Hemophilia C

Hematology

Clinicals - History

Fact Explanation
Introduction Body’s normal mechanisms to stop the bleeding consists of main three responses: vascular, platelet and coagulatory response. Defect in any part of these responses can lead to abnormal bleeding manifestations. Coagulation cascade has main three pathways. Factors VII in extrinsic pathway, factors VIII, IX, XI and XII intrinsic pathway and V, X, fibrinogen and prothrombin in common pathway. Factor XI (F XI) is a plasma protein that involves in the intrinsic blood coagulation pathway. FXI deficiency has an autosomal inheritance with a severe deficiency is manifested in homozygotes and partial deficiency manifested in heterozygotes. Three independent point mutations have been identified in the factor XI gene, such as occurring in the normal mRNA splicing (type I), premature polypeptide termination (type II), and result in a specific amino acid substitution (type III). Though the bleeding manifestations are not severe, occasionally there can be lethal internal bleeding manifestations. The are not correlating with the severity of the deficiency as in contrast to patients with hemophilia A and B. Introduction
Body’s normal mechanisms to stop the bleeding consists of main three responses: vascular, platelet and coagulatory response. Defect in any part of these responses can lead to abnormal bleeding manifestations. Coagulation cascade has main three pathways. Factors VII in extrinsic pathway, factors VIII, IX, XI and XII intrinsic pathway and V, X, fibrinogen and prothrombin in common pathway. Factor XI (F XI) is a plasma protein that involves in the intrinsic blood coagulation pathway. FXI deficiency has an autosomal inheritance with a severe deficiency is manifested in homozygotes and partial deficiency manifested in heterozygotes. Three independent point mutations have been identified in the factor XI gene, such as occurring in the normal mRNA splicing (type I), premature polypeptide termination (type II), and result in a specific amino acid substitution (type III). Though the bleeding manifestations are not severe, occasionally there can be lethal internal bleeding manifestations. The are not correlating with the severity of the deficiency as in contrast to patients with hemophilia A and B.
Easy bruising, excessive bleeding with routine dental procedures, venepuncture, circumcision, bleeding from the umbilical stump and following trauma Defective clotting mechanism leads to easy bleeding particularly after trauma, and even may be spontaneous in severe disease. Easy bruising will become more evident once the child starts the ambulation. Easy bruising, excessive bleeding with routine dental procedures, venepuncture, circumcision, bleeding from the umbilical stump and following trauma
Defective clotting mechanism leads to easy bleeding particularly after trauma, and even may be spontaneous in severe disease. Easy bruising will become more evident once the child starts the ambulation.
Joint and muscle problems: Tingling, cracking, pain, stiffness, and inability to move the joint Weight-bearing joints are commonly affected bleeding in patients with hemophilia. Knee, elbow and ankle are commonly affected. Flexor muscles of the arms and gastrocnemius of the legs and iliopsoas muscles are frequently affected. Joint injury in hemophilia are associated with swelling of the joint, bleeding into soft tissue, increased cellular proliferation in the synovial membrane and intense inflammation. Joint and muscle problems: Tingling, cracking, pain, stiffness, and inability to move the joint
Weight-bearing joints are commonly affected bleeding in patients with hemophilia. Knee, elbow and ankle are commonly affected. Flexor muscles of the arms and gastrocnemius of the legs and iliopsoas muscles are frequently affected. Joint injury in hemophilia are associated with swelling of the joint, bleeding into soft tissue, increased cellular proliferation in the synovial membrane and intense inflammation.
Nasal bleeds, gum bleeds Tissues like oral cavity, or nasopharyngeal area which have a high fibrinolytic activity are more prone to get bleeding following trauma or surgery. Epistaxis is the bleeding from the nose that is due to the deficient clotting mechanism. Nasal bleeds, gum bleeds
