bleeding tendency ron hoffman, md thrombosis & hemostasis unit rambam medical center

Bleeding Tendency

Ron Hoffman, MD

Thrombosis & Hemostasis Unit

Rambam Medical Center

Objectives

I. Clinical aspects of bleedingII. Medical history

• Personal• Family

III. Physical examIV. Approach to laboratory abnormalitiesV. Bleeding disordersVI. Therapy

Primary Hemostasis

XIIa

Coagulation cascade

IIa

Intrinsic system (surface contact)

XII

XI XIa

Tissue factor

IX IXa VIIa VII

VIII VIIIa

Extrinsic system (tissue damage)

X

V Va

II

Fibrinogen Fibrin

(Thrombin)IIa

Vitamin K dependant factors

Xa

Objectives




Clinical Features of Bleeding Disorders

Platelet Coagulation disorders factor disorders

Site of bleeding Skin Deep in soft tissues Mucous membranes (joints, muscles) (epistaxis, gum, vaginal, GI tract)

Petechiae Yes No

Ecchymoses (“bruises”) Small, superficial Large, deep

Hemarthrosis / muscle bleeding Extremely rare Common

Bleeding after cuts & scratches Yes No

Bleeding after surgery or trauma Immediate, Delayed (1-2 days), usually mild often severe

Petechiae

Do not blanch with pressure(cf. angiomas)Not palpable (cf. vasculitis)

(typical of platelet disorders)

Ecchymoses

(typical of coagulation factor disorders)

Objectives




Systemic screening

Epistaxis – age, frequency, spontaneous, how long, way of bleeding arrest, blood products.

Oral cavity : tooth, gums, tonsils + adenoids . Skin Trauma: minor , major GI & urinary tract. Brain Gynecological: menses, pregnancy and deliveries

abortions. Hemarthroses, muscular. Circumcision , umbilical

Important aspects

Differentiation between hemostatic bleeding and surgical.

Immediate vs. late bleeding (primary vs secondary hemostatic problem).

Abnormal blood vessel Normal coagulation factors may be present

in pregnancy!

Medications – most common

COX & ADP inhibitors : Aspirin, Clopidogrel, NSAID

Background disease Acute leukemia (APL) MPD Uremia Cirrhosis

Family history Sex-linked recessive Factors VIII and IX deficiencies cause bleeding

Prolonged PTT; PT normal

Autosomal recessive (rare) Factors II, V, VII, X, XI, fibrinogen deficiencies cause bleeding -

prolonged PT and/or PTT

Factor XIII deficiency is associated with bleeding andimpaired wound healing

PT/ PTT normal; clot solubility abnormal

Factor XII, prekallikrein, HMWK deficienciesdo not cause bleeding

Objectives

I. Clinical aspects of bleeding

II. Medical history• Personal• Family


Clinical bleeding

Senile purpura, purpura simplex

Signs of systemic disease : ED, Cushing,

Amyloidosis, Cirrhosis, MPD

Objectives




CBC and blood smear (thrombocytopenia, thrombocytopathia).

Basic coagulation tests: PT, aPTT, Fibrinogen.

Advanced coagulation tests: TT, Mixing assays, Factor levels , PFA, Fibrinolysis assays.

Laboratory Evaluation of the Coagulation Pathways

Partial thromboplastin time(PTT)

Prothrombin time(PT)

Intrinsic pathway Extrinsic pathway

Common pathwayThrombin timeThrombin

Surface activating agent (Ellagic acid, kaolin)

PhospholipidCalcium

ThromboplastinTissue factor

PhospholipidCalcium

Fibrin clot

Pre-analytic errors

Problems with blue-top tube Partial fill tubes Vacuum leak and citrate

evaporation

Problems with phlebotomy Heparin contamination Wrong label Slow fill Underfill Vigorous shaking

Biological effects Hct ≥55 or ≤15 Lipemia,

hyperbilirubinemia, hemolysis

Laboratory errors Delay in testing Prolonged incubation at

37°C Freeze/thaw deterioration

Initial Evaluation of a Bleeding Patient - 1

Normal PTNormal PTT

Consider evaluating for: Mild factor deficiency Monoclonal gammopathy Abnormal fibrinolysis Platelet disorder (a2 anti-plasmin def) Vascular disorder Elevated FDPs

Ureasolubility

Normal

Abnormal

Factor XIII deficiency


Normal PTAbnormal PTT

Test for factor deficiency: Isolated deficiency in intrinsic pathway (factors VIII, IX, XI) Multiple factor deficiencies (rare)

Repeatwith

50:50mix

50:50 mix is normal

50:50 mix is abnormal

Test for inhibitor activity: Specific factors: VIII,IX, XI Non-specific (anti-phospholipid Ab)

Initial Evaluation of a Bleeding Patient - 3Abnormal PTNormal PTT

Test for factor deficiency: Isolated deficiency of factor VII (rare) Multiple factor deficiencies (common) (Liver disease, vitamin K deficiency, warfarin, DIC)

Repeatwith

50:50mix

50:50 mix is normal


Test for inhibitor activity: Specific: Factor VII (rare) Non-specific: Anti-phospholipid (rare)


Abnormal PTAbnormal PTT

Test for factor deficiency: Isolated deficiency in common pathway: Factors V, X, Prothrombin, Fibrinogen Multiple factor deficiencies (common)(Liver disease, vitamin K deficiency, warfarin, DIC)

Repeatwith

50:50mix

50:50 mix is normal


Test for inhibitor activity: Specific : Factors V, X, Prothrombin, Fibrinogen (rare) Non-specific: anti-phospholipid (common)

