APPROACH TO BLEEDING DISORDER

IN CHILDREN

Dr. Vadapalli SATISH

SMIMS, Gangtok

MD Paeds. 2nd year

DEFINITION A bleeding tendency is a presentation

with bleeding in a patient in whom no anatomical cause for the bleeding (i.e., trauma to a vessel for one of many possible reasons) can be discovered.

It is then inferred that the bleeding is due to a functional impairment of the normal hemostatic process.

This impairment may be due to

1. A functional deficiency in the procoagulant mechanism. This may involvea. The plateletsb. The procoagulant plasma components

2. A functional excess in anticoagulant mechanisms. a. Anticoagulant drugsb. Natural anticoagulants

3. A functional excess in the fibrinolytic mechanism.

Broadly we can identify three types:

‘‘COAGULATION-DEFECT BLEEDS,’’ ‘‘PURPURIC-TYPE BLEEDS,’’ and MIXED bleeds.

Localized cyanosis is differentiated from ecchymosis by the momentary blanching pallor (with cyanosis) occurs after pressure

Finding Disorders of Coagulation

Disorders of Platelets or Vessels

Petechiae Rare Characteristic

Deep dissecting hematomas

Characteristic Rare

Superficial ecchymoses

Common; usually large and solitary

Characteristic; usually small and multiple

Hemarthrosis Characteristic Rare

Delayed bleeding Common Rare

Bleeding from superficial cuts and scratches

Minimal Persistent often profuse

Sex of patient 80–90% of inherited forms occur only in male patients

Relatively more common in females

Positive family history

Common Rare (exc. vWF , hereditary hemorr.telangiectasia)

Table 118–1. Classification of Disorders of Hemostasis

Major Types

Disorders Examples

Acquired Thrombocytopenias

Autoimmune and alloimmune, drug-induced, hypersplenism, hypoplastic (primary, myelosuppressive therapy, myelophthisic marrow infiltration), disseminated intravascular coagulation (DIC), thrombotic thrombocytopenic purpura, hemolytic-uremic syndrome

Liver diseases

Cirrhosis, acute hepatic failure, liver transplantation (see Chap. 129), thrombopoietin deficiency

Renal failureVitamin K deficiency

Malabsorption syndrome, hemorrhagic disease of the newborn, prolonged antibiotic therapy, malnutrition, prolonged biliary obstruction

Hematologic disorders

Acute leukemias (particularly promyelocytic), myelodysplasias, monoclonal gammopathies, essential thrombocythemia

Major Types

Disorders Examples

Acquired Acquired antibodies against coagulation factors

Neutralizing antibodies against factors V, VIII, and XIII, accelerated clearance of antibody-factor complexes, e.g., acquired von Willebrand disease, hypoprothrombinemia associated with antiphospholipid antibodies

DIC Acute (sepsis, malignancies, trauma, obstetric complications) and chronic (malignancies, giant hemangiomas, retained products of conception)

Drugs Antiplatelet agents, anticoagulants, antithrombins, and thrombolytic, hepatotoxic, and nephrotoxic agents

Vascular Nonpalpable purpura ("senile," solar, and factitious purpura), use of corticosteroids, vitamin C deficiency, child abuse, thromboembolic, purpura fulminans; palpable-purpura (Henoch-Schönlein, vasculitis, dysproteinemias; amyloidosis

Table 118–1. Classification of Disorders of Hemostasis

Major Types Disorders Examples

Inherited Deficiencies of coagulation factors

Hemophilia A (factor VIII deficiency), hemophilia B (factor IX deficiency), deficiencies of fibrinogen factors II, V, VII, X, XI, and XIII and von Willebrand disease

Platelet disorders

Glanzmann thrombasthenia, Bernard-Soulier syndrome, platelet granule disorders

Fibrinolytic disorders

2-Antiplasmin deficiency, plasminogen activator inhibitor-1 deficiency

Vascular Hemorrhagic telangiectasias

Connective tissue disorders

Ehlers-Danlos syndrome

STEPWISE APPROACH

HISTORY

1. Patients vary in their responses to hemorrhagic symptoms.

Therefore, some experts believe the question "Do you bruise easily?" is virtually worthless. Women more likely respond that they have excessive bleeding or bruising than do men.