Tissues like oral cavity, or nasopharyngeal area which have a high fibrinolytic activity are more prone to get bleeding following trauma or surgery. Epistaxis is the bleeding from the nose that is due to the deficient clotting mechanism.
Headache, stiff neck, vomiting, lethargy, irritability Spontaneous bleeding inside the central nervous system can cause intracranial haemorrhages and meningeal irritation. But this spontaneous bleeding is rare in haemophilia C patients. Patients with factor level <1% of normal are more susceptible to spontaneous bleeding. Subarachnoid haemorrhage and intraventricular haemorrhage are also seen in these patients. Headache, stiff neck, vomiting, lethargy, irritability
Spontaneous bleeding inside the central nervous system can cause intracranial haemorrhages and meningeal irritation. But this spontaneous bleeding is rare in haemophilia C patients. Patients with factor level <1% of normal are more susceptible to spontaneous bleeding. Subarachnoid haemorrhage and intraventricular haemorrhage are also seen in these patients.
Hematemesis, melena, frank red blood per rectum Spontaneous bleeding is rare even in patients with severe FXI deficiency. If there is a spontaneous bleeding from the mucosal surface of the gastrointestinal tract may cause passage of blood with vomitus, and black tary stools (malena) associated with upper GI bleeding. Hematemesis, melena, frank red blood per rectum
Spontaneous bleeding is rare even in patients with severe FXI deficiency. If there is a spontaneous bleeding from the mucosal surface of the gastrointestinal tract may cause passage of blood with vomitus, and black tary stools (malena) associated with upper GI bleeding.
Hematuria, renal colics Same as above due to the bleeding tendency and clot colics may occur causing loin to groin pain. Haematuria may occur particularly after damaging to the urinary tract by any means. Hematuria, renal colics
Same as above due to the bleeding tendency and clot colics may occur causing loin to groin pain. Haematuria may occur particularly after damaging to the urinary tract by any means.
Muscle pain Bleeding into muscles may form haematoma and may cause severe pain. Muscle pain
Bleeding into muscles may form haematoma and may cause severe pain.
Difficulty in breathing Massive haemothorax can be occured in haemophilic patients. Spontaneous pneumotrhorax may be associated with bleeding into the pleural cavity. Difficulty in breathing
Massive haemothorax can be occured in haemophilic patients. Spontaneous pneumotrhorax may be associated with bleeding into the pleural cavity.
Excess menstrual bleeding Menorrhagia is a frequent finding in females. Excess menstrual bleeding
Menorrhagia is a frequent finding in females.
Excessive bleeding following child birth Excess bleeding following child birth can result in some patients with haemophilia. Other causes of postpartum hemorrhage such as trauma, uterine atony, retained products of conception, uterine inversion and placenta previa need to be excluded. Excessive bleeding following child birth
Excess bleeding following child birth can result in some patients with haemophilia. Other causes of postpartum hemorrhage such as trauma, uterine atony, retained products of conception, uterine inversion and placenta previa need to be excluded.
History of consanguity / family history As this is a autosomal recessive condition, consanguity increases the risk of getting the disease to the offspring.
There can be affected males in the family while females are the carriers.
History of consanguity / family history
As this is a autosomal recessive condition, consanguity increases the risk of getting the disease to the offspring.
There can be affected males in the family while females are the carriers.
History of thromboebbolism/ immobolity Prolonged therapy with antifibrinolytic agents particularly in immobile patients or who are having history of thromboembolism have a high risk thrombus formation. History of thromboebbolism/ immobolity
Prolonged therapy with antifibrinolytic agents particularly in immobile patients or who are having history of thromboembolism have a high risk thrombus formation.

