1. Ron Hoffman, MD Thrombosis & Hemostasis Unit Rambam Medical Center
Bleeding Tendency
Ron Hoffman, MD
Thrombosis & Hemostasis Unit
Rambam Medical Center 2

2. Objectives Clinical aspects of bleeding Medical history Personal
Family
Physical exam
Approach to laboratory abnormalities
Bleeding disorders
Therapy 2

4. Primary Hemostasis

5. Coagulation cascade Intrinsic system (surface contact)
Extrinsic system (tissue damage)
XII
XIIa
Tissue factor XI
XIa IX
IXa
VIIa
VII
VIII
VIIIa
KEY POINT: The efficacy/safety ratio for currently available therapies is less than satisfactory due to their ill-defined, multitargeted activity. New antithrombotic strategies are needed that offer an improved efficacy/safety profile compared with existing antithrombotic agents.1,2
Currently available antithrombotic agents include the heparins (UFH and Enoxaparin), vitamin K antagonists (warfarin), and direct thrombin inhibitors (hirudins).3–6
The most widely used agents, heparins and vitamin K antagonists, have a range of actions on various components of the coagulation cascade. This contributes to the unpredictable clinical responses associated with these agents.3–5
Other limitations of currently available antithrombotics include3–7
High incidence of serious adverse effects, particularly bleeding complications
Routine monitoring of coagulation markers may be needed and represents a substantial
burden in terms of time and costs
Narrow therapeutic margin
Limited effectiveness in preventing VTE
Factor Xa inhibitors are a novel class of antithrombotic agents designed to selectively target only 1 core step in the coagulation cascade, leading to potent and targeted effectiveness.8
Vitamin K dependant factors X Xa V Va II
IIa
IIa
(Thrombin)
Fibrinogen
Fibrin
For training purposes only—Not for distribution

6. Objectives Clinical aspects of bleeding Medical history Personal
Family
Physical exam
Approach to laboratory abnormalities
Bleeding disorders
Therapy 2

7. 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

8. (typical of platelet disorders)
Petechiae
(typical of platelet disorders)
Do not blanch with pressure (cf. angiomas) Not palpable (cf. vasculitis)

9. (typical of coagulation factor disorders)
Ecchymoses
(typical of coagulation factor disorders)

10. Objectives Clinical aspects of bleeding Medical history Personal
Family
Physical exam
Approach to laboratory abnormalities
Bleeding disorders
Therapy 2

11. 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

12. 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!

13. Medications – most common
COX & ADP inhibitors : Aspirin, Clopidogrel, NSAID
Background disease
Acute leukemia (APL)
MPD
Uremia
Cirrhosis

14. Family history prolonged PT and/or PTT 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 and
impaired wound healing
PT/ PTT normal; clot solubility abnormal
 Factor XII, prekallikrein, HMWK deficiencies
do not cause bleeding

15. Objectives Clinical aspects of bleeding Medical history Personal
Family
Physical exam
Approach to laboratory abnormalities
Bleeding disorders
Therapy 2

16. Clinical bleeding Senile purpura, purpura simplex
Signs of systemic disease : ED, Cushing, Amyloidosis, Cirrhosis, MPD

17. Objectives Clinical aspects of bleeding Medical history Personal
Family
Physical exam
Approach to laboratory abnormalities
Bleeding disorders
Therapy 2

18. CBC and blood smear (thrombocytopenia, thrombocytopathia).
Basic coagulation tests: PT, aPTT, Fibrinogen.
Advanced coagulation tests: TT, Mixing assays, Factor levels , PFA, Fibrinolysis assays.

19. Laboratory Evaluation of the Coagulation Pathways
Partial thromboplastin time
(PTT)
Prothrombin time
(PT)
Surface activating agent
(Ellagic acid, kaolin)
Phospholipid
Calcium
Thromboplastin
Tissue factor
Phospholipid
Calcium
Intrinsic pathway
Extrinsic pathway
Thrombin time
Common pathway
Thrombin
Fibrin clot

20. Pre-analytic errors Biological effects Problems with blue-top tube
Hct ≥55 or ≤15
Lipemia, hyperbilirubinemia, hemolysis
Laboratory errors
Delay in testing
Prolonged incubation at 37°C
Freeze/thaw deterioration
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

21. Initial Evaluation of a Bleeding Patient - 1
Normal PT
Normal PTT
Abnormal
Urea
solubility
Factor XIII deficiency
Normal
Consider evaluating for:
Mild factor deficiency Monoclonal gammopathy
Abnormal fibrinolysis Platelet disorder
(a2 anti-plasmin def) Vascular disorder
Elevated FDPs

