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Hereditary bleeding disorders occur due to the absence or deficiency of specific clotting proteins. The three most common hereditary bleeding disorders are hemophilia A (factor VIII deficiency), hemophilia B (factor IX deficiency) and von Willebrand disease. This activity reviews the evaluation and management of hereditary bleeding disorders and highlights the role of the interprofessional team in caring for affected patients. Objectives: Describe the presentation of hereditary bleeding disorders. Describe the evaluation of hereditary bleeding disorders. Review the treatment options for hereditary bleeding disorders. Explain the importance of improving care coordination amongst the interprofessional team to enhance the management of patients with hereditary bleeding disorders. Access free multiple choice questions on this topic.

The body possesses innate mechanisms to control bleeding in the setting of an injury. An understanding of these basic physiologic processes is critical for identifying and diagnosing bleeding disorders. The hemostatic system is responsible for maintaining blood in a fluid state, free of platelet aggregation and thrombus formation, with the help of prostacyclin, antithrombin III, and nitric oxide within endothelial cells. These naturally occurring substances found in the blood help prevent clots by converting plasminogen to plasmin, promoting fibrinolysis. Damage or injury to the endothelium initiates a cascade of events aimed at controlling bleeding. Disruption of the endothelium first causes local vasoconstriction, limiting blood flow to the area. Primary hemostasis is initiated by platelets, which release von Willebrand factor (vWF), a large plasma glycoprotein produced and stored in endothelial cells and megakaryocytes. Platelets and vWF combine to form a plug at the site of injury. Circulating vWF continues to bind with collagen and Factor VIII as well as other endothelial substances, allowing the platelet plug to adhere to the area of injury.[1] Through activation of the clotting cascade (see image) and secondary hemostasis, this initial platelet plug is reinforced to a sturdy fibrin clot. The clotting cascade operates through a dual-process system in which various clotting factors become activated, resulting in the formation of a fibrin strand (clot) at the site of tissue injury. A deficiency of any of the essential clotting factors results in difficulty forming a fibrin clot, and excessive bleeding can occur. See Table. Bleeding Disorders. Bleeding disorders fall into 2 main categories: inherited and acquired. Inherited bleeding disorders have a genetic predisposition and involve a deficiency of coagulation factors. Acquired bleeding disorders can be caused by conditions that an individual may develop at any point during their lifetime. These can be broader in range and dependent on comorbid conditions. The focus of this discussion is on congenital coagulopathies; acquired bleeding disorders are outside the scope of the information presented here.

Hemophilia, an x-linked heredity disorder, is diagnosed by an abnormal concentration of Factor VIII or IX. Approximately one-third of cases arise from a spontaneous mutation. Von Willebrand disease, with autosomal dominant inheritance, has variable penetrance, and clinical symptoms can vary from person to person. The most severe pathology occurs in homozygotes.[2] Neither bleeding disorder is more common in any specific race.

Hereditary bleeding disorders result from the absence or deficiency of specific clotting proteins that act as procoagulants through precise interactions within the clotting cascade. The 3 most common are hemophilia A (Factor VIII deficiency), hemophilia B (Factor IX deficiency), and von Willebrand disease. Hemophilia A is an X-linked recessive genetic disorder affecting 1 in 5000 males, making it the most common congenital coagulopathy. Hemophilia B is an X-linked genetic coagulopathy affecting 1 in 30,000 male births. Hemophilia B is also known as Christmas disease. The origin of its namesake is from Steven Christmas, the first patient diagnosed with Hemophilia B in 1952. Since hemophilia is genetic, its prevalence increases in populations with higher levels of consanguinity. Females may be asymptomatic carriers of the hemophilia gene or may be found to have a partial deficiency of the specific factors involved. Von Willebrand disease is an autosomal dominant trait with no predilection for sex; however, women are more likely to exhibit symptoms as a result of increased bleeding during menstruation.[3] Von Willebrand disease was first described in 1926 by Finnish physician Erik Adolf von Willebrand. According to the CDC, von Willebrand disease affects approximately 1% of the general population.[4]

Bleeding disorders may present in correlation with their severity, and some may be undetected until a major trauma or surgery occurs. Patients with a severe form of hemophilia, categorized as less than 1% of normal plasma levels, often present with 20 to 30 episodes of epistaxis a year, excessive bleeding after minor traumas or into muscles and joints (hemarthrosis). Diagnosis usually occurs within the first 2 years of life and can be immediately evident after circumcision. Newborns can also present with intracranial hemorrhages, cephalohematoma, or umbilical cord bleeding immediately following delivery.[5] Those with a more moderate form of the disease (6 to 30% of normal levels) may only bleed excessively after surgery or a major trauma.

