Dr.M.R.Lokeshwar*, Dr.Nitin Shah**, Dr.Nilesh Lokeshwar***
Department Of Pediatrics*, Department Of Pediatrics**, Department Of Pediatrics***
|Hemostasis is a sum total of specialized functions within the circulating blood and the blood vessels designed to stop hemorrhage. These functions are delicately balanced so that:
- Blood may freely circulate within the intact vessels, and
- The site of bleeding can be effectively sealed
Thus blood is in a dynamic equilibrium between fluidity and coagulation.
The main 3 components of hemostasis are:
- Vascular and extra-vascular factors
- Plasma factors - coagulation factors, fibrinolytic factors, natural inhibitors of coagulation and fibrinolysis.
Successful management of an acute bleeding episode in a child mainly depends on:
- The ability to make a rapid diagnosis.
- Proper detailed history and thorough clinical examination, often suggest the presence and type of bleeding disorder and help selecting further laboratory tests.
- Accurate diagnosis, which is required for specific therapy, depends on specific laboratory tests.
- Prompt implementation of therapeutic measures.
INDICATIONS FOR INVESTIGATIONS
Investigations for bleeding disorders are done when there is:
- Recent bout of bleeding - spontaneous or after injury or surgery - usually prolonged and disproportionate to extent of injury.
- Family history of bleeding episodes.
- Preparation for surgery or invasive procedures.
- Systemic diseases known to be associated with bleeding disorders e.g., liver disorder, renal disorder, DIC and sepsis etc.
Whenever a child presents with bleeding episode it is necessary to decide:
- Whether bleeding is significant? and if yes,
- Whether it is due to local causes,
- Or whether it is a generalized haemostatic defect
- It is acquired or hereditary disorder?
- What is the nature of bleeding episode?
- is it due to vascular, platelet or a coagulation abnormality or a combination of two or more?
The general approach to the bleeding patient requires:
- A detailed history including detailed past history and family history and
- A careful physical examination
- Screening tests as well as
- Specific tests for hemostasis as required, need to be done to define the defect.
Clinical evaluation should be carried out to establish the following:
- Is bleeding due to a systematic disorder of hemostasis or,
- Is it due to a local cause?
Local cause should be suspected when:
- Bleeding is a form of single site and recurs often from the same site e.g., epistaxis, with bleeding from left nostril, recurring every time from the same nostril.
- Such bleeding should lead to a suspicion of local causes such as a polyp or a foreign body. . However if bleeding is from both nostrils or from any of the nostrils and patient gives history of hematuria or a past history of excessive bleeding after tooth extraction, then it is more likely to be due to a systemic defect.
In a generalized bleeding disorders:
- Bleeding is spontaneous or
- Greater than expected for extent of injury or the site of bleeding, and
- Bleeding in the skin and mucous membrane like petechiae, purpura and ecchymosis
- Bleeding into interstitial tissue and joints etc may be present.
Family history of bleeding - Proper family history and noting the pedigree chart helps in realizing the mode of transmission of the disorder such as:
- Sex linked receive
- Autosomal recessive
- Autosomal dominant
One should take a detailed family history covering at least 2-3 generations and also should take note of members who have expired, especially due to bleeding.
Sex linked recessive pattern classically affects male members of the family and the disease is transmitted by females and hence male siblings, male maternal uncles, grandfather may be affected. Bleeding disorders which have a sex linked recessive inheritance are hemophilia A (factor VIII deficiency) and hemophilia B (factor IX deficiency) or platelet disorders such as Wiscott Aldrich's syndrome.
In autosomal recessive disorders, the parents of affected person are heterozygotes and hence have a 50% plasma concentration of the relevant clotting factors. Here, a history of consanguinity may be present. This genetic pattern is typical of disorders of factor II, V, VII, X, XI, XII, XIII, prekallikrein and high molecular weight kininogens. However, lack of plasma factor XII, prekallikrein or high molecular weight Kininogens does not cause a bleeding manifestation clinically.
Autosomal dominant pattern of inheritance is seen in Von Willebrand's disease, some types of qualitative platelet defects, dysfibrinogenemia and hereditary hemorrhagic telangiectasia. This type of inheritance may show a variable penetrance and expressivity. Many members in different generations of the family may be affected.
