Hemophilia pathophysiology
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Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1];Associate Editor(s)-in-Chief: Simrat Sarai, M.D. [2]
Overview
Hemophilia is a genetic bleeding disorder resulting from the insufficient levels of clotting factors in the body. The clotting factors irregularity causes a lack of clumping of blood required to form a clot to plug a site of a wound. The genes involved in the pathogenesis of hemophilia include the F8 gene in hemophilia A and F9 gene in hemophilia B and C. Hemophilia predominantly affects the male population but the sub-type hemophilia C, with an autosomal inheritance pattern, can affect the males as well as females.
Pathophysiology
Physiology
The normal physiology of hemostasis can be summarized as follows:
- Hemostasis is a tightly regulated process whereby the body maintains a homeostatic balance to permit normal blood flow, without thrombosis or bleeding.[1]
- The process of hemostasis involves a fine balance between the procoagulant and anticoagulant factors. It attempts to maintain blood flow within the vascular compartment and promotes the formation of blood clots following vascular injury.[2]
- It also enables repair after vascular injury, promotes vessel healing, and maintains vessel integrity.
- Hemostasis can be divided into three phases. Each phase is explained as follows:
1. Primary hemostasis
- Endothelial damage marks the beginning of this phase.[3]
- It involves platelet adhesion, activation and aggregation, to form a platelet plug at the injury site.
- Circulating platelets and endothelial cells, both provide the source of von Willebrand factor (VWF).
- Von Willebrand factor (VWF) has two main functions. First, it acts as a mediator in binding of platelets to the sub-endothelium. Then it protects the circulating factor VIII from proteolytic degradation.[4][5]
- The endothelial cells, which normally promote anticoagulation, switch from anticoagulant to procoagulant upon vascular injury. They promote platelet aggregation by releasing the contents of their Weibel-Palade bodies and hence leading to enhanced local concentrations of von Willebrand factor (VWF) and tissue factor (TF).[6]
- The released von Willebrand factor (VWF) binds to the collagen on the exposed sub-endothelial surface, and is then utilized for platelet binding via the glycoprotein Ib (GPIb) complex.
- The platelets release their granules after undergoing a shape change. This event marks the formation of a platelet plug.
2. Secondary hemostasis
- The main goal of secondary hemostasis is to stabilize the platelet plug.[7]
- It involves the activation of coagulation system and coagulation factors to eventually produce cross-linked fibrinogen (“fibrin”).
- The process of platelet plug stabilization has been always referred to as the “Coagulation cascade” which can be separated into the intrinsic, extrinsic, and common pathways.
3. Fibrinolysis
- Fibrinolysis involves the process of physiological lysis of the clot, generated by the actions of primary and secondary hemostasis, to permit tissue repair under the supervision and help of multiple proteins.[8]
Cell-Based Model of Coagulation
- The cell-based model of hemostasis basically says that blood has to be exposed to cells containing the tissue factor (TF) for the initiation of the clotting process.[9]
- It better reflects true in vivo hemostasis.
- The model proposes three overlapping phases of hemostasis which are explained as follows:
a. Initiation
- It occurs on the surface of the tissue factor-bearing cell.
- Tissue factor-bearing cells such as the fibroblasts bind to the surface of platelets in an evolving thrombus.[9]
- Factor VII comes into direct contact with the tissue factor-bearing extravascular cells during vascular injury, and rapidly undergoes activation via the extrinsic pathway.
- Effective initiation means bringing FVIIa/TF activity into close proximity to the activated platelet surfaces.
b. Amplification
- It occurs on the surface of the platelets as they get activated.[10]
- Platelets adhere at the site of endothelial injury and get activated by thrombin.
- Platelet activation is marked by the execution of the following processes:
- The release of alpha granules which contain Factor V and von Willebrand factor (VWF)
- Binding to plasma proteins including von Willebrand factor (VWF)
- Promoting the assemblage of procoagulant complexes
- Ensuring prompt thrombin generation.