Clinicals - Examination

Fact Explanation
Tachycardia, tachypnea, hypotension These signs are due to haemorrhage. Tachycardia, tachypnea, hypotension
These signs are due to haemorrhage.
Pallor Low hemoglobin due to anaemia may found as result of acute or chronic blood loss. Pallor
Low hemoglobin due to anaemia may found as result of acute or chronic blood loss.
Joint tenderness, warmth, decreased range of moments Joints are frequently affected with bleeding. Joint may be complicated with effusion on certain situations. Joint tenderness, warmth, decreased range of moments
Joints are frequently affected with bleeding. Joint may be complicated with effusion on certain situations.
Bruising Due to the inufficient clotting mechanism. Bruising
Due to the inufficient clotting mechanism.
Neck stiffness These are due to the bleeding that causes meningeal irritation. Neck stiffness
These are due to the bleeding that causes meningeal irritation.
Altered mental status, focal neurological signs, bulging fontanels Spontaneous bleeding inside the central nervous system can cause intracranial haemorrhages. ICH may increase the intracranial pressure, causes cerebral edema, even neuronal death due to the direct mechanical effect. Altered mental status, focal neurological signs, bulging fontanels
Spontaneous bleeding inside the central nervous system can cause intracranial haemorrhages. ICH may increase the intracranial pressure, causes cerebral edema, even neuronal death due to the direct mechanical effect.
Hepatic/splenic tenderness, and peritoneal signs Hepatic/ splenic haematoma may rarely occur. Hepatic/splenic tenderness, and peritoneal signs
Hepatic/ splenic haematoma may rarely occur.
Tenderness over the costovertebral angle Renal colics may occur due to bleeding inside the urinary tract that causes clot colics. Tenderness over the costovertebral angle
Renal colics may occur due to bleeding inside the urinary tract that causes clot colics.
Dyspnea Hematoma formation can lead to airway obstruction. Dyspnea
Hematoma formation can lead to airway obstruction.
Joint contractures Mismanaged haemophilia with recurrent haemarthrosis will lead to joint damage and contracures. Joint contractures
Mismanaged haemophilia with recurrent haemarthrosis will lead to joint damage and contracures.
Features of compartment syndrome: severe tenderness, decreased sensation, pallor, parasthesia of the limb Compartment syndrome can occur due to the hematoma formation increasing the pressure inside the compartment. Features of compartment syndrome: severe tenderness, decreased sensation, pallor, parasthesia of the limb
Compartment syndrome can occur due to the hematoma formation increasing the pressure inside the compartment.
Signs of dehydration: Sunken eyes, dry skin, reduced skin turgor Dehydration may occur due to severe fluid loss. Signs of dehydration: Sunken eyes, dry skin, reduced skin turgor
Dehydration may occur due to severe fluid loss.

Investigations - Diagnosis

Fact Explanation
Activated partial thromboplastin time Activated partial thromboplastin time (aPTT) (reference interval 23–36 s) measures the activity of the intrinsic pathway of the clotting mechanism, and is prolonged in factor XI deficiency. Normal aPTT may be found in mild to moderate hemophilia. Activated partial thromboplastin time
Activated partial thromboplastin time (aPTT) (reference interval 23–36 s) measures the activity of the intrinsic pathway of the clotting mechanism, and is prolonged in factor XI deficiency. Normal aPTT may be found in mild to moderate hemophilia.
Prothrombin time and International Normalized Ratio (INR) Bleeding time and prothrombin time (reference interval 11.0–15.0 s), and International Normalized Ratio (INR) (reference interval 0.9–1.2) are normal as they assess the extrinsic coagulation pathway. Prothrombin time and International Normalized Ratio (INR)
Bleeding time and prothrombin time (reference interval 11.0–15.0 s), and International Normalized Ratio (INR) (reference interval 0.9–1.2) are normal as they assess the extrinsic coagulation pathway.
Bleeding time Bleeding time assess the Bleeding time
Bleeding time assess the
Factor XI assay Is reduced in haemophilia A due to the deficiency of factor . Factor XI assay
Is reduced in haemophilia A due to the deficiency of factor .
Testing for inhibitors Patient's plasma is mixed with normal plasma at 37°C for 1-2 hours and aPTT is checked. If the prolonged aPTT is not corrected, that is due to the presence of inhibitors and then the level of inhibitors need to be measured using the Bethesda method. Testing for inhibitors
Patient's plasma is mixed with normal plasma at 37°C for 1-2 hours and aPTT is checked. If the prolonged aPTT is not corrected, that is due to the presence of inhibitors and then the level of inhibitors need to be measured using the Bethesda method.
Platelet count and morphology This is important to exclude the other bleeding disorders particularly thrombocytopenia and platelet dysfunction. Platelet count has to be checked and it should be within the normal range as expected. Platelet count and morphology
This is important to exclude the other bleeding disorders particularly thrombocytopenia and platelet dysfunction. Platelet count has to be checked and it should be within the normal range as expected.
Haemoglobin level Hemoglobin/hematocrit is important to assess theblood loss and severity of anemia. Haemoglobin level
Hemoglobin/hematocrit is important to assess theblood loss and severity of anemia.

