PEYMAN ESHGHI MD. Professor of Pediatric Hematology ...

PEYMAN ESHGHI MD. Professor of Pediatric Hematology&Oncology

Mofid children hospital,SBMU TEHRAN 20-10-94

What are we going to manage?

To find significant and pathologic bleeding

To diagnose the disease

To stop & manage bleeding

Main Problem:

which bleeding is significant ?

Prevalent complaint Limited Diagnostin tools

Easy bruising or bleeding ,especially in children remains a challenge for the consulting hematologist to define a “significant bleeding history” :

mild underlying defects such as type 1 VWD or platelet function defects

OR

Normal population

the diagnostic limitations of available laboratory testing for mild bleeding disorders

Other Questions

To distinguish carriers in family members

To select the type of requested special tests(VWD types ;Platelet function tests; other RBDs ;etc.)

Treatment decision: the cases who need prophylaxis, intensified treatment, etc.

Iceberg of VWD Normal population

Expected incidence in IRAN for :

all types of VWD is about1/100

bleeders is about 1/10000

Sever bleeders is about

1/100000

Adults: (http://ds9.rockefeller.edu/RUBHPSR/;

accessed May 1,2012)

25% epistaxis,

18% easy bruising,

18% prolonged bleeding

after a tooth extraction

47% of women reported

heavy menstrual bleeding.

Children: (Nosek-Cenkowska B, et al..

Thromb Haemost. 1991;65(3):237-241).

24% easy bruising

39% epistaxis,

Clinical approach

1. Is the bleeding significant ?

2. Local Vs Systemic ?

3. Platelet Vs Coagulation disorder ?

4. Inherited Vs Acquired ?

Bleeding Assessment Tools (BAT) 1. Vicenza bleeding scores for VWD (from 0 to 3) :

>3

2. European Molecular and Clinical Markers for the Diagnosis and Management MCMDM-1)VWD (-1 to 4):

40 minutes for 17 pages questionair

3. CONDENSED MCMDM-1 VWD BAT: 5-10 minutes for 6-page questionnaire

score of > 3 : 71% ppv; 92% npv for vwd

4. The Pediatric Bleeding Questionnaire (PBQ) of MCMDM-1 VWD BAT

Score>2: 14% ppv ;99%npv for VWD

5. ISTH BAT: based on the 0-3 Vicenza score

used in children and adults to diagnose mild bleeding disorders for the first time

R/O VWD , Possible Platelet dysfunction

20 minutes

The development of the Vicenza bleeding scores Rodeghiero F, Castaman G, Tosetto A, et al. The discriminant power of bleeding history for the diagnosis of type 1 von Willebrand disease: an international, multicenter study. J Thromb Haemost. 2005;3(12):2619-2626 Tosetto A, Rodeghiero F, Castaman G, et al. A quantitative analysis of bleeding symptoms in type 1 von Willebrand disease: results from a

multicenter European study (MCMDM- 1 VWD). J Thromb Haemost. 2006;4(4):766-773..

The Pediatric Bleeding Questionnaire (PBQ) of MCMDM-1 VWD BAT

Bowman M,et al. J Thromb Haemost. 2009;7(8):1418-1421.

CONDENSED MCMDM-1 VWD BAT

Bowman M, et al . J Thromb Haemost. 2008;6(12):2062-2066.

ISTH BAT Rodeghiero F et al. , . J Thromb Haemost 2010; 8: 2063-2065 (plus supplementary material).

Likelihood ratio for VWD using Vicensa BATs

Epistaxis:

What to report(ISTH-BAT) :

R/O other local or systemic causes: seasonal occurrence , URI, Dusty dry air, High BP , etc.

Frequency/Y: more than 5 episodes per year

Duration : more than 10 min. with local manage

* Consultation only: the patient sought medical evaluation and was either referred to a specialist or offered detailed laboratory investigation

Cutaneous bleeding

What to report:

Site and age?

ISTH-BAT:

bruises :5 or more (> 1cm) in exposed areas;

petechiae when adequately described by the patient or relatives; or

hematomas when occurring without trauma.

Bleeding minor wounds

What to report(ISTH-BAT) :

superficial cuts (e.g., by shaving razor, knife, or scissors)

Frequency/Y: more or less than 5 episodes per year

Duration : more or less than 10 min. with local manage

ORAL CAVITY What to report(ISTH-BAT) :

Gum bleeding :when it causes frankly bloody sputum and lasts for 10 minutes or longer on more than one occasion

tooth eruption : when requires assistance or supervision by a physician, or lasts at least 10 minutes

bites to lip and tongue,: at least 10 minutes or causes a swollen tongue or mouth.

TOOTH EXTRACTION/SURGERY What to report : Primitive vs Permanent tooth?

