Background

Factor II deficiency, also known as hypoprothrombinemia, is a rare inherited bleeding disorder by a factor II deficiency, a crucial clotting protein in the blood coagulation cascade. Factor II, also called prothrombin, plays a central role in converting fibrinogen into fibrin, forming stable blood clots to prevent excessive bleeding.

Factor II deficiency is usually inherited in an autosomal recessive manner, and its severity can vary, with some individuals experiencing mild bleeding tendencies, while others may have more significant bleeding complications. The disorder can present at any age, and affected individuals may experience prolonged bleeding after injuries, surgeries, or dental procedures.

Diagnosis is made through laboratory tests measuring factor II levels, and treatment typically involves the administration of clotting factor or fresh frozen plasma to correct clotting abnormalities and manage bleeding episodes effectively. Genetic counseling is essential for affected individuals and their families to understand inheritance patterns and receive appropriate management. 

Epidemiology

• Prevalence: The prevalence of Factor II deficiency is estimated to be less than 1 in 2 million individuals in the general population. It is considered one of the rarer types of inherited bleeding disorders. 
• Inheritance: Factor II deficiency is usually inherited in an autosomal recessive pattern. This means that to have the disorder, an individual must inherit a non-functioning or reduced factor II gene from both parents. If a person inherits one normal and one affected gene, they become carriers of the disorder but typically do not exhibit symptoms. 
• Geographical Distribution: The prevalence of Factor II deficiency is relatively uniform worldwide. It has been reported in various populations across different regions, although specific data on the frequency of the disorder in different ethnic or racial groups are limited due to its rarity. 
• Age of Onset: Factor II deficiency is typically present at birth, as it is an inherited genetic disorder. However, the severity of condition may vary among affected individuals, and symptoms may become apparent at different ages. In some cases, the disorder may only be diagnosed after an injury, surgery, or other traumatic event that triggers bleeding complications. 
• Gender: Factor II deficiency affects both males and females equally, as it is not linked to the sex chromosomes. 
• Complications: Severe cases of Factor II deficiency can lead to spontaneous bleeding, particularly into joints or internal organs, which can be life-threatening. However, many individuals with milder forms of the disorder may not experience significant bleeding episodes and may lead relatively normal lives. 
• Screening and Diagnosis: Factor II deficiency is usually diagnosed based on family history, clinical symptoms, and blood tests to measure prothrombin levels and assess clotting function. Genetic testing can confirm diagnosis & identify specific mutations in the factor II gene. 

Anatomy

Pathophysiology

Normal Blood Clotting Process: The blood clotting process, also known as hemostasis, involves a complex series of interactions between different clotting factors and platelets. When a blood vessel is injured, the body initiates a cascade of reactions to form a stable blood clot to stop bleeding. 

• Vasoconstriction: Blood vessels constrict to reduce blood flow at the site of injury, temporarily slowing bleeding. 
• Platelet Plug Formation: Platelets aggregate at the injury site, forming the temporary plug that helps stop bleeding. 
• Coagulation Cascade: It involves a series of enzymatic reactions that ultimately converts fibrinogen into fibrin. Fibrin forms a mesh-like structure which reinforces the platelet plug thereby creating a stable blood clot. 
• Fibrinolysis: Once the injury is healed, the body initiates fibrinolysis to dissolve the blood clot and restore normal blood flow. 

Factor II Deficiency: Factor II deficiency occurs when there is a deficiency or dysfunction of prothrombin, which is a key factor in the coagulation cascade. Prothrombin is primarily synthesized in the liver and requires vitamin K for its production. 

• Impaired Fibrin Formation: In Factor II deficiency, the conversion of fibrinogen to fibrin is compromised due to the reduced or dysfunctional prothrombin. As a result, the formation of a stable blood clot is impaired. 
• Prolonged Bleeding: The impaired coagulation process leads to prolonged bleeding after injury, surgery, or trauma. Individuals with Factor II deficiency may experience easy bruising, nosebleeds, bleeding gums, and prolonged or excessive bleeding from wounds. 
• Inheritance: Factor II deficiency is usually inherited in an autosomal recessive pattern, which means that an individual must inherit two non-functioning or reduced factor II genes, one from each parent, to develop the disorder. 

