Bleeding Disorders in Children

T.Rettig SMS KNUST 20th January 2011

INTRODUCTION

Blood has to be in a dynamic equilibrium between fluidity and coagulation. The balance is maintained so that neither excessive bleeding nor thrombosis occurs spontaneously or following trivial trauma. Bleeding is more common than hypercoagulation.

INTRODUCTION

Bleeding may result from deficiency or abnormality of any step of the coagulation process. Evaluating: battery of laboratory tests.

SCHEME OF HEMOSTASIS

Primary haemostatic mechanism involves vascular response and platelet plug formation. Secondary mechanism: formation of a stable fibrin clot. It includes the soluble clotting factors.

The vascular endothelium is the first barrier against hemorrhage.

SCHEME OF HEMOSTATIS
Small vessels injury: Active vasoconstriction and local tissue pressure control the areas of bleeding without mobilization of the coagulation process. Platelets are essential for the control of such small blood vessel injury.

SCHEME OF HEMOSTATIS
Larger blood vessels injury: The participation of the coagulation system is required to provide a firm, stable fibrin clot.

The fibrinolytic system ensures that excessive clot formation is prevented and that the clot is retracted.

Process:

After vascular injury, blood is exposed to sub endothelial matrix, VWF provides the glue to which platelets bind. The platelets release stored proteins (e.g.thromboxane); this leads to recruitment of other platelets to form a plug. During the process of platelet activation, platelet phospholipids are released and interact with the clotting factors..

Vascular injury and release of tissue factor initiates the clotting process. Coagulation proceeds in 3 phases;

Phase I involves the formation of prothrombin activator (thrombinase) from either the extrinsic or intrinsic pathway Phase II involves PT T Phase III involves fibrinogen fibrin

HAEMOSTATIC MECHANISM

COAGULATION INHIBITORS

There are 3 clinically important, naturally occurring coagulation inhibitors;

Antithrombin III (AT III), Protein C and S.

AT III inhibits activated coagulation factors in their active site e.g. Thrombin, factor Xlla, Xla, Xa. Protein C uses Protein S as cofactor and when activated, they inhibit factor V & VIII. Deficiency of such inhibitors leads to excessive coagulation (thrombosis). This can cause stroke even in children.

HAEMOSTATIC MECHANISM

Waterfall cascade
= activated clotting factors activate the next sequential clotting factor in a systematic manner Feedback mechanisms enhance clotting at the site where it is needed. The system is always ready to start the process.

Laboratory Investigations

Study of coagulation steps in isolation, as individual steps. In vivo the events are tightly integrated.

Nevertheless the mechanisms studied by the PTT and PT permit us to evaluate clotting factor deficiencies even though these pathways may not be the same as occurring physiologically.

HAEMORRHAGIC DISORDERS
Factor deficiency

Production Site

Synonym Fibrinogen

I II VII VIII:C VIII:R

Liver
Liver K dep. Liver K dep. Vit Vit

Inherit Incidence ance AR Very rare AR AR XR AD Very rare 1:500,000 1:30,000 1:100?

Prothrombin
Proconvertin Hemophilia A Von Willebrand factor

Liver & other Tissue Endothelial cells & Platelets

HAEMORRHAGIC DISORDERS
Factor
deficiency

Production
Site

Synonym

Inheritance

Incidence

IX X XI XII XIII

Vit Christmas factor K dep.

Liver Liver Liver Liver

X-Recessive 1:150,000 A-Recessive 1:150,000

Stuart Prower

Plasma A-Recessive 1:150,000 thromboplast. antecedent

Hageman factor

A-Recessive Very rare A-Recessive Very rare

Liver & Platelet

Fibrin stabilizer

Laboratory Investigations
Single test rarely give conclusive results. Commonly used tests (screening tests): Platelet count Bleeding time Prothrombin time (PT) Partial thromboplastin time (PTT/aPTT) The above screening tests should identify most hemostatic defects.

Laboratory Investigations

Rare tests are

platelet aggregation test thrombin time fibrinogen assay Clotting factor assay

Whole blood clotting tests are no longer used - they lack either sensitivity or specificity.

TESTS
Bleeding time (N 1-6 mins) Assesses the vascular and platelet phase of haemostasis. Using a scalpel blade, drops of blood are blotted from the margin of the incision at 30 sec interval until blood flow stops usually up to 6 mins. It is very sensitive to platelet number In inexperience hands, the test show considerable test-to-test variability

TESTS
Platelet count (N 150-400/nL)

Thrombocytopenia is the most common cause of defective primary hemostatic mechanisms in children. There is a linear relationship between bleeding time and platelet count. Bleeding time (mins) = 30.5 platelet count/L

3850

TESTS cont.
Platelet count (cont.)

