Bleeding and Thrombotic Disorders
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Transcript of Bleeding and Thrombotic Disorders
Bleeding and Thrombotic Disorders
DR. RAKESH VERMA
HEMOSTASISPrimary vs. Secondary vs. Tertiary
• Primary Hemostasis– Platelet Plug Formation– Dependent on normal platelet number & function
• Secondary Hemostasis– Activation of Clotting Cascade Deposition & Stabilization of
Fibrin• Tertiary Hemostasis– Dissolution of Fibrin Clot– Dependent on Plasminogen Activation
MEcHAnISMS Of blEEdIngVascular IntegrityPlateletsClotting factorsFibrinolysis
Derangement of any of these factors can cause abnormal bleeding
Key to diagnosisHistoryHistoryHistory
Bleeding historyEpistaxisGingival hemorrhageMucosal BleedingHeavy MensesChild birthEasy bruisabilityBleeding following tooth extractionsHematomasBleeding following surgeryHemarthrosis
Medication HistoryAspirinWarfarinNSAIDSB- Lactam antibioticsClopidogrel and other antiplatelet agentsHerbal medications.
Nutritional historyVit K deficiencyVit C deficiencyBroad spectrum antibiotics
Clinical Characteristics
Platelet disorder Clotting factor deficiency
Site of bleedingSkin, mucous membranes (gingivae, nares, GI and genitourinary tracts)
Deep in soft tissues (joints, muscles)
Bleeding after minor cuts
Yes Not usually
Petechiae Present Absent
Ecchymoses Small, superficial Large, palpable
Hemarthroses, muscle hematomas
Rare Common
Bleeding after surgery
Immediate, mild Delayed, severe
Petechiae 1-3mmPurpura 3mm-10 mmEcchymosis >10mm
HErEdITAryDeficiency of coagulation factors
HemophiliaFibrinogen deficiencyVon Willebrand disease
Platelet disordersGlanzmann thrombastheniaBernard-Soulier syndromePlatelet granule disorders
Fibrinolytic disordersAlpha 2 antiplasmin deficiencyPAI 1 deficiency
Structural disordersHemorrhagic TelangiectasiasEhler Danlos syndrome
AcquIrEdThrombocytopeniasLiver diseaseVit K deficiencyAcquired antibodies to coagulation factorsDICDrugsVascular
lAb TESTIngPlatelet countBleeding time-Measure of the interaction of platelets with
the blood vessel wall. BT raised in
Thrombocytopenia (platelet count usually below 50,000/microL),
Qualitative platelet abnormalities (eg, uremia), von Willebrand disease (VWD), Vascular purpura, Severe fibrinogen deficiency
blEEdIng TIME vS. PlATElET cOunT
Activated platelets
Platelet function assayExpose platelets within citrated whole blood to high shear (5,000 to
6,000/sec) within a capillary tube and monitor the drop in flow rate as the platelets form a hemostatic plug within the center of a membrane coated with collagen and either ADP or epinephrine
Abnormal closure times are an indication of platelet dysfunction, they are not specific for any disorder
The test is coagulation factor independent PFA-100™ is more sensitive (>70 percent) than the bleeding time
(20 to 30 percent) in detecting all subtypes of von Willebrand's disease (vWD)
Exception is type 2N vWD, in which the hemostatic defect resides in the Factor VIII binding site on vWF
Platelet function assayCollagen/epinephrine closure time (CEPI-CT)- Abnormal in Aspirin intake
Collagen/adenosine diphosphate (CADT-CT)-Normal in aspirin intake
Prothrombin time (10-13sec)
Measure of the extrinsic pathway and common pathwayBypasses the intrinsic pathway and uses tissue factor in
presence of calcium Within the combined pathway, factors VII, X, and
prothrombin are vitamin-K dependent and are altered by warfarin
Prolonged PtVitamin K deficiency Liver disease, which decreases the synthesis of both
vitamin K-dependent and -independent clotting factors. Deficiency or inhibition of factors VII, X, II
(prothrombin), V, or fibrinogen
Heparin does NOT prolong the PT
aPttMeasures the intrinsic and common pathways of coagulationUses partial thromboplastinsProlonged in
deficiency of the clotting factors inhibitor to any of the clotting factors except for factor VIIdeficiency of prekallikrenin, high molecular weight kininogenLupus Anticoagulant.
