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inherited bleeding disorders

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kareeman gomaa

on 7 April 2013

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Transcript of inherited bleeding disorders

INHERITED BLEEDING DISORDERS Haemophilia Von Willebrand
Disease.
A female child 6 years old ,has one elder healthy brother 10 years old ...she is a 1st grade student...there 's no consanguinity between her parents.
2 years ago...Alaa started to experience Attacks of vomiting of blood ...
the blood was bright red and of large amounts .
Her condition recurred many times over the past 2 years...and every time she used to recieve heamostatic drugs ...which some times failed to stop the bleeding ...
she did some laboratory tests and an un Upper GIT.endoscopy and Abdominal Ultrasound ...which were all free
Alaa presented one month ago to the Er at El-Mounira hospital with heamaturia ,melena ,heamatemesis and bleeding gums ...the patient was rescussitated and investigated . CASE 2 Examination:
The patient is Alert and Active and of normal weight for age.
General Exam:
normal(no pallor, no Jaundice no tachycardia ,fever or tachypnea)
Local Exam:
normal Abdominal,chest and Cardiad examination.
no palpable Lymph nodes.
Coagulation screening:

PT: 13 sec.
APTT: 40 sec.
INR: 1.1

The Von Willibrand Factor Antigen immunoassay by ELISA:
25% (Normal:50-160%)...

Upper GIT.endoscopy: Free

The patient was diagnosed as Type 1 Von Willibrand disease ...she is recieving 4 units of cryoprecipitate every 12 hours . Investigations:
Laboratory:
CBC:
WBC: 5.3
HGB: 14.1 gm/dl
PLT: 308
Reticulocytic c.: 2.7
platelets Functions:
platelet Aggregation (Adp): 72% (control:70-140%)
Plate.Aggre. Ristocetin:79% (control:70-140%).
Plate.Aggre.Collagen: 65% (control:60-110%).
Chemistry:
direct Bilirubin:0.3 mg/dl ....High
Total Bilirubin:1.8 mg/dl...High
ALT: 29 U/L ,AST: 15 U/L
BUN:6 mg/dl ,Creat: 0.4 mg/dl TREATMENT
The patient is being considered for Desmopressin treatment .
DDAVP is the treatment of choice
for individuals with vWD type I. OVERVIEW ON

VON WILLEBRAND DISEASE In response to numerous stimuli, vWF is released from storage granules in platelets and endothelial cells.
It performs 2 major roles in hemostasis.
First, it mediates the adhesion of platelets to sites of vascular injury.
Second, it binds and stabilizes the procoagulant protein factor VIII (FVIII). Etiology

With the exception of a rare, acquired form of vWD, caused by antibodies to vWF, vWD is an inherited condition. Classification VWF protein function undetectable abnormal normal Subtype Platelet - associated function FVIII - binding capacity HMW VWF multimers 2N Normal Normal Markedly reduced Absent Normal 2A 2B Decreased Increased affinity for GPIb Normal Usually reduced/absent Normal and occasionally ultra - large forms Normal Decreased 2M Secondary classification of type 2 von Willebrand disease Conditions to consider in the differential diagnosis of von Willebrand disease include the following:

Hemophilia A
Hemophilia B
Bernard-Soulier syndrome
Platelet function defects
Antiplatelet drug ingestion
Fibrinolytic defects
Platelet-type (or pseudo) vWD
Acquired vWD Diagnostic Considerations (2)Preliminary diagnosis:

After obtaining a suggestive personal history and a family history, the preliminary tests required are
1.a full blood count,
2.coagulation screen, Bleeding Time, PT, and aPTT:
Bleeding time:
this test is not currently essential for making the diagnosis.
PT and aPTT:
The aPTT is mildly prolonged in approximately 50% of patients with vWD. The PT should be within reference ranges.

3. FVIII assay, VWF:Ag and

4.a measure of VWF activity, usually ristocetin cofactor activity (VWF:RCo).

The laboratory diagnosis of VWD rests on assessing both the
amount of VWF present VWF:Ag and its functional capacity. FVIII binding.
Assessed first by a FVIII assay and then if this is reduced, by an assay of VWF FVIII - binding capacity using a modified ELISA - based technique

Platelet - dependent function.
The standard assessment of VWF adhesive functional activity remains the ristocetin cofactor assay (VWF:RCo).