If the bleeding time is disproportionate to the platelet count, a qualitative platelet defect should be suspected. Patients with platelet count above 50 x 10 9/L rarely have significant bleeding whereas those with count below 20 x 10 9/L are at risk of intracranial bleed. Platelet activators include: ristocetin, thrombin, adrenalin, collagen & ADP

TESTS
Activated PTT (N 30-40 s)

Evaluates phase I of coagulation It is the time required for plasma to clot when it has been activated by incubation with an inert activator (e.g.. Ground glass, kaolin, celite & ellagic acid). It assesses the adequacy of factors XII (plus prekallikrein, HMW kinogen), XI, IX, VIII and common pathway.

TESTS cont.

Activated PTT cont.

If Phase II & III tests (PT & TT) are intact, a prolonged PTT represent deficiency or inhibition in intrinsic pathway. Prolonged PTT can therefore be due to intrinsic pathway factors (XII, XI, IX, VIII) or common pathway factors (X,V, II, I)

TESTS
Prothrombin Time PT (N 11-13 s)

Assesses Phase II of coagulation It is the time taken for plasma to clot after the addition of exogenous thromboplastin (tissue factor) & Ca2+ If Phase III (TT) is intact, prolonged PT indicates deficiency of factor VII (extrinsic pathway) or V, X, II (common pathway)

TESTS
Thrombin time TT (N 12-20 s)

assesses phase III of coagulation (fibrinogen fibrin) it is the time required for plasma to clot after the addition of factor IIa (thrombin) prolongation of TT limits the defect to fibrinogen only or the presence anticoagulant like heparin

6.

Fibrinogen assay is possible

FACTORS TESTED FROM PT & aPTT

PT
- factor VII - factor X - factor V - factor II - fibrinogen - HMWK - factor X - factor V - factor II - fibrinogen

aPTT
-Prekallikrein - factor XII - factor XI - factor IX - factor VIII

Pathogenesis of Bleeding

Inadaequate vascular constriction Failure to form platelet plug Failure to generate adaequate thrombin for fibrin clot Failure to maintain fibrin clot

Disorders of Primary Haemostasis

Vascular disorders Ehlers Danlos Syndrome Scurvy Von Willebrand Disease Platelet Disorders

Bleeding Pattern: Immediate bleeding and bruising after trauma Petechiae Ecchymoses Epistaxis Gum bleeding Menorrhagia

SPECIFIC VASCULAR DEFECTS

Excessive capillary fragility occurs in hereditary disorders of collagen synthesis e.g.. Ehlers- Danlos Syndrome. Abnormal vessel formation in which vascular abnormality occurs throughout the body esp. mucosal surfaces e.g.. Hereditary hemorrhagic telangiectasis Scurvy (Vit. C def) which leads to impaired collagen synthesis. Walls of blood vessels are fragile due to poor collagen support.

SPECIFIC VASCULAR DEFECTS

1.

2.

3.

Steroid-induced purpura when steroids impair collagen synthesis Henoch-Schonlein purpura a small vessel vasculitis affecting skin, joints, GIT and kidney, with a striking centrifugal distribution of the purpura Other vasculitic syndromes, like hypersensitivity vasculitis, viral and rickettsial infections.

Disorders of Secondary Haemostasis

Factor Deficiency - FVIII - FIX - FVII

Bleeding Pattern: Delayed Deep tissue: - joint - muscle - soft tissue - CNS

Von Willebrand Factor

Synthesized by megacaryocytes and endothelial cells Circulates as a multimer that varies in molecular weight Acts as glue between platelets and subendothelial matrix at injury site Serves as carrier protein for Factor XIII

Von Willebrand Disease

VW disease results from either decrease in VWF number or function Affects up to 1% of population (more females than males why?) Autosomal dominant inherritance with incomplete penetrance Mucocutaneous bleeding pattern

Types of von Willebrand Disease

Type I: low level of all proteins Type II: abnormal protein (2A low HMWM, 2B increased binding to platelets, 2N lack of FVIII binding site and low FVIII level) Type III: absent VWF and very low FVIII Pseudo VWD: abnormal platelet GPIb (glycoprotein Ib), low levels of HMWM

Diagnosis: VWD

Bleeding time prolonged aPTT (usually prolonged) Von Willebrand Factor Antigen -maybe low (levels elevated by stress, exercise, pregnancy, hyperthyroidism; low levels in hypothyroidism) Factor VIII level (maybe reduced) Ristocetin-induced platelet aggregation delayed