Although a positive family history is of great value in the diagnosis of bleeding disorders, a negative family history does not rule out the possibility of inherited bleeding disorders. Family history might be negative, if the coagulation defect is mild or there is a spontaneous mutation, as is seen in 20% of patients with hemophilia A. Exsanguinating bleeding is uncommon due to the bleeding disorders and is more likely to be due to injury to major vessels.
Is the defect inherited or acquired?
- Inherited disorders usually present in infancy and early childhood. History of bleeding from the umbilical cord, without evidence of sepsis or slipped ligature, cephalhematoma during early neonatal period, without history of prolonged and difficult lab our, Bleeding during the eruption or fall of deciduous tooth etc should be enquired. However, acquired hemorrhagic disorders like ITP are often seen during childhood i.e., 3-5 years of age.
- Family history of bleeding may be present. Proper pedigree chart will help in recognizing type of inheritance.
- Hemarthrosis (spontaneous), bleeding in the muscles without significant trauma points towards inherited bleeding disorders
Conversely patients with acquired disorders:
- Usually present later in life
- Have a negative family history
- There may be underlying systemic disorders like kidney diseases, liver disorders, infections, etc.
However, inherited disorders in milder forms may not be seen in early infancy and may present later in life with:
- Bleeding following injury or during surgery like in mild hemophilia. Previous history of operations like circumcision, dental extraction, tonsillectomy or major operation practically rules out the possibility of a moderate to severe inherited bleeding disorder.
- Subject with normal hemostasis or mild bleeding disorder may also have bleeding from non-hematological causes as seen in females with menorrhagia or of molar tooth extraction
- History of ingestion of drugs like aspirin, in the recent past should lead to the suspicion of a transient drug related hemostatic defect.
Certain syndromes known to be associated with bleeding disorders:
- Hereditary hemorrhagic telangiectasia is associated with characteristic telangiectatic lesions in the mucus membrane and skin and may manifest with epistaxis, malena and bleeding per rectum. Presence of telangiectasia in the mucous membrane of nose, bulbar conjunctiva, tongue, lips and tips of fingers is the hallmark of diagnosis.
- Keloids may be seen in children with afibrinogenemia and factor XIII deficiency.
- Cigarette paper scar, hyperextensible joints suggest Ehler-Danlos syndrome.
- Presence of syndactyly with history of bleeding episode is known to be due to factor V deficiency.
- Wiscott Aldrich syndrome is associated with thrombocytopenia, recurrent infection, otitis media, and eczema.
- Children with Albinism may have qualitative functional defects of platelets.
- Thrombocytopenia with absent radius ( T.A.R.Syndrome ) is easy to diagnose because of skeletal anomaly.
- Kasalbach-Merritt syndrome is characterized by giant hemangioma associated with evidence of clinical and sub clinical DIC and thrombocytopenia.
Is the bleeding due to vascular, platelet or a coagulation abnormality or a combination of these?
Though it is not always possible to categorically differentiate the nature of the bleeding, proper history and evaluation of presenting complaints, clinical findings provide valuable clue to decide the type of bleeding.
Bleeding manifestations following vascular disorder, thrombocytopenia or functional platelet disorders are:
- Usually in the form of spontaneous subcutaneous and mucus membrane bleeds like petechiae, purpura, ecchymoses, epistaxis, menorrhagia and these lesions are extremely rare in coagulation disorder except in Von Willebrand's disease.
- Purpuric spots appear and disappear in crops and may be associated with multiple superficial ecchymoses. Bleeding is usually precipitated by injury and it continues for hours (superficial bleeds). It is often controlled by pressure and once controlled, it usually does not recur.
- However in patients with coagulation factor deficiency, hematomas are usually deep (in the muscles) and spreading, bleeding into cavities like joints, retroperitoneal space is known. Posttraumatic bleeds are often delayed, some times hours after the injury. This may recur and pressure may not control bleeding.
Though a thorough history and clinical evaluation help in suspecting the nature and type of bleeding disorder, laboratory investigations are required in order to identify the precise nature of an underlying bleeding disorder. No single test is suitable for the laboratory evaluation or the overall process of hemostasis and blood coagulation.
Laboratory tests can be conveniently divided into screening tests and special tests.
- Screening tests are applied only after evaluating the nature and clinical circumstances of bleeding and prior to surgery, so as to know the presence and nature of bleeding disorder.
- Specific (Special) tests need to be done to confirm the diagnosis thus avoiding a battery of unnecessary tests.