Used to monitor heparin activity
thrombin time Measure conversion of fibrinogen to fibrin monomers and the
formation of initial clot by thrombin Prolonged in
Hypofibrinogenemia Dysfibrinogenenimia Increased fibrin split products (inhibit polymerisation of fibrin
monomers) Heparin; increases TT but not Reptilase Time
factor deficiencies/ inhibitors
A prolonged aPTT can be due to a deficiency (or absence) of a coagulation factor or the presence of a coagulation factor inhibitor
Mixing studies helps in differentiation. Patient sample is mixed with normal plasma in 1:1, and ifPT or PTT get corrected shows deficiency of factorsPT or PTT get corrected partially or uncorrected shows
inhibitorsLupus anticoagulants (antibody against phospholipids)
can result in a prolonged aPTT that is not correctable by the addition of normal plasma
fibrinolysis
Fibrin and fibrinogen degradation products (FDP) are protein fragments resulting from the action of plasmin on fibrin or fibrinogen
ActivatorInhibitorPathway
fibrinolysis
FDP assays do not differentiate between fibrin degradation products and fibrinogen degradation products
Fibrin D-dimers are degradation products of cross-linked fibrin
D-dimers specifically reflect fibrinolysis of cross-linked fibrin (ie, the fibrin clot) – so are more reliable indicators of thrombosis
Normal PT aNd PTT
ThrombocytopeniaFactor 13 deficiencyPlatelet dysfunctionVascular purpurasPsychogenic purpura
Normal PT aNd ProloNged aPTT
Hemophilia AHemophilia BFactor XI deficiencyFactor VIII inhibitor
Malignancy,Clonal lymphoproliferative disorders, Pregnancy, Rheumatologic disorders Lupus anticoagulant
ProloNged PT aNd Normal aPTT
Factor VII deficiencyWarfarin therapyEarly liver diseaseEarly DIC
ProloNged PT aNd PTT
Vit K deficiencyLiver diseaseAcquired inhibitor to factor VFactor X deficiencyDIC
HemoPHiliaHemophilia A (85%) and B(10-15%) are X-linked recessive
diseases Severe disease -<1 % factor activity; bleeding is often
spontaneousModerate disease - 1 to 5 %; require mild trauma to induce
bleedingMild disease - >5 %; prolonged bleeding after dental work,
surgery, or injuries from moderate trauma.
The most common sites are into joints and muscles and from the gastrointestinal tract
The hallmark of hemophilia is the hemarthrosis
•Some female carriers of hemophilia A or hemophilia B will have sufficient reduction of their factor VIII or factor IX through lionization of the X chromosome to produce mild bleeding disorders in carriers
•In severe hemophilia, APTT is usually two to three times the upper limits. other screening tests platelet count, bleeding time, prothrombin time, and thrombin time are normal. Specific assay for factors will confirm the diagnosis.
•Evaluation for inhibitors should also be performed. In such patients the quantitative Bethesda assay for inhibitor should be performed.
TreaTmeNTThe two components to therapy are treatment of active bleeding and
inhibitor ablation via immune tolerance induction Cryoprecipitate has high levels of factor VIIIPorcine Factor VIIIRecombinant human Factor VIIIA recombinant factor VIIa is for treating factor VIII or factor IX
inhibitor patients.The choice of factor VIII product usually is based upon safety, purity,
and cost. Prophylaxis is the Standard care of treatment for severe diseaseMild hemophilia A - Desmopressin acetate.
Desmopressin is ineffective in hemophilia B.The prevention of trauma, avoidence of Aspirin and other
nonsteroidal anti-inflammatory drugs.
dosiNgOne international unit (IU) of clotting factor is that
amount present in 1 mL of pooled normal plasma
Dose of F VIII (IU) = Weight (kg) x (Desired % increase) x 0.5 Dose of F IX (IU) = Weight (kg) x (Desired % increase) x 1.4
Depends on the presence or absence of inhibitors.
