Approach to bleeding disorders
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The document discusses common platelet and coagulation disorders causing bleeding in children, outlining a systematic approach to diagnosis and management. Key disorders include inherited conditions such as hemophilia and von Willebrand disease, as well as acquired issues like immune thrombocytopenic purpura and vitamin K deficiency. The management strategies include stabilization of the child, factor replacement therapies, and transfusion protocols tailored to specific conditions such as DIC and liver disease.
![Dose of factor VIII units = Desired rise X weight of the patient kg X 0.5
Factor IX
One unit of plasma derived factor IX raises the measured
factor level by 1 %.
Dose of factor IX units = Desired rise X weight of the patient kg X 0.5
One ml of FFP will provide 0.8-1 unit, and 1 unit of cryoprecipitate contains 80–
110 units of factor VIII. To raisethe factor level by 20 %, the dose of FFP and
cryoprecipitate will therefore be 200 ml and 2 units (40 ml), respectively.
Cryoprecipitate is preferred over FFP due to lower chances of volumeoverload.
The corresponding doseof recombinant factor IX in a child with hemophilia B,
who presents with similar scenario will be 480 units (40 X 10 X 1.2), to raise the
factor IX level by 40 U/dl. Itis a common practice to round the dose to
the nearestvial size, to preventwastage of the expensive factors.
RICETherapy
Along with the factor replacement, analgesics, Rest, Immobilization, Cold
compression and Elevation (RICE) should be advised as well.
Rest is done in the position of function (a sling for an upper limb bleed and bed
rest or splint for lower limb bleed) for one day, followed by avoidanceof weight
bearing for next 3–4 d. Application of ice aids by decreasing pain and swelling. It
can be performed with crushed ice cubes wrapped in a wet towel or with cold
packs, intermittently for a period of 5–15 min over 24–48 h. Iceshould not be
applied directly to the skin, as prolonged application can lead to skin damage. Itis
not useful, if applied beyond 48 h [8]. Wrapping the jointgently with bandageor
elastic stocking may help in limiting the bleeding and supporting the joint. The
application of these adjunctive interventions is not evidence based; however,
they are commonly recommended, as they help in reducing pain, swelling and
promoting early mobilization.](https://image.slidesharecdn.com/approachtobleedingdisorders-160816194620/85/Approach-to-bleeding-disorders-10-320.jpg)
![Antifibrinolytic Therapy
Control of bleeding frommucosal surfaces, particularly epistaxis, gum bleeding
and menorrhagia in platelet or coagulation disorders, can be aided with
antifibrinolytic agents.
Two agents, aminocaproic (Hamostat; 1 vial of 5000 mg costs~Rs 75, onetablet of
500 mg costs~Rs 6) and tranexamic acid (Trenaxa; 1 injection of 500 mg costs~
Rs 45, one tablet of 500 mg costs~Rs 13) areavailable.
Tranexamic acid is preferred due to its longer half-life, higher potency and lower
toxicity. Aminocaproic acid is administered as a stat doseof 100–200 mg/kg
(maximum: 10 g), followed by 50–100 mg/kg/doseq 6 hourly (maximum dose: 5
g). The doseof tranexamic acid is 25–50 mg/kg q 6–8 h [1]. Tranexamic acid is
absorbed from the buccal mucosa and subsequently secreted in the saliva.
Hence, in oral bleeding, hemostasis is better achieved with a mouth-wash rather
than by swallowing. Patientshould be advised to crush the tablets in 10–15 ml of
water and retain the solution in the mouth for nearly 5 min before swallowing
(‘swish and swallow’). For younger children, tablets can be crushed and made into
paste with water; this can be applied at the site of bleeding in the mouth.
Antifibrinolytic agents are contraindicated in hematuria; formation of clots
can result in colic and obstruction of outflow fromthe renal pelvis.
