Hemophilia A and B

I. What every physician needs to know.

Both hemophilia A and hemophilia B are rare congenital X-linked deficiencies in clotting factor VIII or IX, respectively. Though there is a positive family history of hemophilia in most individuals, up to 30% can be new mutations. Hemophilia B is also known as Christmas disease.

II. Diagnostic Confirmation: Are you sure your patient has hemophilia A and B?

Since both hemophilia A and B are X-linked genetic diseases, it is exceedingly rare to encounter a female with this disorder. In most patients, the activated partial thromblastin time (aPTT) will be prolonged, an aPTT mixing study will correct and a confirmatory factor level (VIII or IX respectively) will be low:

  • factor level of under 1 % indicates severe disease

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  • factor level of 1-5 % indicates moderate disease

  • factor level of 6-40% indicates mild disease

A. History Part I: Pattern Recognition:

Seventy percent of people born with hemophilia will have a positive family history, the diagnosis is anticipated and can be verified on cord blood sampling shortly after birth. In cases without a family history, boys may present with excessive bleeding after circumcision.

In rare cases patients with moderate or severe disease may present with intracranial bleeding after prolonged, vacuum or forceps deliveries. Often the first presentation of prolonged bleeding can be after circumcision. If it does not present earlier, infants older than 6 months of age can present with soft tissue swelling after they become more mobile. Spontaneous joint bleeding in severe hemophilia usually does not start until the child starts walking around, age 1 year and are often recurrent and disabling thereafter. Mild and moderate cases may not have spontaneous bleeds except for easy bruising, but have increased bleeding with trauma and surgery (including dental extractions). Some patients with mild or moderate hemophilia are not diagnosed until they have an aPTT drawn for pre-operative evaluation.

B. History Part 2: Prevalence:

Hemophilia is a genetic disease and is equally distributed among different races and ethnicities. Hemophilia A occurs in 1 out of 5,000 live male births and hemophilia B in 1 out of 30,000.

C. History Part 3: Competing diagnoses that can mimic hemophilia A and B.

Von Willebrand disease, especially type 2N or type 3, can mimic congenital hemophilia. Other factor deficiencies that elevate the aPTT (XI, XII, prekallikrein and high molecular weight kininogen) can be mistaken for hemophilia A or B.

It is also important to know that there is an acquired form of hemophilia (usually A), which is not a genetic but rather an autoimmune condition where people develop auto-antibodies against their own factor (this usually cannot be treated with clotting factor replacement). Acquired hemophilia is extremely rare and tends to occur in older people (male or female) with otherwise no bleeding history.

D. Physical Examination Findings.

Mild hemophilia can present with increased bleeding after surgery or trauma, or may be detected due to an elevated aPTT on routine lab work. Moderate hemophilia has more severe symptoms and may exhibit spontaneous bleeding. Severe hemophilia often presents with spontaneous bleeding, especially into the joints (knees, ankles, elbows, hips, shoulder). Early joint bleeds are characterized by a prodrome, pain and heat felt by the patient and are not easily visualized by a health care provider. Patients with any disease severity can present after trauma with excessive bleeding or bruising for the inciting incident.

E. What diagnostic tests should be performed?

A careful family and personal history for bleeding symptoms is essential.

1. What laboratory studies (if any) should be ordered to help establish the diagnosis? How should the results be interpreted?

Usually the aPTT is prolonged (might not be in mild cases, depending on the sensitivity of the assay). A baseline factor VIII or IX level is essential for diagnosis:

  • Below 1% indicates severe hemophilia

  • 1-5 % moderate hemophilia

  • 6-40% mild hemophilia

If there is no family history of Hemophilia in a patient with Factor VIII deficiency it is prudent to rule-out von Willebrand type 3 disease by checking vWF (von Willebrand Factor) Antigen.

2. What imaging studies (if any) should be ordered to help establish the diagnosis? How should the results be interpreted?

