Inherited Bleeding Disorders Flashcards
CBC with peripheral smear review platelet morphology & number Abnormalities on smear which may aid diagnosis schistocytes, helmet cell microangiopathic process: HUS, TTP large platelets, number, normal RBC, WBC production defect immune mediated process: ITP, drug induced antibody large inclusion granules Chediak - Higashi large platelets Bernard - Soulier and May Heggelin small platelets, number Wiskott - Aldrich gray or washed-out platelets Gray Platelet Syndrome
<p>What is the diagnostic approach to a patient with a possible bleeding disorder?</p>
<ul>
<li>Ask about previous bleeding problems</li>
<li><strong>Easy bruising</strong> can be a clue, though many who do not have a hemorrhagic disorder will have easy bruising</li>
<li>Inquire whether any <strong>excessive bleeding</strong> occurs with <strong>menses or after surgical procedures</strong>; e.g. dental extraction, tonsillectomy, etc.</li>
<li>Inquire about any <strong>past bleeding with trauma</strong> or daily activities.</li>
<li><strong>Ask about medications</strong> - particularly aspirin, over-the-counter medications, use of herbals.</li>
<li>Inquire about a <strong>family history</strong> of a bleeding disorder or bleeding symptoms</li>
<li><strong>Laboratory tests</strong> for coagulation disorders:
<ul>
<li>Prothrombin time (PT)</li>
<li>Activated Partial Thromboplastin Time (PTT)</li>
<li>PT or PTT mixing study</li>
<li>Thrombin time</li>
<li>Specific clotting factor activity assays</li>
<li>Genetic sequencing of specific clotting factor genes</li>
</ul>
</li>
</ul>
<p>What are the major types of vascular purpuras?</p>
<ul>
<li><strong>Anatomic malformations</strong>
<ul>
<li><u>Hemangiomas</u>
<ul>
<li>may be extensive in the newborn</li>
<li>if small and confined to skin, only a <em>cosmetic problem</em></li>
<li>In organs such as gut or brain, may be associated with <em>bleeding, abscesses</em></li>
</ul>
</li>
<li><u>Hereditary Hemorrhagic Telangiectasia</u>
<ul>
<li><em>Etiology</em>: mutations in endoglin or ALK1 genes result in dysregulated transforming growth factor-b</li>
<li><em>Autosomal dominant</em> inheritance</li>
<li><em>Dilated vascular channels</em> in dermis, recurrent epistaxis, gastrointestinal bleeding, organ dysfunction due to lesions in lung & liver</li>
<li>Develop severe <em>iron deficiency anemia</em></li>
<li><em>Management</em>: iron replacement, occasionally estrogens, anti-fibrinolytics</li>
</ul>
</li>
</ul>
</li>
<li><strong>Connective tissue disorders</strong>
<ul>
<li><u>Ehlers-Danlos Syndrome</u>
<ul>
<li>mutations in genes coding for <em>collagen type III</em> cause <em>weak-walled arteries</em> resulting in aneurysms, dissections, ruptures</li>
<li>clinically, hyperextensibility of joints, thin skin, poor wound healing</li>
</ul>
</li>
</ul>
</li>
</ul>
<p>What are the bleeding vs. nonbleeding clotting factor disorders? How are they differentiated?</p>
<ul>
<li>The non-bleeding disorders are recognized by a <strong>prolonged aPTT</strong> test, but patients are <strong>asymptomatic</strong>
<ul>
<li>Specific assays are available to distinguish the various types</li>
</ul>
</li>
<li><strong>Bleeding</strong>:
<ul>
<li>factor XI</li>
<li>factor IX</li>
<li>factor VIII</li>
<li>von Willebrand factor</li>
</ul>
</li>
<li><strong>Non-bleeding</strong>:
<ul>
<li>non-bleeding</li>
<li>factor XII</li>
<li>pre-kallikrein</li>
<li>high molecular-weight</li>
<li>kininogen</li>
</ul>
</li>
</ul>
<p>What is the incidence of the bleeding disorders due to clotting factor deficiency?</p>
<ul>
<li><strong>Factor VIII deficiency</strong>
<ul>
<li>1/5000 live male births</li>
</ul>
</li>
<li><strong>Factor IX deficiency</strong>
<ul>
<li>1/30000 live male births</li>
</ul>
</li>
<li><strong>Factor XI deficiency</strong>
<ul>
<li>Rare, except ~9% Ashkenazi Jews carry mutation</li>
</ul>
</li>
<li><strong>Von Willebrand Disease</strong>
<ul>
<li>Up to 1/1000 persons</li>
</ul>
</li>
</ul>
<p>What are some causes of hemophilia A and B?</p>
<ul>
<li><strong>Characteristics of Classical (factor VIII or IX) Hemophilia</strong>:
<ul>
<li>X-linked disorder – Gene is on X chromosome. </li>
</ul>
</li>
<li>Half of the severe FVIII type is due to <strong>inversion & translocation of exons 1-22 away from exons 23-26</strong> due to <strong>homologous recombination</strong> between the F8A gene in intron 22 and one of the extragenic F8A copies 400 kb 5’ to the FVIII gene
<ul>
<li>Other causes of FVIII hemophilia and FIX hemophilia are due to <strong>gene deletions, point mutations</strong>, etc.</li>
</ul>
</li>
</ul>
<p>What is the role of factors VIII and IX in the clotting cascade?</p>
<ul>
<li>Factors VIII and IX, when activated in the presence of phospholipid and calcium, form the <strong>tenase complex</strong> which <strong>activates factor X</strong>: a critical step in coagulation</li>
<li>Although factor X may be activated by tissue factor-factor VIIa complex, <strong>only small amounts are formed</strong> and these are quickly <strong>inactivated by the tissue factor pathway inhibitor (TFPI) and the Z-protease inhibitor (ZPI)</strong></li>
