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