Kembara Xtra - Medicine - Hemophilia

Kembara Xtra - Medicine - Hemophilia 
Introduction 
Individuals with hemophilia A or B have a tendency to bleed easily due to a deficiency in the coagulation proteins factor VIII or factor IX. The majority of instances are brought on by inherited genetic alterations in the coagulation proteins factor VIII or factor IX. However, it is believed that spontaneous mutations cause 30% of all hemophilia cases.
Clinical tests cannot discriminate between hemophilia A and B, but tests that look for levels of factors VIII and IX can.
Serum coagulation factor levels correlate with disease severity as follows: - Severe: frequent spontaneous bleeding (factor activity 1%); - Moderate: sporadic spontaneous bleeding; - Prolonged bleeding with minor trauma or surgery (factor activity 1-5%); - Mild: infrequent spontaneous bleeding; severe bleeding with major trauma or surgery (factor activity 5-40%).
Hemophilia A and B both cause frequent bleeding and have comparable degrees of factor deficiency.


Epidemiology 
Hemophilia affects 1,125,000 persons worldwide, according to estimates.

80–85% of those with hemophilia have hemophilia A, and the remaining 15–20% have hemophilia B.
Prevalence
Hemophilia A is estimated to affect 24.6 out of every 100,000 male babies (9.5 of these babies had severe hemophilia A).
According to estimates, there are 5 instances of hemophilia B per 100,000 male infants (1.5 cases of severe hemophilia B).


Pathophysiology and Etiology 
When vascular endothelium is damaged, subendothelial tissue factors are made visible. These factors interact with platelets, plasma proteins, and coagulation factors to form a localized platelet plug that aids in hemostasis. Factor X, FXa, is activated by complexes including factors VIII and IX through the intrinsic coagulation route. The conversion of prothrombin to thrombin, which is the result of interactions with FXa downstream, mediates platelet activation and fibrin deposition required for stabilizing the platelet plug.
Factor VIII or factor IX deficiency reduces the amount of FXa produced, which causes an unstable platelet plug and poor hemostasis.

Genetics
Displays an X-chromosome-linked pattern of inheritance.
Female carriers are typically asymptomatic; males are nearly entirely affected. Both of the X chromosomes in females with hemophilia are affected, or one X chromosome is diseased and the other is inactive.
Carriers may have symptomatically low levels of the clotting factor, which could cause them to bleed after surgery.
Due to the same genetic abnormality, males in the same family have identical impairments and to varying degrees of severity.

Prevention 
The type of treatment items utilized, the factor deficit, inhibitor status, and the starting treatment doses for mild, moderate, or severe bleeding should all be listed on the medical ID badges that patients should wear.
Prior to invasive surgeries, births, and if bleeding tendencies appear, factor VIII and IX levels in affected individuals' immediate families should be assessed.
In order to facilitate genetic counseling, at-risk female family members should be offered genetic testing.
To stop gum bleeding, regular dental visits and good oral hygiene are advised.

Diagnosis 
History and initial presentation: Two thirds of hemophilia patients who present have a favorable family history. Testing for factor levels should be performed on all male newborns born to known carriers.
Early childhood excessive or easy bruising; spontaneous bleeding, especially in joints, muscles, or soft tissue; typical age of presentation: mild (36 months), moderate (8 months), severe (1 month); pregnancy considerations; genetic counseling should be given to asymptomatic carriers either prior to or during pregnancy. Treat all male infants born to a carrier as though they have hemophilia; if a male infant is possibly impacted, suggest planned cesarean delivery. Avoid vacuum or forceps births and placing electrodes on the fetal scalp (1)[A].
- If mild hemophilia A or B is suspected, test the infant's clotting factor levels at birth and again at 6 months of age (factor levels may be normal at birth in minor hemophilia instances). Testing can be done on cord blood.
Life-threatening bleeding include intracranial hemorrhage, which is typically caused by trauma, and hematomas of the gut wall, which can result in obstruction or intussusception with pain that looks like an appendicitis.
- Bleeding in the neck or throat: may result in airway obstruction
Infants may display irritability or diminished limb use as a result of serious bleeds, known as hemarthrosis, which typically affect the ankles, elbows, and knees.
Adults may experience prodromal stiffness, severe pain, and joint swelling.
 Repeated joint bleeding damages cartilage and subchondral bone and causes arthopathy:
Muscular hematomas commonly affect the quadriceps, iliopsoas, and forearm. They may cause compartment syndrome and ischemic nerve damage, such as femoral nerve neuropathy brought on by undetected retroperitoneal hemorrhage, mucous membrane bleeding, such as in the genitourinary tract, resulting in hematuria, and pseudotumor syndrome, which is caused by untreated hemorrhage that results in

