Please enable JavaScript.
Coggle requires JavaScript to display documents.
Coagulation disorders in children (quantitative or qualitative…
Coagulation disorders in children
quantitative or qualitative abnormalities
in plasma procoagulant factors
Haemostasis
refers to the stoppage of blood flow.
requires a coordinated interaction between platelets, vascular endothelial cells, and plasma clotting factors.
regulated by a complex array of activators and inhibitors that maintain blood fluidity and prevent blood from leaving the vascular compartment (by forming a haemostatic clot at the site of vascular injury).
normal when it seals a blood vessel to prevent blood loss and haemorrhage
abnormal when it causes inappropriate blood clotting or when clotting is insufficient to stop the flow of blood from the vascular compartment
process of Haemostasis divided into 5 stages:
(1) vessel spasm
(2) formation of the platelet plug
(3) blood coagulation or development of an insoluble fibrin clot
(4) clot retraction
(5) clot dissolution
Coagulation can be activated by two pathways:
Intrinsic blood coagulation is initiated by contact of the flowing blood with a foreign surface
Extrinsic pathway is thought to be primarily responsible for initiating haemostasis
Both pathways converge on the activation of factor X.
Coagulation disorders
result from defects in any of the factors that contribute to haemostasis
Hereditary coagulation disorders
•von Willebrand disease •haemophilia A •haemophilia B
Acquired (secondary) coagulation disorders
•vitamin K deficiency •liver disease •others: renal disease, disseminated intravascular coagulation (DIC), infection, medications, malignancy, massive transfusion, post-surgery, and autoimmunity or alloimmunity
haemophilia A and von Willebrand disease are two of the most common inherited bleeding disorders
Acquired bleeding disorders are much more common
Basic laboratory tests
CBC:
providing a platelet count to identify suspected thrombocytopenia
abnormalities in the white blood cell count or red cells
PT = prothrombin time
measures the extrinsic pathway (factors VII, X, V, II)
aPTT = activated partial thromboplastin time
measures the intrinsic pathway (factors XII, XI, IX, VIII, X, V, II)
TT = thrombin time
measures the last step in the common pathway, the rate of conversion of fibrinogen to fibrin clot
BT =(template) bleeding time
performed with a blood pressure cuff, it detects a platelet functional defect in a bleeding patient with a normal platelet count, it can also detect patients with clinically significant von Willebrand disease
Fibrinogen functional level by clotting assay
HAEMOPHILIAS
Haemophilia A (classic haemophilia) is factor VIII deficiency, and accounts for 80–85% of haemophilias
Haemophilia B (Christmas disease) is factor IX deficiency, which accounts for 15–20% of haemophilias
both are X-linked recessive conditions
clinically, it is not possible to distinguish between them
Over 60% of cases have a positive family history.
Inheritance
Males with a haemophiliac gene on their single X chromosome (XH) suffer from haemophilia.
Heterozygous females are carriers and do not express the full clinical disease because of the paired normal X-chromosome.
Females with two copies of the defective XH chromosome may rarely suffer from haemophilia.
manifestations
Individuals with more than 30% F-VIII or F-IX clotting activity usually do not spontaneously bleed and may not need supplemental clotting factor in the setting of minor surgery.
Mild disease, infers > 5% (6–35%) of F-VIII or F-IX clotting activity
+These children may have bleeding with trauma or surgery.
+Some carrier females, who have low levels of these factors, may present clinically with gynaecological or obstetric haemorrhage.
Moderately severe haemophilia
means 1–5% F-VIII or F-IX clotting activity
These children rarely have spontaneous haemorrhages, but may have significant haemorrhage with mild or moderate trauma.
The usual age at diagnosis is before 5 years.
Severe haemophilia
corresponds to <1% F-VIII or F-IX clotting activity
These children are predisposed to having spontaneous bleeding into joints, muscles and deep organs, including central nervous system bleeds.
Without preventative treatment, these children have two to five spontaneous bleeding episodes each month.
The usual age of diagnosis is within the first year of life.
Complications
Haemarthrosis
result in destructive arthritis, joint instability and ankylosis. With modern treatment, severe arthritis is now uncommon in children with haemophilia.
The commonest joints affected are the knees, followed by the elbows, ankles and shoulders.
Neurological bleeding
Intracranial haemorrhage
common causes of death.
Haemorrhage into vertebral canal
Rare; 75% are extramedullary and 25% intramedullary.
Presents with severe neck or back pain, followed by ascending paralysis.
Peripheral nerve compression
External compression or traction from intramuscular bleeds.