Investigations - Management

Fact Explanation
Factor XI level This will give a guide to the current state of disease. Particularly after a surgery, the factor level needs to be maintained at least 5-7 days following minor surgery and and 10-14 days after major surgery. Factor XI level
This will give a guide to the current state of disease. Particularly after a surgery, the factor level needs to be maintained at least 5-7 days following minor surgery and and 10-14 days after major surgery.
Factor innhibitor testing It is important to check the level of inhibitors as patients with high-titer inhibitors (> 5-10 BU)may need bypass clotting factors such as activated prothrombin complex concentrate, or rVIIa. Factor innhibitor testing
It is important to check the level of inhibitors as patients with high-titer inhibitors (> 5-10 BU)may need bypass clotting factors such as activated prothrombin complex concentrate, or rVIIa.
Hemoglobin and hematocrit levels Hemoglobin and hematocrit levels may vary from normal as in a rapid blood loss, both blood (fluid) and cells are loss maintaining the relative ratio hence the concentration and the time is taken for the fluid balances to occur following an acute bleeding. It may be decreased depending on the type and severity of the bleeding problem in bleeding disorders. Hemoglobin and hematocrit levels
Hemoglobin and hematocrit levels may vary from normal as in a rapid blood loss, both blood (fluid) and cells are loss maintaining the relative ratio hence the concentration and the time is taken for the fluid balances to occur following an acute bleeding. It may be decreased depending on the type and severity of the bleeding problem in bleeding disorders.
Factor XI level Should be done prior to any surgery as correction of the deficient state is needed before the surgery. (as mentioned in the management section) Factor XI level
Should be done prior to any surgery as correction of the deficient state is needed before the surgery. (as mentioned in the management section)
Serum bilirubin Serum bilirubin may be elevated due to excessive catabolism of red blood cells. Serum bilirubin
Serum bilirubin may be elevated due to excessive catabolism of red blood cells.
CT / MRI scan of the brain Spontaneous or traumatic intracranial hemorrhage may be evaluated using CT/MRI scan. Joint cartilage, synovium, and joint space evaluation may also be possible with MRI. CT / MRI scan of the brain
Spontaneous or traumatic intracranial hemorrhage may be evaluated using CT/MRI scan. Joint cartilage, synovium, and joint space evaluation may also be possible with MRI.
Ultrasonography USS is useful to evaluate the joints with effusions. Ultrasonography
USS is useful to evaluate the joints with effusions.

Management - Supportive

Fact Explanation
Immediate management Assessment of airway and breathing, is particularly important as they can present with upper airway obstruction following retropharyngeal. The immediate surgical airway may be needed. Circulatory collapse may occur in a massive haemorrhage. Disability and exposure will follow later. Immediate management
Assessment of airway and breathing, is particularly important as they can present with upper airway obstruction following retropharyngeal. The immediate surgical airway may be needed. Circulatory collapse may occur in a massive haemorrhage. Disability and exposure will follow later.
Multidesciplinary approach Haematologist, physician, orthopedic surgeon, physiotherapist etc should be involved in the management of haemophilic patients. Multidesciplinary approach
Haematologist, physician, orthopedic surgeon, physiotherapist etc should be involved in the management of haemophilic patients.
Patient education Parents of the affected child need a full explanation of the nature of the disease, its complications and importance of complying with the treatment. Precautions to minimize bleeding tendency such as avoiding contact sports, injuries when handling the equipments are needed. It is better to inform the teachers at school with permission of the parents and educate them on what to do as immediate measures. Patient education
Parents of the affected child need a full explanation of the nature of the disease, its complications and importance of complying with the treatment. Precautions to minimize bleeding tendency such as avoiding contact sports, injuries when handling the equipments are needed. It is better to inform the teachers at school with permission of the parents and educate them on what to do as immediate measures.
Management of other complications Upper GI bleeding, haematuria, intracranial haemorrhage may need specific supportive management after correcting the factor level. Associated psychological disturbances , learning problems due to recurrent school abstinence may need special attention. Management of other complications
Upper GI bleeding, haematuria, intracranial haemorrhage may need specific supportive management after correcting the factor level. Associated psychological disturbances , learning problems due to recurrent school abstinence may need special attention.
Follow up Apart from the routine assessment for features of bleeding manifestations, patients with complications such as intracranial haemorrhages need specific attention as they are more likely to have neurocognitive, academic, behavioral, adaptive, and motor functioning deficienciesrequiring long-term follow-up. Follow up
Apart from the routine assessment for features of bleeding manifestations, patients with complications such as intracranial haemorrhages need specific attention as they are more likely to have neurocognitive, academic, behavioral, adaptive, and motor functioning deficienciesrequiring long-term follow-up.