2. Unprovoked hemarthroses and muscle hemorrhages suggest one of the hemophilias.

mucocutaneous bleeding (epistaxis, gingival bleeding, menorrhagia) are more characteristic of patients with qualitative platelet disorders, thrombocytopenia, or von Willebrand disease.

3. Assessing the extent of hemorrhage against the background of any trauma or provocation that may have elicited the hemorrhage is important.

If a patient has never had a significant hemostatic challenge (such as tooth extraction, surgery, trauma, or childbirth), the lack of a significant bleeding history is much less valuable in excluding a mild hemorrhagic disorder.

4. Obtaining objective confirmation of the subjective information conveyed in the bleeding history is valuable.

Objective data include (a) previous hospital or physician visits for

bleeding symptoms, (b) results of previous laboratory

evaluations, (c) previous transfusions of blood

products for bleeding episodes, and (d) a history of anemia and/or previous

treatment with iron.

5. A medication history esp. non-prescription drugs.

A medication history is especially important in patients with thrombocytopenia, because drug-induced thrombocytopenia is common.

Medication also may affect hemostasis through deleterious effects on the liver or kidney functions.

Herbal and alternative medicines poses particular problems, because patients may not readily share information about the drug and the dose they are taking of any particular active ingredient may be difficult to determine.

Ginkgo biloba and ginseng are the most commonly used herbals that can cause platelet dysfunction and induce bleeding.

Other dietary supplements.

6. A nutrition history should be obtained to assess the likelihood of

(a) vitamin K deficiency, especially if the patient also is taking broad-spectrum antibiotics,

(b) vitamin C deficiency, especially if the patient has skin bleeding consistent with scurvy (perifollicular purpura), and

(c) general malnutrition and/or malabsorption.

7. Several tissues have an increased local fibrinolytic activity.

urinary tract, endometrium, and mucous membranes of the nose and

oral cavity. These sites are particularly likely to

have prolonged oozing of blood after trauma in patients with hemostatic abnormalities. Excessive bleeding following tooth extraction is one of the most common manifestations.

8. Bleeding isolated to a single organ or system (e.g., hematuria, hematemesis, melena, hemoptysis) is less likely to result from a hemostatic abnormality than from a local cause such as neoplasm, ulcer, or angiodysplasia. Thus, careful anatomic evaluation of the involved organ or system should be performed.

9. Bleeding may result from blood vessel disorders such as hereditary hemorrhagic telangiectasias, Cushing disease, scurvy, or Ehlers-Danlos syndrome. Many primary dermatologic disorders also have a purpuric or hemorrhagic component and must also be considered in the differential diagnosis.

10. A family history is particularly important when hereditary disorders are considered.

consanguinity, genealogic tree, extending back at least

two generations for genetic disorders. A sex-linked pattern hemophilia A or B An AD, most forms of vWD An AR, coagulation factor deficiencies,

inherited platelet disorders, and the rare, severe, type 3 von Willebrand disease.

11. Population genetic information may be helpful; for example, the higher prevalence of factor XI deficiency in Ashkenazi Jews

12. Diseases and organs that may affect hemostasis, such as cirrhosis, renal insufficiency, myeloproliferative disorders (e.g., essential thrombocythemia), acute leukemia, myelodysplasia, systemic lupus erythematosus, and Gaucher disease.

CLINICAL FEATURES

Table 118–2. Clinical Manifestations Typically Associated with Specific Hemostatic Disorders

Clinical Manifestations Hemostatic Disorders

Mucocutaneous bleeding Thrombocytopenias, platelet dysfunction, von Willebrand disease

Cephalhematomas in newborns, hemarthroses, hematuria, and intramuscular, intracerebral, and retroperitoneal hemorrhages

Severe hemophilias A and B, severe deficiencies of factor VII, X, or XIII, severe type 3 von Willebrand disease, afibrinogenemia

Injury-related bleeding and mild spontaneous bleeding

Mild and moderate hemophilias A and B, severe factor XI deficiency, moderate deficiencies of fibrinogen and factors II, V, VII, or X, combined factors V and VIII deficiency, 2-antiplasmin deficiency

Table 118–2. Clinical Manifestations Typically Associated with Specific Hemostatic Disorders

Bleeding from stump of umbilical cord and habitual abortions

Afibrinogenemia, hypofibrinogenemia, dysfibrinogenemia, factor XIII deficiency

Impaired wound healing Factor XIII deficiency

Facial purpura in newborns Glanzmann thrombasthenia, severe thrombocytopenia

Recurrent severe epistaxis and chronic iron deficiency anemia

Hereditary hemorrhagic telangiectasias

1. Epistaxis is one of the most common symptoms of platelet disorders & vWD.

It also is the most common symptom of hereditary hemorrhagic telangiectasia. epistaxis - more severe with advancing age.

