HEMOSTASIS, BLEEDING AND CLOTTING DISORDER
Presented by :
Nik Khairiyah Bt Raja Mohammed
Mohamad Nizar B. Muhamad Yatim
Nuradibah Bt Shahrul
Nuramalina Bt Ahmad Ehsan
In the absence of blood vessel damage :
platelets are repelled from each other
and from endothelium of blood vessel.
endothelial cell secretes prostacyclin
and nitric oxide (NO) -act as vasodilator & inhibit platelet aggregation.
plasma membrane of endothelial cell
contain enzyme (CD39) - breakdown
ADP to AMP + Pi.
Def : consequence of tightly regulated
processes that maintain blood in a fluid, clot-free state in normal vessels while
introducing the rapid formation of a
localized hemostatic plug at the site of vascular injury.
- from Robbins Basic Pathology 8th edition
formation of platelet plug
Def : Bleeding disorders is a general term for a wide range of medical problems that lead to poor blood clotting and continuous bleeding.
characterized clinically by abnormal bleeding, which can either be spontaneous or become
evident after some inciting event.
can result from :
defects in the blood vessel
abnormalities in the blood itself
blood clotting factor
Source from : National Haemophilia Association
Source from : Nelson Essential of Pediatrics 5th edition
1) Identify clinical features
a) age of onset
b) family history
- family tree
c) bleeding history
- previous surgical / dental
- presence of systemic
- drug history
- unusual pattern or
d) pattern of bleeding
- mucous membrane
bleeding & skin
- bleeding into muscles or
- scarring and delayed
Source from : Tom Lissauer, Graham Clayden Illustrated Textbook of Paediatric 3rd edition
2) Screening test
Bleeding time (BT)
Hemostasis, capillary & platelet function
3-7 min beyond neonate
Thrombocytopenia, von Willebrand disease
150 000 – 450 000 / mm^3
Extrinsic & common pathway
< 12 sec beyond neonate; 12-18 sec in term neonate
Defect in Vit K-dependent factor, liver disease, DIC
Activated partial thromboplastin time
Intrinsic & common pathway
25-40 sec beyond neonate; 70 sec in term neonate
Hemophilia, von Willebrand disease, DIC
Source from : Nelson Essential of Pediatrics 5th edition
in neonate (term infant), the level of all clotting factors except factor VIII & fibrinogen are
LOWER, much lower in preterm infants.
therefore, the results have to be compared with normal values in infants of a
SIMILAR GESTATIONAL & POSTNATAL AGE.
sometimes necessary to exclude an Inherited
Coagulation Factor Deficiency by testing the
coagulation of both parents.
PLATELET DISORDER, what is it?
MUHAMMAD NIZAR BIN MOHAMMAD YATIM
WHAT IS PLATELET ?
Oblong disk shape
Size- 2-4 µm on the long axis
Volume- 5-12 fL
Produced in bone marrow by megakaryocte cell
Platelet count in blood- 150,000-350,000 µL
Life span- ????
Classification of platelet disorders
Decreased production (leukemia and some anemia)
Inherited disorders (rare)
Acquired disorders (medication, chronic renal failure, cardiopulmonary bypass)
Defined as reduced in the platelet count< 150, 000µL that characterized by spontaneous bleeding, a prolonged bleeding time, and a normal PT and PTT.
The risk of bleeding depends on the level of the platelet count:
Mild thrombocytopenia (platelet <150 000 cells/µL)
Moderate thrombocytopenia (platelet 20 000 - 50 000 cells/µL)
Severe thrombocytopenia (platelet <20 000 cells/µL)
Sign and symptom
bruising, petechiae, purpura and mucosal bleeding (epistaxis @ gum bleeding)
major haemorrhage like severe GI bleeding, intracranial bleeding or haematuria is less common
normal platelet count may present in platelet dysfunction
1.IDIOPATHIC THROMBOCYTOPENIC PURPURA (ITP)
Isolated thrombocytopenia with otherwise normal blood count in a patient with no clinically apparent associated conditions that can cause thrombocytopenia (such as HIV infection, SLE, lymphoproliferative disorders, alloimmune thrombocytopenia, and congenital or hereditary thrombocytopenia).
Caused by immune- mediated destrcuction of circulating platelet d/t anti-platelet autiantibodies
There are two clinical subtypes of ITP:
Chronic ITP (starts after the disease has been present for > 6 months).
