10c. Bleeding Disorders (kbi).pptx

Sony Wicaksono Susanto Nugroho

Lab/SMF Ilmu Kesehatan Anak FK Universitas Brawijaya/RS Dr. Saiful Anwar

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An autoimmune disorder characterized by a low platelet count and mucocutaneous bleeding The estimated incidence is 100 cases per 1 million persons per year, and about half of these cases occur in children Classified as primary or as secondary to an underlying disorder and as acute (of six months or less in duration) or chronic

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The platelet count is usually 10-50 x 109/L. The blood film shows reduced numbers of platelets, those present often being large. The bone marrow shows normal or increased numbers of megakaryocytes. Sensitive tests are able to demonstrate specific antiflycoprotein GPIIb/IIIa or GPIb antibodies on the platelet surface or in the serum in most patients.

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Detection of PlateletSpecific Antibodies with a MonoclonalAntigen–Capture Assay In this test, platelets from a patient suspected of having immune thrombocytopenic purpura are coated with an autoantibody — in this case, an autoantibody against the glycoprotein IIb/IIIa complex (orange).

Hemophilia is one of the oldest described genetic diseases & congenital deficiency of factor VIII (FVIII), and hemophilia B is a consequence of a congenital deficiency of factor IX (FIX).  This deficiency results in insufficient generation of thrombin by FIXa and FVIIIa complex through the intrinsic pathway of the coagulation cascade.  They account for 90-95% of severe congenital coagulation deficiencies.  Hemophilia A (HA), which comprises approximately 80% of cases, is considered the classic form of hemophilia, and hemophilia B (HB) is termed Christmas disease. 

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Hemophilia A is approximately 1 case per 5000 male individuals, with approximately one third of affected individuals not having a family history

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Hemophilia B occurs in 1 case per 25,000 male individuals and represents one fourth to one fifth of all patients with hemophilia

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Both forms of hemophilia are sex-linked coagulopathies because they are inherited as X-linked traits

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Female individuals who carry the affected genes usually do not have bleeding manifestations

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Hemophilia A and hemophilia B are found in all ethnic and racial groups.

Persons with 1-5% normal factor (0.01-0.05 IU/mL) are considered to have moderately sev hemophilia. Persons with more than 5% but less than 20% normal factor (>0.05 to <0.20 IU/mL) considered to have mild hemophilia. Clinical bleeding symptom criteria have been used becau patients with FVIII or FIX levels less than 1% occasionally have little or no spontaneous bleeding a appear to have clinically moderate or mild hemophilia. Furthermore, the reverse is true for patie with procoagulant activities of 1-5%, who may present with symptoms of clinically severe disease.

Table 1. Correlation of Coagulation Factor Activity and Disease Severity in Hemophilia A Hemophilia B Coagulation factor activity (% of normal) <1

Clinical manifestation Severe disease Frequent spontaneous bleeding episodes from early life Joint deformity and crippling if not adequately treated

1–5

Moderate disease Post-traumatic bleeding Occasional spontaneous episodes

5 – 20

Mild disease Post-traumatic bleeding

CLINICAL FEATURES Approximately 30-50% of patients with severe hemophilia present with manifestations neonatal bleeding (eg, after circumcision). Approximately 1-2% of neonates have intracran hemorrhage. Other neonates may present with severe hematoma and prolonged bleeding from

! Usually, von Willebrand factor (vWF) levels are also measured. The combination of low FVIII and low vWF may indicate vWF deficiency as the primary diagnosis. ! Because FVIII and FIX are large molecules that do not cross the placenta, the diagnosis can be made at birth with quantitative assay of coagulation factors in the cord blood. ! Early diagnosis of FIX deficiency is complicated by the physiologic reduction of vitamin K– dependent factors in young infants. Table 2. Main Clinical and Laboratory Findings in Hemophilia A and Hemophilia B Hemophilia A

Hemophilia B

Inheritance

Sex-linked

Sex-linked

Main site of hemorrhage

Muscle, joints, post-trauma or postoperative

Muscle, joints, post-trauma or postoperative

Platelet count

Normal

Normal

Bleeding time

Normal

Normal

Prothrombine time

Normal

Normal

Partial thromboplastin time

Prolonged

Prolonged

Factor VIII

Low

Normal

Factor IX

Normal

Low

vWF

Normal

Normal

Normal

Normal

Ristocetin-induced aggregation

platelet

! Other laboratory evaluations in the patient with hemophilia include periodic screening for the