Management - Specific

Fact Explanation
Management of high risk bleeding situations Central nervous system hemorrhage including intracranial hemorrhage and spinal hematoma, soft-tissue hemorrhage predisposing to airway compromise retropharyngeal hemorrhage, hemorrhage along facial planes, neck hematoma associated with dissection, large tongue hematoma, gastrointestinal bleeding including hematemesis, hematochezia or melena from bleeding telangiectasia, splenic rupture, kidney capsular rupture, liver laceration, hematoma of bowel wall and haemorrhage around the eye are some of these high risk bleeding manifestations. Hemostasis has to be restored and blood should be sent for investigations. Immediate infusion of factor 8, 50 IU/kg body weight. Continuous clotting factor infusions needs to be given with measured factor level til the acute bleeding is settled. Management of high risk bleeding situations
Central nervous system hemorrhage including intracranial hemorrhage and spinal hematoma, soft-tissue hemorrhage predisposing to airway compromise retropharyngeal hemorrhage, hemorrhage along facial planes, neck hematoma associated with dissection, large tongue hematoma, gastrointestinal bleeding including hematemesis, hematochezia or melena from bleeding telangiectasia, splenic rupture, kidney capsular rupture, liver laceration, hematoma of bowel wall and haemorrhage around the eye are some of these high risk bleeding manifestations. Hemostasis has to be restored and blood should be sent for investigations. Immediate infusion of factor 8, 50 IU/kg body weight. Continuous clotting factor infusions needs to be given with measured factor level til the acute bleeding is settled.
Factor replacement Factor XI replacement ia done with antifibrinolytics, fresh-frozen plasma (FFP), and factor XI concentrates. The plasma factor XI level does not respond to L-desamino-8-D-arginine vasopressin, and cryoprecipitate as it does not contain factor XI. The plasma half-life of factor XI is usually 45 h, and once-daily administration of a factor XI-containing product is recomended. Factor replacement
Factor XI replacement ia done with antifibrinolytics, fresh-frozen plasma (FFP), and factor XI concentrates. The plasma factor XI level does not respond to L-desamino-8-D-arginine vasopressin, and cryoprecipitate as it does not contain factor XI. The plasma half-life of factor XI is usually 45 h, and once-daily administration of a factor XI-containing product is recomended.
Preparing for a surgery Major surgeries involving the central nervous system, cardiothoracic, vascular, head and neck and abdomen or procedures involving tissues with high fibrinolytic activity (oropharynx or urinary tract) are at high risk of bleeding in patients with haemophilia C. They should be given prophylactic therapy with factor replacement upto 40–45% for 10–14 days in severe deficiency. Preparing for a surgery
Major surgeries involving the central nervous system, cardiothoracic, vascular, head and neck and abdomen or procedures involving tissues with high fibrinolytic activity (oropharynx or urinary tract) are at high risk of bleeding in patients with haemophilia C. They should be given prophylactic therapy with factor replacement upto 40–45% for 10–14 days in severe deficiency.
Prophylaxis Bleeding risk is more with surgical prcedures than spontaneous bleeding as in haemophilia A and B. Factor replacement should be used for epidural anesthesia. Dental procedures such as tooth extraction and minor surgical procedures are given antifibrinolytic therapy (ε-amino caproic acid 5–6 g four-times daily or tranexamic acid 1 g four-times daily), starting 12 h prior to the procedure and continuing for 7 days, as prophylaxis. These drugs inhibit urokinase and fibrinolytic activity. Prophylaxis
Bleeding risk is more with surgical prcedures than spontaneous bleeding as in haemophilia A and B. Factor replacement should be used for epidural anesthesia. Dental procedures such as tooth extraction and minor surgical procedures are given antifibrinolytic therapy (ε-amino caproic acid 5–6 g four-times daily or tranexamic acid 1 g four-times daily), starting 12 h prior to the procedure and continuing for 7 days, as prophylaxis. These drugs inhibit urokinase and fibrinolytic activity.
Management of inhibitor formation Patients with very low (<1%) plasma factor XI levels are more likely to develop inhibitory antibodies when exposed to plasma products. High-titer inhibitors (> 5-10 BU) or patients who are having an anamnestic response to FVIII will be treated with bypass clotting factors such as an activated prothrombin complex concentrate, or rVIIa. Management of inhibitor formation
Patients with very low (<1%) plasma factor XI levels are more likely to develop inhibitory antibodies when exposed to plasma products. High-titer inhibitors (> 5-10 BU) or patients who are having an anamnestic response to FVIII will be treated with bypass clotting factors such as an activated prothrombin complex concentrate, or rVIIa.

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