Bleeding disorders in childhood

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Bleeding disorders in childhood
Monika Csóka M.D., PhD 2nd Dept. of Pediatrics
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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.

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Hemostasis

• Cessation of blood loss from a damaged vessel.

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Coagulation

• blood vessels
• platelets
• coagulation factors

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Disturbances of hemostasis

• vasculopathy
• platelet disorders
• coagulation disorders

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Testing of coagulation

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

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Testing of coagulation
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Testing of coagulation
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Laboratory tests
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Vasculopathy

• Prolonged bleeding time
• Normal platelet count and aggregation
• Vascular fragility test (Rumpel-Leed test)

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Schönlein-Henoch purpura

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

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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

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Thrombocytopathy

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

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Thrombocytopathy

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

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Thrombocytopathia

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

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Bernard-Soulier syndrome

• Deficiency of platelet glycoprotein protein Ib
• Decreased ristocetin aggregation
• Thr count decreased
• Large platelets

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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.
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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

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Granule deficiency

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

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Platelet dysfunction

• Drug induced
• aspirin
• indomethacin
• non-steroid antiinflammatory drugs

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Thrombocytopenia

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

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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.)

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ITP laboratory tests

• blood count, smear
• Antibodies against thrombocyte surface antigens
• Bone marrow aspiration

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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!!!

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ITP

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

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TTP/HUS

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

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TTP/HUS

microangiopathic hemolytic anemia acute renal
failure thrombocytopenia
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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

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TTP/HUS

• Therapy fluid-electrolite
• Blood pressure
• Dialysis

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Coagulopathy

• bleeding
• thrombosis

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Coagulation

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

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PLASMA-PHASE
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Coagulopathy 1.

• PTT U
• PT Ú
• haemophilia
• vWD
• circulating anticoagulant
• heparin

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Coagulopathy 2.

• PTT Ú
• PT U
• Factor VII deficiency

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Coagulopthy 3.

• PTT U
• PT U
• TT U
• afibrinogenaemia
• dysfibrinogenaemia
• DIC
• liver inssufficience
• heparin

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Coagulopathy 4.

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

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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

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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

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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.

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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.

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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.

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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.

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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.

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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).

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Haemophilia

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

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Clinical picture

• ecchymosis, haematom
• Deep tissue bleeding (muscle, joint)

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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.

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Haemophilia A

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

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Haemophilia A
Carrier mother
Hemophilic father
Carrier mother and hemophilic father
Healthy male
Healthy female
Carrier
Hemophilic male
Hemophilic female
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Haemophilia A

• lt1 severe
• 1-5 intermediate
• gt5 mild

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Clinical signs

• at birth or in neonate
• childhhod

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Therapy

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

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Complications

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

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Complications

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

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Haemophilia B (Christmas)

• 150.000
• XR
• FIX
• Bleeding time, PTT U
• PT Ú/U

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Haemophilia B

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

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Von Willebrand disease

• The condition first aroused his interest in the
  case of a 5-year-old girl from Åland 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
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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
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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
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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.

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Von Willebrand disease

• Physiological function
• Endothel-platelet binding
• Binding and stabilisation of ciculating FVIII

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von Willebrand disease

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

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von Willebrand disease

• LABORATORY PARAMETERS
• Screening APTI
• thr
• bleeding time
• RIPA
• Repeated examinations!

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von Willebrand disease

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

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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)

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Vitamin K deficiency

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

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Vitamin K deficiency

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

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Vitamin K deficiency

• clinic
• acute bleeding
• lab
• PTT U
• PT U
• TT Ú

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Consumptive coagulopathy

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

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Consumptive coagulopathy

• DIC
• diffuse intravascular thrombosis
• local thrombosis

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DIC

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

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Local thrombosis

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

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DIC -diagnosis

• Clinical signs Laboratory tests together

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DIC - therapy

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

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Bleeding disorder in neonate

• physiologic low level of factors
• liver immature
• Vitamin K deficiency

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Summary

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

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THANK YOU FOR THE ATTENTION!