Inappropriate immune recovery follows an acute viral infection in children.
Autoantibodies (IgG or IgM) directed against platelet membrane antigens (especially glycoprotein complex IIb/IIIa).
Phagocytosis of antibody-coated platelets by the reticuloendothelial system.
Increased destruction of platelets – Thrombocytopenia.
Onset is usually sudden for acute ITP and in chronic ITP, it is insidious onset.
Petechiae or purpura
Feet, legs, arms, and buttocks.
Palatal petechiae, epistaxis, hematuria, menorrhagia, GI bleeding.
Rarely, intracranial hemorrhage may occur in long standing severe thrombocytopenia.
Signs of bleeding (petechiae and purpura).
Full blood count.
Low platelet count.
Platelets are normal in size or may appear larger than normal.
Normal red blood cells morphology.
Normal white blood cells morphology.
Prolong bleeding time, normal PT and PTT.
Not all children with acute ITP need hospitalization.
Treatment is indicated if there is:
Life threatening bleeding episode (e.g. ICH) regardless of platelet count.
Platelet count < 20,000/mm³ with mucosal bleeding.
Platelet count < 10,000/mm³with any bleeding.
Choice of treatment:
Oral prednisolone - 4 mg/kg/day for 7 days, taper and discontinue at 21 days.
IV Methylprednisolone - 30 mg/kg/day for 3 days.
IV Immunoglobulin - 0.8 g/kg/dose for 1 day OR 250 mg/kg for 2 days.
IV Anti-Rh(D) immunoglobulin - (50 – 75 µ/kg) in Rhesus positive patients – may cause haemolytic anaemia.
TREATMENT & MANAGEMENT
Splenectomy is only for life threatening in acute ITP
For chronic ITP:
Repeated treatment with IV immunoglobulin or IV anti-D or high dose pulse steroids are effective in delaying the need for splenectomy
Splenectomy is effective in inducing remission in 70-80% of childhood chronic ITP
Intracranial hemorrhage - 50% mortality rate.
Risk of ICH highest in:
Platelet count < 20 000/mm³.
History of head trauma.
Uses of aspirin (inhibitor of platelet aggregation).
Presence of cerebral arteriovenous malformation.
50% of all ICH occurs after 1 month of presentation, 30% after 6 months.
2. Hemolytic Uremic Syndrome (HUS)
Related to TTP in which the number of platelets suddenly decreases, RBC are destroyed and the kidney stop functioning
HUS is rare, but can occur with certain bacterial infection (E.coli or shigelladysenteriae) and with the use some drugs (quinine, cyclosporine, mitomycin C)
Toxin producing organism such as E.coli cause endothelial damage that activates localized clotting, leading to platelet aggregation and consumption
Common in infants, young children and pregnant women
3.Thrombotic Thrombocytopenic Purpura (TTP)
Resembles hemolytic uremic syndrome but occur more commonly in adults than in children
Spontaneous aggregation of platelets and activation of coagulation in small blood vessels
In TTP, platelet consumption, precipitated by a congenital or acquired deficiency of metalloproteinase that cleaves vWF
THROMBOTIC THROMBOCYTOPENIC PURPURA (TTP)
HEMOLYTIC – UREMIC SYNDROME (HUS)
Severe deficiency of the vWF – cleavage protease Platelet activation Platelet thrombi formation.
4.Marrow infiltration eg: leukemia
A progressive, malignant disease of the blood forming organs, marked by distorted proliferation and development of leukocytes and their precursors in the blood and the bone marrow
Overproduction of these white cells, which are immature or abnormal forms, suppresses the production of normal WBC, RBC and platelets
Lead to increase susceptibility to infection,anemia and bleeding
Result from infiltration of bone marrow or other organs with leukemic blast cells
Mostly presents insidiously over several weeks with some or all of following signs and symptoms:
Progress rapidly in some children
Blood count is abnormal, low hemoglobin,thrombocytopenia and evidence of circulating blast cells in most children
Bone marrow examination to confirm the diagnosis
5.Disseminated Intravascular Coagulation (DIC)
Disorder characterized by coagulation pathway activation leading to diffuse fibrin deposition in the microvasculature and consumption of coagulation factors and platelets.
Occurs as secondary complication of variety diseases.
