[Int. med] bleeding disorders from SIMS Lahore

Bleeding and clotting disorder

Dr Nighat majeed

Assistant professor

Medical unit 11

SIMS/SHL Lahore

Bleeding and clotting disorder

• Bleeding is a breakdown in hemostasis.

Normal physiology ofHemostasis

• Vascular factors

• Platelet factors

• Plasma factors

Vascular Factors

• Local vasoconstriction • Vessel wall injury triggers the attachment and

activation of platelets and production of fibrin; platelets and fibrin combine to form a clot.

Platelet Factors

Preventing platelet stasis and dilating intact blood vessels.

• . Endothelial cell nitric oxide.• Prostacyclin These mediators are no longer produced when

the vascular endothelium is disrupted. • After vascular injury initial platelet adhesion is to

von Willebrand's factor (VWF), previously secreted by endothelial cells into the subendothelium.(binds to 1b/1X).

Platelet Factors

During activation

platelets release• Adenosin diphosphate (ADP).• Biochemical changes

• Arachidonic acid is converted to thromboxane A2;

this reaction requires cyclooxygenase.

Platelet Factors

• ADP, thromboxane A2, and other mediators

promotes platelet aggregation and activate them.• Another receptor is assembled on the platelet

surface membrane from glycoproteins IIb and IIIa. Fibrinogen binds to the glycoprotein IIb-IIIa complexes of adjacent platelets, connecting them.

Platelet Factors

• Platelets provide surfaces for the assembly and activation of coagulation complexes and the generation of thrombin.

• Thrombin converts fibrinogen to fibrin.• Fibrin strands bind aggregated platelets to help

secure the platelet-fibrin hemostatic plug.

Plasma Factors

• Plasma coagulation factors interact to produce thrombin, which converts fibrinogen to fibrin.

Plasma Factors

The blood clothing system or coagulation pathway, like the complement system, is a proteolytic cascade.

The ultimate goal of the pathway is to produce thrombin, which can then convert soluble fibrinogen into fibrin, which forms a clot.

The generation of thrombin, 1-The intrinsic pathway. (generation of factor X). 2-Extrinsic pathways (generation of factor X). 3-Final common pathway which results in

thrombin formation.

Plasma Factors

Intrinsic pathway

• Factor XII, high mol wt kininogen, prekallikrein, and activated factor XI (factor XIa) produce factor IXa from factor IX. Factor IXa then combines with factor VIIIa and procoagulant phospholipid (present on the surface of activated platelets and tissue cells) to form a complex that activates factor X.

Extrinsic pathway

• There are two components unique to the extrinsic pathway, tissue factor or factor III, and factor VII.

Plasma Factors

• People with hereditary deficiencies of factor XII, high mol wt kininogen, or prekallikrein have no bleeding abnormality.

• People with hereditary factor XI deficiency have a mild to moderate bleeding disorder. In vivo, factor XI (an intrinsic pathway factor) is activated when a small amount of thrombin is generated.

Plasma Factors• Activation of the intrinsic or extrinsic pathway activates the

common pathway, resulting in formation of the fibrin clot. • Three steps are involved: • 1- A prothrombin activator is produced on the surface of

activated platelets and tissue cells. The activator is a complex of an enzyme, factor Xa, and 2 cofactors, factor Va and procoagulant phospholipid.

• 2- The prothrombin activator cleaves prothrombin into thrombin and another fragment.

• 3 Thrombin induces the generation of fibrin polymers from fibrinogen.

Plasma Factors

• Thrombin also activates factor XIII, an enzyme that catalyzes formation of stronger bonds between fibrin molecules, as well as factor VIII and factor XI.

• Ca ions are needed in most thrombin-generating reactions (Ca-chelating agents (e.g., citrate, ethylenediaminetetraacetic acid) are used in vitro as anticoagulants).

Extrinsic pathway

•

.

Pathways in blood coagulation.Extrinsic pathway

Fibrinolytic pathway

• • 2-Ehlers danlos syndrome.

