Disorders of Secondary Hemostasis

• All disorders of secondary hemostasis are due to issues with plasma clotting factors
• Defects in factors can impair hemostasis through 1. decreased factor synthesis, 2. Production of weird molecules that interfere with coagulation pathways, 3. Loss or consumption of coag factors, and 4. inactivation of a factor by inhibitors or antibodies
• Factor I disorders include a -, hypo - , dys -, and hyper - fibrinogenemia
• Afibrinogenemia is rare and genetic and results in an absence of fibrinogen. Severe bleeding. Treatment is fresh frozen plasma (FFP) bc it has fibrinogen or direct fibrinogen given
• Hypofibrinogenemia is a disorder where too little fibrinogen is present in blood. Often secondary to liver disease. Most factors are produced in the liver!
• Dysfibrinogenemia is a genetic disorder causing structural defects to fibrinogen which affects clotting (e.g., altered adhesion to GPIIb-IIa)
• Hyperfibrinogenemia is when there's too much fibrinogen in the blood/. Pregnancy can cause this but overall is not a health risk
• Disorders of factor II include hypothrombinemia and prothrombin G20210 mutation
• Vitamin K is an essential cofactor that thrombin needs to activate fibrinogen.
• The vitamin K dependent proteins include II, VII, IX, and X. This group is also known as prothrombin complex concentrate when given as a treatment.
• Hypothrombinemia is autosomal recessive (and not very common). Anything less than 50 % thrombin activity will cause issues after trauma or surgery.
• Vitamin K is produced by microbiota
• Thrombosis is blood clotting and can lead to stroke, heart attack, and pulmonary embolism
• For disorders of factor II, give factor II, FFP, or prothrombin complex concentrate (PCC)
• Prothrombin G20210A mutation is caused by a single point mutation in the prothrombin gene causing elevated prothrombin. Elevated levels cause increase risk of thrombosis
• Prothrombin G20210 mutation generally in Caucasian people. Is worse for people with lupus and who are pregnant. Women with this mutation should not be on oral contraceptives!!
• Disorder of factor V include parahemophilia and Factor V Leiden Mutation
• Parahemophilia is an autosomal recessive disorder that is very rare. You can have skin discoloration, (eccymoses), menorrhagia (heavy periods) and bleeding. Treatment can be direct factor V or FFP
• Factor V is a very important cofactor whose production can be ramped up or down.
• Factor V Leiden Mutation is a common point mutation and causes a resistance to protein c, which inactives factor V to slow clot formation
• Thrombomodulin is a protein on the surface of endothelial cells that binds to thrombin, modulating its activity. The thrombomodulin-thrombin complex activates protein C, which inactivates V and VIII
• In Factor V Leiden Mutation, the binding site has a shape change and protein C can't bind there.
• Factor V Leiden Mutation causes increased risk of thrombosis. Treatment is anticoagulants like heparin for life
• Disorder of factor VIII is Hemophilia A
• Hemophilia A was very common in the royal house of Stuart and likely arose around Queen Victoria's time. It is a sex-linked recessive disorder
• Hemophilia A is more common in males because mutation is on X chromosome.
• The carrier protein for factor VIII is von Willebrand factor
• von Willebrand disease is the most common disorder of hemostasis and hemophilia A is the 2nd most common
• Factor VIII is the coagulant part of vWF
• Any less than 1% activity in hemophilia A will lead to severe bleeding. more than 30 % is not a concern.
• Hemophilia B has the same symptoms as A and is also sex-linked, but is caused by a deficiency in factor IX (aka christmas factor)
• Hemophilia B used to lump in with A until a doctor discovered that mixing blood of both patients caused normal clotting
• Clinical symptoms of Hemophilia A and B are internal bleeding, spontaneous hemorrhage and issues with injury or surgery.
• Treatment of Hemophilia A is giving factor VIII and FFP, and for B its giving factor IX, FFP, or PCC
• Hemophilia C is caused by a deficiency in factor XI. Unlike A and B, it is not sex linked, it is autosomal recessive (affects male and female equally)
• Frequency of hemophilia C carriers (heterozygous) in Ashkenazi Jewish popns nearly 1 in 8.
• If hemophilia C results in 10-15% activity, they don't need therapy. If they have less than 10%, they need therapy.
• Congenital Factor XIII deficiency is autosomal recessive. Being homozygous results in moderate to severe hemorrhaging disease. People undergoing major surgery are checked for this before then are sent home.
• Congenital F XIII deficiency can be treated with FFP, direct XIII, and even viral-inactivated concentrates
• In disseminated intravascular coagulation, (DIC) bleeding and clotting is NOT in balance. Either excess clotting or bleeding is occuring.