Duration : more than 2hr with compression

occurring after leaving the dentist’s office and requiring a new, unscheduled visit

PBQ:

Any report of bleeding stopped without consultation : 1

With consultaion only:2

Example: 1 extraction/surgery resulting in bleeding (100%): the score to be assigned is 2; 2 extractions/surgeries, 1 resulting in bleeding (50%): the score to be assigned is 2; 3 extractions/surgeries, 1 resulting in bleeding (33%): the score to be assigned is 2; 4 extractions/surgeries, 1 resulting in bleeding (25%): the score to be assigned is 1

Surgery What to report (ISTH-BAT):

judged by the surgeon to be abnormally prolonged

PBQ:Any report of bleeding stopped

without consultation : 1

With consultaion only:2

Example: 1 extraction/surgery resulting in bleeding (100%): the score to be assigned is 2; 2 extractions/surgeries, 1 resulting in bleeding (50%): the score to be assigned is 2; 3 extractions/surgeries, 1 resulting in bleeding (33%): the score to be assigned is 2; 4 extractions/surgeries, 1 resulting in bleeding (25%): the score to be assigned is 1

Menorrhagia points(ISTH-BAT) Severity : more than 80 ml/period

More than 30 of tampons/pads used for a typical menstrual cycle Hourly (0.5–2.0 h) change of tampon/pad on the heaviest day of

menstrual period

use a tampon and a pad at the same time OR a super-absorbent tampon or pad

Clot >1 cm or flooding

frequently stain through clothes during menses pictorial blood loss assessment chart (PBAC) >100

Duration: More than 7 days ; Present since menarche and > 12

months

Needs to treatment : OCP; Antifibrinolytics; DDAVP; anaemic or low in iron; Transfusion;surgical intervention

lost time from work or school ≥ 2 times in the past year because of heavy periods

Menorrhagia Severity : more than 80 ml/period ; More or less than 7 days Needs to treatment Postpartum hemorrhage uterine discharge (lochia) that lasts for more

than 6 weeks judged by the obstetrician as abnormally heavy

or prolonged Frequency Needs to treatment

Pictorial Blood loss Assessment Chart (PBAC)

Condense MCMDM1

ISTH-BAT

Judged by the obstetrician as abnormally heavy or prolonged

Condense MCMDM1

ISTH-BAT

OTHER BLEEDINGS

Umbilical stump bleeding,

Cephalohematoma,

Post-circumcision bleeding,

Post-venipuncture bleeding

Macroscopic hematuria

Spontanous or Repeated abortion(?)

Delayed wound healing (?)

0 No/trivial

1 Present

2 Consultation only

3 Surgical hemostasis, antifibrinolytics or iron therapy

4 Blood transfusion, replacement therapy or desmopressin

Other points

a positive family history increases the risk of a bleeding disorder

Circumcision (with cutting methods) and ear ring replacement as a haemostatic challenge ?

History of Renal, Liver or Hematological disease

Drug history

Distinction between 0 and 1 is of critical

importance

Pre-operative recommendations The European Society of Anaesthesiology specifically

recommends the use of a structured patient interview or questionnaire before surgery or invasive procedures.

The British Committee for Standards in Haematology recommends a bleeding history be taken in all patients preoperatively and prior to invasive procedures

Bleeding history may be negative in paediatric patients due to lack of haemostatic challenges. Therefore, if a positive family history exists, some laboratory workup will be required to confirm or exclude a bleeding disorder

1. Chee YL, Crawford JC, Watson HG and Greaves M. Guidelines on the assessment of bleeding risk prior to surgery or invasive procedures. British Committee for Standards in Haematology. British Journal of Haematology, 2008;140:496–504.

2. Kozek-Langenecker SA, Afshari A, Albaladejo P, Santullano CA, De Robertis E, et al. Management of severe perioperative bleeding: guidelines from the European Society of Anaesthesiology. Eur J Anaesthesiol. 2013;30:270-382.

Drug History

Drugs Proved or Suspected to Induce Drug-Dependent Antibody- Mediated Immune Thrombocytopenia

Platelet Vs Coagulation disorder

Symptom Platelet Coagulation

Petechiae Yes No

Sites Skin & Mucosa

Deep Tissue

Time Immediate Delayed

Ecchymoses/Hematomas

Yes Yes

Note: Local pressure is effective in platelet bleeding but not in coagulation dis.

1. Demonstration of the defect

2. Identification of the defect(s)

3. Assessment of severity

4. Consequential studies eg. carrier detection

5. Monitoring of treatment

Laboratory Approach

1. Platelet count & morphology

2. Bleeding Time

3. Clotting Time?

4. Prothrombin Time

5. Activated Partial Thromboplastin Time

6. Thrombin Time

7. Clot lysis test

Screening Tests

Bleeding time (Ivy Method)

•Inflate and Fix the pressure cuf on arm at 40 mmHg

• make a horizontal incision (1mm depth, 5 mm length) on volar surface of the forearm;2 inches below the elbow line

• dry the bleeding border with drying paper every 30 Sec.

•No blood spot on paper shows the end of the test.