<li>Activated factors VIII and IX greatly augment factor Xa production and this greatly <strong>enhances thrombin generation</strong> and fibrin formation
<ul>
<li>Thus, defects in factors VIII or IX are associated with <u>impaired thrombin generation and clinically important bleeding</u></li>
</ul>
</li>
</ul>
<p>What affects the severity of hemophilia A and B? What are the clinical presentations?</p>
<ul>
<li><strong>Severity of Disease</strong>:
<ul>
<li>Clotting factor activity determines whether it is <u>clinically mild</u> (>5%), <u>moderate</u> (1%-5%), or <u>severe</u> (<1%)</li>
</ul>
</li>
<li><strong>Clinical Features of Severe Hemophilia A or B</strong>:
<ul>
<li>In infancy they may present with:
<ul>
<li>bleeding from circumcision</li>
<li>bruising</li>
<li>bleeding from frenulum</li>
</ul>
</li>
<li>When an infant starts to crawl or walk then they can present with <u>bleeding into the large joints</u></li>
<li>Spontaneous joint bleeds (hemarthroses) occur most often in those with <u>severe disease</u>, and sometimes in those with moderate disease</li>
<li>Potentially fatal bleeding can occur from injuries, especially to the <u>head or abdomen</u></li>
<li>Persistent <u>oozing after dental extractions</u> may also be present</li>
<li>Sometimes those with mild disease are not diagnosed until they are adults when they have a <u>traumatic injury</u> or undergo <u>surgery</u> or an <u>invasive procedure</u></li>
</ul>
</li>
</ul>
<p>What is the treatment protocol for hemophilia A and B?</p>
<ul>
<li><strong>Replacement of the missing clotting factor</strong> quickly prevents or controls bleeding
<ul>
<li>However, clotting factor concentrates <u>must be infused intravenously</u></li>
<li>These are either <u>high purity concentrates</u> made from plasma, or proteins prepared by <u>recombinant DNA</u> technology</li>
<li><u>They may be given on demand</u> - that is, to treat a bleeding episode, or as prophylaxisto prevent bleeding</li>
</ul>
</li>
<li>If a patient with hemophilia is bleeding, or suspected to be bleeding, the appropriate clotting factor (FVIII or FIX) is <strong>given immediately</strong> and then studies are performed to determine the extent and location of bleeding
<ul>
<li>If prophylaxis is required, FVIII concentrates must be given at least <u>every other day</u> because the half-life of FVIII is only <u>12 hrs</u></li>
<li>FIX has a <u>half-life of up to 20 hrs</u> so may be given twice weekly</li>
<li>The two major problems are providing <u>long term venous access</u>, and the <u>high costs</u> of the products. </li>
</ul>
</li>
<li>Transmission of infectious agents is <strong>very infrequent</strong> now because of the high purity and viral inactivation procedures used to make concentrates, although <strong>prion particles and some non-enveloped viruses</strong> such as hepatitis A and parvovirus may resist inactivation steps</li>
</ul>
<p>What are some complications of treatment for hemophilia A and B?</p>
<ul>
<li>As many as 25% of patients with FVIII mutations may develop <strong>antibodies</strong> (known as inhibitors) to FVIII concentrates, rendering them <strong>resistant to treatment</strong></li>
<li><strong>Less than 5%</strong> of those with FIX deficiency develop such antibodies</li>
<li>There is some success in <strong>inducing immune tolerance</strong> in patients with antibodies</li>
</ul>
<p>What is the etiology, presentation, and management of factor XI deficiency?</p>
<ul>
<li>Factor XI activates factor IX to augment factor Xa production and thereby <strong>increase thrombin generation</strong></li>
<li>Thrombin forms a <strong>complex with thrombomodulin</strong> that activates the <strong>thrombin activatable fibrinolysis inhibitor (TAFI)</strong></li>
<li>Factor XI deficiency results in <strong>less thrombin and less TAFI</strong>, promoting more active fibrinolysis</li>
<li>Bleeding associated with increased fibrinolytic activity is usually from <strong>mucous membranes and onset delayed</strong></li>
<li><strong>Genetics: Autosomal inheritance</strong>
<ul>
<li><u>Type II and III</u> molecular defects occur in Ashkenazi Jews</li>
<li><u>Type II</u> is more severe, and ⅓ develop antibodies when treated with plasma</li>
</ul>
</li>
<li>For all types, severity of bleeding is <strong>poorly correlated</strong> with factor XI levels</li>
<li><strong>Replacement therapy</strong> with fresh frozen plasma is necessary for serious bleeding/surgery</li>
</ul>
<p>What are the presentation of factor XIII deficiency?</p>
<ul>
<li>Very rare, recessive bleeding disorder</li>
<li>Characterized by delayed, <strong>recurrent bleeding from wounds</strong> and <strong>poor wound healing</strong></li>
</ul>
<p>What are some deficiencies of the extrinsic and common pathways?</p>
<ul>
<li>Congenital deficiencies of these factors (<strong>I, II, V, VII, X</strong>) are quite rare, but <strong>all result in bleeding</strong></li>
<li><strong>Fibrinogen (factor I)</strong> – Abnormalities include:
<ul>
<li>afibrinogenemia</li>
<li>hypofibrinogenemia</li>
<li>dysfibrinogenemia</li>
</ul>
</li>
<li>Severity of bleeding is <strong>variable</strong> and is most severe in those with <strong>afibrinogenemia</strong></li>
</ul>
