Title: Hemophilia A and B<br/>Author: To-Lam Nguyen<br/><a href='http://umem.org/profiles/resident/2182/'>[Click to email author]</a><hr/><p>
Since Christmas is coming up, let's talk about Hemophilia A (factor VIII deficiency) and Hemophilia B (factor IX deficiency, also known as Christmas disease)</p>
<p>
<strong>Deficiencies in Factors VIII and IX are the most common severe inherited bleeding disorders.</strong></p>
<p>
<strong>Pathophysiology: </strong></p>
<ul>
<li>
Factors VIII and IX are required for activation of factor X.</li>
<li>
<strong>In patients with Hemophilia A </strong>(factor VIII deficiency) <strong>or Hemophilia </strong>B (factor IX deficiency, also known as Christmas disease), after an injury,<strong> clot formation is delayed. </strong></li>
<li>
Inadequate thrombin generation leads to failure to form a tightly crosslinked fibrin clot to support platelet plug, which leads to easy bleeding.</li>
<li>
Clot that is formed may be friable and rebleeding occurs during physiologic lysis of clots or with minimal new trauma</li>
</ul>
<p>
<strong>Clinical Manifestations:</strong></p>
<ul>
<li>
2% of neonates with hemophilia have intracranial hemorrhages</li>
<li>
30% of male infants with hemophilia bleed with <strong>circumcision</strong></li>
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Continued bleeding from <strong>umbilical stump </strong>in neonate</li>
<li>
In absence of positive family history (hemophilia has high rate of spontaneous mutation), hemophilia may go undiagnosed in a newborn</li>
<li>
<strong>Easy bruising, intramuscular hematomas, and hemarthroses (hallmark for hemophilic bleeding) </strong>begin when child begins to cruise</li>
<li>
Bleeding from minor traumatic lacerations of the mouth <strong>(e.g. torn frenulum) can persist for hours or days</strong></li>
<li>
<strong>Iliopsoas hemorrhage: </strong>patient may lose large volumes of bleed into the muscle, leading to hypovolemic shock, with only a vague complaint of area of referred pain in the groin. Hip is held in a <strong>flexed, internally rotated position</strong>, due to irritation of the iliopsoas.
<ul>
<li>
<strong>Confirmed on CT or US</strong></li>
<li>
<strong>Clinically unable to extend hip</strong></li>
</ul>
</li>
<li>
<strong>Hemarthrosis rare </strong>in patients with <strong>acquired hemophilia</strong></li>
</ul>
<p>
<strong>Lab findings and diagnosis</strong></p>
<ul>
<li>
Reduced levels of factor VIII or factor IX will cause higher <strong>PTT </strong></li>
<li>
PTT is usually 2-3x upper limit of normal in patients with severe hemophilia.</li>
<li>
<strong>Platelet count, bleeding time, prothrombin time, and thrombin time </strong>are all <strong>normal</strong></li>
<li>
If PTT is <strong>not </strong>corrected after administration of factor VIII or IX, an <strong>inhibitor </strong>may be present.
<ul>
<li>
<strong>25-35% </strong>of patients with hemophilia who received infusions of factor VIII or factor IX, a factor specific antibody may develop (inhibitor)</li>
</ul>
</li>
</ul>
<p>
<strong>Genetics</strong></p>
<ul>
<li>
Hemophilia occurs in 1:5000 males, with <strong>85% </strong>having <strong>factor VIII deficiency</strong> and <strong>10-15%</strong> having factor IX deficiency</li>
<li>
No apparent racial predilection, appearing in all ethnic groups</li>
</ul>
<p>
</p>
<p>
<strong>Classification</strong></p>
<ul>
<li>
<strong>Severe hemophilia</strong>: <1% activity of specific clotting factor and bleeding is often <strong>spontaneous</strong></li>
<li>
<strong>Moderate hemophilia</strong>: 1-5% activity and require mild</li>
</ul>
<p>
trauma to induce bleeding</p>
<ul>
<li>
<strong>Mild hemophilia</strong>: >5% activity and can go many years before diagnosis and usually require significant trauma to induce bleeding.</li>
</ul>
<p>
<strong>Treatment</strong></p>
<ul>
<li>
<strong>Ask patient or family if they brought their dosing information with them or their factor replacement with them. In many cases, they have it!</strong></li>
<li>