Other clotting factor deficienciesFactor Feature Management
Factor XI Haemophilia C
deficiency autosomal, deficiency associated with mild to moderate bleeding symptoms
FFP
Factor V Para-hemophilia
mucocutaneous bleeding and hematomas are the most common symptoms, rarely hemarthroses; severe menorrhagia is a frequent symptom in women
FFP
Factor VII homozygous state, deficiency may have spontaneous intracranial hemorrhage and frequent mucocutaneous bleeding
Recombinant factor VIIa
Factor X rare autosomal disorder that results in mucocutaneous and post-traumatic bleeding
FFP
Factor XIII (Fibrin-Stabilizing Factor or Transglutaminase Deficiency)
symptoms of delayed hemorrhage, patients will have trauma one day and then develop a bruise or hematoma on the following day. Diagnosed by clot solublility in the presence of 5 M urea
FFP or cryoprecipitate
Contact factors XII,PK,HMWK
Prolong PTT but no bleeding No treatment
voN WillebraNd’s diseaseMost common of the inherited bleeding disorders 1% -2% in
general population.In 1926, Erik von Willebrand described the disease.Multimeric molecules, synthesises in
Platelets’ alpha granulesEndothelial cell’s Weibel – Palade bodies
Von Willebrand factor (VWF) binds to both platelets and endothelial components, forming an adhesive bridge between platelets and vascular subendothelial structures and between adjacent platelets at sites of endothelial injury
von Wil lebrand disease subtypes
Type Defect Genetics
Bleeding symptoms
Response to DDAVP
Type 1 (common)
Quantitative: Decreased vWF
AD Mild Good
Type 2 (uncommon)
Qualitative: Normal vWF levels
2A vWF not "sticky" enough AD/AR Variable Mild to mod.
2B vWF too "sticky" ADPotentially severe
Contraindicated
2M
Lacking receptor for platelet binding
AD Fairly mildMild to mod.
2N
Lacking receptor for factor VIII binding
ARSimilar to hemophilia A
Mild
Type 3 (rare) Absent vWF AR Severe No Response
Condition Prothrombin timePartial thromboplastin timeBleeding time Platelet count
Vitamin K deficiency or warfarin
Prolonged Normal or mildly prolonged
Unaffected Unaffected
Disseminated intravascular coagulation
Prolonged Prolonged Prolonged Decreased
Von Willebrand disease Unaffected Prolonged or unaffected Prolonged Unaffected
Hemophilia Unaffected Prolonged Unaffected Unaffected
Aspirin Unaffected Unaffected Prolonged Unaffected
Thrombocytopenia Unaffected Unaffected Prolonged Decreased
Liver failure, early Prolonged Unaffected Unaffected Unaffected
Liver failure, end-stage Prolonged Prolonged Prolonged Decreased
Uremia Unaffected Unaffected Prolonged Unaffected
Congenital afibrinogenemia Prolonged Prolonged Prolonged Unaffected
Factor V deficiency Prolonged Prolonged Unaffected Unaffected
Factor X deficiency as seen in amyloid purpura
Prolonged Prolonged Unaffected Unaffected
Factor XII deficiency Unaffected Prolonged Unaffected Unaffected
DIC Prolonged Prolonged Prolonged Decreased
Laboratory findings in various platelet and coagulation disorders
Blood component therapyComponent Constituent Indications Dose
FFP All clotting factors Many coagulation factor deficiency state
15ml/kg (gives 20-30%)
Cryoprecipitate I, VIII, XIII, vWF Corresponding deficiencies
30ml/kg
Random donor plateletI (RDP)
Platelet atleast5.5x1010
Thrombocytopenia 1unit/10kgRaise 30,000-50,000/cumm
Single donor platelet (SDP)
Platelet atleast3x1011
Thrombocytopenia 1 collection equals 6RDP
Whole blood All Acute blood loss Severe trauma
PLATELET
AND
BLOOD VESSEL DISORDERS
IdIopathIc (autoImmune) thrombocytopenIc purpura
The most common cause for acute onset of thrombocytopenia in an otherwise well child
Presentation •1-4 yr child •Sudden onset of generalized petechiae and purpura. •leeding from the gums and mucous•Splenomegaly is rare•Chronic ITP or thrombocytopenia may be manifestation of a systemic illness such as SLE.
