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Bleeding disorders in childhood

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Title: Bleeding disorders in childhood


1
Bleeding disorders in childhood
Monika Csóka M.D., PhD 2nd Dept. of Pediatrics
2
Bleeding disorder
  • Bleeding disorders is a general term for a wide
    range of medical problems that lead to poor blood
    clotting and continuous bleeding.
  • Tendency to bleed longer or regularly with or
    without injury.

3
Hemostasis
  • Cessation of blood loss from a damaged vessel.

4
Coagulation
  • blood vessels
  • platelets
  • coagulation factors

5
Disturbances of hemostasis
  • vasculopathy
  • platelet disorders
  • coagulation disorders

6
Testing of coagulation
  • history (family, medication, circumstances)
  • phisical examination (type of bleeding)
  • laboratory tests

7
Testing of coagulation
8
Testing of coagulation
9
Laboratory tests
10
Vasculopathy
  • Prolonged bleeding time
  • Normal platelet count and aggregation
  • Vascular fragility test (Rumpel-Leed test)

11
Schönlein-Henoch purpura
  • Vasculitis (small arterial vessels)
  • non thrombocytopenic haemorrhagic syndrome
  • origin unknown (postinfectious?)
  • Circulating immune komplexes (IgA, C3)

12
Schönlein-Henoch purpura
  • immunkomplex deposits in the skin, joints, GI
    tract, kidney
  • Skin rash associated with arthritis and cramping
    abdominal pain
  • Treatment anti-inflammatory drug, corticosteroid

13
Thrombocytopathy
  • Dysfunctional platelets
  • Tendency to bleeding
  • Inherited (rare) or acquired

14
Thrombocytopathy
  • Bleeding petechia, epistaxis, menorrhagia,
    mucosal bleeding, moderate bleeding after surgery
  • PLT count norm., moderate decreased
  • Bleeding time prolonged

15
Thrombocytopathia
  • Bernard-Soulier sy.
  • Glanzmann thrombasthaenia
  • Wiskott-Aldrich sy.
  • Abnormalities of thrombocyta granules

16
Bernard-Soulier syndrome
  • Deficiency of platelet glycoprotein protein Ib
  • Decreased ristocetin aggregation
  • Thr count decreased
  • Large platelets

17
Glanzmann thrombasthenia
  • Deficiency of GP IIb/IIIa komplex
  • Type I complete absence
  • Type II some complex is retained
  • Platelets fail to aggregate
  • Thr count normal

Both Glanzmann's thrombasthenia and
Bernard-Soulier disease respond to platelet
transfusion but this should be reserved for
severe problems as alloantibodies may form.
18
Wiskott-Aldrich syndrome
  • X-linked recessive disease (WASP gene codes for
    the protein by the same name, which is mainly
    expressed in hematopoietic cells)
  • Thrombocytopenia
  • Eczma
  • Immune deficiency
  • Therapy hematopoietic stem cell transplant
    (allogeneic)
  • supportiv care

19
Granule deficiency
  • denz granule deficiency
  • Storage pool disease
  • Chediak-Higashi sy.
  • alfa granule deficiency
  • Gray Platelet Syndrome

20
Platelet dysfunction
  • Drug induced
  • aspirin
  • indomethacin
  • non-steroid antiinflammatory drugs

21
Thrombocytopenia
  • Autoimmune (ITP)
  • Alloimmune (neonatal)
  • Non-immun
  • (HUS, TTP, DIC, Kassabach-Merritt sy.)

22
ITP
Dendroica petechia
  • Acute or chronic
  • Bleeding on skin or mucosa
  • Virus infection in anamnesis (1-3 weeks before)
  • age 2-4 y
  • in 90 remission within 6 months
  • associated with other autoimmune disorder (Evans
    sy.)

23
ITP laboratory tests
  • blood count, smear
  • Antibodies against thrombocyte surface antigens
  • Bone marrow aspiration

24
ITP therapy
  • Goal to avoid life threatening bleeding
  • mild close observation
  • severe IVIG or corticosteroid
  • azathioprin, CP, rituximab
  • Splenectomy (vaccination, penicillin)
  • Thrombocyte concentrates only in life threatening
    bleeding!!!