BT more than 8-9 min. means prolonged and seen in

platelet count less than 80000-100000 (some times less than 40000 in acute ITP)

Platelet dysfunction Dis. oMedication oAzotemia oVWD oPlatelet aggregation

Collection of blood sample

1. Minimum circulatory stasis

2. Clean venous puncture

3. Proper anticoagulant

4. Proportion of blood to anticoagulant

5. Separation of plasma and storage

6. Effect of stress, pregnancy, drugs

7. Effect of PCV on the proportion of plasma to

anticoagulant

Summary Hemostatic Disorders

BT Plt PT PTT

Vascular Dis - - - -

PLT Disorder - - - -

Factor 8/9

*Congenital - - -

Vit K / Liver

*Acquired - - -

Combined (DIC) -

Factor XIII deficiency

Thrombasthenia

congenital drug induced

Disorders of vascular hemostasis

VWD (Bleeding Score OR family history is enough for more investigation)

PT, APTT, TT, PLC - Normal

Factor XIII - clot solubility

Platelet function tests

BT clot retraction 1 minute platelet count Platelet aggregation

Tourniquet test

VWF:Rco ; VWF:Ag

;FVIII:C

Asymptomatic Patient Routine screening tests shows prolonged APTT

Inhibitor - lupus anticoagulant

Factor XII deficiency

Mild congenital factor deficiency

When to refer or admit Need to perform advanced coagulation assay according

to clinical and screening evaluation

high suspicion based on personal and family history and BAT even with normal screening tests

Thrombocytopenia without definite diagnosis should be referred for diagnostic W/U(BMA; Imaging ; ANA;anti-DNA;C3;C4;CH50; Virological assay; H. pylori,etc.)

Neonates with any sign or symptom of thrombocytopenia and/or coagulopathy

Once DIC was supposed ,to diagnose and treatment the underling disease (infection,malignancies,crush injury,etc.)

Points on outpatient Management of ITP

Competitive contact sports should be avoided

Aspirin, NSAIDS, and any other drugs that interfere with platelet function should not be given.

When to treat ITP: Platelet count less than 10000

Platelet count less than 20000 and petechiae on H&N

Mucosal bleeding OR more sever bleeding

NOT to transfuse platelet except in refractory life threatening status

IVIG should be given under supervision and addmison

Steroid therapy should be postponed till R/O the other causes

How to treat ITP with steroid in outpatient clinic:

A course of prednisone, 2 mg/kg/day (maximum 60

mg/day), is given in divided doses. Prednisone is reduced in a stepwise fashion at 5- to 7-day intervals, irrespective of the platelet count, and is stopped at most at the end of 21–28 days, regardless of the response.

A shorter course of prednisone at 4 mg/kg/day for 4 days has also been used with success.

In severe cases, methylprednisolone (Solu-Medrol) 30 mg/kg/day (500 mg/m2/day; maximum 1 g/day) for 3 days produces a more rapid response than steroids in conventional doses.

Prolonged use of steroids in ITP is undesirable : may

depress platelet Production;leads to steroid side effects Platelet transfusion is not effective and should be avoided.

Platelet transfusion Indications:

Hypoprolipherative

Infiltrative

Non-immunological

Isoimmune NATP

Paltelet count level:

major bleed, major surgery >100,000

minor bleed, minor procedure >50,000

prevent spontaneous bleed > 10,000

Consider functional abnormality

Leukoreduced platelets are preferred for multiple transfused patients

Treatment outline for coagulopathies Factor Replacement

Non replacement therapy: Medications:DDAVP;Antifibrinolytics; Hormon

therapy;etc

Local hemostatic agents

Local Physical supports: Non-weight bearing; Imobilization;Ice;Compression;Elevation;Exrcise;[NICE] Physiotherapy

Plasmapheresis

Other:Conjucted surgeries; continious infusion methods;

etc

Oral contraceptives (OCs) Are very effective in raising the level of all clotting factors

except factor IX. In qualitative vWF defects, the effectiveness of OCs

diminishes, )since the hormones raise the level of vWF but do not correct the inherent structural defect.(For these women, OCs will probably still

be of some benefit in helping to regulate their menstrual periods and to diminish the amount of bleeding, but other therapies may also be necessary.

OCPs 1. OCP-LD

2. OCP-HD

3. For bleeding that is not responsive to OCs, the use of pure progestational agents such as Norlutate and Provera can be very helpful because they cause a thickening of the uterine lining (a secretory myometrium) and stop the bleeding.

The question here is, how long can you inhibit menstruation?

Injectable agents

Injectable progestational agents such as Depo-Provera are not preferred because : they require an IM injection which is not advised in people

with bleeding disorders;

It is in the body for a few months versus the much shorter half life for oral agents;

the dosage can be controlled better with oral administration.

For acute life-threatening bleeding, the use of intravenous conjugated estrogens (Premarin) can be effective.25 mg slow iv /stat

Antifibrinolytic agents

Could be useful alone or as adjuncts to other treatments:

Tranexamic acid [ vial 250 mg;cap 250 mg]

25 mg/kg PO Q6-8 h OR 10 mg/kg IV Q6-8 h

one vial in 10 cc DW for local use

Occasional side effects: nausea,diarrhea, orthostatic hypotention

are not recommended during the first trimester of pregnancy ; upper UT bleeding ; at the same time with FEIBA