• 3-Hereditary haemorragic talengiectasia.

Bleeding disorders (classification)

Defects of blood vessels

• 1-Vascular purpura.

• Meningococcal infection.

• Septicemia.

• Henoch schonlein purpura.

• Uremia.

• Scurvy.


• Platelet disorders.• Thrombocytopenia.

Idiopathic

Secondary• Thrombocythamia• Thromboasthenia


Clotting disorders Hereditary• Hemophilia.• Christmas disease.• Von willebrand disease. Acquired• Vitamin K deficiency.• Oral anticoagulant therapy. • Advanced liver disease.

Platelet disorders (thrombocytopenia)

Causes of thrombocytopenia• Bone marrow disorders• Aplastic anemia• Hematologic malignancies• Myelodysplasia• Megaloblastic anemia• Chronic alcoholism


Nonmarrow disorders• Immune disorders• Idiopathic thrombocytopenic purpura• Drug-induced• Secondary (CLL, SLE)• Posttransfusion purpura


• Hypersplenism.• Disseminated intravascular coagulation.• Thrombotic thrombocytopenic purpura.• Hemolytic-uremia syndrome.• Sepsis.• Hemangiomas.• Viral infections, AIDS. • Liver failure.• chronic lymphocytic leukemia; systemic lupus

erythematosus.

Platelet disorders

Qualitative platelet disorders

• Congenital.• Glanzmann's thrombasthenia.• Bernard–Soulier syndrome.• Storage pool disease.

Platelet disorders

• Acquired• Myeloproliferative disorders.• Uremia.• Drugs: aspirin, anti-inflammatory agents.• Autoantibody.• Paraproteins.• Acquired storage pool disease.• Fibrin degradation products.• von Willebrand's disease.

Diagnostic approach (History)

• Weather the patient has experienced abnormal bleeding or bruising in the past.

• The site, extent and duration of previous hemorrhagic phenomenon.

• Response to treatment.• History of bleeding with minor

injuries,lacerations, circumcision, tooth extraction, appendectomy, menses, and umbilical cord, as well as delayed bleeding and keloid formation.


• History of use of medicines that interfere with hemostasis, e:g oral contraceptives, aspirin, NSAIDS, antibiotics, sodium warfarin or heparin.

• A positive family history of bleeding suggests the presence of sex linked or autosomal dominant disorders.

• Vascular wall defect may be congenital.


• In platelet and capillary dysfunction there is superficial bleeding from skin and mucous membrane.

• In coagulation defect bleeding occurs deep into the tissues and surgery is not possible without prior treatment of defect.


• Patient presents with bleeding from various sites.• Common presentations are bleeding from gums,

epistaxis, hematemesis, hemoptysis, haematuria, menorragia.

• History of neoplasia, uremia, liver disease.

Characteristics of bleeding in hemorrhagic disorders

Petechia• Punctate;about 1mm in diameter.on extremities

usually absent over pressure points,occur due to vascular defect or platelet abnormality.


Purpura

1mm to 1cm, generally truncal, occasionally extremities.it is usually due to vascular abnormalities.


Ecchymosis

• Larger bleed with local extravasation.It occurs on soft tissues and joints.it occur due to factor deficiency or open blood vessel.


Generalized• Diffuse or generalized ecchymosis, occurs on

larger areas, mucous membranes and wounds.• Usually associated with disseminated intravascular

clotting or primary fibrinolysis.


• Hereditary hemorrhagic telangiectasia

A congenital vessel wall abnormalities, such as, defect in a gene coding for endoglin and TGF-ß which are angiogenic cytokines concerned with vascular modeling leading to formation of telangiectasias or small aneurysms.

Patient presents with recurrent bleed(epistaxis), or with iron deficiency due to gastrointestinal bleed.


• Ehler-Danlos disease a congenital disorder of collagen synthesis ecchymoses occur commonly in skin because capillaries are poorly supported by subcutaneous collagen.

• Vasculitis an inflammation of arterial wall may be acquired.