Etiology

• Genetic Mutation: The F2 gene is located on chromosome 11 (11p11-q12), and mutations in this gene can result in reduced or dysfunctional prothrombin production. The majority of Factor II deficiency cases are inherited in an autosomal recessive manner. This means that an individual must inherit two non-functioning or reduced F2 gene copies, one from each parent, to develop the disorder. 
• Inheritance: When both parents are carriers of a single defective F2 gene and do not exhibit symptoms of Factor II deficiency, each child has a 25% chance of inheriting two copies, a 50% chance of being a carrier (asymptomatic carrier), and a 25% chance of inheriting two non-functioning or reduced copies (affected with the disorder). 
• De Novo Mutations: In rare cases, Factor II deficiency may occur due to de novo mutations, where a genetic mutation spontaneously arises in an individual with no family history of the disorder. These cases are not inherited from parents and occur sporadically. 
• Genetic Heterogeneity: Factor II deficiency is a genetically heterogeneous disorder, meaning that different mutations in the F2 gene can cause the condition. Different mutations may lead to varying degrees of prothrombin deficiency and, consequently, different clinical manifestations. 
• Acquired Factor II Deficiency: In some rare cases, Factor II deficiency can be acquired rather than inherited. Acquired factor II deficiency may occur due to certain medical conditions or the use of medications that interfere with prothrombin production or function.  
• Risk Factors: The primary risk factor for Factor II deficiency is having parents who are carriers of the defective F2 gene. Individuals with a history of the disorder are may have an increased risk of inheriting the condition. 

Genetics

Prognostic Factors

Severity of Factor II Deficiency: 

• The severity of Factor II deficiency is a crucial prognostic factor. Individuals with more significant reductions in prothrombin levels are more likely to experience severe bleeding symptoms, such as spontaneous bleeding into joints or internal organs. Mild cases of Factor II deficiency may not lead to significant bleeding episodes. 

Frequency and Severity of Bleeding Episodes: 

• The frequency & severity of bleeding episodes are essential prognostic factors. Individuals with frequent and severe bleeding episodes may experience a significant impact on daily lives and require more intensive management. 

Age of Onset: 

• The age at which Factor II deficiency symptoms become evident can influence the prognostic outlook. Early identification and management of the disorder may help prevent complications and improve outcomes. 

Type of Bleeding Symptoms: 

• The type of bleeding symptoms experienced by the individual can also affect the prognosis. Spontaneous bleeding into joints or internal organs can lead to more severe complications compared to minor skin bleeding or easy bruising. 

Compliance with Treatment: 

• Compliance with prescribed treatments and management strategies can significantly impact the prognosis. Individuals who adhere to treatment plans and preventive measures may experience better outcomes and a reduced risk of complications. 

Presence of Comorbidities: 

• The presence of other medical conditions or comorbidities can influence the overall prognosis. Individuals with Factor II deficiency who have other medical conditions may require more comprehensive management and monitoring. 

Genetic Mutation Type: 

• The specific genetic mutation in the F2 gene causing Factor II deficiency can vary among individuals. Some mutations may result in more severe deficiency, while others may cause milder effects. 

Clinical History

Age at Presentation: 

• Factor II deficiency is typically present from birth due to its inherited nature. However, the age at which symptoms become noticeable can vary among affected individuals. Some individuals may have mild or asymptomatic forms of the disorder and may not be diagnosed until later in life, while others may experience noticeable bleeding tendencies from an early age. 

Physical Examination

Skin Examination: 

• The skin is carefully examined for signs of bleeding, such as bruises (ecchymosis), petechiae (tiny red or purple spots caused by small blood vessel bleeding), and hematoma (a localized collection of blood outside the blood vessels). 

Mucous Membrane Examination: 

• The mucous membranes, such as the oral cavity and conjunctiva, are assessed for any signs of bleeding, including gum bleeding (gingival bleeding), epistaxis (nosebleeds), or other bleeding from mucous membranes. 