Bleeding disorders may present in correlation with their severity, and some may be undetected until a major trauma or surgery occurs. Patients with a severe form of hemophilia, categorized as less than 1% of normal plasma levels, often present with 20 to 30 episodes of epistaxis a year, excessive bleeding after minor traumas or into muscles and joints (hemarthrosis). Diagnosis usually occurs within the first 2 years of life and can be immediately evident after circumcision. Newborns can also present with intracranial hemorrhages, cephalohematoma, or umbilical cord bleeding immediately following delivery.[5] Those with a more moderate form of the disease (6 to 30% of normal levels) may only bleed excessively after surgery or a major trauma. Von Willebrand factor (vWF) is a glycoprotein produced in endothelial cells and megakaryocytes that is responsible for facilitating platelet binding after injury of the endothelial surface occurs. Von Willebrand disease is a common congenital bleeding disorder characterized by a deficiency or dysfunction of vWF. Factor VIII levels can be affected as well. The disease presents similarly to a platelet abnormality and can exhibit variable clinical symptomatology, ranging from mild mucocutaneous bleeding of the nose or gingiva to menorrhagia to hemarthrosis in more severe cases. The disease is categorized into 3 types. Type I is the most common, representing 60 to 80% of cases. Type 1 von Willebrand disease is a heterozygous deficiency in which there may be only 20% to 40% of normal levels of vWF in addition to a reduction in Factor VIII levels. Patients with Type I von Willebrand disease can present with mild clinical symptoms like a propensity for easy bruising, mucosal bleeding, or menorrhagia.[6] Medications that inhibit prostaglandin and thromboxane synthesis may significantly exacerbate symptoms and can often aid in initial diagnosis.[7] Type 2 von Willebrand disease is less common, accounting for approximately 17% of reported cases, and is characterized by a qualitatively abnormal vWF, which can also be associated with thrombocytopenia and decreased Factor VIII. There are 4 distinct subtypes within the Type 2 category. Type 2A lacks a normal vWF multimer because of abnormal proteolysis or reduced secretion of the factor. Type 2B is a mutation that causes vWF to be hyperactive and to have increased binding affinity for platelets, leading to the formation of complexes that are quickly cleared from the circulation, ultimately resulting in thrombocytopenia.[8] Type 2M possesses a decreased platelet binding ability to vWF with depleted factor levels, and Type 2N exhibits a decrease in binding of vWF to Factor VIII. Type 3 is the rarest and most severe form of the disease, accounting for approximately 3% of cases, in which there are markedly diminished levels of vWF and FVIII.

Hemophilia: While mild hemophilia may only present after a traumatic injury or surgery, those with a moderate to severe form of the disease may exhibit hallmark characteristics such as mucosal or gingival bleeding, easy bruising, and hematoma formation. The concern is bleeding into joints, particularly in the ankles, knees, and elbows, known as hemarthrosis. Hemarthrosis can initiate an inflammatory process, in which the joints become painfully swollen and eventually limit motion.[9] There is potential for the perpetuation of a vicious cycle whereby the joints are damaged, resulting in synovitis, and an area for subsequent bleeding can occur. Over time, hemophilic arthropathy results in joint space narrowing, bone cysts, and decreased range of motion. Bleeding into muscle tissue from minor traumas can result in anemia and compression of vital structures and nerves, leading to compartment syndrome. Bleeding less frequently occurs in the urinary and gastrointestinal tracts. These patients are at significant risk of intracranial bleeds, which would be a life-threatening emergency. Hemophilia can present in infancy with cephalohematoma formation after vaginal birth and with significant bleeding after circumcision. Von Willebrand Disease Von Willebrand disease can exhibit clinical signs and symptoms starting in childhood, with a history of easy bruising and bleeding. While patients with a very mild version of the disease may not have clinical symptoms at all, patients with vWF that is qualitatively or quantitatively low may present with a predisposition to mucosal bleeding and episodic epistaxis. Women with von Willebrand disease may have significant menorrhagia, which is often a presenting sign of the illness, precipitating a workup and eventual diagnosis.[10] These patients can also go unrecognized until undergoing major surgery or experiencing a traumatic injury.