Screening tests - These are the tests for the initial assessment for bleeding tendency and include:
- CBC and PS examination
- Platelet count
- Bleeding time, Clotting time
- Clot retraction
- Prothrombin time
CBC and peripheral smear examination is required for hematological evaluation:
- To know the extent of anemia and involvement of other cell lines in cases suspected to have leukemia, aplastic anemia etc.
- Proper smear examination also helps in evaluating extent of thrombocytopenia if present.
- Presence of clumps of platelets rules out platelet deficiency and absence of platelets indicates severe thrombocytopenia usually less than 10,000 - 20,000/cu mm.
- Presence of platelets but not in clumps - indicates absence of aggregation, suggesting platelet functional disorder.
- Large platelets simulating size of the lymphocytes suggest possibility of Bernard Soulier syndrome.
- Large platelets also indicate younger platelets as seen in regenerative type of thrombocytopenia where there is peripheral destruction of platelets.
It is a simple first step in evaluating the cellular aspect of hemostasis. However, manual count is not reliable and not reproducible and hence platelet count should be done on particle cell counter or using phase contrast microscope . If platelet type of bleeding (petechiae, purpura, mucosal bleeding) if seen with normal platelet count or marginally low platelet count, then platelet functional disorders should be kept in mind.
This test evaluates primary hemostatic stage and is ideally done with the help of template. The normal bleeding time is 4 to 7 minutes and prolongation of bleeding time usually occurs at platelet count <50,000/cumm. At counts below 10,000/cumm, bleeding time is usually prolonged and is often 15 min, or longer and hence B.T. in severe thrombocytopenia is not required.
Qualitative platelet disorders have prolonged bleeding time with nearly normal platelet count as seen in Glanzmann's thrombasthenia, Bernard Soulier syndrome, storage and disorder, Wiscott Aldrich syndrome with various drugs like aspirin and non-steroidal anti-inflammatory agents like ibuprofen etc . In Von Willebrand's disease also, bleeding time is usually prolonged as Von Willebrand factor is involved in binding of platelets to matrix protein or to other cells.
Retraction and exudation of the serum after one hour is observed in the clotting tube. Normally, 50% exudation at the end of one hour of the original blood volume is taken as normal retraction.
PT & APTT:
APTT is an excellent screening test for determining abnormality of intrinsic and common pathway and is sensitive to activities of approximately 20% or less of factor VIII and IX, APTT is prolonged during deficiency or abnormalities of high molecular weight kininogen, prekallikrein, factor XII & XI, IX, VIII, X, V, II and fibrinogen and by inhibitors of blood coagulation such as lupus inhibitors, heparin, fibrin / fibrinogen degradation product. Normal APTT is around 25-40 sec .
PT measures extrinsic clotting system and the common pathway. PT is prolonged with deficiencies of plasma factor VII, X, V, II and fibrinogen and inhibitors of these factors . A prolongation of PT with normal PTT indicates factor VII deficiency that occurs with congenital deficiency or early during oral anticoagulant therapy, or Vit. K deficiency or liver diseases.
Thrombin clotting time (TCT):
TCT measures thrombin induced conversion of fibrinogen to fibrin TCT is abnormal in patients with hypofibrinogenmia whether acquired or congenital or dysfibrinogenemia and in presence of inhibitors like heparin, myeloma proteins and fibrin degradation products which block. Either thrombin cleavage of fibrinopeptide or fibrin monomer polymerization. Bleeding disorders not associated with any abnormalities in screening tests are:
- Senile purpura
- Simple purpura seen in 10% of women
- Factor XIII deficiency
- Alpha, antiplasmin deficiency
- Amyloidosis (may or may not be associated with factor X deficiency)
- Vascular disorders like hemorrhagic telangiectasia (Pender-Osler-Weber syndrome)
- Ehlers' - Danlos syndrome
- Henoch-Schonlein purpura and mild factor deficiency.
Special confirmatory tests:
- Detailed history, through clinical examination and screening tests usually give sufficient information to decide.
- Whether bleeding is due to local cause or generalized bleeding disorder and type and nature of the bleeding disorder.
- Depending upon type and nature of the bleeding disorder, further tests such as factor assay, aggregation tests etc have to be carried out to confirm the diagnosis.