Caused by the systemic activation of coagulation pathways, leading to formation of thrombi throughout the microcirculation and widespread thromboses. There is consumption of platelets and coagulation factors and secondarily activation of fibrinolysis. As consequence, there is depletion of the elements required for hemostasis ( consumptive coagulopathy)
May be acute or chronic.
Initiated through the tissue factor pathway.
The commonest causes of activation of coagulation are severe sepsis or shock due to circulatory collapse, e.g in meningococcal septicemia or extensive tissue damage from trauma or burn.
Other gram –vebact (Salmonella, E.coli, Haemophilus)
Virus (CMV, herpes, hemorrhagic fevers)
Rickettsia, Malaria and fungus
CNS trauma, crush injury
Multiple fracture with fat emboli
Profound shock of asphyxia
Acute promyelocytic leukemia
Acute monoblastic or myelocytic leukemia
widespread malignancies (neuroblastoma)
Severe TTP/ hemolytic uremic syndrome
Hereditary thrombotic disorders
Antithrombin iii def.
Homozygous protein C def.
G. B strep. Infection
Congenital viral disease (CMV, herpes)
Severe acute graft rejection
Acute hemolytic transfusion reaction
Heparin induced thrombosis
Pathophysiology of DIC
Massive tissue destruction
Release of tissue factor
Activation of plasmin
Widespread microvascular thrombosis
Proteolysis of clotting factor
Consumption of clotting factors and platelets
Fibrin split products
Microangiopathic hemolytic anemia
Ischemic tissue damage
Inhibition of thrombin, platelet aggregation and fibrin polymerization
The diagnosis of DIC usually suspected clinically and confirmed by a laboratory finding of a decline in platelets and fibrinogen associated with elevated PT time, PTT time, levels of fibrin(ogen) degradation products and D-dimers.
There is also marked reduction of naturally occuring anticoagulants, protein C, S and antithrombin.
In severely ill patient, there will be sudden occurrence of bleeding from venepuncture or incision site, gastrointestinal or pulmonary hemorrhage, petechiae or ecchymosis or evidence of peripheral gangrene or thrombosis.
Depending on the balance between clotting and bleeding tendencies.
In acute DIC (e.g., associated with obstetric complication) is dominated by a bleeding diathesis.
In chronic DIC (e.g., as occur in an individual with cancer) tends to present with symptom related to thrombosis.
Typically, the abnormal clotting occurs only in the microcirculation, although large vessels are involved occasionally.
Treat the disorder inducing the DIC first such as sepsis.
Support the patient by correcting hypoxia, acidosis and poor perfusion.
Replace depleted blood clotting factors, platelets and anticoagulant proteins by transfusion.
Heparin may be used to treat significant arterial or venous thrombotic disease unless sites of life-threatening bleeding coexist. Thus, the use of heparin remains controversial.
Treatment with anticoagulants or coagulants contained in fresh-frozen plasma usually needed in acute case.
Drotregocinalfa (recombinant activated protein C) reduces mortality in adults with DIC and sepsis.
Disorder Of Platelet Function
Deficiency of glycoprotein Ib complex (vWF receptor)
Autosomal recessive coagulapathy
Abnormally large platelets
Deficiency of glycoprotein IIb-IIIa (fibrinogen receptor)
Bleeding time is prolonged
A 15 years old girl comes to your clinic with complain of heavy menses (menorrhagia). She also complain sometimes she had mild nose bleed (epistaxis) and easy bruising. She had previous surgical history of tonsillectomy at 6 years of age, which required blood transfusion for excessive bleeding. Her mother required a hysterectomy after giving birth to her younger brother because of excessive hemorrhage. Her mother is planning for her brother to join for circumcision in this school holiday.
Haemophilia – overview
A group of blood disorders in which there is defect in clotting factors
70% are X-linked recessive disorder. 30% spontaneous mutation.
The bleeding patterns of haemophilia are similar.
A:Deficiency in factor VIII (classic haemophilia)
B: Deficiency in factor IX (Christmas disease)
C: Deficiency in factor XI
Haemophilia - investigation
Full blood count
Activated partial thromboplastin time (aPTT) – PROLONGE
Normal Prothrombin Time, Platelet Count, Bleeding Time.