Platelet disorders• Spontaneous bleeding occur if platelet count falls

below 30*109/l.• Purpura and spontaneous bruising are

characteristic.• There may be oral, nasal,gastrointestinal or

genitourinary bleeding.• Severe thrombocytopaenia cause optic fundal

hemorrhage or intracranial bleed.


Drugs inhibiting platelet functions

NSAIDS

Aspirin

Indomethacin

Antibiotics

Penicillins

Dextran

Heparin

B blockers

Phenylbutazone

Sulfinpyrazone

cephalosporins


Coagulation disorders

Hazards of coagulation disorders is increased with • surgical procedures.• Cardiopulmonary bypass procedures. • hypothermia.• prostate surgery, cardiovascular surgery.• trauma and massive bleeding without replacement

of clotting factors.

Laboratory tests of bleeding patient

• Prothrombin time.• Activated partial thromboplastin time.• Platelet count.• Fibrinogen level.• Fibrin split products or D-dimer or both.• Bleeding time.• Hemoglobin or haematocrit.• Peripheral blood smear.• Specific factor assay.• Assays for inhibitors and antibodies.• Platelet aggregation and antibody studies.


Prothrombin time• The prothrombin time (PT) and its derived

measures of prothrombin ratio (PR) and international normalized ratio (INR) are measures of the extrinsic pathway of coagulation.

• PT measures factors II, V, VII, X and fibrinogen.

Prothrombin time

Prothrombin time time is prolonged in,• Vitamin K deficiency.• Disseminated intravascular coagulation.• Haemophilia.PT is unaffected.• Heparin overdose.

Prothrombin time

• The INR is the ratio of a patient's prothrombin time to a normal (control) sample, raised to the power of the ISI value for the analytical system used.

Pttest

INR = ( --------- )

Ptnormal

Prothrombin time

• The reference range for prothrombin time is usually around 12–15 seconds; the normal range for the INR is 0.8– 1.2.

• International normalized ratio

• The result (in seconds) for a Prothrombin time performed on a normal individual will vary depending on what type of analytical system it is performed on. This is due to the differences between different batches of manufacturer's tissue factor used in the reagent to perform the test. The INR was devised to standardize the results.

• Each manufacturer assigns an ISI value (International Sensitivity Index) for any tissue factor they manufacture. The ISI value indicates how a particular batch of tissue factor compares to an internationally standardized sample. The ISI is usually between 1.0 and 2.0.

• The INR is the ratio of a patient's prothrombin time to a normal (control) sample, raised to the power of the ISI value for the analytical system used.


Activated partial thromboplastin time• The partial thromboplastin time (PTT) or activated

partial thromboplastin time (aPTT or APTT) is a measure of the efficacy of both the "intrinsic" and the common coagulation pathways.

• Apart from detecting abnormalities in blood clotting, it is also used to monitor the treatment effects with heparin, a major anticoagulant. It is used in conjunction with the prothrombin time (PT) which measures the extrinsic pathway.


Partial thromboplastin time is prolonged in,

• Vitamin K deficiency.• Disseminated intravascular coagulation.• Haemophilia.• Heparin overdose.

Bleeding time

• Bleeding time is a medical test done on someone to assess their platelet function.

• It involves cutting the underside of the subject's forearm, in an area where there is no hair or visible veins. The cut is of a standardized width and depth, and is done quickly by an automatic device.

• A normal value is less than 9 and a half minutes.


Vascular defects and von willebrand,s disease• Bleeding time is prolonged.• Ristocetin cofactor assay of VWF antigen.• VWF antigen.• VWF multimeric assay.


Platelet defects

Direct examination of stained smear.

Platelet count.

Bleeding time.

Platelet adhesion.

Platelet aggregation.

Assay for platelet factor 3.

Clot retraction.


Factor deficiencies Factor V111 deficiency classic Hemophilia.• Factor V111 assay.• APTT.

Factor 1X deficiency in Christmas disease.• Factor 1X assay.• APTT.

Health & Medicine

[Int. med] bleeding disorders from SIMS Lahore