Nerves affected and relevant muscles often affected: femoral (iliopsoas), ulnar and median (forearm flexors), sciatic (glutei).
Retropharyngeal haemorrhage:
associated with pharyngitis.
Presents with dysphagia and drooling.
diagnosed by lateral neck X-ray.
Retroperitoneal haemorrage
Diagnosed by ultrasound or CT scan.
Laboratory findings
Bleeding time: normal
PT: normal
aPTT: prolonged
Platelet number: normal
Clotting time: prolonged
Factor VIII or IX assay: decreased – essential for the diagnosis
Management
Concentrates – recombinant DNA-engineered F-VIII and F-IX are the treatments of choice
Antifibrinolytics – epsilon-aminocaproic acid (EACA) and tranexamic acid
Desmopressin (1-deamino 8-D arginine vasopressin: DDAVP) – synthetic analogue of vasopressin that raises the F-VIII level by up to five times in normal subjects and seven times in some mild haemophiliacs, but has no effect in patients with severe disease
Corticosteroids – prednisolone used for haematuria or joint bleeds
Fresh frozen plasma (FFP) – contains all the clotting factors
VON WILLEBRAND DISEASE
deficiency of vWF (von Willebrand factor) – a protein present in plasma, which binds factor VIII and is a cofactor for platelet adhesion to the endothelium
inherited, affecting males and females equally
Types
70–80% of all patients with vWD have classic vWD (type 1), which is caused by a partial quantitative deficiency of vWF
vWD type 2 (a and b) involves a qualitative deficiency of (ie, dysfunctional) vWF
vWD type 3 is characterized by a nearly complete deficiency of vWF
Etiology
most often transmitted as an autosomal dominant trait, but can be autosomal recessive
can also be acquired, developing in association with hypothyroidism, Wilms tumor, cardiac disease, renal disease, or systemic lupus erythematosus and in individuals receiving valproic acid
acquired vWD is most often caused by the development of an antibody to vWF or increased turnover of vWF
Clinical presentation
history of increased bruising and excessive epistaxis is often present
prolonged bleeding also occurs with trauma or at surgery
menorrhagia is often a presenting finding in females
majority (> 80%) of individuals with type 1 disease are asymptomatic
Laboratory findings
PT is normal, and aPTT is sometimes prolonged
Platelet count normal (may be decreased in type 2b vWD).
Factor VIII and vWF antigen are decreased in types 1 and 3,
but may be normal in type 2 vWD.
vWF assay (eg, ristocetin cofactor or collagen binding) active vWF level is decreased.
Prolongation of the PFA-100 or bleeding time is usually present
Treatment
Desmopressin acetate, which causes release of vWF from endothelial stores (intravenously, nasal spray)
vWF-replacement therapy (eg, plasma-derived concentrate)
Antifibrinolytic agents (eg, -aminocaproic acid)
Topical thrombin and fibrin glue
Estrogen-containing contraceptive therapy for menorrhagia
quantitative or qualitative abnormalities
of platelets
Quantitative platelet disorders:
Thrombocytopenia: Increased destruction, Decreased production, Sequestration, Dilutional
Thrombocytosis
Qualitative platelet disorders
Hereditary: Defective adhesion of platelets, Disorders of platelet secretion,Defective platelet aggregation
Acquired
Quantative
normal platelet count ranges from 150,000 - 400,000/cu mm (150–400 × 109/L)
normal life span is 8-10 days
THROMBOCYTOPENIA
platelet count below the lower limit of 150,000/cu mm (150 × 109/L)
causes excessive or abnormal bleeding
often immune-mediated (eg, ITP, neonatal auto- or alloimmune thrombocytopenia, heparin-induced thrombocytopenia)
also caused by consumptive coagulopathy (eg, DIC, Kasabach-Merritt syndrome), acute leukemias, rare disorders such as Wiskott-Aldrich syndrome and type 2b vWD, and artifactually in automated cytometers (eg, Bernard-Soulier syndrome), where giant forms may not be enumerated as platelets by automated cell counters
Severity of bleeding depends upon a platelet count:
20,000 to 50,000 = Post-traumatic bleeding
<20.000 (<20 × 109/L) Spontaneous bleeding
<10,000 (<10 × 109/L) Intracranial bleeding life-threatening !!!
Skin manifestations
Purpura is discoloration of the skin or mucous membranes due to extravasation of red blood cells. The appearance of these lesions do not change on pressure.
Petechiae are pinhead-sized macules of blood in the skin.
Ecchymosis describes larger spots (> 5 mm in diameter).