25
ITP
  • Dentistry gt 10 G/l
  • Tooth extraction gt 30 G/l
  • Minor surgery gt 50 G/l
  • Major surgery gt 80 G/l

26
TTP/HUS
  • TTP
  • thrombotic microangiopathy combining
    microangiopathic haemolysis and thrombocytopenia
    causing arteriolar occlusion by microaggregates
    of platelets

27
TTP/HUS

microangiopathic hemolytic anemia acute renal
failure thrombocytopenia
28
TTP/HUS
  • lt 5 year
  • After bloody diarrhea
  • E. coli (verotoxin O157H7)
  • Shigella disenteriae (shiga toxin)
  • idiopathic, familial
  • Prodromal phase diarrhea
  • 7-10 days later acute renal failure

29
TTP/HUS
  • Therapy fluid-electrolite
  • Blood pressure
  • Dialysis

30
Coagulopathy
  • bleeding
  • thrombosis

31
Coagulation
  • coagulation (fibrin)
  • intrinsic way (plasma)
  • extrinsic way (tissue)
  • fibrinolisis
  • control systems

32
PLASMA-PHASE
33
Coagulopathy 1.
  • PTT U
  • PT Ú
  • haemophilia
  • vWD
  • circulating anticoagulant
  • heparin

34
Coagulopathy 2.
  • PTT Ú
  • PT U
  • Factor VII deficiency

35
Coagulopthy 3.
  • PTT U
  • PT U
  • TT U
  • afibrinogenaemia
  • dysfibrinogenaemia
  • DIC
  • liver inssufficience
  • heparin

36
Coagulopathy 4.
  • PTT U
  • PT U
  • TT Ú
  • liver disorder
  • vitamin K deficiency
  • Warfarin
  • Factor II, V, X deficiency
  • early DIC
  • dysprothrombinaemia
  • ciculating anticoagulants

37
Coagulopathy
  • inherited
  • VIII, vWf, IX, XI
  • fibrinogen, II, V, VII, X, XII, XIII, combination
  • acquired
  • K vit., DIC, liver, heart, kidney, inhibitors
  • neonatal
  • haemorrhage, inherited, acquired

38
Haemophilia (Greek word)
  • Hereditary genetic disorder, that impair the
    body's ability to control blood clotting or
    coagulation.
  • John Conrad Otto american medical doctor
    described a disease in 1803 with prolonged
    clotting time

39
Haemophilia
  • The earliest possible implicit reference to
    hemophilia may have been in the Talmud7, a
    Jewish holy text, which states that males did not
    have to be circumcised if two brothers had
    already died from the procedure.

40
Haemophilia
  • The Jewish physician Moses Maimonides (1135-1204)
    applied this ruling to the sons of a woman who
    had married twice, thus apparently appreciating
    the hereditary nature of the condition.

41
Haemophilia
  • In 1000 CE, the Arab physician, Abu al-Qasim
    al-Zahrawi (known as Albucasis in the West),
    wrote the first explicit description of
    hemophilia in his Al-Tasrif, in which he wrote of
    an Andalusian family whose males died of bleeding
    after minor injuries.

42
Haemophilia
  • "the royal disease"
  • Queen Victoria passed the mutation to her son
    Leopold and, through several of her daughters, to
    various royals across the continent, including
    the royal families of Spain, Germany, and Russia.
    Two of her daughters, Aliz and Beatrix were
    carriers her son, Leopold had hemophilia.

43
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44
Haemophilia
  • Tsarevich Alexei Nikolaevich, son of Nicholas
    II, was a descendant of Queen Victoria and
    suffered from hemophilia. It was claimed that
    Rasputin was successful at treating the Tsarevich
    Alexei of Russia's hemophilia. Rasputin could
    bring visible and significant improvement to the
    condition of Alexei.

45
Haemophilia
  • Second common inherited coagulopathy. Prevalence
    13-18/100 000 male
  • 1 instance in every 10,000 births for hemophilia
    A and 1 in 50,000 births for hemophilia B. About
    18,000 people in the United States have
    hemophilia. Hemophilia usually occurs in males
    and less often in females. It is estimated that
    about 838 Hungarian have hemophilia A and about
    192 Hungarian have hemophilia B (data from 2007).

46
Haemophilia
  • Haemophilia A - 90 of cases
  • Haemophilia B - Christmasdisease
  • Haemophilia C Factor XI deficiency
  • Haemophilia A  Haemophilia B 41

47
Clinical picture
  • ecchymosis, haematom
  • Deep tissue bleeding (muscle, joint)

48
Clinical picture
  • Umbilical cord bleeding
  • Túlzott véraláfutások, belso vérzés általában a
    6-9. hónapban jelentkezik, amikor a járni tanuló
    gyermek elesik. Haemarthros, és intramuscularis
    haematoma.
  • Nyomásos neuropathia, ha a vérzés idegek
    közelében van. (Pl. m. iliopsoas vérzése járhat a
    nervus femoralis kompressziójával).
  • Központi idegrendszeri vérzés
  • Húgyúti vérzés, mely hasi fájdalommal és
    haematuriával jár.
  • A bélfalba töro vérzés bélelzáródást okozhat.