Laboratory Evaluation for Bleeding Disorders Laboratory testing is essential for diagnosing bleeding disorders. However, the specific panels necessary for an accurate diagnostic evaluation are not standardized and may vary significantly between hospitals and regions. Routine laboratory analysis for clotting disorders starts with platelet count, prothrombin time (PT), partial thromboplastin time (aPTT), the international normalized ratio (INR), and bleeding time. The platelet count should not only be sufficient (normal = 150,000 to 500,000/ml) but also functional. The bleeding time assesses platelet function. Bleeding times can be delayed in a patient with vWF deficiency or from specific medications that interfere with platelet function (NSAIDS, aspirin, and valproic acid). PT (normal = 11.5 to 14s) represents the function of coagulation factors II, V, VII, and X, which are the hepatically synthesized vitamin K-dependent factors. The PT and INR are affected by patients taking warfarin, as it interferes with the synthesis of vitamin K-dependent factors. The INR (normal=0.8 to 1.2) is a ratio used to estimate the percentage of functional clotting factors. For example, an INR of between 2 and 3 correlates approximately to 10% of active clotting factors present. At least 30% of the clotting factors must be present for normal coagulation. Partial thromboplastin time (normal = 25 to 40s) measures the efficacy of von Willebrand Factor and factors VIII, IX, XI, and XII.[11] Hemophiliacs have an elevated aPTT and a normal PT/INR, as well as normal bleeding time and platelet count. The aPTT, a measure of the intrinsic pathway, is elevated due to low FVIII levels. An elevated aPTT should prompt investigation into individual factor levels, specifically Factor VIII and IX.[12] When evaluating specific factor levels, the amount of the factor present determines the severity of the disease. When the diagnosis is suspected, the emphasis must also include family history, including maternal male family members.

Hemophiliacs have an elevated aPTT and a normal PT/INR, as well as normal bleeding time and platelet count. The aPTT, a measure of the intrinsic pathway, is elevated due to low FVIII levels. An elevated aPTT should prompt investigation into individual factor levels, specifically Factor VIII and IX.[12] When evaluating specific factor levels, the amount of the factor present determines the severity of the disease. When the diagnosis is suspected, the emphasis must also include family history, including maternal male family members. Diagnosis of von Willebrand disease is represented by increased bleeding time and a decrease in vWF levels as measured by the ristocetin cofactor collagen binding, in addition to a history of bleeding and a positive family history of von Willebrand disease. The recommendation is that patients be tested at least 3 times before the official diagnosis, as vWF levels fluctuate with stress, pregnancy, exercise, and inflammatory processes. There are also subtle differences in vWF levels by gender and blood type.[13] Von Willebrand disease requires factor multimer assays to diagnose the specific subtype. Additionally, the aPTT may be mildly elevated in approximately 50% of patients with von Willebrand disease, secondary to low factor VIII levels.

The mainstay treatment for hemophilia is factor replacement, either prophylactically or on an as-needed basis. Recombinant-derived Factor VIII and IX concentrates are available and help prevent viral transmission.[14] Recombinant Factor VIII increases the plasma concentration by 2% for every 1 IU/kg, and recombinant Factor IX produces an increase of 0.8% for every 1IU/kg given. The goals of correction are to achieve a 50% plasma value for bleeding risk management, such as surgery, and 100% correction in the setting of major trauma. These levels should be achieved 30 minutes before surgery and maintained for 2 to 7 days after surgery. The timing of subsequent doses is determined based on the factor half-life, which is typically 8 to 12 hours.