If study suggests that it is coagulation factor disorder and PT or APTT is prolonged with normal platelet count, then next step to be performed is correction study. In this, normal plasma is added to patients plasma and APTT is carried out in this mixture. If the resulting APTT is normal (i.e., patients abnormal APTT is corrected) then deficiency state is present. If however mixture APTT remains prolonged, an inhibitor is present. Correction of abnormal APTT in mixing study in a patient with bleeding disorder indicates deficiency of Factor VIII, IX, XI and if not associated with clinical bleeding tendency, indicates deficiency of factor XII, Prekallikrein, high molecular weight kininogen. Mixing patient's plasma with known deficient plasma or artificially preparing deficient plasma can then confirm deficiency of particular factor.
Adsorbed plasma is deficient in factor IX where as aged serum is deficient in factor VIII. If not corrected then it is due to factor that is deficient in this known deficient plasma / serum.
Screening Laboratory Tests in Selected Hemostatic Disorders
|Clinical Bleeding||APTT||PT||TCT||Bleeding Time||Platelet Count||Possible|
prekallikrein,Factor XII,lupus inhibitor
|Present||Abnormal||Normal||Normal||Normal||Normal|| XI, IX, VIII*|
|Present||Abnormal||Abnormal||Normal||Normal||Normal||V,X,II, coumarin,vitamin K deficiency,mild hepatic disease|
|Present||Abnormal||Normal||Normal||Abnormal||Normal||Von Willebrand disease|
|Present||Normal||Normal||Normal||Abnormal||Normal||Qualitative platelet disorder |
coagulation, severe liver
*PC = platelet count, BT = bleeding time, PT = prothrombin time, PTT = partial thromboplastin time, N = Normal, L = Low, P = Prolonged.
Platelet phase of coagulation affection when suspected, do screening tests like peripheral smear examination particularly for presence, size, aggregation of platelets to each other.
- Bleeding time and clot retraction are very useful.
- When platelet count is normal or mildly decreased and bleeding time prolonged, clot retraction is poor, then one should suspect the possibility of platelet functional disorders and should do specialized tests like.
- Aggregation test with low and high concentration of ADP, Epinephrine, Collagen and Ristocetin. First phase of aggregation is induced by low concentration of ADP and by direct effect of certain agents notably epinephrine and thrombin. Second phase is mediated by thromboxane A 2 and endogenous ADP released in response to numerous pharmacological and naturally occurring substance like ADP itself. Absence of first phase of aggregation - unresponsiveness to ADP in any concentration is characteristic defect of Glanzmann's disease. Deficiency of platelet fibrinogen and specific glycoproteins GP-II and GP-III confirm the diagnosis.
- In Von Willebrand disease, aggregation to ristocetin is lacking whereas aggregation to other agents may be normal.
- The classical laboratory findings in Bernard-Soulier syndrome are - prolonged bleeding time, thrombocytopenia, very large platelets on peripheral smear, deficient platelet adhesion and normal platelet aggregation with ADP, epinephrine and collagen but absence of platelet aggregation with restocitin and they have normal levels of Von Willebrand factor.
Solitary thrombocytopenia may be due to either reduced production or increased destruction of the platelets. Idiopathic thrombocytopenic purpura is characterized by acute onset of thrombocytopenia with markedly increased megakaryocytes in bone marrow and often associated with anti-platelet antibodies, which can be demonstrated by direct as well as indirect Fluorescence antibody technique.
Platelet Aggregation Response
|Cyclo-oxygenase deficiency Thromboxane synthetase def.||N||ABN||ABN||N|
|Storage Pool Disorder||N||ABN decreased||ABN||ABN||N||N or decreased|
|Aspirin defect||N||ABN |
Thrombocytopenia due to decreased production may be either due to involvement of only megakaryocytes as seen in TAR syndrome or in megakaryocytic thrombocytopenic purpura characterized by thrombocytopenia and platelet type of bleeding disorder and conspicuous absence of megakaryocytes in the bone marrow or may be associated with suppression of other cell lines in the bone marrow as in hypoplastic or aplastic anemia. Thus, when faced with a patient who comes with a bleeding problem a careful history including family history and past history, thorough detailed clinical examination, few important screening tests and then appropriate specialized tests will help in the diagnosis of bleeding disorder and hence the better management of these children.
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|Dr.M.R.Lokeshwar, Shah D, Lokeshwar D.. Available From : http://www.pediatriconcall.com/fordoctor/ Conference_abstracts/report.aspx?reportid=439|