There are no imaging studies needed for the diagnosis of hemophilia. However plain x-rays and magnetic resonance imaging (MRI) can be useful in establishing synovitis (synovial hypertrophy in response to repeated joint bleeding) or more advanced arthropathy.

F. Over-utilized or “wasted” diagnostic tests associated with this diagnosis.

If a family history of hemophilia is established, testing for other than the factor level of concern is likely not warranted.

III. Default Management.

The management of bleeding episodes in patients with moderate or severe hemophilia is the immediate administration of intravenous clotting factor concentrate. The factor dosing and duration varies according to the severity of bleeding, type of bleeding, patient’s weight, and baseline factor activity. The World Federation of Hemophilia Treatment Guidelines Working Group published detailed disease management recommendations (http://www.wfh.org/en/resources/wfh-treatment-guidelines).

The patient usually carries the factor with him. In the case of a joint bleed, it is also important to rest the joint and elevate it. Ice may be applied.

Patients with mild hemophilia A without severe bleeding may be treated with desmopressin which can boost the concentration of Factor VIII.

A. Immediate management.

It is imperative to treat a bleed as early as possible with factor replacement (treat first and do imaging or other diagnostic studies later, for example in a questionable intracranial bleed after trauma). The longer until treatment is initiated, the more likely the bleed is to expand and cause permanent damage.

B. Physical Examination Tips to Guide Management.

History and exam of the affected body part will help to assess improvement in bleeding.

C. Laboratory Tests to Monitor Response To, and Adjustments in, Management.

If a patient receives a bolus treatment of factor concentrate, one can check a factor level immediately prior to the bolus and 15-30 minutes after bolus to assure an appropriate rise (also called recovery). Every patient metabolizes factor level differently, but a bolus should raise the factor level at least 66% of the expected increase calculated. One can also calculate the factor half-life by checking serial factor levels after the initial bolus. A normal factor VIII half-life is 8-12 hours and for factor IX is 18-24 hours.

During hospitalization or surgery, a patient may be on a continuous infusion of factor concentrate. In such a case it would be advisable to get a factor level at least once a day. During more severe bleeding episodes, monitoring periodic hemoglobin/hematocrit can indicate whether bleeding is controlled.

D. Long-term management.

Most people with hemophilia treat minor bleeds by self-infusion at home. They are usually followed in a designated Hemophilia Treatment Center with 24-hour phone access. Many take prophylactic factor several times a week to prevent/reduce bleeding.

E. Common Pitfalls and Side-Effects of Management

The most significant side effect of treatment with clotting factor concentrates is the development of an allo-antibody against the factor (also called an inhibitor). This happens in about 25-30% of people with severe hemophilia A and 5% with hemophilia B. If the inhibitor is high enough (> 5 Bethesda units), factor concentrates are no longer efficient in treating bleeds and so called “bypassing agents” (activated prothrombin complex or recombinant factor VII) have to be employed. This should be done under the guidance of an experienced hematologist.

IV. Management with Co-Morbidities

A. Renal Insufficiency.

No change in standard management.

B. Liver Insufficiency.

Several people who received clotting factor concentrates in the 1980’s contracted hepatitis C virus (HCV) and people with hemophilia may have liver insufficiency because of that or from other causes. If the liver insufficiency is resulting in an additional coagulopathy (due to decreased vitamin K dependent clotting factors being produced by the liver, disseminated intravascular coagulopathy [DIC], or thrombocytopenia), bleeding in a hemophilia patient can be very difficult to control.

C. Systolic and Diastolic Heart Failure

No change in standard management.

D. Coronary Artery Disease or Peripheral Vascular Disease

Theoretically, giving clotting factor concentrates can make a hemophilia patient “pro-coagulable”. It is important not to give too much clotting factor, especially in the elderly. The guidance of an experienced hematologist is advised.

E. Diabetes or other Endocrine issues

No change in standard management.

F. Malignancy

If thrombocytopenia develops due to malignancy or secondary to the treatment of the malignancy (e.g., chemotherapy) the hemophilic patient is at even higher risk for bleeding and needs to be monitored very carefully. Some treatments (tyrosine kinase inhibitors) for chronic myelogenous leukemia have been associated with reduced platelet function and can also contribute to increased bleeding in a patient who has both conditions.