Recombinant Factor VIIa
Recombinant factor VIIa acts by producing a ‘thrombin burst’ on the surfaceof
activated platelets. This results in activation of platelets at the site of injury,
increased platelet adhesion and activation of factor XIII. Itleads to the formation
of a tight fibrin hemostatic plug. Ithas the potential to enhance hemostasis in
patients with severebleeding, even in the absenceof underlying coagulation
defect. Hence, it is referred to as a ‘generalhemostatic agent’. This has led to
severalofflabel uses of the drug. The FDA approved indications include](https://image.slidesharecdn.com/approachtobleedingdisorders-160816194620/85/Approach-to-bleeding-disorders-15-320.jpg)
Approach to bleeding disorders
- 1. Common platelet and coagulation disorders causing bleeding in children Indian J Pediatr (May 2013) 80(5):411–420
- 2. Approachto the bleeding patient: History 1. Location and type of bleeding – petechiae, purpura, epistaxis, melena, haemarthroses, haemoptysis, haematemesis, haematuria etc 2. Ask for family history of bleeding disorders ? Make a pedigree chartif significant. Inherited disorders- Hemophilia A/B (X Linked Recessive), Von Willebrand disease (AutosomalDominant/ Recessive) and platelet function defects Acquired - immune thrombocytopenic purpura (ITP), liver disease, vitamin K deficiency, disseminated intravascular coagulation (DIC), sepsis, aplastic anemia and leukemia. 3. Similar episodes in the past? Frequency and duration ? 4. Systemic bleeding Vs Local etiology? If all bleeding episodes are fromsame site – probably local etiology. eg: epistaxis (due to nose picking), tumours, trauma, surgery 5. Type of bleeding: 6. Age of onset and Gender: These providevaluable clues towards the diagnosis. Inherited coagulation disorders typically manifestwhen a child begins to bear weight in infancy.
- 3. Infants with Wiskott-Aldrich syndrome, an X-linked recessive immunodeficiency disorder, may presentwith thrombocytopenic purpura and/or eczema beginning in early infancy. Clinical presentation of Vitamin K deficiency bleeding (VKDB), earlier known as hemorrhagic disease of newborn may rangefrom ecchymosis to an intracranial bleed in infancy. Itis commonly observed in infants who have not received vitamin K prophylaxis at birth, typically in the setting of a home delivery. In older children, it may occur due to underlying liver disease, malabsorption or chronic diarrhea. Acute ITP typically occurs in children 2–6 y of age. Acute onset, widespread mucocutaneous bleeds (petechiae, purpura or epistaxis) in an otherwise well-child, following a viralinfection is the typical presentation. Children with severeVWD or platelet function defect usually presentwith mucocutaneous bleeding in early childhood. Less severediseasemay manifest in adolescence with recurrentepistaxis or menorrhagia. 7. Drug History Recent ingestion of drugs that effect platelet function/number, including aspirin, valproate, chloramphenicol, or non-steroidalanti-inflammatory drugs, should be explored.
- 4. Examination > Petechiae >Ecchymosis >Joint bleed & deepseated hematomas > Hepatosplenomegaly >Significant lymphadenopathy > Active and playful vs. Illlooking > Dysmorphic features > Café-au-lait spots >Telangiecatic vessels >Hemangiomas DDx of Petechiae andPurpura Infectious – Meningococcemia – Rickettsial – Group A strep – Atypicalmeasles – Dengue Non-infectious:
- 5. • Normal platelets � HSP � Coagulation disorders � Trauma • Low platelets � ITP � Leukemia Investigations The initial laboratory evaluation for bleeding disorder includes a complete blood count with review of the peripheral smear, prothrombin time (PT) and activated partial thromboplastin time (aPTT) Complete Blood Count -Identify or refute thrombocytopenia as the causeof bleeding. - A low hemoglobin may be secondary to the underlying bleed. - Anemia disproportionateto bleeding – red cell destruction, bone marrow failure or leukemia. - WBC count provides information suggestiveof sepsis or leukemia. Peripheral Blood Smear Platelet size, morphology and presenceof clumping. Giant sized platelets- ITP or inherited disorders including Bernard-Soulier syndrome.
- 6. Wiskott-Aldrich syndromeis characterized by microthrombocytopenia. Schistocytes may suggestmicroangiopathic hemolytic anemia, observed in hemolytic uremic syndrome, thrombotic thrombocytopenic purpura or sepsis. PT (Prothrombin time) and aPTT (Activated Partial Thromboplastin Time) -The approximate normal values for children are: PT: 10–11 s and aPTT: 26–35 s. -Prothrombin time is prolonged due to deficiency of extrinsic pathway (tissue factor, factor VII) or common pathway factors (II, V, X, and fibrinogen). -aPTT is prolonged due to deficiency of intrinsic pathway (VIII, IX, XI, or XII), common pathway factors, or in the presence of inhibitors (e.g., lupus anticoagulant and heparin). Mixing Studies In a child with suspected coagulation disorder, resultof an abnormalPT or aPTT should be followed by a mixing study. This aids in differentiating between a clotting factor deficiency and presence of an inhibitor (e.g., lupus anticoagulant or antibodies to factor). Patient's plasma is mixed in a 1:1 ratio with normalpooled plasma, and the abnormaltest is repeated. Normalization of clotting test (PT or aPTT) following a 1:1 dilution with normalpooled plasma indicates deficiency of a factor. Majority of inhibitors will not be effectively diluted following the addition of normal pooled plasma. Thus, an abnormaltest following dilution indicates the presenceof an inhibitor. Coagulation-Factor Assay When a factor deficiency is suggested by clinical history or a mixing study, specific
- 7. coagulation-factor assay is performed to confirmthe diagnosis and assess the severity of deficiency. Fibrinogen, Fibrin Degradation Products and D-dimer Normal plasma fibrinogen level is 200–400 g/L. Fibrinogen is decreased in congenital afibrinogenemia, hypfibrinogenemia and in consumption states, e.g., DIC. Fibrin degradation products and D-dimer are indicators of a fibrinolytic state. Elevated levels are observed in DIC, recenttrauma or surgery and venous thromboembolism. Bleeding Child with Normal FirstLine Investigations In a bleeding child with normalplatelet count and PT/aPTT, possiblediagnosis include VWD, factor XIII deficiency, platelet function disorder and vascular abnormality.