The mainstay treatment for hemophilia is factor replacement, either prophylactically or on an as-needed basis. Recombinant-derived Factor VIII and IX concentrates are available and help prevent viral transmission.[14] Recombinant Factor VIII increases the plasma concentration by 2% for every 1 IU/kg, and recombinant Factor IX produces an increase of 0.8% for every 1IU/kg given. The goals of correction are to achieve a 50% plasma value for bleeding risk management, such as surgery, and 100% correction in the setting of major trauma. These levels should be achieved 30 minutes before surgery and maintained for 2 to 7 days after surgery. The timing of subsequent doses is determined based on the factor half-life, which is typically 8 to 12 hours. The treatment of von Willebrand disease consists of desmopressin (DDAVP) or cryoprecipitate. DDAVP enhances vWF release in patients with Type 1 von Willebrand disease. DDAVP is a synthetic derivative of antidiuretic hormone that acts on type 2 vasopressin receptors. It works by stimulating the release of vWF from endothelial cells via signaling through the cyclic adenosine monophosphate pathway, which prompts the release of Weibel-Palade bodies into the endothelial cells and eventually into the plasma.[15] Additionally, DDAVP works on the renal collecting duct as an anti-diuretic. It reduces the amount of water that is eliminated in the urine, potentially causing dilutional hyponatremia; therefore, patients should have fluid restriction maintained while receiving this medication.[16] DDAVP, administered intravenously (0.3 mcg/kg), increases plasma Factor VIII and VWF levels by 3 to 5 times their baseline levels within 30 to 60 minutes. DDAVP can also be administered subcutaneously (0.3 mcg/kg) or at fixed intranasal doses, which is convenient for prophylactic treatment at home. DDAVP administration is expected to raise levels to 30 to 50% in patients with a baseline of 10% factor activity, which may be sufficient for low-risk procedures but may require further supplementation to achieve adequate vWF levels for trauma or major surgery. Patients with a baseline factor level of 20% who receive DDAVP can see levels rise to 60 to 100%, which is suitable for most surgical procedures. Approximately 10% of patients in the Type 1 category may fail to respond to DDAVP; therefore, the recommendation is to administer a trial of DDAVP at diagnosis or before clinical need. Patients with Type 2 and 3 von Willebrand disease typically require replacement products consisting of Factor VIII and vWF. It is also important to note that patients with Type 2a and 3 do not respond to DDAVP, as Type 2a has dysfunctional vWF and Type 3 lacks releasable vWF stores. Type 2b should never be given DDAVP, as it is contraindicated due to its potential thrombogenicity.[17]

The treatment of von Willebrand disease consists of desmopressin (DDAVP) or cryoprecipitate. DDAVP enhances vWF release in patients with Type 1 von Willebrand disease. DDAVP is a synthetic derivative of antidiuretic hormone that acts on type 2 vasopressin receptors. It works by stimulating the release of vWF from endothelial cells via signaling through the cyclic adenosine monophosphate pathway, which prompts the release of Weibel-Palade bodies into the endothelial cells and eventually into the plasma.[15] Additionally, DDAVP works on the renal collecting duct as an anti-diuretic. It reduces the amount of water that is eliminated in the urine, potentially causing dilutional hyponatremia; therefore, patients should have fluid restriction maintained while receiving this medication.[16] DDAVP, administered intravenously (0.3 mcg/kg), increases plasma Factor VIII and VWF levels by 3 to 5 times their baseline levels within 30 to 60 minutes. DDAVP can also be administered subcutaneously (0.3 mcg/kg) or at fixed intranasal doses, which is convenient for prophylactic treatment at home. DDAVP administration is expected to raise levels to 30 to 50% in patients with a baseline of 10% factor activity, which may be sufficient for low-risk procedures but may require further supplementation to achieve adequate vWF levels for trauma or major surgery. Patients with a baseline factor level of 20% who receive DDAVP can see levels rise to 60 to 100%, which is suitable for most surgical procedures. Approximately 10% of patients in the Type 1 category may fail to respond to DDAVP; therefore, the recommendation is to administer a trial of DDAVP at diagnosis or before clinical need. Patients with Type 2 and 3 von Willebrand disease typically require replacement products consisting of Factor VIII and vWF. It is also important to note that patients with Type 2a and 3 do not respond to DDAVP, as Type 2a has dysfunctional vWF and Type 3 lacks releasable vWF stores. Type 2b should never be given DDAVP, as it is contraindicated due to its potential thrombogenicity.[17] Replacement Products