G. Immunosuppression (HIV, chronic steroids, etc).

No change in standard management.

H. Primary Lung Disease (COPD, Asthma, ILD)

No change in standard management.

I. Gastrointestinal or Nutrition Issues

Gastrointestinal (GI) bleeding can be difficult to control. Whether the bleeding is due to the hemophilia or other causes, the patient should be receiving factor concentrates until the bleeding is controlled.

J. Hematologic or Coagulation Issues

Patients with hemophilia can have other bleeding diastheses (for example DIC associated with infection or liver disease). It is important not to overlook them.

K. Dementia or Psychiatric Illness/Treatment

No change in standard management.

V. Transitions of Care

A. Sign-out considerations While Hospitalized.

A hemophilic patient in the hospital should always be followed by a hemophilia team or hematologist, if available. Any reported increased bleeding has to be taken seriously and should be brought to the attention of consulting team or hematologist.

B. Anticipated Length of Stay.

The length of stay varies tremendously and depends on the type of bleed or procedure, and the response to treatment. After routine surgical procedures (e.g., tonsillectomy, cholecystectomy, knee replacement) a longer than usual hospitalization can be expected to assure for closer monitoring and sufficient hemostasis.

C. When is the Patient Ready for Discharge.

The patient is ready for discharge if sufficient hemostasis is assured (the initial bleeding episode is controlled and symptoms are decreasing, sufficient time has passed since a procedure/surgery and there are no signs of excessive bleeding) and the patient has access to factor replacement at home.

D. Arranging for Clinic Follow-up

The closest Hemophilia Treatment Center (HTC) should be informed of the patient’s admission. The patient will likely know which center this is and will have a phone contact for it.

1. When should clinic follow up be arranged and with whom.

The HTC will arrange follow-up.

2. What tests should be conducted prior to discharge to enable best clinic first visit.

This should be discussed with the HTC on an individual basis but it is unlikely that there will be specific tests.

3. What tests should be ordered as an outpatient prior to, or on the day of, the clinic visit.

This should be discussed with the HTC on an individual basis.

E. Placement Considerations.

This should be discussed with the HTC on an individual bases. Most patients will be able to go home, some may require home health, physical or occupational therapy. It should be noted that factor replacement and bypassing agents are very expensive so working with a Social Worker or other individual experienced in the logistics of financial constraints is essential.

F. Prognosis and Patient Counseling.

Today, people with hemophilia have a close to normal life expectancy.

VI. Patient Safety and Quality Measures

B. Appropriate Prophylaxis and Other Measures to Prevent Readmission.

Most people with hemophilia are followed routinely at a hemophilia treatment center where they have a comprehensive visit about once a year. The center usually prescribes factor concentrates for use in case of bleeding and is administered by the patient or a family member at home. Patients with repeated joint bleeds are usually started on prophylactic treatment with factor several times a week to prevent bleeding.

People with hemophilia are encouraged to follow normal activities and sports except for high impact sports (risk for head injury – football, boxing, rugby, wrestling, etc.). Helmets and protective gear are recommended for some sports (skateboarding, skiing, baseball, etc.). Patients on prophylaxis are encouraged to take their prophylactic dose prior to engaging in sports activities.

What's the evidence?

Fijnvandraat, K, Cnossen, MH. “Diagnosis and management of haemophilia”. BMJ. vol. 344. 2012. pp. e2707

Manco-Johnson, MJ, Abshire, TC, Shapiro, AD. “Prophylaxis versus episodic treatment to prevent joint disease in boys with severe hemophilia”. N Engl J Med. vol. 357. 2007. pp. 535-44.

Peyvandi, F, Garagiola, I, Young, G. “The past and future of haemophilia: diagnosis, treatments, and its complications”. Lancet. 2016 Feb 17. pp. S0140-6736(15).

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