- 8. Indian J Pediatr (May 2013) Management Initial Stabilization
- 9. Stabilization of airway, breathing and circulation is the priority in any child in a decompensated state. Specific Management This is directed towards the underlying etiology. Undiagnosed Coagulation Disorder In the setting of severe hemorrhageoccurring in an undiagnosed coagulation disorder, fresh frozen plasma (FFP) should beadministered, as it contains all the clotting factors. The average concentration of factor in FFP is 1 unit/ml; the typical doseis 15 ml/kg. Hemophilia Acute Hemarthrosis In a child presenting with acute hemarthrosis, initial replacement with factor (factor VIII in hemophilia A and factor IX in hemophilia B) should be given to raise the factor level to 40-60 %. A lower goal of 10-20 % may be acceptable if there is resourceconstraint. If symptoms do notabate, or if the hemarthrosis is severe, a second dose should be given 12–24 h later. Factors areoften not an option to a large majority of patients in India due to cost constraints (1 vial of 250 units of factor VIII: ~Rs 2800; 1 vialof 600 units of factor IX: ~Rs 11,000). Thus, FFP or cryoprecipitate are often administered as the only feasible, though, inferior alternative. FFP can be administered to patients with hemophilia A as well as B, whereas cryoprecipitatecan only be used in hemophilia A, as it does not contain factor IX. The formula for calculating the replacement doseof factor VIII and IX in patients with haemophilia is outlined below. Factor VIII One unit of recombinantor plasma derived factor VIII raises the measured factor level by 2 %.
- 10. Dose of factor VIII units = Desired rise X weight of the patient kg X 0.5 Factor IX One unit of plasma derived factor IX raises the measured factor level by 1 %. Dose of factor IX units = Desired rise X weight of the patient kg X 0.5 One ml of FFP will provide 0.8-1 unit, and 1 unit of cryoprecipitate contains 80– 110 units of factor VIII. To raisethe factor level by 20 %, the dose of FFP and cryoprecipitate will therefore be 200 ml and 2 units (40 ml), respectively. Cryoprecipitate is preferred over FFP due to lower chances of volumeoverload. The corresponding doseof recombinant factor IX in a child with hemophilia B, who presents with similar scenario will be 480 units (40 X 10 X 1.2), to raise the factor IX level by 40 U/dl. Itis a common practice to round the dose to the nearestvial size, to preventwastage of the expensive factors. RICETherapy Along with the factor replacement, analgesics, Rest, Immobilization, Cold compression and Elevation (RICE) should be advised as well. Rest is done in the position of function (a sling for an upper limb bleed and bed rest or splint for lower limb bleed) for one day, followed by avoidanceof weight bearing for next 3–4 d. Application of ice aids by decreasing pain and swelling. It can be performed with crushed ice cubes wrapped in a wet towel or with cold packs, intermittently for a period of 5–15 min over 24–48 h. Iceshould not be applied directly to the skin, as prolonged application can lead to skin damage. Itis not useful, if applied beyond 48 h [8]. Wrapping the jointgently with bandageor elastic stocking may help in limiting the bleeding and supporting the joint. The application of these adjunctive interventions is not evidence based; however, they are commonly recommended, as they help in reducing pain, swelling and promoting early mobilization.