Collagen - binding function (VWF:CB).
This recently introduced measurement is performed in an ELISA - based assay in which a well coated with collagen is used to capture VWF. vWF:Ag

This assay is usually performed (with rabbit antibody to vWF) using either a quantitative immunoassay or an enzyme-linked immunosorbent assay.

A discrepancy between the vWF:Ag value and RCoF activity suggests a qualitative defect that should be further investigated by characterization of the vWF multimeric distribution. Secondary tests for classification of VWD If a deficiency suggestive of VWD is detected then further tests ,in particular multimeric analysis and ristocetin - induced platelet aggregation (RIPA), are recommended to allow accurate subtyping of the VWD. vWD type I

vWD type I causes a mild to moderate quantitative deficiency of vWF (ie, about 20-50% of normal levels).

vWD type II

vWD type II is due to qualitative vWF abnormalities and is subdivided into types IIA, IIB, IIN, and IIM.

vWD type IIA
, the most common qualitative abnormality of vWF, is associated with selective loss of large and medium-sized multimers. vWD type IIB

characterized by the loss of large multimers occurs through a mechanism distinct from that of type IIA.

Observations to date have identified a critical region of vWF involved in the binding of vWF to the platelet receptor glycoprotein Ib (GpIb).

Each of the identified single amino acid substitutions is thought to result in a gain of function, leading to spontaneous binding of vWF to platelets.

In vWD type IIB, the mutant vWF spontaneously binds to GpIb in the absence of subendothelial contact. Function of vWF vWD type IIN,
sometimes referred to as vWD Normandy (after the province of origin of one of the first families identified with the disease),
is characterized by a defect residing within the patient's plasma vWF that interferes with its ability to bind FVIII.
This has important implications in the differential diagnosis of haemophilia.

vWD type IIM (for multimer)
involves qualitative variants with decreased platelet-dependent function not resulting from absence of high–molecular weight multimers. vWD type III:

Patients with vWD type III, a severe, quantitative deficiency associated with very little or no detectable plasma or platelet vWF, have a profound bleeding disorder.

vWD type III appears to result from the inheritance of a mutant vWF gene from both parents. In the most straightforward model, vWD type I would simply represent the heterozygous form of vWD type III Sub classification Type of VWF
deficiency VWF protein
function Type 1 Quantitative partial deficiency normal Type 2 Qualitative functional deficiency abnormal Type 3 Quantitative complete deficiency undetectable Primary classification of von Willebrand disease History and Clinical Examination

The most common symptoms of von Willebrand disease (vWD) include nose bleeds and hematomas.

Easy bruising - Common but nonspecific
A Male child 8 years old,the 2nd child of non consanguinous marriage ,having a free natal history and family history.

His condition started when he was only 40 days old ...on a post cercumcision event ,his mother noticed bleeding from the wound which lasted for 3 days ...the mother sought medical advice & was given a medication (a local heamostatic ) with no response .

The mother then came to Abo-El riesh hospital where the child was investigaated and diagnosed as (Heamoplilia A).

The patient then recieved plasma for 3 days, blood transfusion once,Vitamin k inj.and heamostatics...yet still he had the bleeding.
The patient was discharged after managing to stop the bleeding ...and was advised to follow up and with cryoprecipitate transfusion when bleeding recurs.

His bleeding attacks recured in the form of:tongue bleeding following a laceration in tooth extraction,frequent heamarthroses post trauma or even after along walk in his ankles and knees.

When he was 3 years old,he stopped Cryo.transfusion and started factor (VIII) concentrate.

Know: The patient has a huge elbow heamatoma after a canula insertion to recieve his Cryo limiting the movement of his joint. Examination;

The patient is vitally stable...

Has pallor

Has right knee heamarthrosis with very limited mobility and swelling

Has right elbow heamatoma.

Otherwise his examination is free Investigations 8 years ago ...in 22/4/2005:

Coagulation Screen:

Bleeing time:
1.5 min
Prothrombin time:
14 sec
Prothrombin concentration :
85%
Activated partial thromboplastin time:
> 3 min.
Thrombin generation test:
defective

Factor VIII assay:
<1%...severe heamophilia A. Now:

After recieving factor VIII concentrate:

Now the Patient's Activated partial athromboplastin time is:
130 sec.

