemophilia treatment center:

• Factor replacement: concentrates of the missing factor, either plasma-derived or recombinant, given into a vein to treat bleeding, before surgery, or regularly as prevention (prophylaxis).
• Emicizumab: an injection under the skin that mimics factor VIII, used to prevent bleeds in hemophilia A.
• Fresh frozen plasma or prothrombin complex concentrate: for rare deficiencies without a specific concentrate, and to reverse warfarin.
• Desmopressin (DDAVP): releases stored factor VIII and von Willebrand factor in mild hemophilia A and many types of von Willebrand disease.
• Tranexamic acid: an antifibrinolytic that stabilizes clots, useful for mouth bleeding, nosebleeds and heavy periods.
• Vitamin K: for vitamin K deficiency and warfarin excess.
• Gene therapy: approved for some adults with severe hemophilia A or B.

Living with a factor deficiency

• Avoid aspirin and NSAIDs such as ibuprofen, which impair platelets. Use acetaminophen (paracetamol) for pain.
• Carry a medical alert card or bracelet.
• Tell dentists and surgeons before any procedure, so a treatment plan is in place.
• Keep vaccinations up to date, given under the skin where possible.
• Stay active with low-contact exercise to protect joints.

Frequently asked questions

What are the most common clotting factor deficiencies?

Von Willebrand disease is the most common inherited bleeding disorder, followed by hemophilia A (factor VIII) and hemophilia B (factor IX). Among acquired causes, liver disease, vitamin K deficiency and blood thinner medicines are by far the most common.

What are the symptoms of a clotting factor deficiency?

Common symptoms include easy bruising, frequent nosebleeds, bleeding gums, heavy periods, and prolonged bleeding after cuts, dental work, surgery or childbirth. Severe deficiencies can cause bleeding into joints and muscles, or into the brain after minor injury.

Can women have a clotting factor deficiency?

Yes. Von Willebrand disease and most rare factor deficiencies affect women and men equally. Women who carry the hemophilia gene can also have low factor levels. In women, heavy periods and heavy bleeding after childbirth are often the main signs.

Which factor deficiency has normal PT and aPTT?

Factor XIII deficiency. Standard clotting tests stay normal because they finish before factor XIII acts, so a specific factor XIII test is needed. Mild von Willebrand disease and platelet disorders can also give normal PT and aPTT results.

Can a clotting factor deficiency develop later in life?

Yes. Acquired deficiencies develop with liver disease, vitamin K deficiency, blood thinners, severe infection (DIC) or amyloidosis. Acquired hemophilia, caused by antibodies against factor VIII, appears suddenly, most often in older adults or after pregnancy.