Epistaxis is not uncommon in normal children, usu. resolves before puberty.

Dry air heating systems can provoke epistaxis even in normal individuals. Bleeding confined to a single nostril - local vascular problem than a systemic coagulopathy.

2. Gingival hemorrhage is very common in patients with both qualitative and quantitative platelet abnormalities and von Willebrand disease.

Occasional gum bleeding occurs in normal. 3. Oral mucous membrane bleeding in the

form of blood blisters is a common manifestation of severe thrombocytopenia. Such bleeding usually has a predilection for sites where teeth can traumatize the inner surface of the cheek.

4. Skin hemorrhage in the form of petechiae and ecchymoses are common manifestations of hemostatic & non-hemostatic disorders.

Excessive bruising is more common in women than men.

Bruising varies with the phase of their menstrual cycle.

Severity of skin hemorrhage include the size, the frequency, spontaneously or only with trauma, and bruises on non traumatized regions, such as the trunk and back.

5. The color of the bruise Red bruises on the extensor surfaces of

the arms and hands indicate loss of supporting tissues, as occurs in Cushing syndrome, glucocorticoid therapy, senile purpura, and damage from chronic sun exposure.

Jet-black bruises-warfarin induced skin necrosis.

Easy bruising can also occur in patients with Ehlers-Danlos syndrome manifested by distensible skin or extraordinary ligament laxness, and in patients with hyperflexibility of the thumb.

6.Tooth extractions - helpful in defining the risk of bleeding. Molar extractions >> extractions of other teeth.

Objective data regarding excessive bleeding based on the need for blood products or the need to pack or suture the extraction site are valuable.

7. Excessive bleeding in response to razor nicks is common in patients with platelet disorders or von Willebrand disease.

8. Hemoptysis- never a bleeding disorder and is rare even in patients with serious bleeding disorders.

However, blood-tinged sputum in association with upper respiratory tract infections may be more common in patients with hemostatic disorders.

9. Hematemesis- never a hemostatic disorder. However, a hemostatic disorder may lead to hematemesis because of an anatomic abnormality in the upper gastrointestinal tract.

Some hemostatic disorders more likely result in hematemesis because of a combination of effects, such as liver disease with deficient synthesis of coagulation proteins and with esophageal varices and aspirin ingestion with gastritis.

10. Hematuria-rarely presenting c/o -exc. for the hemophilias.

However, hemostatic disorders-exacerbate hematuria caused by other disorders,eg. UTI.

11. Rectal bleeding-in normal-hemorrhoids.

von Willebrand disease and platelet disorders - associated with a number of different underlying causes, including diverticuli, hemorrhoids, or angiodysplasia.

Melena-rarely the presenting symptom. But, repeated episodes-hemor. disorders.

12. Menorrhagia is common in women with platelet disorders and von Willebrand disease. In general, menstrual bleeding is considered excessive if the patient indicates she has heavy flow for more than 3 days or total flow for more than 7 days.

objective distinction b/w menorrhagia (loss of more than 80 mL blood per period) and normal blood loss can only be made by a visual assessment technique using pictorial charts of towels or tampons.

13. Postpartum hemorrhage- bleeding disorders commonly manifest excessive bleeding during or after labor necessitating blood transfusion.

14. Habitual spontaneous abortions raise the possibility that the patient has a quantitative or qualitative abnormality of fibrinogen, factor XIII deficiency, or the antiphospholipid syndrome.

15.Hemarthroses are the hallmark abnormality in the hemophiliac; severe factor VII deficiency and type 3 von Willebrand disease

patients may not recognize that their symptoms (pain, swelling, and limitation of motion) are caused by bleeding into their joints.

16. Excessive hemorrhage associated with surgical procedures is common in patients with hemorrhagic disorders. Procedures involving tissues with increased local fibrinolytic activity like urinary tract, nose, tonsils and oral cavity are particularly prone to bleed.