Joint Examination: 

• If there is a history of joint bleeding (hemarthrosis) or joint pain, the joints are examined for signs of swelling, tenderness, and limited range of motion. 

Assessment of Wounds and Scars: 

• Any existing wounds or scars are evaluated for healing patterns and any signs of delayed healing or excessive bleeding associated with these wounds. 

Menstrual Examination (for females): 

• In females of reproductive age, the menstrual history may be reviewed to assess the pattern and severity of menstrual bleeding (menorrhagia). 

Evaluation of Past Bleeding Episodes: 

• The patient is questioned about any past bleeding episodes, surgeries, or traumatic injuries to understand their bleeding history comprehensively. 

Family History: 

• A family history is taken to determine if there are other family members with bleeding disorders or a history of consanguinity, as Factor II deficiency is inherited. 

Laboratory Investigations: 

• Laboratory tests, such as coagulation studies, are typically performed to measure prothrombin levels and assess the clotting function. These tests help confirm the diagnosis of Factor II deficiency and determine the severity of the disorder. 

Age group

Associated comorbidity

Factor II deficiency is a primary bleeding disorder, and its clinical history primarily revolves around bleeding tendencies. However, individuals with this condition may not have other associated comorbidities directly related to Factor II deficiency.  

Associated activity

Acuity of presentation

• The acuity of presentation refers to the speed and severity with which symptoms of Factor II deficiency become apparent. This can vary among affected individuals. 
• Asymptomatic Presentation: Some individuals with Factor II deficiency may have mild or asymptomatic forms of the disorder. They may not experience significant bleeding symptoms and may only be identified as carriers of the defective F2 gene through family testing or screening. 
• Mild Bleeding Symptoms: Mild presentations of Factor II deficiency may involve occasional and minor bleeding symptoms, such as easy bruising, nosebleeds, or bleeding gums. These symptoms may not significantly impact daily activities. 
• Moderate to Severe Bleeding Episodes: In more severe cases, individuals with Factor II deficiency may experience moderate to severe bleeding episodes, such as prolonged bleeding after injuries or surgeries, heavy menstrual bleeding in females, or spontaneous bleeding into joints or internal organs. 

Differential Diagnoses

Von Willebrand Disease (VWD): 

• It is the most common bleeding disorder and is characterized by a deficiency or dysfunction of von Willebrand factor and stabilization of factor VIII. Like Factor II deficiency, VWD can lead to easy bruising, mucous membrane bleeding, and prolonged bleeding after injuries or surgeries. 

Hemophilia: 

• Hemophilia is another inherited bleeding disorder that affects the coagulation cascade. Hemophilia is primarily due to deficiencies in either factor VIII (Hemophilia A) and factor IX (Hemophilia B). In severe cases, hemophilia can cause spontaneous joint bleeding and internal bleeding, similar to the more severe forms of Factor II deficiency. 

Vitamin K Deficiency: 

• Vitamin K is essential for several clotting factors synthesis, including prothrombin. Severe vitamin K deficiency can lead to impaired clotting function, resembling the bleeding symptoms seen in Factor II deficiency. 

Liver Disease: 

• The liver is responsible for producing many clotting factors, including prothrombin. Liver disease like cirrhosis, can lead to reduced clotting factor production, resulting in bleeding tendencies. 

Disseminated Intravascular Coagulation (DIC): 

• It is a serious condition characterized by widespread clot formation and simultaneous depletion of clotting factors, including prothrombin. This depletion can lead to bleeding complications. 

Acquired Factor II Inhibitor: 

• In rare cases, individuals may develop acquired inhibitors against factor II, leading to reduced prothrombin function and bleeding symptoms. 

Platelet Disorders: 

• Platelet disorders, such as immune thrombocytopenic purpura (ITP) or platelet function defects, can cause bleeding symptoms similar to those seen in Factor II deficiency. 