VWD Treatment

DDAVP (desmopressin): can increase VWF release and elevate levels 2-3x oral contraceptives (menorrhagia) Replacement therapy: cryoprecipitate, plasma derived VWF preparation (also containing FVIII), fresh frozen plasma (needs large volumes)

Platelet Disorders
Quantitative platelet disorders: - Thrombocytopenia due to * increased destruction * decreased production * splenic sequestration Qualitative platelet disorders - disorders in platelet function

Platelets: Increased Destruction

Immune mediated causes

ITP idiopathic thrombocytopenic purpura Drug-induced Infection-induced Auto-immune disorders Post-transfusion purpura Neonatal

Acute ITP

Common childhood disease Presentation: Healthy child with sudden onset of petechiae and bruising. Viral illness or immunization 1-3weeks before onset. Peak age 2-4years, M=F 90% resolve within 6 months

Acute ITP
Opsonised platelets are trapped and destroyed in the RES Physical examination normal except signs of platelet-type bleeding, lymphnodes not enlarged Labs: - isolated thrombocytopenia - normal WBC and RBC - increased mean platelet volume - bone marrow shows normal or increased megacaryocytes DD: HIV, EBV, CMV, ANA, Coombs test...

ITP treatment

Mild cases need no specific treatment except protection from falls & trauma Vit K & Vit C has no place Fresh blood /platelet concentrate provide transient benefit Infusion of gamma immunoglobulin IVIG is the treatment of choice (expensive) Steroids controversial, may provide benefit if given earlyPrednisolone 1-2mg/kg/day in divided doses for 3 weeks or till platelet count normalizes. Splenectomy & other immunosuppressive agents in refractory cases

Chronic ITP

Thrombocytopenia persists >6months If <1year or >10years at time of ITP onset, increased risk of chronic disease F:M 3:1 May have associated immunodeficiency or autoimmune disease Prolonged fluctuating course, may last months or years Platelet usually 40-80/nl

Drug-induced ITP

Heparin Quinidine Penicillins Digoxin Valproic acid

Neonatal alloimmune thrombocytopenia

Occurs in 1-2 per 5000 newborns - Affected infants have platelets containing different antigens from their mothers - Maternal IgG alloantibodies cross the placenta and destroy infants platelets Presents as severe thrombocytopenia in healthy infants - Resolves in 1-3 weeks of life - Serious haemorrhage in 10-20% of cases - Treat with maternal platelets

Non-immune causes of Platelet Destruction

Haemolytic uraemic syndrome:

affect infants and young children usually follows acute gastroenteritis consists of triad of thrombocytopenia , hemolytic anemia and acute renal insufficiency

Kasbach Merrit syndrome:Thrombocytopenia with cavernous haemangioma Congenital cyanotic heart disease DIC

Platelets: decreased production

Thrombocytopenic absent radii (TAR) syndrome Aplastic anaemia Drug induced (chemotherapy) Radiation induced Metabolic disorders Bone marrow infiltration (leucaemia)

Platelets: Qualitative disorder

= Platelet sufficient in number but dysfunction in hemostasis evident by prolonged bleeding time.
Congenital disorder e.g. Glanzmans thrombasthenia= intrinsic disorder in which platelet membrane glycoprotein is lacking and therefore cannot bind to each other. Acquired cases like uremia and drugs (NSAIDs, esp. aspirin). The inhibition of PG synthesis via cyclo-oxygenase prevents endogenous ADP and TXA2 which is needed for platelet aggregation.

Platelets: Qualitative disorders

Bernard Soulier syndrome Wiskott Aldrich syndrome a combined immunodeficiency disorder with associated eczema Platelet granule defects

Coagulopathies: Phase I defects

Hemophilia: Factor VIII deficiency Defective gene is carried on x-chromosome Factor VIII is a complex of 2 proteins each with specific but different function VIII: C (anti hemophilic factor) is the procoagulant protein and smaller VIII: R (VWF) is the related/carrier protein and is needed for platelet adhesion.

Causes of Haemophilia A+B

Inherited X-linked recessive pattern. The genes for FVIII and factor IX (FIX) are located on the long arm of the X chromosome in bands q28 and q27, respectively. The factor VIII gene is one of the largest genes; it is 186 kilobases (kb) long..

Cont.

Numerous mutations in the gene structure have been described. Genetic abnormalities include genetic deletions, abnormalities with stop codons,. Data suggest that 45% of severe hemophilia A cases result from an inversion mutation. Several hundred mutations with different amino acid substitutes have been described in hemophilia B result in decreased or absent production of FIX. Evaluation and knowledge of the specific gene defect in families with severe hemophilia enables accurate gene tracking, carrier analysis, and prenatal diagnosis.