Investigations •Severe thrombocytopenia•Platelet size is normal or increased•Prolong bleeding time•Hb, WBC, DLC can be normal•Normal or increased numbers of megakaryocytes
Management•70-80% with acute ITP, spontaneous resolution will occur within 6 mo•Platelet transfusion•Intravenous immunoglobulin - dose of 0.8-1 g/kg/day × 1-2 days•Prednisone.•IV Anti- D Therapy
WELLWELL
Decrease synthiesis
•TAR•Wiskott Aldrich•X- linked Amegakayocyte•Toxins •Radiations
Decrease synthiesis
•TAR•Wiskott Aldrich•X- linked Amegakayocyte•Toxins •Radiations
Consumption
•ITP•Secondary to SLE•drug induced•Maternal ITP•NATP•2B vWD
Consumption
•ITP•Secondary to SLE•drug induced•Maternal ITP•NATP•2B vWD
Large plateletNormal Hb & WBC
Large plateletNormal Hb & WBC
Small plateletIncrease MCV
Congenital anomalies
Small plateletIncrease MCV
Congenital anomalies
chIldhood thrombocytopenIa Differential diagnosis
IllIll
Decrease synthiesis
MalignancyStorage disorder
Decrease synthiesis
MalignancyStorage disorder
Consumption
HUSTTP
Thombosis Sepsis
Consumption
HUSTTP
Thombosis Sepsis
Decrease FibrinogenIncrease FDPsLarge platelet
Decrease FibrinogenIncrease FDPsLarge platelet
Small plateletHepato-spleenomegaly
Small plateletHepato-spleenomegaly
Sequestration
HaemangiomaHyperspleenism
Sequestration
HaemangiomaHyperspleenism
Mass Mass
chIldhood thrombocytopenIa
Differential diagnosis
Feature HUS TTP
Age usually <3 yr usually 3rd decade
Gender M=F F>M
Prodrome infection, diarrhea less common
Recurrence rare common
Diagnosis
Triad: Acute renal failure, thrombocytopenia, microangiopathic anemia.
Pentad: CNS disturbance, thrombocytopenia, microangiopathic anemia, renal dysfunction, fever.
Etiologic factors E. Coli (verotoxin), Shigella gastroenteritis, pneumococcus
Pregnancy, autoimmune disease, malignancy, drugs.Decrease ADAM-TS
TreatmentRenal dialysis, corticosteroids do not help, transfuse only if necessary.
Plasma exchange, corticosteroids, avoid transfusions.
Prognosis Good Poor
mIcroangIopathIc haemolytIc anemIa
Congenital Abnormalities of Platelet Function
Condition Platelet aggregation studies
Platelet count Other
Glanzmann thrombasthenia Abnormal to all agonists Normal
Bernard-Soulier syndrome Abnormal to ristocetin Decreased Giant platelets.
Storage pool defect 1.Dense body deficiency
2.Gray platelet syndrome
Abnormal 2nd phase of aggregation Normal
Abnormal platelet granules on electron microscopy
ASA/NSAIDAbnormal COX or Tx synthase
Abnormal to arachidonic acid and abnormal secondary aggregation to ADP and epinephrine
Normal
Drug induced enzyme effect inhibiting platelet granule release. This is the most common cause of platelet dysfunction.
Managment
Desmopressin
platelet transfusions
recombinant factor VIIa
stem cell transplants
Thrombotic disorders
A hereditary predisposition to thrombosis can be caused by deficiencies of the regulatory proteins:
•Protein C •Protein S•Antithrombin III•Plasminogen;•Factor V Leiden•Prothrombin mutation (G20210A)•Homocystinuria. •Lipoprotien (a)
Investigationsno screening testsspecific testing is required for each componentfamily history Genetic DNA testing for factor V Leiden and the prothrombin mutation
TreatmentFresh frozen plasma Protein C concentrate, Warfarin
dIc
A conditions resulting in consumption of clotting factors, platelets, and anticoagulant proteins. Causing widespread intravascular deposition of fibrin leading to tissue ischemia and necrosis, a generalized hemorrhagic state, and hemolytic anemia.
Clinical Manifestations.Bleeding frequently occurs from venipuncture or surgical incision. Petechiae and ecchymoses. Infarction of skin, subcutaneous tissue, or kidneys. Anemia caused by microangiopathic hemolytic anemia.
Labprolongation of the PT, PTT and TT.Platelet counts may be profoundly depressed.Smear shows fragmented, burr, and helmet-shaped, schistocytes. FDPs, D-dimers elevated (The D-dimer is more specific for activation of coagulation and fibrinolysis than the FDP )
Treatment – two steps(1) treat the trigger that caused the DIC (2) restore normal homeostasis by correcting the shock, acidosis, and hypoxia that usually complicate the DICBlood componentsIn DIC associated with sepsis, activated protein C (APC) drotrecogin alpha can be givenHeparin in patient who have vascular thrombosis