c. Propagation
- Propagation occurs on the surface of activated platelets.[11]
- It involves the assembly of “tenase” (FVIIa and FIXa/FVIIIa) and “prothrombinase” (FXa/FVa) complexes on the platelet surface, thus allowing thrombin generation to take place on a large scale which is necessary to form a hemostatic fibrin clot.[12]
Pathogenesis
- Hemophilia is an X-linked bleeding disorder caused by a deficiency or complete absence of coagulation factor VIII (hemophilia A) or factor IX (hemophilia B).[13]
- Bleeding in hemophilia occurs due to the failure of secondary hemostasis.[14]
- Primary hemostasis and the formation of platelet plug occurs normally but stabilization of the plug by fibrin is defective because of the generation of inadequate amounts of thrombin.[14]
- Clinical expression of hemophilia usually correlates with the activity of the coagulation factor and the disease can be classified as:
- Mild (factor level > 0.05–0.40 IU/mL)
- Moderate (factor level = 0.01–0.05 IU/mL)
- Severe (factor level < 0.01 IU/mL)
- Excessive bleeding in mild hemophilia patients occurs only after major injuries, surgery, or other invasive procedures.[13]
- In patients with moderate hemophilia, hemarthroses and muscle hematomas may occur after relatively minor injuries.[13]
- Bleeding occurs frequently and spontaneously in patients with severe hemophilia and this group can rarely also experience life-threatning episodes such as retroperitoneal and intracranial bleeds.[13][15]
Peculiar pathology of the types of hemophilia is discussed below:
Hemophilia A
- Hemophilia A is caused by an absence or deficiency of factor VIII (FVIII) protein activity.[16]
- It is a lifetime disease that is transmitted from usually asymptomatic carrier females to their male offspring.[16]
- Hemophilia A is characterized by recurrent bleeding, in particular into joints.[14]
- The recurrent bleeding in joints leads almost inevitably to severe arthropathy.[17]
- The molecular causes of FVIII deficiency can be divided into 3 main categories:
- Classic mutations in the F8 gene that cause structural changes in the FVIII molecule or even produce a truncated protein lacking essential functional domains.[18][19]
- Mutations in proteins that interact intracellularly in the correct folding and trafficking of the FVIII protein or mutations in extracellular plasma proteins such as von Willebrand factor (VWF).[20][21][22][23]
- The third category encompasses patients who have the clinical disease but have no mutations in the F8 gene or in any of the known interacting partners.[16]
- Less than 1/3 of the patients (mostly elderly with comorbidities) of hemophilia develop autoantibodies (inhibitors) against factor VIII (FVIII) that can lead to spontaneous and severe bleeding.[24]
Genes affected in Hemophilia
- Changes in the F8 gene are responsible for hemophilia A, while mutations in the F9 gene cause hemophilia B. The F8 gene provides instructions for making a protein called coagulation factor VIII. A related protein, coagulation factor IX, is produced from the F9 gene. Coagulation factors are proteins that work together in the blood clotting process. After an injury, blood clots protect the body by sealing off damaged blood vessels and preventing excessive blood loss.
- Mutations in the F8 or F9 gene lead to the production of an abnormal version of coagulation factor VIII or coagulation factor IX, or reduce the amount of one of these proteins. The altered or missing protein cannot participate effectively in the blood clotting process. As a result, blood clots cannot form properly in response to injury. These problems with blood clotting lead to continuous bleeding that can be difficult to control. The mutations that cause severe hemophilia almost completely eliminate the activity of coagulation factor VIII or coagulation factor IX. The mutations responsible for mild and moderate hemophilia reduce but do not eliminate the activity of one of these proteins.
- Another form of the disorder, known as acquired hemophilia, is not caused by inherited gene mutation. This rare condition is characterized by abnormal bleeding into the skin, muscles, or other soft tissues, usually beginning in adulthood. Acquired hemophilia results when the body makes specialized proteins called auto antibodies that attack and disable coagulation factor VIII. The production of auto antibodies is sometimes associated with pregnancy, immune system disorders, cancer, or allergic reactions to certain drugs. In about half of cases, the cause of acquired hemophilia is unknown.[25]
References
- ↑ Lippi G, Favaloro EJ, Franchini M, Guidi GC (February 2009). "Milestones and perspectives in coagulation and hemostasis". Semin. Thromb. Hemost. 35 (1): 9–22. doi:10.1055/s-0029-1214144. PMID 19308889.
- ↑ Lippi G, Franchini M, Guidi GC (2007). "Diagnostic approach to inherited bleeding disorders". Clin. Chem. Lab. Med. 45 (1): 2–12. doi:10.1515/CCLM.2007.006. PMID 17243907.
- ↑ Favaloro, Emmanuel (2017). Hemostasis and thrombosis : methods and protocols. New York: Humana Press Springer. ISBN 9781493971961.
- ↑ Sadler JE, Budde U, Eikenboom JC, Favaloro EJ, Hill FG, Holmberg L, Ingerslev J, Lee CA, Lillicrap D, Mannucci PM, Mazurier C, Meyer D, Nichols WL, Nishino M, Peake IR, Rodeghiero F, Schneppenheim R, Ruggeri ZM, Srivastava A, Montgomery RR, Federici AB (October 2006). "Update on the pathophysiology and classification of von Willebrand disease: a report of the Subcommittee on von Willebrand Factor". J. Thromb. Haemost. 4 (10): 2103–14. doi:10.1111/j.1538-7836.2006.02146.x. PMID 16889557.
- ↑ Yee A, Kretz CA (February 2014). "Von Willebrand factor: form for function". Semin. Thromb. Hemost. 40 (1): 17–27. doi:10.1055/s-0033-1363155. PMID 24338608.
- ↑ Favaloro, Emmanuel (2017). Hemostasis and thrombosis : methods and protocols. New York: Humana Press Springer. ISBN 9781493971961.
- ↑ Favaloro, Emmanuel (2017). Hemostasis and thrombosis : methods and protocols. New York: Humana Press Springer. ISBN 9781493971961.