Thrombin Time

Bypasses factors II-XII

Measures rate of fibrinogen conversion to fibrin

Procedure: Add thrombin with patient plasma Measure time to clot

Variables: Source and quantity of thrombin

Objectives




Thrombocytpenia and thrombocytopathia, Hemophilia A,B, Acquired VWD Acquired coagulations factors deficiency:

Cirrosis

Classification of platelet disorders

Quantitative disorders

Abnormal distribution Dilution effect Decreased production

Increased destruction

Qualitative disorders Inherited disorders

(rare) Acquired disorders

Medications Chronic renal failure Cardiopulmonary bypass MPD

Inherited platelet disorders

Thrombocytopenia

• Immune-mediated• Idioapthic (ITP)

• Drug-induced

• Collagen vascular disease

• Lymphoproliferative disease

• Viral (HIV)• Non-immune mediated• DIC

• Microangiopathic hemolytic anemia

• Drugs

Features of Acute and Chronic ITP

Features Acute ITP Chronic ITP

Peak age Children (2-6 yrs) Adults (20-40 yrs)Female:male 1:1 3:1Antecedent infection Common RareOnset of symptoms Abrupt Abrupt-indolentPlatelet count at presentation <20,000 <50,000Duration 2-6 weeks Long-termSpontaneous remission Common Uncommon

Initial treatment of ITPPlatelet count Symptoms Treatment (per µl)

>50,000 None

20-50,000 Not bleeding NoneBleeding Glucocorticoids

IVIG

<20,000 Not bleeding GlucocorticoidsBleeding Glucocorticoids

IVIG

Coagulation factor disorders

Inherited bleeding disorders

Hemophilia A and B

vonWillebrands

disease

Other factor

deficiencies

Acquired bleeding Disorders

Liver disease Vitamin K

deficiency/warfarin overdose

DIC

Hemophilia A and BHemophilia A Hemophilia B

Coagulation factor deficiency Factor VIII Factor IX

Inheritance X-linked X-linkedrecessive recessive

Incidence 1/10,000 males 1/50,000 males

Severity Related to factor level<1% - Severe - spontaneous bleeding1-5% - Moderate - bleeding with mild injury5-25% - Mild - bleeding with surgery or trauma

Complications Soft tissue bleeding

Hemarthrosis (acute)

Treatment of Hemophilia A

Intermediate purity plasma products Virucidally treated May contain von Willebrand factor

High purity (monoclonal) plasma products Virucidally treated No functional von Willebrand factor

Recombinant factor VIII Virus free/No apparent risk No functional von Willebrand factor

Acquired hemophilia

Associated with: auto immunity, post partum, cancer and drugs

Bleeding manifestations : muscular, internal, usually not hemarthroses

Diagnosis : prolonged aPTT, mixing FVIII levels, r/o LAC

Responding to immuno suppressive (IVIG) Control of bleeding by: high dose FVIII, Porcine

FVIII, APCC, rFVIIa

Congenital Coagulopathies

FXII deficiency FXI deficiency Hemophilia A + B Afibrinogenemia FV + FVIII deficiency FVII deficiency FXIII deficiency Type 3 VWD

VWD Clinical Features

von Willebrand factor Synthesis in endothelium and megakaryocytes Forms large multimer Carrier of factor VIII Anchors platelets to subendothelium Bridge between platelets

Inheritance - autosomal dominant Incidence - 1/10,000 Clinical features - mucocutaneous bleeding

Laboratory evaluation of VWD

Classification Type 1 Most common Partial quantitative deficiency Type 2 Qualitative deficiency Type 3 Total quantitative deficiency

Diagnostic tests:

Assay VWD type

1 2 3

vWF antigen low normal very lowvWF activity low low very lowFVIII low normal absentMultimer analysis normal abnormal normal

Treatment of VWD

Cryoprecipitate Source of fibrinogen, factor VIII and VWF Only plasma fraction that consistently contains VWF multimers

DDAVP (deamino-8-arginine vasopressin) plasma VWF levels by stimulating secretion from endothelium Duration of response is variable Not generally used in type 2 disease Dosage 0.3 µg/kg q 12 hr IV

Factor VIII concentrate (Intermediate purity) Virally inactivated product

Vitamin K deficiency

Source of vitamin K Green vegetables Synthesized by intestinal

flora

Required for synthesis Factors II, VII, IX ,XProtein C and S

Causes of deficiency MalnutritionBiliary obstruction

MalabsorptionAntibiotic

therapy(coumadin)

Treatment Vitamin KFresh frozen plasma

Liver Disease and Hemostasis

1. Decreased synthesis of II, VII, IX, X, XI, and fibrinogen

2. Dietary Vitamin K deficiency (Inadequate intake or malabsortion)

3. Dysfibrinogenemia

4. Enhanced fibrinolysis (Decreased alpha-2-antiplasmin)

5. DIC

6. Thrombocytoepnia due to hypersplenism

Objectives




Treatment Approaches to the Bleeding Patient

Red blood cells Platelet transfusions Fresh frozen plasma Cryoprecipitate Amicar DDAVP Recombinant Human factor VIIa

Approach to bleeding disorders

Medical history – the most important diagnostic “test”

Identify and correct any specific defect of hemostasis Laboratory testing is almost always needed to establish the cause of

bleeding

Screening tests (PT,PTT, platelet count) will often allow placement into one of the broad categories

Specialized testing is usually necessary to establish a specific diagnosis.

bleeding tendency ron hoffman, md thrombosis & hemostasis unit rambam medical center

Documents

bleeding slide

hemostatic bleeding

clinical aspects of

mpd slide

umbilical slide

cuts scratchesyesno

way of bleeding arrest

primary hemostasis slide