49
Haemophilia A
  • 110.000 (80-85)
  • XR
  • FVIII C
  • PTT U
  • PT Ú
  • Bleeding time, PLT Ú

50
Haemophilia A
Carrier mother
Hemophilic father
Carrier mother and hemophilic father
Healthy male
Healthy female
Carrier
Hemophilic male
Hemophilic female
51
Haemophilia A
  • lt1 severe
  • 1-5 intermediate
  • gt5 mild

52
Clinical signs
  • at birth or in neonate
  • childhhod

53
Therapy
  • factor substitution
  • FFP
  • Cryoprecipitate
  • FVIII concentrate from plasma
  • recombinant FVIII
  • rehabilitation
  • surgery

54
Complications
  • Infection
  • HIV
  • Hepatitis (B, A, E, non A, non B, C, parvovirus)
  • haemarthrosis
  • hematoma

55
Complications
  • pseudotumor
  • mucosal bleeding
  • dentistry
  • hematuria
  • neurology
  • CNS
  • Spinal cord
  • Periferal nerves

56
Haemophilia B (Christmas)
  • 150.000
  • XR
  • FIX
  • Bleeding time, PTT U
  • PT Ú/U

57
Haemophilia B
  • klassification, clinical picture as in
    haemophilia A
  • Dg. later, not in neonates
  • in carrier women factor level lower (25-40)

58
Von Willebrand disease
  • The condition first aroused his interest in the
    case of a 5-year-old girl from Ã…land with an
    extensive history of bleeding in her family.
  • Mapping her family history, von Willebrand found
    23 of the girl's 66 family members were affected,
    and that the disease was more common in women.

Erik Adolf von Willebrand
59
Von Willebrand disease
New type bleeding disorder, different from
haemophilia 1. Mucosal bleeding (menorrhagia,
metrorrhagia, epistaxis, GI) 2. Male and female
in the same family bleed (autosomal
inheritance) 3. Bleeding time prolonged
60
Von Willebrand disease
Type 1 (60-80) quantitative deficiency of vWF
(de valamennyi multimer jelen van) Type 2
(15-30) qualitative deficiency of vWF Type 3
(1-5) lack of vWF
61
Von Willebrand disease
  • most common hereditary coagulation abnormality
    (110000)
  • the vWF gene is located on chromosome twelve
    (12p13.2). It has 52 exons spanning 178kbp
  • Types 1 and 2 are inherited as autosomal dominant
    traits and type 3 is inherited as autosomal
    recessive. Occasionally type 2 also inherits
    recessively.

62
Von Willebrand disease
  • Physiological function
  • Endothel-platelet binding
  • Binding and stabilisation of ciculating FVIII

63
von Willebrand disease
  • inherited
  • acquired (collagen vasc. disease, Wilms tu.)

64
von Willebrand disease
  • LABORATORY PARAMETERS
  • Screening APTI
  • thr
  • bleeding time
  • RIPA
  • Repeated examinations!

65
von Willebrand disease
  • LABORATORY PARAMETERS
  • Special tests vWFAg
  • vWFRCo
  • FVIIIC
  • multimer analysis (SDS elektroforesis)
  • collagen-binding aktivity
  • PFA-100
  • Repeated tests!

66
Therapy
  • no regular treatment
  • combined oral contraceptive pill
  • human derived medium purity factor VIII
    concentrates complexed to WF(antihemophilic
    factor, more commonly known as Hemate-P)
  • Mild cases of vWD can be trialled on desmopressin
    (1-desamino-8-D-arginine vasopressin, DDAVP)

67
Vitamin K deficiency
  • vitamin K dependent coagulation factors
  • II (prothrombin)
  • VII
  • IX
  • X

68
Vitamin K deficiency
  • Primer
  • neonatal haemorrhagia (early, late)
  • parenteral feeding, antibiotic treatment
  • Malabsorption
  • biliary atresia
  • intestinal disease (CF)
  • medicaments
  • kumarin, phenytoin, salicylat

69
Vitamin K deficiency
  • clinic
  • acute bleeding
  • lab
  • PTT U
  • PT U
  • TT Ú

70
Consumptive coagulopathy
  • association with other diseases
  • disturbed coagulation and fibrinolysis
  • acute/subacute/chronic

71
Consumptive coagulopathy
  • DIC
  • diffuse intravascular thrombosis
  • local thrombosis

72
DIC
  • Infection (bact., parasita, fungal, Rickettsia)
  • RDS
  • Asphyxia
  • tumor
  • Purpura fulminans
  • Snake-bite
  • Trauma/burn
  • Haemolytic complication after transfusion

73
Local thrombosis
  • big haemangioma (Kasabach-Merritt sy.)
  • Aorta thrombosis in neonate
  • Extended venous thrombosis
  • Snake-bite

74
DIC -diagnosis
  • Clinical signs Laboratory tests together

75
DIC - therapy
  • Blood transfusion
  • FFP
  • Thr-cc
  • Heparin i.v.
  • AT III
  • EACA

76
Bleeding disorder in neonate
  • physiologic low level of factors
  • liver immature
  • Vitamin K deficiency

77
Summary
  • Coagulation is complicated, well controlled
    system. We must learn much more about it.

78
THANK YOU FOR THE ATTENTION!
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