The treatment of von Willebrand disease consists of desmopressin (DDAVP) or cryoprecipitate. DDAVP enhances vWF release in patients with Type 1 von Willebrand disease. DDAVP is a synthetic derivative of antidiuretic hormone that acts on type 2 vasopressin receptors. It works by stimulating the release of vWF from endothelial cells via signaling through the cyclic adenosine monophosphate pathway, which prompts the release of Weibel-Palade bodies into the endothelial cells and eventually into the plasma.[15] Additionally, DDAVP works on the renal collecting duct as an anti-diuretic. It reduces the amount of water that is eliminated in the urine, potentially causing dilutional hyponatremia; therefore, patients should have fluid restriction maintained while receiving this medication.[16] DDAVP, administered intravenously (0.3 mcg/kg), increases plasma Factor VIII and VWF levels by 3 to 5 times their baseline levels within 30 to 60 minutes. DDAVP can also be administered subcutaneously (0.3 mcg/kg) or at fixed intranasal doses, which is convenient for prophylactic treatment at home. DDAVP administration is expected to raise levels to 30 to 50% in patients with a baseline of 10% factor activity, which may be sufficient for low-risk procedures but may require further supplementation to achieve adequate vWF levels for trauma or major surgery. Patients with a baseline factor level of 20% who receive DDAVP can see levels rise to 60 to 100%, which is suitable for most surgical procedures. Approximately 10% of patients in the Type 1 category may fail to respond to DDAVP; therefore, the recommendation is to administer a trial of DDAVP at diagnosis or before clinical need. Patients with Type 2 and 3 von Willebrand disease typically require replacement products consisting of Factor VIII and vWF. It is also important to note that patients with Type 2a and 3 do not respond to DDAVP, as Type 2a has dysfunctional vWF and Type 3 lacks releasable vWF stores. Type 2b should never be given DDAVP, as it is contraindicated due to its potential thrombogenicity.[17] Replacement Products There is a human plasma-derived Factor VIII concentrate with an even higher vWF concentration. This product has been the subject of extensive study and is deemed the safest option for factor replacement, as it has undergone pasteurization to inactivate blood-borne viruses. It has approval from the Food and Drug Administration (FDA) for the treatment and prevention of bleeding disorders in adult patients with Hemophilia A, as well as adult and pediatric patients with von Willebrand disease.[18]

There is a human plasma-derived Factor VIII concentrate with an even higher vWF concentration. This product has been the subject of extensive study and is deemed the safest option for factor replacement, as it has undergone pasteurization to inactivate blood-borne viruses. It has approval from the Food and Drug Administration (FDA) for the treatment and prevention of bleeding disorders in adult patients with Hemophilia A, as well as adult and pediatric patients with von Willebrand disease.[18] Factor VIII replacement with a human plasma-derived Factor VIII concentrate requires a simple weight-based calculation. The patient’s weight (in kg) is multiplied by the desired percent level of Factor VIII, assuming the starting level is 0. That number then gets multiplied by the volume of distribution, which is approximately 0.5.[19] Thus, the dose of human plasma-derived concentrate of Factor VIII = weight in kg x desired Factor VIII level x 0.5. For a 60kg female, with a target goal of 50% Factor VIII level: 60 x 50 x 0.5 = 1500 units of Factor VIII. Alphanate is another commercially available, virally inactivated product with Factor VIII and ristocetin cofactor activity essential for vWF support. The FDA has approved its use for both adults and children with Hemophilia A or von Willebrand disease who require treatment or prevention of spontaneous or trauma-related bleeding, including surgery. Factor IX concentrate is a commercially available product and has been subjected to various purification techniques to eliminate the risk of viral transmission upon administration. These products have FDA approval for use in the prevention and control of bleeding in patients with factor IX deficiency.[20]. Dosing of Factor IX concentrate = weight in kg x desired factor level x volume of distribution (which is 1 for Factor IX). For a 60kg female with a target goal of 100% Factor IX level: 60 x 100 x 1 = 6000 units. Allogenic Replacement Therapy Fresh frozen plasma (FFP) contains Factor VIII and vWF, but large volumes are needed to obtain adequate factor levels (20 to 25mL/kg).