- ↑ Kwaan H, Lisman T, Medcalf RL (March 2017). "Fibrinolysis: Biochemistry, Clinical Aspects, and Therapeutic Potential". Semin. Thromb. Hemost. 43 (2): 113–114. doi:10.1055/s-0036-1598000. PMID 28253534.
- ↑ 9.0 9.1 Hoffman, Maureane (2003). "A cell-based model of coagulation and the role of factor VIIa". Blood Reviews. 17: S1–S5. doi:10.1016/S0268-960X(03)90000-2. ISSN 0268-960X.
- ↑ Favaloro, Emmanuel (2017). Hemostasis and thrombosis : methods and protocols. New York: Humana Press Springer. ISBN 9781493971961.
- ↑ Favaloro, Emmanuel (2017). Hemostasis and thrombosis : methods and protocols. New York: Humana Press Springer. ISBN 9781493971961.
- ↑ Bonar RA, Lippi G, Favaloro EJ (2017). "Overview of Hemostasis and Thrombosis and Contribution of Laboratory Testing to Diagnosis and Management of Hemostasis and Thrombosis Disorders". Methods Mol. Biol. 1646: 3–27. doi:10.1007/978-1-4939-7196-1_1. PMID 28804815.
- ↑ 13.0 13.1 13.2 13.3 Mannucci PM, Tuddenham EG (June 2001). "The hemophilias--from royal genes to gene therapy". N. Engl. J. Med. 344 (23): 1773–9. doi:10.1056/NEJM200106073442307. PMID 11396445.
- ↑ 14.0 14.1 14.2 Bolton-Maggs, Paula HB; Pasi, K John (2003). "Haemophilias A and B". The Lancet. 361 (9371): 1801–1809. doi:10.1016/S0140-6736(03)13405-8. ISSN 0140-6736.
- ↑ Berntorp E, Shapiro AD (April 2012). "Modern haemophilia care". Lancet. 379 (9824): 1447–56. doi:10.1016/S0140-6736(11)61139-2. PMID 22456059.
- ↑ 16.0 16.1 16.2 Oldenburg, Johannes; El-Maarri, Osman (2006). "New Insight into the Molecular Basis of Hemophilia A". International Journal of Hematology. 83 (2): 96–102. doi:10.1532/IJH97.06012. ISSN 0925-5710.
- ↑ Roosendaal G, Lafeber FP (July 2006). "Pathogenesis of haemophilic arthropathy". Haemophilia. 12 Suppl 3: 117–21. doi:10.1111/j.1365-2516.2006.01268.x. PMID 16684006.
- ↑ Morris JA, Dorner AJ, Edwards CA, Hendershot LM, Kaufman RJ (February 1997). "Immunoglobulin binding protein (BiP) function is required to protect cells from endoplasmic reticulum stress but is not required for the secretion of selective proteins". J. Biol. Chem. 272 (7): 4327–34. PMID 9020152.
- ↑ Pipe SW, Morris JA, Shah J, Kaufman RJ (April 1998). "Differential interaction of coagulation factor VIII and factor V with protein chaperones calnexin and calreticulin". J. Biol. Chem. 273 (14): 8537–44. PMID 9525969.
- ↑ Nichols WC, Seligsohn U, Zivelin A, Terry VH, Hertel CE, Wheatley MA, Moussalli MJ, Hauri HP, Ciavarella N, Kaufman RJ, Ginsburg D (April 1998). "Mutations in the ER-Golgi intermediate compartment protein ERGIC-53 cause combined deficiency of coagulation factors V and VIII". Cell. 93 (1): 61–70. PMID 9546392.
- ↑ Zhang B, Cunningham MA, Nichols WC, Bernat JA, Seligsohn U, Pipe SW, McVey JH, Schulte-Overberg U, de Bosch NB, Ruiz-Saez A, White GC, Tuddenham EG, Kaufman RJ, Ginsburg D (June 2003). "Bleeding due to disruption of a cargo-specific ER-to-Golgi transport complex". Nat. Genet. 34 (2): 220–5. doi:10.1038/ng1153. PMID 12717434.
- ↑ Nishino M, Girma JP, Rothschild C, Fressinaud E, Meyer D (October 1989). "New variant of von Willebrand disease with defective binding to factor VIII". Blood. 74 (5): 1591–9. PMID 2506947.
- ↑ Gaucher C, Mercier B, Jorieux S, Oufkir D, Mazurier C (August 1991). "Identification of two point mutations in the von Willebrand factor gene of three families with the 'Normandy' variant of von Willebrand disease". Br. J. Haematol. 78 (4): 506–14. PMID 1832934.
- ↑ Kruse-Jarres R, Kempton CL, Baudo F, Collins PW, Knoebl P, Leissinger CA, Tiede A, Kessler CM (July 2017). "Acquired hemophilia A: Updated review of evidence and treatment guidance". Am. J. Hematol. 92 (7): 695–705. doi:10.1002/ajh.24777. PMID 28470674.
- ↑ "NIH Hemophilia Pathophysiology".