HEMOPHILIA A AND B
- Both hemophilia A and B are X-linked, recessive, so they are seen almost exclusively in males.
- Hemophilia A results from inad equate or ineffective factor VIII.
- Factor VIII, which is inactive until it is cleaved from von Willebrand factor (vWF), is synthesized within megakaryocytes and endothelial cells.
- Factor VIII coagulant (FVIII:C) is also known as antihemophilic factor (AHF).
- Hemophilia B is due to inadequate or ineffective factor IX (also known as Christmas factor or plasma thromboplastin component).
- Severity of disease is determined by effectiveness of the variant factor.
- Sixty percent of patients with hemo philia A or B have a family history.
- Major bleeding issues are common— hemarthrosis, hematuria, hematospermia, menorrhagia, large hematomas.
- Delayed bleeding can occur after minor trauma/surgery.
- Hemostasis is a significant concern following major surgery.
- Chronic synovitis and hemophiliac arthropathy may develop in the context of recurrent hemarthrosis.
- With recurrent treatment, alloanti bodies may develop, which can render factor replacement ineffective.
- Factor VIII and factor IX deficiency cannot be differentiated clinically, but doing so is important because treatment is not the same.
- Factor VIII deficiency
- Bleeding time, prothrombin time (PT), platelet count, and vWF multimers are normal.
- FVIII:C and vWF assays show low concentration and/or low functional activity.
- Partial thromboplastin time (PTT) is prolonged, indicating that levels of FVIII:C are decreased or absent.
- PTT will correct when mixed with pooled normal serum (mixing study) unless the patient has inhibitors (alloantibodies).
- Factor IX deficiency
- Bleeding time, PT, and thrombin time (TT) are normal.
- Factor IX assay will show low to absent levels or activity.
- PTT is prolonged but corrects when mixed with pooled normal plasma (mixing study) unless the patient has inhibitors (alloantibodies).
- Desmopressin acetate (DDAVP)
- May be effective for mild factor VIII deficiency/inactivity (hemophilia A) or mild bleeding episodes but will not be effective for factor IX deficiency (hemophilia B).
- Beware of tachyphylaxis after multiple doses.
- In more severe bleeding or severe deficiency/inactivity, factor replacement will be necessary.
- If alloantibodies develop and factor replacement is no longer effective, treatment may require
- Larger doses of factor VIII or IX if inhibition is weak.
- Recombinant activated factor VII (rFVIIa).
- Activated prothrombin complex concentrate (PCC); risk of thrombosis is increased with this treatment.
- Underlying cause is a deficiency in factor XI.
- An autosomal recessive disease, hemophilia C is rare but more common among Ashkenazic Jews (heterozygote frequency 8%-10% in this population).
- Both men and women are affected, but women pose greater concern because of menorrhagia.
- Hemophilia C is generally a less severe disease than hemophilia A or B.
- Predominant manifestation is muco cutaneous bleeding, with spontaneous bleeds occurring rarely.
- Menorrhagia occurs in some affected women.
- vWF deficiency may also be present.
- The main concern arises in trauma or surgery.
- Bleeding time, TT, and PT are normal.
- Prolonged PTT corrects with mixed pooled plasma (mixing study).
- Factor XI assay demonstrates decreased or absent levels that also correct when mixed with pooled normal plasma (mixing study).
- For many patients, monitoring is sufficient. No treatment is needed.
- Prophylactic fresh frozen plasma (FFP) may be required before such procedures as tonsillectomy, prostatectomy, or dental extractions.
- FFP is given for surgery or major bleeding.
- Factor XI is not currently available in the United States, but antifibrinolytics (epsilon-aminocaproic acid or tranexamic acid) can be helpful for dental procedures or for women with severe menorrhagia.
- DDAVP has been tried in hemo philia C but with no clear evidence that it is helpful.
»QUESTIONS & ANSWERS«
1. A 3-year-old boy presents with a history of a fall in which he hit his mouth on the edge of a table. His mother is frantic because she cannot stop the bleeding despite applying pressure and ice. She reports that the boy has always been clumsy and that his legs are often covered in bruises. She also says that he seems to take longer to stop bleeding from minor scrapes than his twin sister does. There is no known history of bleeding problems in the family. If the boy suffers from hemophilia B, which of the following will be true?
a. He should receive desmopressin (DDAVP) treatment.
b. His bleeding time and partial thromboplastin time (PTT) will be prolonged.
c. A factor VIII assay will show low concentration or decreased activity.
d. Factor IX is the indicated treatment in this scenario.
Explanation: Factor IX is indicated as the treatment of choice in hemophilia B. Since hemophilia B is an X-linked, recessive disorder, it is rarely diagnosed in females. This is consistent with the boy's history and his twin sister's lack of bleeding episodes. Factor IX assays must be performed to confirm a diagnosis of hemophilia B. DDAVP will not be effective in factor IX deficiency. A prolonged PTT with a normal bleeding time is characteristic of hemophilia B.
2. A 16-year-old female of Eastern European descent is being worked up for menorrhagia with mild to moderate iron deficiency anemia. Her periods are regular but quite heavy. She has no other history of abnormal bleeding but is unsure whether she might bruise more easily than others. Thyroid functions and an assay for von Willebrand factor (vWF) are normal, and results of beta-human chorionic gonadotropin (β-HCG) testing are negative. Her prothrombin time (PT) is normal, and the PTT is prolonged but corrects on mixing studies. What is the most appropriate first step in the management of this patient?
a. DDAVP intranasally in advance of each menses
b. Tranexamic acid supplementation at the time of menses
c. Oral contraceptives (OCs) and iron supplementation
d. Factor XI concentrate administered before menses and dental extractions
Explanation: This history is most consistent with either von Willebrand disease or factor XI deficiency. Since there is no evidence for deficient or inactive vWF, factor XI deficiency is more likely. OCs and iron supplementation would be the most appropriate first step. For many women with hemophilia C, this approach will adequately control menorrhagia, with resolution of the anemia. Tranexamic acid may also be useful but may not be needed if menorrhagia is satisfactorily controlled with OCs alone. DDAVP has not been shown to be helpful in hemophilia C, and factor XI concentrate is not available in the United States.
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