Factor IX concentrate is a commercially available product and has been subjected to various purification techniques to eliminate the risk of viral transmission upon administration. These products have FDA approval for use in the prevention and control of bleeding in patients with factor IX deficiency.[20]. Dosing of Factor IX concentrate = weight in kg x desired factor level x volume of distribution (which is 1 for Factor IX). For a 60kg female with a target goal of 100% Factor IX level: 60 x 100 x 1 = 6000 units. Allogenic Replacement Therapy Fresh frozen plasma (FFP) contains Factor VIII and vWF, but large volumes are needed to obtain adequate factor levels (20 to 25mL/kg). Cryoprecipitate is a human plasma-derived product containing high levels of Factor VIII, vWF, and fibrinogen (Factor I). It comes packaged in small volumes, so multiple bags are often required to obtain the desired level of the factor. Virus inactivation is not routinely applied to these products; therefore, virally inactivated replacement products are considered a safer alternative to FFP and cryoprecipitate. The absence of factor IX in cryoprecipitate negates its use in Hemophilia B. Platelet transfusions are necessary when bleeding continues despite normal Factor VIII levels. Platelets can transport and localize vWF to the site of vascular injury. Antifibrinolytic Acid Therapy Aminocaproic acid is a synthetic analog of lysine used to control or prevent hemorrhage. It competitively reduces the conversion of plasminogen to plasmin, thereby inhibiting fibrinolysis and promoting clot formation. It is typically administered as an intravenous infusion during a surgical procedure, but is also available in an oral form for home use in patients with bleeding disorders. It is available as a mouthwash or as a tablet for the treatment of oral bleeding, recurrent epistaxis, or menorrhagia. This agent is FDA approved in the treatment of patients with bleeding disorders and is often useful as an adjunct therapy in patients with coagulopathic potential.

Aminocaproic acid is a synthetic analog of lysine used to control or prevent hemorrhage. It competitively reduces the conversion of plasminogen to plasmin, thereby inhibiting fibrinolysis and promoting clot formation. It is typically administered as an intravenous infusion during a surgical procedure, but is also available in an oral form for home use in patients with bleeding disorders. It is available as a mouthwash or as a tablet for the treatment of oral bleeding, recurrent epistaxis, or menorrhagia. This agent is FDA approved in the treatment of patients with bleeding disorders and is often useful as an adjunct therapy in patients with coagulopathic potential. Tranexamic acid is a synthetic medication made from lysine, which acts by competitively inhibiting plasminogen activation and is considered more potent than aminocaproic acid. At higher concentrations, it can act as a non-competitive inhibitor of plasmin. It has 10 times the potency of aminocaproic acid and is FDA-approved for use in patients with bleeding disorders. It is available in intravenous and oral formulations. The oral preparation can also help with the treatment of minor recurrent bleeding at home and with preparation for dental work.[21] Hormonal Treatments Oral contraceptives such as oral progestins and depot medroxyprogesterone have been shown to be effective in women with Type 1 von Willebrand disease with menorrhagia by significantly elevating circulating vWF levels. While the exact mechanism of estrogen's influence on vWF is not entirely understood, it is hypothesized to occur through its lipophilic nature, allowing it to penetrate the cytoplasm and bind to nuclear receptors, thereby increasing transcription of various clotting proteins.[22]

The differential diagnosis for bleeding disorders includes: Malignancy Severe liver failure Thrombocytopenia Vitamin K deficiency Antithrombin III deficiency Massive transfusion Disseminated intravascular coagulation Lupus anticoagulant Protein C deficiency Protein S deficiency Idiopathic thrombocytopenic purpura (ITP) Medication side effects

Patients living with congenital bleeding disorders can expect to live full, productive lives with appropriate medical treatment, education, and a management plan in case of trauma or surgery. Patients should consider wearing a medical identification bracelet so that they can receive proper management in case they are involved in significant trauma or are unable to communicate their medical history verbally.

The World Bleeding Disorder Registry (WBDR) comprises a record of patients with bleeding disorders who receive care through Hemophilia Treatment Centers worldwide and have voluntarily allowed their identities and private healthcare information to be entered into a web-based platform. This global data collection aids the advancement of understanding the disease through evidence-based advocacy initiatives. The WBDR is the only global registry of people with bleeding disorders around the world. The accessibility of the information collected in this database strengthens the ability to diagnose and treat people with hemophilia.[23] Hematology nurses, internists, and hematologists should be familiar with the WBDR, as it provides online access to patient data. The management and treatment of bleeding disorders require the collaborative efforts of an interprofessional health team that includes physicians, specialists, specialty-trained nurses, and pharmacists, all working and communicating across disciplines to bring about the most effective treatment and outcomes.