For life-threatening or major hemorrhages, dose should aim to achieve levels of 100% activity
<ul>
<li>
Hemophilia A: <strong>50U/kg</strong> recombinant Factor VIII (each U/kg of factor VIII in hemophilia A increases factor by 2%)</li>
<li>
Hemophilia B: <strong>100U/kg </strong>recombinant Factor IX (each U/kg of factor VIII in hemophilia A increases factor by 1%)</li>
<li>
Aim for <strong><u>50% correction in moderate bleeds </u></strong>and <strong><u>100% correction in severe bleeds</u></strong></li>
<li>
If you don’t have factor-specific products:
<ul>
<li>
<strong>Hemophilia A</strong>
<ul>
<li>
can give <strong>1U cryoprecipitate</strong> (~80U of factor VIII) or try PCC (as it contains factors II, VII, IX, and X)</li>
<li>
<strong>activated PCC (FEIBA) 75-100U/kg</strong></li>
</ul>
</li>
<li>
<strong>Hemophilia B</strong>
<ul>
<li>
<strong>FFP NO LONGER RECOMMENDED</strong> (volume of FFP required has high risk of volume overload)</li>
<li>
Cryoprecipitate does <strong>NOT </strong>contain factor IX, so will not work.</li>
</ul>
</li>
</ul>
</li>
</ul>
</li>
<li>
For acute bleeding in patients with <strong>mild</strong> <strong>hemophilia A:</strong>
<ul>
<li>
Can give <strong>DDAVP: </strong>increases factor VIII by 3-5x by encouraging release of endogenous factor VIII. Recommended dose: <strong>0.3mcg/kg/dose IV</strong></li>
</ul>
</li>
<li>
<strong>For mild bleeding:</strong>
<ul>
<li>
<strong>TXA </strong>(clot stabilizer)</li>
<li>
<strong>Desmopressin</strong></li>
<li>
<strong>Aminocaproic acid</strong></li>
</ul>
</li>
<li>
If patient has inhibitors:
<ul>
<li>
<strong>Hemophilia A: </strong>
<ul>
<li>
<strong>Activated PCC</strong> (75-100U/kg) (do NOT give if on patient is on emicizumab (Hemlibra) due to risk of thrombosis)</li>
<li>
Recombinant factor VII 90mcg/kg</li>
</ul>
</li>
<li>
<strong>Hemophilia B:</strong>
<ul>
<li>
Recombinant factor VII 90mcg/kg</li>
</ul>
</li>
</ul>
</li>
</ul>
<p>
</p>
<p>
<strong>Summary:</strong></p>
<ul>
<li>
Aim for <strong><u>50% correction in moderate bleeds </u></strong>and <strong><u>100% correction in severe bleeds</u></strong></li>
<li>
<strong>Hemophilia A:</strong> <strong>50U/kg</strong> recombinant Factor VIII (each U/kg of factor VIII in hemophilia A increases factor by 2%)</li>
<li>
<strong>Hemophilia B:</strong> <strong>100U/kg </strong>recombinant Factor IX (each U/kg of factor VIII in hemophilia A increases factor by 1%)</li>
<li>
Treatment if patient has <strong>no inhibitors:</strong>
<ul>
<li>
<strong>Hemophilia A: </strong>
<ul>
<li>
Severe bleed: Give full dose factor XIII (50U/kg), even if the patient is on prophylaxis</li>
<li>
Mild bleeds: factor XIII replacement (25U/kg), TXA, DDAVP, aminocaproic acid</li>
</ul>
</li>
<li>
<strong>Hemophilia B: </strong>
<ul>
<li>
Severe bleed: Give full dose factor IX (100U/kg), even if the patient is on prophylaxis</li>
<li>
Mild bleeds: factor IV replacement (50U/kg), TXA, aminocaproic acid</li>
</ul>
</li>
</ul>
</li>
<li>
Treatment if patient <strong>has inhibitors</strong>:
<ul>
<li>
<strong>Hemophilia A: </strong>
<ul>
<li>
Activated PCC (75-100U/kg) (do NOT give if on patient is on emicizumab (Hemlibra) due to risk of thrombosis)</li>
<li>
Recombinant factor VII 90mcg/kg</li>
</ul>
</li>
<li>
Hemophilia B:
<ul>
<li>
Recombinant factor VII 90mcg/kg</li>
</ul>
</li>
</ul>
</li>
</ul>
<p>
</p>
<p>
</p>
<fieldset><legend>References</legend>
<p>
Kliegman R, Stanton B, St. Geme JW, Schor NF, Behrman RE. <em>Nelson Textbook of Pediatrics</em>. Edition 20. Elsevier; 2016. Accessed December 2, 2023. https://search.ebscohost.com/login.aspx?direct=true&db=cat01362a&AN=hshs.004567758&site=eds-live</p>
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Kliegman R, Stanton B, St. Geme JW, Schor NF, Behrman RE. <em>Nelson Textbook of Pediatrics</em>. Edition 20. Elsevier; 2016. Accessed December 2, 2023. https://search.ebscohost.com/login.aspx?direct=true&db=cat01362a&AN=hshs.004567758&site=eds-live</p>
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