IDIOPATHIC THROMBOCYTOPENIC PURPURA
an autoimmune disorder in which platelet destruction results from the formation of antiplatelet autoantibodies.
Two major subtypes: acute ITP vs chronic ITP
ACUTE ITP
the most common bleeding disorder of childhood.
in children aged 2–5 years and often presents 1 to 3 weeks after viral (measles, rubella, EBV) infection.
Anti-platelet antibodies are IgM type.
Most patients recover spontaneously within a few months.
20% of the children, have persistent low platelet counts beyond 6 months similar to chronic ITP.
n severe cases IVIG are needed. Steroid therapy is indicated only if thrombocytopenia is severe and the bone marrow aspiration was performed to exclude leukemia.
CHRONIC ITP
more than 6 months' duration occurs in 10–20% of affected patients
Usually seen in adults.
Anti-platelet antibodies are IgG type.
Clinical findings
Onset of ITP is usually acute, with the appearance of multiple petechiae and ecchymoses.
Epistaxis, gum bleeding and fever are also common at presentation.
Rarely, concurrent infection with EBV or CMV may cause hepatosplenomegaly or lymphadenopathy, simulating acute leukemia.
The size of the spleen is normal
Laboratory findings
platelet count is markedly reduced (usually < 50,000/ L and often < 10,000/ L), and platelets frequently are of larger size on peripheral blood smear, suggesting accelerated production of new platelets.
white blood count, red blood cells, haemoglobin is normal unless haemorrhage has been significant.
Bone marrow: the number of megakaryocytes is increased. Erythroid and myeloid cellularity is normal.
Platelet-associated IgG or IgM, or both, may be demonstrated on the patient's platelets or in the serum.
PT and aPTT are normal.
Bleeding time is prolonged.
Management
Aspirin and other medications that compromise platelet function should be avoided.
Platelet transfusion should be avoided except in circumstances of life-threatening bleeding, in which case emergent splenectomy is to be pursued.
Corticosteroids, Intravenous Immunoglobuin (IVIG), Anti-Rh(D) Immunoglobulin, Splenectomy, Rituximab (anti-CD20 monoclonal antibody)
vascular abnormalities
structural damage to either the endothelium or the supporting collagen may result in bleeding.
Vascular purpura is a group of disorders of blood vessels which result in bleeding, sometimes called nonthrombocytopenic purpura.
relatively common disorders and usually do not cause serious bleeding and induce small lesions – petechiae and purpura.
platelet count, bleeding time and results of the coagulation tests (PT, PTT) are usually normal.
Aquired
Decreased connective tissue: Collagen is required for the support of the blood vessel wall. Any impairment may result in bleeding from the microvasculature.
Scurvy: lack of vitamin C
Cushing syndrome and steroid therapy: causes loss of perivascular
supporting tissue
Vasculitis: Inflammation of small blood vessels due to the immune complexes that attach to the endothelial cells (or the subendothelial matrix).
Henoch-Schönlein purpura: a systemic, idiopathic hypersensitivity due to the deposition of circulating immune complexes within vessels
Infections: may produce petechiae and purpura – especially meningococcemia, septicemia, infective endocarditis and several of the rickettsioses. Mechanisms include invasion of vessel, septic emboli, immune complex vasculitis or result of disseminated intravascular coagulation (DIC).
Drug reactions: may cause petechiae and purpura without thrombocytopenia. The vascular injury is mediated by drug-induced antibodies and deposition of immune complexes in the vessel walls, leading to hypersensitivity vasculitis.
Associated with plasma cell dyscrasias
Amyloidosis: systemic perivascular deposition of amyloid may weaken the blood vessel wall and cause purpura. This is most commonly seen in plasma cell neoplasms and presents as mucocutaneous petechiae.
Miscellaneous
Simple easy bruising: purpuric lesions seen usually in women. Bruises appear spontaneously on arms and legs and resolve rapidly. Haemostatic tests are within normal range.
Inherited
Hereditary Haemorrhagic Telangiectasia (Weber-Osler-Rendu syndrome)
an autosomal dominant disorder of vascular malformation characterized by dilated, tortuous, thin walled blood vessels of the skin and mucous membranes.
They bleed easily in to the mucous membranes of the nose (epistaxis), tongue, mouth and eyes and the gastrointestinal tract. Repeated bouts of bleeding may result in iron deficiency anemia.
Ehlers-Danlos Syndrome
a congenital disorder of defective collagen synthesis characterized by joint hyper-mobility, skin laxity and easy bruising.
The capillaries are poorly supported by subendothelial collagen and result in bleeding mainly in the form of ecchymoses.
accelerated fibrinolysis