22. Initial Evaluation of a Bleeding Patient - 2
Normal PT
Abnormal PTT
50:50 mix is abnormal
Repeat
with
50:50
mix
Test for inhibitor activity:
Specific factors: VIII,IX, XI
Non-specific (anti-phospholipid Ab)
50:50 mix is normal
Test for factor deficiency:
Isolated deficiency in intrinsic pathway (factors VIII, IX, XI)
Multiple factor deficiencies (rare)

23. Initial Evaluation of a Bleeding Patient - 3
Abnormal PT
Normal PTT
50:50 mix is abnormal
Repeat
with
50:50
mix
Test for inhibitor activity:
Specific: Factor VII (rare)
Non-specific: Anti-phospholipid (rare)
50:50 mix is normal
Test for factor deficiency:
Isolated deficiency of factor VII (rare)
Multiple factor deficiencies (common)
(Liver disease, vitamin K deficiency, warfarin, DIC)

24. Initial Evaluation of a Bleeding Patient - 4
Abnormal PT
Abnormal PTT
50:50 mix is abnormal
Repeat
with
50:50
mix
Test for inhibitor activity:
Specific : Factors V, X, Prothrombin, Fibrinogen (rare)
Non-specific: anti-phospholipid (common)
50:50 mix is normal
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)

25. 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

26. Objectives Clinical aspects of bleeding Medical history Personal
Family
Physical exam
Approach to laboratory abnormalities
Bleeding disorders
Therapy 2

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

28. 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

29. Inherited platelet disorders

30. Thrombocytopenia Immune-mediated Idioapthic (ITP) Drug-induced
Collagen vascular disease
Lymphoproliferative disease
Viral (HIV)
Non-immune mediated
DIC
Microangiopathic hemolytic anemia
Drugs

31. 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 3:1
Antecedent infection Common Rare
Onset of symptoms Abrupt Abrupt-indolent
Platelet count at presentation <20,000 <50,000
Duration weeks Long-term
Spontaneous remission Common Uncommon

32. Initial treatment of ITP
Platelet count Symptoms Treatment
(per µl)
>50,000 None
20-50,000 Not bleeding None
Bleeding Glucocorticoids
IVIG
<20,000 Not bleeding Glucocorticoids

33. 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

34. Hemophilia A and B Hemophilia A Hemophilia B
Coagulation factor deficiency Factor VIII Factor IX
Inheritance X-linked X-linked
recessive recessive
Incidence 1/10,000 males 1/50,000 males
Severity Related to factor level
<1% - Severe - spontaneous bleeding
1-5% - Moderate - bleeding with mild injury
5-25% - Mild - bleeding with surgery or trauma
Complications Soft tissue bleeding

35. Hemarthrosis (acute)

36. Treatment of Hemophilia A
Intermediate purity plasma products
Virucidally treated
May contain von Willebrand factor
High purity (monoclonal) plasma products
No functional von Willebrand factor
Recombinant factor VIII
Virus free/No apparent risk

37. 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

38. Congenital Coagulopathies
FXII deficiency
FXI deficiency
Hemophilia A + B
Afibrinogenemia
FV + FVIII deficiency
FVII deficiency
FXIII deficiency
Type 3 VWD

39. 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

40. 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
vWF antigen low normal very low
vWF activity low low very low
FVIII low normal absent
Multimer analysis normal abnormal normal

41. 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

42. Vitamin K deficiency
Source of vitamin K Green vegetables Synthesized by intestinal flora
Required for synthesis Factors II, VII, IX ,X Protein C and S
Causes of deficiency Malnutrition Biliary obstruction Malabsorption Antibiotic therapy
(coumadin)
Treatment Vitamin K Fresh frozen plasma

43. Liver Disease and Hemostasis
Decreased synthesis of II, VII, IX, X, XI, and fibrinogen
Dietary Vitamin K deficiency (Inadequate intake or malabsortion)
Dysfibrinogenemia
Enhanced fibrinolysis (Decreased alpha-2-antiplasmin)
DIC
Thrombocytoepnia due to hypersplenism

44. Objectives Clinical aspects of bleeding Medical history Personal
Family
Physical exam
Approach to laboratory abnormalities
Bleeding disorders
Therapy 2

45. Treatment Approaches to the Bleeding Patient
Red blood cells
Platelet transfusions
Fresh frozen plasma
Cryoprecipitate
Amicar
DDAVP
Recombinant Human factor VIIa

46. 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.