17. Excessive bleeding following circumcision is common in males with severe hemostatic disorders such as hemophilia A, hemophilia B, or Glanzmann thromboasthenia, and often is the patient's first symptom.

18. Bleeding from the umbilical stump is characteristic of factor XIII deficiency and afibrinogenemia.

BASIC LAB. TESTS

PROTHROMBIN TIME PT measures – THE EXTRINSIC PATHWAY PT is prolonged with deficiencies of

factors VII, V, X, II, I. In most laboratories, the normal PT

value is 10-13 sec. PT has been standardized using the International Normalized Ratio (INR) so that values can be compared from 1 laboratory or instrument to another. This ratio is used to determine similar degrees of anticoagulation with warfarin (Coumadin)–like medications.

PARTIAL THROMBOPLASTIN TIME This test measures the – INTRINSIC

PATHWAY- initiation of clotting at the level of factor XII through sequential steps to the final clot end-point.

In vivo, activation of factor XII, by prekallikrein and HMWK.

In lab, factor XII is activated using a surface (silica or glass) or a contact activator, such as ellagic acid.

Factor XIIa => factor XI - XIa, => factor IX to factor IXa. On the platelet phospholipid surface, factor IXa complexes with factor VIII and calcium to activate factor X (“tenase”complex).

accelerated by interaction with phospholipid and calcium, involving factors V and VIII.

An isolated deficiency of a single clotting factor may result in isolated prolongation of PT, PTT, or both, depending on the location of the factor in the clotting cascade.

This approach is useful in determining hereditary clotting factor deficiencies; however, in acquired hemostatic disorders encountered in clinical practice, > 1 clotting factor is frequently deficient, so the relative prolongation of PT and PTT must be assessed.

Normal ranges for PTT are much more variable from laboratory to laboratory than those for PT.

Thus, the mechanisms studied by PT and PTT allow the evaluation of clotting factor deficiencies, even though these pathways may not be the same as those occurring physiologically.

In vivo, factor VIIa activates factors IX and X,

Lab.- factor VIIa => factor X only. This explain why the most severe

bleeding disorders are hemophilias factor VIII & IX.

In vivo, II feeds back to XI and accelerate the clotting process.

PTT can be prolonged by deficiencies of factor XII, prekallikrein, and HMWK, yet NO BLEEDING.

MIXING STUDIES If prolong. PT, PTT, or TT=> a mixing

study. Normal plasma is added to the patient's

plasma, and the PT or PTT is repeated. Correction of PT or PTT => def. of a

clotting factor, (because a 50% level of individual clotting proteins is sufficient to produce normal PT or PTT.)

If the clotting time is not corrected or only partially corrected, an inhibitor is usually present.

An inhibitor of clotting may be - -either a chemical similar to heparin

that delays coagulation -or an antibody directed against a

specific clotting factor.(MC- VIII, IX, or XI, may be present).

-or the phospholipid used in clotting tests.

In the inpatient setting, the most common cause of this finding is heparin contamination of the sample. The presence of heparin in the sample can be ruled in or out with the use of thrombin time and reptilase time.

If no bleeding and both PTT and the mixing study are prolonged, a lupus-like anticoagulant is often present.(clinical predisposition to excessive clotting)

THROMBIN TIME.(TT)Prolongation of thrombin time occurs in- -reduced fibrinogen levels (hypofibrinogenemia or afibrinogenemia).-dysfunctional fibrinogen (dysfibrinogenemia), or-the use of substances that interfere with fibrin polymerization, such as heparin or fibrin split products.

TT measures the final step in the clotting cascade, (fibrinogen => fibrin). The normal TT is usu. 11–15 sec.

In heparin contamination, RT is usually ordered.

REPTILASE TIME.(RT) RT uses snake venom to clot fibrinogen. Unlike TT, RT is not sensitive to heparin RT is inc. only by reduced or

dysfunctional fibrinogen and fibrin split products.

If TT is inc and RT is N = Heparin (not reduced concentration or function of fibrinogen)

BLEEDING TIME Bleeding time assesses the function of

platelets and their interaction with the vascular wall.

Disposable standardized devices have been developed that control the length and depth of the skin incision. A blood pressure cuff is applied to the upper arm and inflated to 40 mm Hg for children and adults. In term newborns and younger children, a modified device has been developed that is used with a lower blood pressure cuff pressure.