Specific factor assay : VIII or IX - LOW
Hepatitis B, Hepatitis C, HIV serology
Diagnosis for carrier status for genetic counseling
Haemophilia - treatment
First aid: Pressure, Rest, Ice, Elevation (PRICE)
Blood transfusion – severe blood lost
Factor concentrates; continuous infusion (severe) or intermittent bolus (prophalaxis).
Factor VII given every 8-12 hours
Factor IX given every 12-24 hours
Desmorpressin acetate (DDAVP); mild & moderate, not for severe.
Antifibrinolytics: Aminocaproic acid (Amicar)
Fresh Frozen plasma (high risk for virus)
Haemophilia - complication
Factor concentrate infusion at home as prophylaxis;
Need for venous access
Developed Inhibitors ??????
Joint destruction; inflammation, swelling, fibrosis.
Acquisition of virus (Hep B, Hep C, Hep D & HIV)
Haemophilia - inhibitors
It’s a IgG antibodies directed against transfused factor VIII (30%), rarely happens with factor IX (2%)
Making treatment for haemophilia difficult.
Can be low titer Porcine factor VIII or continue infusion of factor VIII.
Can be high titer recombinant factor VIIa as bypassing agent.
Von willerbrand disorder - overview
Most common hereditary deficiency caused abnormality in von Willerbrand protein.
Functions on both primary & secondary homestasis.
1. To act as bridge between subendothelial collagen and platelets
2. Bind and protect factor VIII from rapid clearance then delivers it to site of injury.
Von willerbrand disorder - types
Type I (70%-80%) – Quantitative,
Partial decrease in quantity vWF
Mild clinical symptoms
Type 2 (15%-20%)– Qualitative,
Decrease affinity toward Factor VIII and platelet
Type 3 – Quantitative,
Absence of von Willerbrand factor
Severe clinical symptoms
Lack of response to Desmorphine (DDAVP)
Full Blood Count – platelet normal
aPTTPROLONGE or normal
Factor VIII LOW or normal.
von Willerbrand Factor activity (ristocetin cofactor)
Ristocetin, an antibiotic that causes vWF to bind to platelet taken from plasma.
In healthy people, platelet rapidly agglutinate.
von Willerbrand Factor antigen
Measure vWF protein and binding sites.
Desmopressin (DDAVP) – Treatment of choice for patients with vWD types 1 and 2 .
Concentrate of von Willerbrand Factor (Humarate P) when high levels of vWF are needed but cannot achieved with DDAVP (type 3)
Contraceptive for menorrhagia
Clot-stabilizing medications (antifibrinolytic medications) -
Prognosis & complications
Lifelong tendency toward easy bruising, frequent epistaxis, and menorrhagia.
Register with Malaysia Hemophilia Society.
Carry medic-alert bracelet or chain & carry books diagnosis, types etc.
Vitamin k deficiency
3 main types of VK are
K-1, phylloquinone, derived from plants;
K-2, menaquinone, produced by the intestinal flora
K-3, menadione which is a synthetic, water-soluble form used for treatment.
Required for synthesis of Plasma factor II, VII, IX, and X
Hemorrhagic disease in infant that breastfeed exclusively.
Give parenteral vitamin K (0.5 to 1 mg) to all newborns shortly after birth.
Severe impairment of hepatic functions or severe necrosis of hepatocytes in the absence of pre-existing liver disease
Fatal for most affected children.
The mortality rate may reach 80-90% in the absence of liver transplantation.
Nelson, Essential of Peadiatrics
Tom, Illustrated Textbook Paediatric
Paediatric Protocol for Malaysians Hospitals
Thank you for your attention.. Questions?
Should children with severe clotting disorder undergo circumcisions?
Can we infuse bovine or porcine products in medical treatment?
von Willerbrand Disorder
Circumcision is not compulsory, can if only procedure is monitored by specialist & prohylaxis is available.
Can use porcine or bovine products as it has already undergone multiple process. Proceed with halal product if available.
CAUSES OF BLEEDING:
Nuramalina Bt. Ahmad ehsan
NELSON ESSENTIALS of PEDIATRICS, 5th EDITION; page 712
A vessel defect either congenital or acquired resulting in abnormal bleeding despite an otherwise normal coagulation factor and platelet.
Vasculitis of unknown etiology characterized by inflammation of small blood vessel associated with leukocytic infiltration of tissue, hemorrhage, and ischemia.