- 11. IntracranialBleed and Other Hemorrhages In patients with head trauma, a quick neurological examination, followed by CT head should be performed. Factor replacement should not be delayed pending the imaging. Raised intracranial pressure, if any, should be managed with medical measures. Level of the appropriatefactor should be immediately raised to 100 % and a level of 50-60 % should ideally be maintained for at least 2 wk. If resources arelimited, a doseof 30–50 U/kg of factor VIII or 60–100 U/kg of factor IX may be used for 3–5 d, followed by maintenance with lower doses, depending on the response. In children with known inhibitors to factor VIII or IX, administration of activated prothrombin complex (FEIBA, 1 vial of 500 units costs~Rs 25,000) or activated factor VIIa may beconsidered, in consultation with a hematologist. Bleeding in Platelet Disorders Platelets are transfused to control bleeding in quantitative or qualitative platelet disorders. Platelets are available as random donor platelets (RDP) or as single donor apheresis platelets (SDAP). Although both are effective, SDAP is better than RDP in ease of leucoreduction, decreasing risk of septic platelet transfusion reactions, reducing exposures to multiple donors and transfusion frequency, and in treating alloimmunization. Indication and doseof platelets is often a dilemma. It is important to remember that transfusion trigger in a thrombocytopenic patient depends not only on the platelet count, but also on its etiology and the clinical condition of the patient. Platelet transfusion is futile and not indicated in majority of patients with ITP as the transfused platelets arequickly destroyed due to circulating antibodies. In stable children with non-immunethrombocytopenia, a transfusion trigger of 10×106/μL is now widely accepted. A few studies have even recommended a lower threshold of 5×106/μL.
- 12. Indications for platelet transfusion in children Indications of prophylacticplatelet transfusions ■ Platelet count <10×106/μLa ■ Platelet count 20–40×109/μl and one or more of the following ● DIC in association with induction therapy for leukemia e.g., acute promyelocyticleukemia ● Extreme hyperleukocytosis ● Prior to invasive procedures Indications of therapeutic platelet transfusions ■ ITP with major and/or dangerous bleeding (e.g., severe intestinal, intracranial or intraocular haemorrhage) ■ Acute disseminated intravascular coagulation with major bleeding and platelet count <50×106/μL ■ Platelet function defects (congenital or acquired) with active bleeding ■ Surgical patient with active bleeding and platelet count <50-100×106/μL ■ During massive transfusions with platelet count <75×106/μL Bleeding in Von Willebrand Disease Desmopressin is helpfulin controlling mild bleeding in patients with type 1 and 2A VWD, but not in type 2B and 3. Itis recommended that every patient with VWD should have therapeutic trial of desmopressin to assess the responseat diagnosis or when the patient is not bleeding. In responsivepatients, 0.3 μg/kg (maximum 20 μg) of desmopressin diluted in 50 mL saline is administered i.v over 20–30 min. Although i.v route is the most effective, subcutaneous injection or nasalspray (150 μg/puff) can be used as well. The desired concentration of the drug as a nasalspray is not available in India. The commercially available nasalspray (Minirin: 10 μg/puff), indicated for nocturnalenuresis and diabetes insipidus, is too dilute to be used for VWD. Facial flushing, headache, hyponatremia, hypo/hypertension and tachyphylaxis are common adverseeffects. VWF concentrate is preferred for major bleeds. High purity VWF concentrate is not available in the market. Hence, intermediate purity factor VIII concentrates containing VWF are used (Immunate: 1 vial0500 units of factor VIII and 290 units of VWF; cost~Rs 3400).