His knee joint is being considered for synovectomy to decrease the disability.

An MRI will be done to evaluate his elbow heamatoma. OVERVIEW ON HAEMOPHILIA Overview on Haemophilia Haemophilia A and B are caused by deficiency of factor (F)VIII and FIX respectively.

FVIII and FIX are the two components of the intrinsic tenase .

In both cases, failure to form the intrinsic tenase complex results in failure to produce the thrombin burst characteristic of normal coagulation. FVIII (units/dL)

Bleeding tendency

Relative incidence

50 % 30 % 20 %

Severe frequent spontaneous bleeding into joints muscle Moderate some “spontaneous” bleeds, bleeding after minor trauma Mild bleeding only after significant trauma, surgery

< 1 2 – 5 > 5 – 45

Haemophilia A : clinical severity

Haemophilia A affects approximately 1 in 10 000 live births FVIII (units/dL)

Bleeding tendency

Relative incidence

50 % 30 % 20 %

Severe frequent spontaneous bleeding into joints muscle Moderate some “spontaneous” bleeds, bleeding after minor trauma Mild bleeding only after significant trauma, surgery

< 1 2 – 5 > 5 – 45

Haemophilia A : clinical severity

Haemophilia A affects approximately 1 in 10 000 live births FVIII (units/dL)

Bleeding tendency

Relative incidence

50 % 30 % 20 %

Severe frequent spontaneous bleeding into joints muscle Moderate some “spontaneous” bleeds, bleeding after minor trauma Mild bleeding only after significant trauma, surgery

< 1 2 – 5 > 5 – 45

Haemophilia A : clinical severity

Haemophilia A affects approximately 1 in 10 000 live births FVIII
(units/dL) Bleeding tendency Relative
incidence 50 %


30 %




20 % Severe frequent spontaneous bleeding into joints muscle

Moderate some “spontaneous” bleeds, bleeding after minor trauma


Mild bleeding only after significant trauma, surgery > 1 %:

2– 5 %:


5 – 45%: Haemophilia A : clinical severity Haemophilia A affects approximately 1 in 10 000 live births Laboratory diagnosis of haemophilia Laboratory diagnosis of haemophilia Initial tests show a prolonged APTT, normal PT and thrombin time (if performed) and a normal platelet count.

This will usually prompt specific factor assays of FVIII, FIX and FXI and,
in the case of haemophilia A, results shows FVIII clotting activity below 50 units/dL, with all other factors normal.

Von Willebrand factor (VWF) antigen and activity (ristocetin cofactor) are also normal
.
FVIII assays TREARMENT 1. management of bleeding episodes,

2.use of factor replacement products ,

3.treatment of patients with factor inhibitors, and

4.treatment and rehabilitation of patients with hemophilia synovitis.

Factor VIII is the treatment of choice for acute or potential hemorrhage.
Recombinant factor VIII concentrate is the preferred source of factor VIII. Prophylactic administration of factor VIII is often recommended for pediatric patients with severe disease.

Other medicinal adjuncts to factor VIII (eg, desmopressin acetate [DDAVP], antifibrinolytics) often are useful in achieving hemostasis and can lessen the need for factor VIII infusion.

Antifibrinolytic agents, such as aminocaproic acid and tranexamic acid, are contraindicated as initial therapies for hemophilia-related hematuria originating from the upper urinary tract because they can cause obstructive uropathy or anuria. Haemophilia B Inheritance and diagnosis

Haemophilia B is an X - linked deficiency of FIX and

the clinical manifestations are essentially the same as for haemophilia A.

It is less common than haemophilia A and has an incidence of approximately 1 in 50 000 live births. Treatment The Main stay in treatment is Factor IX concentrate.Previously Intermediate purity Prothrombin complex concentrates containing All the Vitamin K dependent factors was used.
Recombinant Factor IX is now widely used and although it's clinically effective the recovery is only 80% of that observed with plasma derived Factor IX. Thank you for your kind Attention.
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