Laboratory Studies

Imaging Studies

Procedures

Histologic Findings

Staging

Treatment Paradigm

• Replacement Therapy: The cornerstone of treatment involves providing factor II replacement to raise the level of prothrombin in the blood and correct clotting abnormalities. Factor II concentrate or fresh frozen plasma (FFP) containing prothrombin is administered intravenously to manage bleeding episodes or to prevent bleeding in high-risk situations, such as surgery or dental procedures. 
• Prophylactic Treatment: In some individuals with severe Factor II deficiency or a history of recurrent bleeding, prophylactic factor II replacement therapy may be considered to prevent spontaneous bleeding episodes. Prophylactic treatment is especially important before surgeries or invasive procedures. 
• Genetic Counseling: Genetic counseling is crucial for affected individuals & their families to understand the inheritance pattern of Factor II deficiency, assess the risk of passing on the genetic mutation, and receive guidance for family planning. 
• Management of Bleeding Complications: For individuals with Factor II deficiency experiencing bleeding episodes, prompt treatment with factor II concentrate or FFP is essential to control bleeding and prevent complications. 
• Monitoring and Follow-Up: Regular monitoring of prothrombin levels and factor II activity is important to assess the effectiveness of treatment and adjust management as needed. Periodic follow-up with healthcare professionals, including hematologists or specialists in bleeding disorders, is necessary to ensure optimal care and address any concerns. 
• Lifestyle Modifications: Encouraging a healthy lifestyle, including a regular exercise, balanced diet, and avoidance of activities that may increase the risk of injury, is important to minimize the risk of bleeding complications. 
• Education and Preparedness: Individuals with Factor II deficiency should be educated about their condition, including recognizing signs of bleeding, knowing when to seek medical attention, and having a plan in place for managing bleeding episodes. 
•  

by Stage

by Modality

Chemotherapy

Radiation Therapy

Surgical Interventions

Hormone Therapy

Immunotherapy

Hyperthermia

Photodynamic Therapy

Stem Cell Transplant

Targeted Therapy

Palliative Care

non-pharmacological-treatment-of-factor-ii-deficiency

• Regular Medical Follow-Up: Regular visits to a hematologist or a specialist in bleeding disorders are essential to monitor Factor II levels, assess bleeding tendencies, and adjust treatment as needed. 
• Medication Adherence: If prescribed by a healthcare provider, it is crucial to follow the treatment plan, which may include prophylactic or on-demand clotting factor replacement therapy or other medications to manage bleeding episodes. 
• Avoiding Traumatic Injuries: Minimize the risk of injuries that could cause bleeding. Use appropriate safety measures during activities that may pose a risk of injury, such as sports or handling sharp objects. 
• Dental Care: Inform dental professionals about the Factor II deficiency before any dental procedures. Special precautions may be necessary to minimize bleeding risk during dental treatments. 
• Avoiding Certain Medications: Some medications, such as nonsteroidal anti-inflammatory drugs (NSAIDs) and certain blood-thinning drugs, can increase bleeding risk.  
• Gentle Physical Activities: Engage in regular physical activities, but avoid activities that carry a high risk of injury or trauma.  
• Healthy Diet: A balanced diet rich in vitamin K-containing foods can support clotting factor production. However, it’s important not to make significant dietary changes without consulting a healthcare provider, as vitamin K intake may affect blood clotting. 
• Genetic Counseling and Family Screening: If there is a known genetic mutation causing Factor II deficiency, genetic counseling can help individuals understand the inheritance pattern and assess the risk of passing the condition to their children. Family screening may be recommended to identify other family members with the deficiency. 
• Bleeding Management Plan: Develop a bleeding management plan with a healthcare provider to know what steps to take in case of bleeding episodes and when to seek medical attention. 

Use of Antithrombin Supplements in the treatment of Factor II Deficiency

Antithrombin III, human (ATnativ, Thrombate III): 

• It is a naturally occurring anticoagulant protein that inhibits several clotting factors, including thrombin (factor IIa), and helps to prevent blood clot formation. 
• In the context of Factor II deficiency, ATIII can be administered as a supplement to increase the overall anticoagulant activity and reduce the risk of bleeding episodes. 
• ATIII is typically administered intravenously and may be used for both prophylactic purposes in individuals with severe deficiency and as part of the treatment of bleeding episodes. 