Factor VIII deficiency

In hemophilia VIII: C level is , VIII: R level normal

Female carriers, male sufferers 80% of cases have +ve family history sporadic cases may represent new mutation degree of severity consistent in a given family

Secondary Hemostasis: Hemophilia

Hemophilia A Factor VIII deficiency X-linked recessive 85% 1 in 10.000 males?

Hemophilia B Factor IX deficiency X-linked recessive 15% 1 in 25.000 males?

Classification
Mild Moderate

Factor VIII activity %

>5 - 40 1-5

Cause of haemorrhage
Major trauma or surgery Mild to moderate trauma

Severe

<1

Spontaneous , haemarthrosis

Diagnosis: PTT is greatly prolonged normal PT, bleeding time or platelet count. Specific assay for factor VIII activity with normal VIII:R confirms the Diagnosis

Hemophilia

Common sites of hemorrhage Hemarthrosis Muscle hematoma Mucous membrane hemorrhage High risk hemorrhage: CNS, retropharyngeal, retroperitoneal

PHASE II DISORDERS
Factor II, V, X and VII are involved in the 2nd phase of coagulation and are designated prothrombin complex. These factors are produced in the liver and require Vit K except factor V. Deficiency of a factor in the PT complex is rare and is inherited as AR.

ACQUIRED COAGULATION DISORDERS

Vit K deficiency mimic Phase II disorder e.g. Hemorrhagic Disease of Newborns

Manifests in 1st week of life (days 2-4 of life) Late manifestation in breastfed infants may occur after 3 months Lab. PT and PTT . Normal bleeding time and Normal platelet count Management: Vit K iv Prophylaxis

LIVER DISEASE

All the clotting factors are made in the liver. In severe liver damage coagulopathy is common. Hepatic clearance of activated clotting factors may also be impaired in severe liver damage leading to thrombosis and DIC
Lab: PTT & PT Treatment: FFP, cryoprecipitate, Vit K. Avoid PT complex concentrate because activated factors may not be cleared by damage liver leading to thrombosis and DIC.

DIC/Consumptive Coagulopathy
Occurs with other disease processes like septic shock (esp. G-ve), ricketsial infection, snake bite, malignancy, hypoxia, acidosis, tissue necrosis, shock and endothelial damage. Pathogenesis: intravascular activation of coagulation fibrin deposit in small vessel tissue ischemia release of tissue thromboplastin consumption of labile factors (platelets, factor II, V & VIII) and activation of fibrinolytic system.

In DIC
Features bleeding is diffuse, with oozing from venopuncture sites or surgical incisions, around indwelling catheters. Also petechieae and ecchymosis, Gl & pulmonary bleeding, hematuria. Tissue thrombosis may involve many organs and large areas of the skin, subcutaneous tissue, kidney & brain may be infarcted

APPROACH TO MANAGEMENT

Avoid drugs that compromise platelet function, e.g. Aspirin Avoid deep venopunctures (e.g.. Femoral tap) as well as IM injections. Patients should be protected against trauma (esp. the head) In life-threatening bleeding, Fresh frozen plasma (FFP) 10-20 mls/ Kg can be used temporary for defective coagulation until a specific deficiency is identified. When the nature of the defect is identified; specific replacement is made.

Hemophilia: treatment with factor concentrate

Factor VIII: Dose(units) = wt(kg)x % desired factor level x 0.5 Example: child 10kg, desired level 100% 10kg x 100 x 0.5 = 500Units

Factor IX: Dose(units) = wt(kg) x % desired level x 1

Example: 10kg child, desired level 80% 10 x 80 x 1= 800Units

Haemarthrosis

Stage 0: Normal joint I: Normal bone; soft-tissue swelling present. II: Osteoporosis, overgrowth of the epiphysis, no cysts, no narrowing of the cartilage III: Early sub-chondral bone cysts, squaring of the patella, widened notch of the distal femur or humerus, preservation of the cartilage space IV: narrowed cartilage space V: Fibrous joint contracture, loss of the joint cartilage space, extensive enlargement of the epiphysis, substantial disorganization of the joint

Factor VII Lack

Prolonged PT with normal PTT

Management: FFP, PT complex concentrate Deficiency in factor II, V and X (common pathway) will lead to a prolonged PT & PTT

PHASE III DISORDERS

(Fibrinogen fibrin)

Congenital afibrinogenemia (AR) and Congenital dysfibrinogenemia (AD) defective function with normal fibrinogen level but prolonged thrombin time.