- 13. Initial doseof 40–60 units/kg followed by 20–40 units/kg q 12–24 h is recommended. Antifibrinolytic agents should be used concomitantly in patients with mucosalbleeds. Disseminated Intravascular Coagulation The cornerstoneof treatment of DICis the aggressive managementof the underlying etiology. In somechildren, this may resolve the DIC, however, in some it may not. Patients with persistentcoagulation abnormalities are at risk of hemorrhageor thrombosis and require supportive care, including component replacement and/or anticoagulation. Transfusion of platelets or FFP is not indicated to correctthe coagulation abnormalities in a child who is asymptomatic or has minor bleeds (e.g., skin petechiae). Itshould be reserved for children with active bleeding or prior to invasive procedures, with an aim of maintaining the platelet countabove 50×106/μL and fibrinogen concentration above 1 g/L. Clotting factors arereplaced by FFP or by cryoprecipitate. The latter is particularly indicated for hypofibrinogenemia (fibrinogen <1 g/L). The benefit of routine anticoagulation has not been proven by randomized controlled trials. However, recent guidelines do recommend prophylactic doses of heparin or low molecular weight heparin in non-bleeding critically ill patients with DIC due to increased risk of thromboembolism. Therapeutic useof heparin is generally limited to the situations where thrombosis predominates, such as arterial or venous thromboembolism, severepurpura fulminans associated with acral ischemia or vascular skin infarction without evidence of clinical bleeding. Continuous infusion of unfractionated heparin is probably the best choice given the risk of bleeding in these children. The monitoring of aPTT may be intricate because of already prolonged aPTT due to DIC. Thus, instead of conventional doses, weightadjusted doses (e.g., 10 U/kg/h) of unfractionated heparin
- 14. may be administered withoutthe intention of prolonging the aPTT to 1.5-2.5 times the control. Vitamin K Deficiency Bleeding Infants with vitamin K deficiency bleeding should receive 250–300 μg/kg (maximum 10 mg) of i.v vitamin K without any delay. As a rough guide, 1–2 mg of vitamin K is more than sufficientto correctthe deficiency in majority of infants. It may be administered by subcutaneous route, but not by intramuscular route, if venous access is difficult. Correction of coagulation parameters within 2–6 h of administration of vitamin K is diagnostic of VKDB. FFP (10–15 ml/kg) is indicated if urgent control of bleeding is desired in caseof life threatening hemorrhage. Bleeding in Liver Disease Treatment of bleeding in a child with hepatic failure is arduous. Enhanced hemostasis following FFP or other plasma products is usually transient. Recombinant Factor VIIa rapidly normalises PTin these patients, however the efficacy in on-going bleeding is unclear. Thus, it should be reserved for rescue therapy in active hemorrhage. Bleeding in Cyanotic Congenital Heart Disease Children with cyanotic heart diseasecan presentwith bruising or mucocutaneous bleeding due to hemostatic abnormalities resulting from chronic hypoxic state. The abnormalities include thrombocytopenia, abnormal platelet function, reduced coagulation factors and elevations of PT/aPTT. Phlebotomy performed for symptomatic hyperviscosity helps to restore hemostasis as well. However, in severehemorrhage, FFP and platelet transfusions should be given to controlbleeding.
- 15. Antifibrinolytic Therapy Control of bleeding frommucosal surfaces, particularly epistaxis, gum bleeding and menorrhagia in platelet or coagulation disorders, can be aided with antifibrinolytic agents. Two agents, aminocaproic (Hamostat; 1 vial of 5000 mg costs~Rs 75, onetablet of 500 mg costs~Rs 6) and tranexamic acid (Trenaxa; 1 injection of 500 mg costs~ Rs 45, one tablet of 500 mg costs~Rs 13) areavailable. Tranexamic acid is preferred due to its longer half-life, higher potency and lower toxicity. Aminocaproic acid is administered as a stat doseof 100–200 mg/kg (maximum: 10 g), followed by 50–100 mg/kg/doseq 6 hourly (maximum dose: 5 g). The doseof tranexamic acid is 25–50 mg/kg q 6–8 h [1]. Tranexamic acid is absorbed from the buccal mucosa and subsequently secreted in the saliva. Hence, in oral bleeding, hemostasis is better achieved with a mouth-wash rather than by swallowing. Patientshould be advised to crush the tablets in 10–15 ml of water and retain the solution in the mouth for nearly 5 min before swallowing (‘swish and swallow’). For younger children, tablets can be crushed and made into paste with water; this can be applied at the site of bleeding in the mouth. Antifibrinolytic agents are contraindicated in hematuria; formation of clots can result in colic and obstruction of outflow fromthe renal pelvis. Recombinant Factor VIIa Recombinant factor VIIa acts by producing a ‘thrombin burst’ on the surfaceof activated platelets. This results in activation of platelets at the site of injury, increased platelet adhesion and activation of factor XIII. Itleads to the formation of a tight fibrin hemostatic plug. Ithas the potential to enhance hemostasis in patients with severebleeding, even in the absenceof underlying coagulation defect. Hence, it is referred to as a ‘generalhemostatic agent’. This has led to severalofflabel uses of the drug. The FDA approved indications include
- 16. treatment of bleeding in children with hemophilia with inhibitors and congenital factor VII deficiency. In addition, European guidelines recommend its use for bleeding in platelet function defects (e.g., Glanzmann's thrombasthenia), which is not responsiveto platelet concentrates. Off-labeluses include, ITP with severe haemorrhagenot responding to standard therapies, post-surgical/traumatic hemorrhage, intracranialbleed and liver transplantation. The benefit is unproven in these conditions, and hence may be used as a ‘last resort’. Standard doseis 90–120 μg/kg q 2–3 h, till the cessation of bleeding. The high cost (Novo-seven: 1 vial01 mg, cost~Rs 42,000)precludes administration in majority.