Bleeding episodes are treated with factor VIII or factor IX (plasma-derived or recombinant) replacement therapy and spontaneous bleeding is usually controlled if the patient’s factor VIII or factor IX level is raised above 20% of normal. For major surgery, serious post-traumatic bleeding or when hemorrhage is occurring at a dangerous site, however, the factor VIII level should be elevated to 100% and then maintained above 50% when acute bleeding has stopped, until healing has occurred (Table 3). Table 3. Replacement Therapy for Hemorrhage in Hemophilia A and B

Joint

Required Factor Level (%) 30-50

60-100 U/k/d

30-40 U/kg q2d

Muscle

40-50

20-40 U/kg/d

40-60 U/kg q2d

Oral mucosa

50, add EACA

25 U/kg

50 U/kg

Epistaxis

80-100, then 30 until healed

40-50 U/kg, then 30-40 U/kg/d

80-100 U/kg, then 70-80 U/kg q2d

GI tract

100, then 30 until healed

40-50 U/kg, then 30-40 U/kg

80-100 U/kg, then 70-80 U/kg q2d

Genitourinary tract

100, then 30 until healed

40-50 U/kg, then 30-40 U/kg/d

80-100 U/kg, then 70-80 U/kg q2d

CNS

100, then 50-100 for 10-14 d

50 U/kg, then 25 U/kg q12h or continuous infusion

100 U/kg, then 50 U/kg/d

Trauma or surgical site

100, then 30-50 until healed

50 U/kg, then q12h or continuous infusion

100 U/kg, then qd

Site of Bleeding

Dose in Hemophilia A

Dose in Hemophilia B

Desmopressin vasopressin analog, or 1-deamino-8-D-arginine vasopressin (DDAVP) is considered the treatment of choice for mild and moderate hemophilia A. It is not effective in the

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Prophylactic Gene Therapy Inhibitor?

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Hemorrhagic disease of newborn (HDN) = vitamin K deficiency bleeding (VKDB) VKDB is bleeding due to inadequate activities of VK-dependent coagulation factors (II, VII, IX, X), correctable by VK replacement. The frequency of VKDB varies with the use of vitamin K prophylaxis, the efficacy of prophylaxis programs, frequency of breastfeeding, and the vitamin K content of locally available formulas Late VKDB has fallen from 4.4-7.2/100,000 births to 1.46.4/100,000 births in reports from Asia and Europe after regimens for prophylaxis were instituted Intracranial hemorrhage (ICH) is uncommon in classic VKDB but can be observed in more than 50% of infants with late-onset VKDB

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Vitamin K is a fat-soluble vitamin that can be absorbed from the GI tract in the presence of bile salts  is required for the production of coagulation factors II, VII, IX, and X in the liver

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Short half-life of these factors, and the small amounts of vitamin K that can be stored in the body, inadequate intake of vitamin K can result in deficiency in a short period of time

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Maternal factor:  Inadequate intake  Not nursing long enough or frequently enough  Medications taken during pregnancy  Maternal diabetes, toxemia, or placental

problems.  Undue stress during the pregnancy.

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Newborn factor  Poor feeding, or not nursing enough.  Gastro-intestinal disease or homeostasis (blockage of

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bile drainage ducts in the liver, caused by hepatitis, undeveloped bile ducts or other congenital defects, or infection) Medications that the mother has taken A particularly difficult birth, resulting in birth trauma. Prematurity Hypoxia (lack of oxygen) Diarrhea

mmediate investigation/treatment of “warning bleeds”, help prevent the worst consequences of VKDB; oo often is VKDB the presenting feature of a serious underlying disease which could have been ecognized earlier.

Table 1. Forms of VKDB in Infancy

DIAGNOSIS Clinical Features

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VKDB includes bleeding at any site and whether spontaneous or iatrogenic The common sites for spontaneous bleeding are the umbilicus, mucous membranes, skin, gastrointestinal and urinary tract, and retroperitoneum Intracranial bleeding can occur

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Prothrombin time (PT), activated partial thromboplastin time (aPTT), fibrinogen levels, and a platelet count in the initial workup for bleeding in a newborn

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A prolonged PT usually is the first laboratory test result to be abnormal in VKDB

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NO laboratory test can confirm the diagnosis of VKDB.

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Vitamin K is the mainstay of treatment for VKDB Severe bleeding may warrant the use of fresh frozen plasma Surgery when needed

Vitamin K after birth Diet and supplementation  Breast feeding  

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Too much Vitamin K may be harmful to baby. Levels remain 1,000 times higher in the blood for 3-4 days after the shot Jaundice Bleeding may still occur Anaphylactic shock Trauma at injection site (pain, swelling)

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3 major factors affecting coagulation Inherited and acquired