Multiple Diagnoses 
Von Willebrand syndrome
Anticoagulant medication (e.g., warfarin, rivaroxaban, heparin) for vitamin K deficiency (Factor IX is vitamin K dependent).
Hemophilia C and acquired hemophilia A are examples of other factor deficiencies, along with afibrinogenemia, dysfibrinogenemia, fibrinolytic abnormalities, and platelet diseases.
Abuse of children

Laboratory Results 
Initial examinations (lab, imaging)
Screening tests include the CBC with platelet count, PT, aPTT, platelet function, or bleed time; the aPTT is typically prolonged. Patients with moderate hemophilia may have normal aPTT levels.
- PT, function, and platelet count are all normal.
Follow-up tests include mixing studies, vWF, and assessments of the activity of factors VIII:C and IX. In a mixing study, the patient's plasma is combined with a pool of healthy plasma. In the absence of inhibitors, such as acquired factor inhibitors and lupus anticoagulants, prolonged aPTT corrects.
vWF is typical.
Diagnosis based on factor VIII:C or IX activity - Mild: 5 to 40 IU/dL - Moderate: 1 to 5 IU/dL - Severe: 1 IU/dL

Tests in the Future & Special Considerations
It is advised that affected individuals and their families seek genetic counseling and take part in genotyping to discover a specific underlying mutation; this information may assist forecast inhibitor risk/bleeding severity and individualize treatment.
Inhibitors of factors VIII and IX: - Screen before invasive procedures and at regular intervals using the Nijmegen or Bethesda assay, which measures the alloantibody titer.
Diagnostic Techniques/Other Genetic testing of a sample of chorionic villus or fluid collected by amniocentesis should be made available to pregnant female carriers as a prenatal diagnosis option.
Pathology of the afflicted joints, as determined by the test results, includes synovial hemosiderosis, articular cartilage degradation, thickening of the periarticular tissues, and bone hypertrophy.

Management 
An integrated, multidisciplinary, comprehensive care paradigm that includes a hematologist, physical therapist, nurse, and social worker delivers the best care.

 Treat acute bleeds as soon as possible; start treatment right away.
Fibrin glue products may be helpful for oozing. For surgical prophylaxis, if major surgery is performed, factor levels should be kept at >30-50% for around 2 weeks after the procedure.
Antifibrinolytics (aminocaproic acid, tranexamic acid) may be administered during dental extractions.
- In hemophilia A, desmopressin (DDAVP) may be used in minor procedures.
It is important to teach patients and their caregivers how to manage their care at home, including bleed recognition, self-infusion techniques, self-care, and pain control.
Acetaminophen, selective COX-2 inhibitors, and opioids may be used to treat the pain associated with persistent hemophilic arthropathy (other NSAIDs should be avoided).

Vaccinations against hepatitis A and B are advised.
Encourage patients to exercise: Patients should stay away from contact sports with high impact. Sports leagues should be promoted.


Medication 
Initial Line
Low frequency of acute bleeds and episodes of life-threatening hemorrhage compared to on-demand therapy. Standard of care for children with severe hemophilia A or B to prevent joint bleeds and joint degeneration. Prophylaxis: administration of specific factor replacement therapy in the absence of bleeding to maintain adequate baseline plasma levels sufficient for hemostasis in all severity categories.
In order to lessen the risk of bleeding, gene therapy, extended half-life recombinant factor VIIa, and other nonfactor agents like fitusiran (RNAi therapy), as well as antitissue factor pathway inhibitor agents, are currently being developed.
- On-demand therapy: medication given in reaction to a bleeding episode
The location and intensity of the bleeding affect the amount and length of factor replacement:
Mild bleedings are accurate to a factor level of roughly 30–50%. Large muscle bleeds and significant hemorrhages call for correction to levels between 50% and 100%.
Levels between 50% and 100%, maintained with bolus dose or continuous infusion, are necessary for life-threatening bleeding.

Specific agents include: - Hemophilia A: The preferred method of treatment is replacement with factor VIII concentrates; there are two sources of the factor available: - Recombinant factor VIII
Dosage: Giving 1 IU of factor VIII (the equivalent of 1 mL of plasma) per kilogram of body weight will result in a 2% increase in the recipient's plasma level.
Purified plasma-derived factor VIII: The plasma-derived factor is treated to inactivate viruses (HIV, hepatitis B, and hepatitis C), although there are still theoretical dangers. Donor pool is vetted.
- Hemophilia B: Plasma-derived factor IX and recombinant factor IX (preferred) are both commercially available. Replacement with factor IX concentrates is the preferred treatment.