Incidence 13/100 000 children
occur in children age 3-15 years.
Likely mechanism thought to be an immune-complex mediated disease with deposits of IgA in the glomerular capillaries, dermal capillaries and GI tract.
Mesangial deposition of IgA and C3 in the kidney.
Rash of palpable purpura:
below the waist on the butocks and lower extremeties. Can be accompanied by edema of the calves,dorsum of the feet, scalp, and scrotum or labia.
acute, tend to affect the lower extremeties; ankle and knees. joint swelling.
3. Gastrointestinal :
mild to moderate crampy abdominal pain, abdominal distension, bloody diarrhea, intussusception or abdominal perforation.
4. Renal: heamaturia, hypertension
LABORATORY AND IMAGING STUDIES
Elevated ESR, CRP and WBC count.
Normal platelet count
Urinalysis ( Hematuria)
Serum BUN and Creatinine
CT scans show multifocal areas of bowel-wall thickening, mesenteric edema, vascular engorgement, and nonspecific lymphadenopathy.
Renal biopsy may show IgAmesangial deposition and occasionally IgM, C3, and fibrin. Patients with IgA nephropathy may have elevated plasma antibody titers against H. parainfluenzae.
Presence of 2 of 4 criteria:
Palpable purpura- raises, palpable hemorrhagic skin lesions in the absence of thrombocytopenia.
Bowel angina - diffuse abdominal pain or the diagnosis of bowel ischemia
Diagnostic biopsy- histologic changes showing granulocytes in the walls of arterioles or venules
Pediatric age group- age < 15 years at onset of symptoms
Varices?-Varices are dilated blood vessels ( veins) usually in the esophagus or stomach.- eg due to Portal hypertension.
The varices are fragile and can rupture easily, resulting in a large amount of blood loss.
Symptoms of bleeding varices include:
Vomitting of blood
Black, tarry, or bloody stool
Low blood pressure
Rapid heart rate
Shock (in severe cases)
Burning epigastric several hour after meal & night.
GI bleed (hematemesis,melena)
H. Pylori infection
Endoscopy-mandatory with alarm symptoms
Test for H.Pylori
Amylase and lipase
Omeprazole-clarithromycin-metronidazole (associate with H.pylori)
Proton pump inhibitor
7. EHLER- DANLOS SYNDROME
Congenital disorder of defect in collagen synthesis.
Patient’s skin lacks its normal resistance to traction and can be easily pulled away from underlying structures.
This condition places blood vessels at great risk for disruption even with
Cutaneous findings – hyperextensible and
fragile skin, poor wound healing, easy bruising,molluscoidpseudotumors.
Systemic features – joint hypermobility,
scoliosis, significant risk of spontaneous arterial, intestinal or uterine rupture
Both DNA and biochemical studies
There is no known cure for Ehlers Danlos Syndrome.
The treatment is supportive.
Close monitoring of the cardiovascular system.
An autosomal dominant disorder of the connective tissue.
Clinically symptoms mostly involve three systems:
Cardiac ( dissecting aorta, aortic valve regurgitation, mitral valve prolapse)
MSK ( dolichostenomalia, arachnodactyly, abnormalities of the sternum, kyphoscoliosis)
Ophtalmology (dislocated lens, cataracts)
Diagnosed by :
[ Diagnostic criteria for Marfan syndrome ]-
**presence of 2 major criteria(organ systems) and 1minor criteria
( third organ system). [ NELSON ESSENTIALS of PEDIATRICS, 5th EDITION; page223 ]
Thin and tall body habitus
Congenital defects of the vessel wall that can result to abnormal bleeding tendency.
Eg: Hereditary hemorrhaghictelangiectasia
Progressive degenaration of the vessel wall leading to development of widespread angiomatous lesion.
On PE, small violaceous non pulsatiletelangiectasias can be found over lips and mucous membrane.( They blanch with pressure).
This disease not limited to the skin– Telangiectasias in lung, liver.
angiodysplasia is a small vascular malformation of the gut. it resembles telangiectasia.
common cause of unexplained GI bleeding (recurrent bleeding per rectum) and anemia.
cecum or ascending colon
Diagnosis of angiodysplasia is often accomplished with endoscopy, either colonoscopy or EGD.
Colonoscopy of angioydsplasia in the Sigmoid colon