After an incision is made with the bleeding time device, blood is blotted from the margin of the incision at 30-sec intervals until bleeding ceases.

usually stops within 4-8 min. Bleeding time is a difficult laboratory test

to standardize, and there is much interlaboratory and interindividual variation.

prolonged bleeding time, qualitative platelet defect or VWD, PLC< 1 lakh/cu.mm

INTERPRETATION OF LAB TESTS AND

CLINICAL

INTRINSIC

EXTRINSIC

COMMON

OTHERS

BLEEDING DISORDERS

VON WILLEBRAND DISEASE Essentials of Diagnosis & Typical

Features -Easy bruising and epistaxis from early

childhood. -Menorrhagia. -Prolonged PFA-100 (or bleeding time);

normal platelet count; absence of acquired platelet dysfunction.

-Reduced activity or abnormal structure of vWF.

GENERAL CONSIDERATIONS the most common inherited bleeding

disorder among Caucasians, with a prevalence of 1%. vWF is a protein present as a multimeric complex in plasma, which binds factor VIII and is a cofactor for platelet adhesion to the endothelium.

An estimated 70–80% - classic vWD (type 1) -partial quantitative deficiency of vWF.

vWD type 2 involves a qualitative deficiency of (ie, dysfunctional) vWF, and

vWD type 3 - nearly complete deficiency of vWF.

The majority (> 80%) with type 1 disease are asymptomatic. vWD is most often transmitted as AD trait, but can be AR.

The disease 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 FINDINGS A 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.

LABORATORY FINDINGS PT is normal, and aPTT is sometimes prolonged. Prolongation of the PFA-100 or bleeding time is

usually present since vWF plays a role in platelet adherence to endothelium.

Dec PLC 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 activity (eg, ristocetin cofactor or collagen

binding) is decreased in all types. BGT important - normal vWF antigen levels.( O

has least levels) vWF multimer assay- complete classification

TREATMENT The treatment to prevent or halt

bleeding for most patients with vWD types 1 and 2 is desmopressin acetate, release of vWF from endothelial stores.

Desmopressin may IV / Intranasal. Because response to vWF is variable

among patients, factor VIII and vWF activities are typically measured before and 60 minutes after infusion.

Desmopressin may cause fluid shifts, hyponatremia, and seizures in children younger than 2 years of age.

Tachyphylaxis- limited stores. vWF-replacement therapy (eg, plasma-

derived concentrate) is recommended; Antifibrinolytic agents (eg, -aminocaproic acid) , Topical thrombin and fibrin glue may be useful for control of mucosal bleeding.

Estrogen-OCP-for menorrhagia.

TREATMENT desmopressin via release of endothelial

stores of factor VIII and vWF into plasma exogenous factor VIII. The in-vivo half-life

of factor VIII is generally 8–12 hours. Non–life-threatening, non–limb-threatening

hemorrhage is treated initially with 20–30 U/kg of factor VIII- rise in plasma factor VIII activity to 40–60%.

Large joint hemarthrosis and life- or limb-threatening hemorrhage is - 50 U/kg.

Prophylactic factor VIII infusions (eg, two or three times weekly)

PROGNOSIS With the availability of effective

treatment and prophylaxis for bleeding, life expectancy in vWD is normal.

Comparison of vWD and Hemophilias

Hemophilia A Hemophilia Bvon Willebrand Disease

Factor VIII coagulant activity

Low Normal Low or normal

von Willebrand factor antigen

Normal Normal Low

von Willebrand factor activity

Normal Normal Low

Factor IX Normal Low Normal

Ristocetin-induced platelet agglutination

Normal Normal Normal, low, or increased at low-dose ristocetin

Platelet aggregation

Normal Normal Normal

Treatment DDAVP* or recombinant VIII

Recombinant IX

FACTOR VIII DEFICIENCY (HEMOPHILIA A, CLASSIC HEMOPHILIA)

Essentials of Diagnosis & Typical Features

Bruising, soft-tissue bleeding, hemarthrosis.

Prolonged activated partial thromboplastin time (aPTT).

Reduced factor VIII activity.

General Considerations Factor VIII activity is reported in units

per milliliter, with 1 U/mL equal to 100% of the factor activity found in 1 mL of normal plasma. The normal range for factor VIII activity is 0.5–1.5 U/mL (50–150%). Hemophilia A occurs predominantly in males as an X- linked disorder. One third of cases are due to a new mutation. The incidence of factor VIII deficiency is 1:5000 male births.