Antithrombin, recombinant (Atryn): 

• Recombinant antithrombin (rAT) is a synthetic form of antithrombin produced using genetic engineering techniques. It has a structure and function identical to naturally occurring AT. 
• Like ATIII, recombinant antithrombin can be administered intravenously to individuals with Factor II deficiency to supplement the deficient or dysfunctional prothrombin and restore anticoagulant activity. 
• Recombinant antithrombin has the advantage of being a more standardized product compared to plasma-derived AT concentrates and carries a lower risk of transmitting infections. 

The use of antithrombin supplements, whether ATIII or recombinant antithrombin, is typically reserved for individuals with severe Factor II deficiency or those with recurrent bleeding episodes who require additional support to prevent and manage bleeding complications. 

Use of Antihemophilic Agents in the treatment of Factor II Deficiency

• Antihemophilic agents, including pooled plasma, solvent-detergent treated (PLAS+SD), are not typically used in the treatment of Factor II deficiency (prothrombin deficiency). These agents are primarily utilized in the treatment of hemophilia, a different bleeding disorder caused by deficiencies or dysfunction of clotting factor VIII (hemophilia A) or clotting factor IX (hemophilia B). 
• Factor II deficiency is a distinct bleeding disorder characterized by reduced levels or dysfunction of clotting factor II (prothrombin), which is involved in the blood clotting process. The treatment of Factor II deficiency usually involves the use of antithrombin supplements, such as Antithrombin III, human (ATnativ, Thrombate III), or Antithrombin, recombinant (Atryn), as mentioned in the previous response. 
• Antihemophilic agents like pooled plasma, solvent-detergent treated (PLAS+SD), are specifically indicated for the treatment of hemophilia and are used to replace the missing or deficient clotting factor VIII or factor IX in individuals with hemophilia A or B, respectively. These agents are derived from pooled human plasma and are treated with solvent-detergent to inactivate any potential viruses, ensuring their safety. 

Use of Vitamins, Fat-Soluble in the treatment of Factor II Deficiency

• Transfusion of Blood Products: Transfusion of red blood cells, platelets, or clotting factor concentrates (PCC or FFP) may be necessary to restore clotting factors and control bleeding. 
• Surgical Hemostasis: In cases of severe bleeding from surgical sites or traumatic injuries, surgical interventions to achieve hemostasis may be required. 
• Interventional Radiology Procedures: In certain situations, interventional radiology procedures, such as embolization or catheter-directed therapies, may be used to control bleeding in specific vascular locations. 

management-of-factor-ii-deficiency

Diagnosis and Evaluation: 

• The initial phase involves diagnosing Factor II deficiency through laboratory tests to measure prothrombin levels and identify any genetic mutations associated with the condition. 
• Further evaluation may be done to assess the extent of the deficiency, identify any underlying conditions or risk factors, and rule out other potential causes of abnormal bleeding. 

Acute Treatment and Bleeding Management: 

• In the acute setting, such as when a patient presents with bleeding episodes, the focus is on providing prompt and appropriate treatment to control bleeding and manage complications. 
• Based on the severity of bleeding episode, interventions such as administration of clotting factor concentrates (e.g., prothrombin complex concentrate, fresh frozen plasma) or blood transfusions may be necessary to restore clotting factors and achieve hemostasis. 

Long-Term Management: 

• Once acute bleeding episodes are controlled, the long-term management phase begins. This phase involves ongoing treatment and preventive measures to minimize the risk of bleeding. 
• Antithrombin supplements, such as Antithrombin III, human (ATnativ, Thrombate III), or Antithrombin, recombinant (Atryn), are typically administered to supplement the deficient or dysfunctional prothrombin and restore anticoagulant activity. 

Monitoring and Follow-Up: 

• Regular monitoring of prothrombin levels, clotting factors, and bleeding tendencies is essential to assess the effectiveness of the management plan and make necessary adjustments as needed. 
• Regular follow-up with healthcare providers, including hematologists or specialists in bleeding disorders, is crucial to ensure ongoing care and address any concerns. 

Medication

Future Trends

Media Gallary

References

www.Factor II (Prothrombin) Deficiency.hemophilia.org 

www.causes of factor II deficiency.mountsinai.org