Dosage: Administration of 1 IU/kg body weight will result in a 1% increase in plasma factor IX levels.
Inhibitor development should be suspected in hemophilia patients with inhibitors (neutralizing alloantibodies to factors VIII or IX) (1)[A] when treatment with the deficient factor fails to reverse coagulopathy.
- Low-titer patients should be given high dosages of the deficient factor to replace the low concentration of the circulating inhibitor.
Two bypassing agents are available: Activated prothrombin complex concentrate (known to have increased thromboembolic risks when administered to patients receiving emicizumab for prophylaxis), and high doses of the specific deficient factor. - High-titer patients should be treated using products that avoid the factor neutralized by the alloantibody.
Recombinant activated factor VII is recommended for patients with hemophilia B who also experience allergies or anaphylaxis after receiving factor IX therapy.
immunological tolerance induction (ITI) regimens involve recurrent exposure to high-dose factor VIII therapy over the course of 12 to 18 months, with or without immunosuppressive therapy (mycophenolate mofetil, rituximab), in an effort to remove immunological inhibitors and induce immune tolerance. Patients with severe hemophilia A have success rates between 70 and 80 percent.
Because hemophilia B has a low inhibitor prevalence, there is little data on the use of ITI in hemophilia B patients.
With quick access to clotting factor made possible by home therapy, people's quality of life is increased while their pain, dysfunction, and long-term disability are reduced.

Next Line
When the specific factor concentrate is not available for emergent hemostasis, cryoprecipitate and fresh frozen plasma (FFP) can be employed.
All coagulation factors are present in FFP, but it is typically challenging to achieve significant amounts of factors VIII or IX.
Starting dose: 15 to 20 mL/kg - Cryoprecipitate: made from the precipitates of chilled FFP; contains large quantities of factor VIII (up to 100 IU/bag) but not factor IX: Dosing: 1 mL cryoprecipitate has about 3 to 5 IU factor VIII.
DDAVP is a synthetic vasopressin that is used to treat mild hemophilia A. It induces the natural release of factor VIII (and vWF) from endothelial reserves and is given intravenously (IV) or subcutaneously (SC) 30 minutes before to the treatment. If necessary, it may be repeated. DDAVP use is restricted to 3 consecutive days due to tachyphylaxis and the relationship with negative side effects with prolonged use. Alternate dose if 50 kg: 150 g once.
- Unwanted outcome: hyponatremic seizures, particularly in youngsters; limit fluid intake and keep an eye on sodium levels and urine output.
Only patients with a clinically substantial elevation in factor VIII levels seen in earlier tests are advised to take DDAVP therapeutically.
Antifibrinolytic agents are effective at controlling mucosal bleeding, including oral bleeding, epistaxis, and menorrhagia. They can also be used prophylactically (for instance, before tooth extractions) or in conjunction with first-line treatment options.
ISSUES FOR REFERRAL Patients with persistent hemophilic arthropathy should be referred to a physical therapist and an orthopedic surgeon for consideration of surgery. Tranexamic acid (25 mg/kg PO q6-8h or 10 mg/kg IV q8-12h) is used less commonly.


Alternative Therapies 
Complementary pain management strategies like mindfulness, meditation, or music therapy may help with the pain management of chronic hemophilic arthropathy.


Take Action 
Patient Monitoring Regular assessments every six to twelve months, including checks for musculoskeletal problems, inhibitor screens, liver testing, and HIV and hepatitis B antibody levels.

Prognosis 
Those with modest disease and access to healthcare have a great prognosis; however, those with intermediate to severe disease have a higher mortality rate.
One of the main causes of death in hemophilia is liver failure.
The main cause of morbidity in those with severe hemophilia is hemophilic arthropathy.

Complications 
The signs of hemophilic arthropathy include pain, stiffness, and contractures.
 The risk of theoretical transfer of blood-borne illnesses including hepatitis A, B, C, and D and HIV has been significantly lowered thanks to the testing of blood products currently in use.
Development of inhibitor autoantibodies is more common in hemophilia A (20-30% of patients with severe hemophilia compared to 5% in hemophilia B) and in patients with severe disease requiring multiple transfusions. In hemophilia B, the risk of inhibitor development is associated with family history and/or specific genetic defects.
- There is no increased risk of bleeding, but when bleeding does happen, it is more challenging to achieve hemostasis because factor replacement is less effective.

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