CLINICAL FINDINGS severe hemophilia A (< 1% plasma factor

VIII activity) spontaneous bleeding episodes involving skin, mucous membranes, joints, muscles, and viscera.

Those with moderate hemophilia A (1% to < 5% factor VIII activity) typically have intermediate bleeding manifestations

mild hemophilia A (5–40% factor VIII activity) bleed only at times of trauma or surgery.

recurrent hemarthroses that incite joint destruction.

LABORATORY FINDINGS prolonged aPTT, (PT) is normal. Diagnostic- decreased factor VIII activity with

normal vWF activity. In 2/3rds of families of hemophilic patients,

the females are carriers and some are mildly symptomatic.

Carriers of hemophilia can be detected by determination of the ratio of factor VIII activity to vWF antigen and by molecular genetic techniques. In a male fetus or newborn with a family history of hemophilia A, cord blood sampling for factor VIII activity is accurate and important in subsequent care.

COMPLICATIONS Intracranial hemorrhage. Hemarthroses begin early in childhood- joint

destruction (ie, hemophilic arthropathy). Large intramuscular hematomas -

compartment syndrome with resultant muscle and nerve death.

A serious complication - acquired circulating antibody to factor VIII after treatment with factor VIII concentrate. 15–25% of patients with severe hemophilia A, - desensitization -immunosuppressive therapy

recombinant factor VIIa has become a therapy of choice.

infection with the human immunodeficiency virus (HIV), hepatitis B virus (HBV), and hepatitis C virus (HCV).

Inactivation methods do not eradicate viruses lacking a lipid envelope, however, so that transmission of parvovirus and hepatitis A remains a concern with the use of plasma-derived products.

Immunization with hepatitis A and hepatitis B vaccines is recommended for all hemophilia patients

FACTOR XI DEFICIENCY (HEMOPHILIA C)

Factor XI deficiency is an AD, with mild to moderate bleeding symptoms. It is frequently encountered in Ashkenazi Jews but has been found in many other ethnic groups. In Israel,1-3/1,000 individuals are homozygous for this deficiency.

The bleeding tendency is not as severe and not correlated with the amount of factor XI.

Some patients with severe deficiency may have minimal or no symptoms at the time of major surgery.

Because factor XI => + thrombin => + fibrinolytic inhibitor TAFI , surgical bleeding is more prominent in sites of high fibrinolytic activity like the oral cavity.

Unless the patient previously had surgery without bleeding, replacement therapy should be considered and given preoperatively, depending on the nature of the surgical procedure. No approved concentrate of factor XI is available in the USA; therefore, the physician must use fresh frozen plasma (FFP).

Bleeding during minor surgery can be controlled with local pressure. Patients undergoing dental extractions can be monitored closely and may benefit from treatment with fibrinolytic inhibitors like aminocaproic acid, with plasma replacement therapy used only if hemorrhage occurs. In a patient with homozygous deficiency of factor XI, PTT is often longer than it is in patients with either severe factor VIII or factor IX deficiency.

Chronic joint bleeding is rarely a problem in factor XI deficiency, and for most patients, the deficiency is a concern only at the time of major surgery unless there is a second underlying hemostatic defect (e.g.,von Willebrand disease)

The paradox of fewer clinical symptoms in combination with longer PTT is surprising, but it occurs because factor VIIa can activate factor IX in vivo.

Diagnostic- specific factor XI assays. Plasma infusions of 1 IU/kg usually

increase the plasma concentration by 2%. Thus, infusion of plasma at 10-15 mL/kg will result in a plasma level of 20-30%,which is usually sufficient to control moderate hemorrhage.

half-life of factor XI is usually ≥48 hr,

DEFICIENCIES OF THE CONTACT FACTORS (NONBLEEDING DISORDERS) Deficiency of the “contact factors”

(factor XII, prekallikrein, and high molecular weight kininogen) causes prolonged PTT but no bleeding symptoms.

the paradoxical situation in which PTT is extremely prolonged with no evidence of clinical bleeding.

they do not need treatment, even for major surgery.

FACTOR VII DEFICIENCY Factor VII deficiency is a rare autosomal bleeding

disorder- detected only in homozygous. Severity of bleeding varies from mild to severe

with hemarthroses, spontaneous intracranial hemorrhage, and mucocutaneous bleeding, especially nosebleeds and menorrhagia.

markedly prolonged PT,normal PTT,& dec Factor VII assays.

Because the plasma half-life of factor VII is 2-4 hr, therapy with FFP is difficult and is often complicated by fluid overload.

A commercial concentrate of recombinant factor - not approved by the FDA yet.

FACTOR X DEFICIENCY Factor X deficiency is a rare (estimated

1/1,000,000) autosomal disorder with variable severity.

Mild deficiency -mucocutaneous and post-traumatic bleeding, severe deficiency - hemarthroses and intracranial hemorrhages.

Factor X deficiency is the result of either a quantitative deficiency or a dysfunctional molecule.

prolongation of both PT and PTT.

Rx-FFP or prothrombin complex concentrate. The half-life of factor X is approximately 30 hr, and its volume of distribution is similar to that of factor IX. Thus, 1 U/kg will increase the plasma level of factor X by 1%.

rarely, systemic amyloidosis-X deficiency, adsorption of factor X on amyloid protein. transfusion therapy often is not successful

because of the rapid clearance of factor X.

PROTHROMBIN DEFICIENCY By reduced prothrombin level

(hypoprothrombinemia) , or by functionally abnormal prothrombin

(dysprothrombinemia). Laboratory testing in homozygous

patients shows prolonged PT and PTT. Factor II, or prothrombin, assays show a markedly reduced prothrombin level. Mucocutaneous bleeding in infancy and post-traumatic bleeding later are common.

Rx- FFP or, rarely, prothrombin complex concentrates. FFP is useful, because the half-life of prothrombin is 3.5 days.

Administration of 1 IU/kg of prothrombin will increase the plasma activity by 1%.

FACTOR V DEFICIENCY autosomal recessive, mild to moderate

bleeding disorder that has also been termed parahemophilia.

mucocutaneous bleeding and hematomas MC symptoms. Severe menorrhagia is a frequent symptom in women. Hemarthroses occur rarely.

Lab- prolonged PTT and PT. Specific assays for factor V show a reduction.

FFP is only option. V is lost rapidly from stored FFP.

Patients with severe factor V deficiency are treated with infusions of FFP at 10 mL/kg every 12 hr.

Rarely, acquired antibody to factor V . Such pt. does not bleed because the factor V in platelets prevents excessive bleeding.

COMBINED DEFICIENCY OF FACTORS V AND VIII secondary to the absence of an

intracellular transport protein that is responsible for transporting factors V and VIII from the endoplasmic reticulum to the Golgi compartments.

paradoxical deficiency of 2 factors, one encoded on chromosome 1and X chromosome. Bleeding symptoms are often milder than for hemophilia A .

Rx- FFP to replace both factors V and VIII.

FIBRINOGEN (FACTOR I) DEFIC. rare autosomal recessive disorder in

which there is an absence of fibrinogen. do not bleed as frequently as

hemophiliacs, rarely have hemarthroses. neonatal period with GI hemorrhage or

hematomas after vaginal delivery. marked prolongation of PT and PTT,

thrombin time . an unmeasurable fibrinogen level is

diagnostic.

dysfunctional fibrinogens have been reported (dysfibrinogenemia). present with thrombosis.

half-life of fibrinogen is 2-4 days, treatment with either FFP or cryoprecipitate is effective.

Fibrinogen are inhibited by high doses of heparin. Prolonged reptilase time confirms that functional levels of fibrinogen are low and that heparin is not present.

FACTOR XIII DEFICIENCY (FIBRIN-STABILIZING FACTOR OR TRANSGLUTAMINASE DEFICIENCY)

Because factor XIII is responsible for the cross linking of fibrin to stabilize the fibrin clot, symptoms of delayed hemorrhage are secondary to instability of the clot.

Typically, patients have trauma 1 day and then have a bruise or hematoma the next day. Clinical symptoms include mild bruising, delayed separation of the umbilical stump beyond 4 wk in neonates, poor wound healing, and recurrent spontaneous abortions Rare hemarthroses and intracranial hemorrhage have been described.

PT, PTT, TT, BT are Normal there is increased solubility of the clot

because of the failure of cross linking. The normal clot remains insoluble in the presence of 5M urea, whereas in a patient with XIII deficiency, the clot dissolves.

More specific assays for factor XIII a. half-life of factor XIII is 5-7 days and the

hemostatic level is 2-3% activity, infusion of FFP or cryoprecipitate will correct the deficiency.

ANTIPLASMIN OR PLASMINOGEN ACTIVATOR INHIBITOR DEFICIENCY Deficiency of either antiplasmin or

plasminogen activator inhibitor, both of which are antifibrinolytic proteins=> increased plasmin => premature lysis of fibrin clots.

mild bleeding disorder, mucocutaneous bleeding but rarely have joint hemorrhages.

usual hemostatic tests are normal+ positive bleeding history => euglobulin clot lysis time, which measures fibrinolytic activity = shortened result.

Specific assays for α2-antiplasmin and plasminogen activator inhibitor are available.

Bleeding episodes are treated with FFP; bleeding in the oral cavity may respond to aminocaproic acid

ACTIVATED PROTEIN C ACTIVITIES

The clinical phenotype of severe protein C deficiency in neonatal purpura fulminans implies that APC exerts multiple physiologically essential activities, including potent anticoagulant and anti-inflammatory actions .

Recent advances establish that APC's antiinflammatory actions are but one manifestation of its ability to interact directly with cell receptors to provide multiple cytoprotective activities. These two distinct types of activities of APC, intravascular anticoagulant activity and initiation of cell signaling, are mediated by different sets of molecular interactions, and both types of activities are clinically relevant.

Component

Content Indication Dose

Outcome expectd

Fresh frozen plasma

1unit/mL of each clotting factor

Multiple clotting factor deficiency

10-15 mL/kg

Improvement in prothrombin and partial thromboplastin times

Cryoprecipitate

Fibrinogen, factor VIII, vWF, factor XIII

Hypofibrinogenemia, factor XIII deficiency

1 bag/5 kg ↑ Fibrinogen by 50-100 mg/dL

Recombinant factor concentrates

Units as labeled

Hemophilic bleeding or prophylaxis

F VIII: 20-50 units/kg*

FVIII: 2%/unit/kgFIX: 0.7/unit/kg

F IX: 40-120 units/kg*

Recombinant factor VIIa (NovoSeven)

μg Hemophilic bleeding in inhibitor patient; uncontrolled post operative hemorrhage

90 μg/kg q3 h

Cessation of bleeding

Comparison of vWD and Hemophilias

Hemophilia A

Hemophilia B

von Willebrand Disease

Inheritance X-linked X-linked Autosomal dominant

Factor deficiency Factor VIII Factor IX von Willebrand factor and VIIIC

Bleeding site(s) Muscle, joint, surgical

Muscle, joint, surgical

Mucous membranes, skin, surgical, menstrual

Prothrombin time

Normal Normal Normal

Activated partial thromboplastin time

Prolonged Prolonged Prolonged or normal

Bleeding time Normal Normal Prolonged or normal

FINAL WORD1. In hematology – we cant do without

blood test.2. Only Blood test are not enough.

THANK YOU

CASE STUDY A 15-year-old boy with chronic strep throat has

presented with excessive bruising. His coagulation results were as follows:

PT 15.5 seconds (Reference range, 10.8 to 13.5)

aPTT 42.1 seconds (Reference range, 28.5 to 35.5)

Platelets 325,000 (Reference range, 150,000 to 400,000)

Bleeding 5 minutes (Reference, 8 minutes) Which coagulation tests are abnormal, and

how should this physician proceed in his treatment of this patient?

INSIGHTS TO THE CASE STUDY In this case, two parameters, the PT and aPTT,

are elevated. The patient is not bleeding, but he shows a history of recent bruising. Since both the PT and the aPTT are affected, one can assume the problem is in the common pathway, specifically factors I, II, V, and X.

Factor assays could be performed to assess the level of activity of each of these clotting factors;

however, a closer examination into the patient’s history might reveal an additional feature. Since this patient has had chronic strep throat, it is logical to assume that he has been on long-term antibiotics.

Antibiotics may deplete the normal flora, a source of vitamin K synthesis. Factors II, VII, IX, and X are vitamin K–dependent factors. Vitamin K is the essential cofactor for the gamma carboxyglutamic acid residues necessary to activate these factors. When vitamin K is in short supply or depleted, these factors fail to function properly. In our patient, vitamin K can be given by mouth to resume normal coagulation and correct bruising.