The document outlines an approach to evaluating and diagnosing bleeding disorders. It discusses: 1. Obtaining a clinical history and performing screening laboratory tests like PT, PTT, and platelet count to classify the bleeding as a platelet, coagulation factor, or other disorder. 2. Using specialized tests like mixing studies and inhibitor assays to identify specific factor deficiencies or inhibitors. 3. Considering rare causes if screening tests are normal, like defects in fibrinolysis or factor XIII. 4. Evaluating acquired bleeding in settings like liver disease and surgery. A detailed approach with diagnostic algorithms is provided.

1. An Approach to Bleeding Disorders
Rekha Parameswaran, MD

2. Objectives
I. Clinical aspects of bleeding
II. Approach to laboratory work-up
III. Hematologic disorders causing bleeding
• Coagulation factor disorders:
• Platelet disorders
IV. Approach to acquired bleeding disorders
• Hemostasis in liver disease
• Surgical patients
• DIC

3. Objectives - I
 Clinical aspects of bleeding

4. Overview
Cause of bleeding can be :
Localized pathologic process : Postop bleeding consults
Disorders involving vascular integrity : All coag labs
and CBC normal
Disorders involving platelet number and/or
function: CBC, Platelet function assay abnormal
Disorders of procoagulant factors: PT/PTT
abnormalities
Defects of fibrinolytic pathway :PT, PTT normal

5. 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

6. Petechiae
Do not blanch with pressure
(cf. angiomas)
Not palpable
(cf. vasculitis)
(typical of platelet disorders)
Gernsheimer, MD, T., & Frank, MD, M. B. (2006). Thrombocytopenia. Retrieved from http://teachingcases.hematology.org/Gernsheimer/index.cfm

7. Ecchymoses
(typical of coagulation
factor disorders)

8. Objectives - II
 Laboratory approach to workup

9. Coagulation and Fibrinolysis
Pathways
Holly, MD, J. L. (2007). Cardiometabolic risk syndrome part v: Fibrinolytic dysfunction. Your Life Your Health - The Examiner, Retrieved
from http://www.setma.com/article.cfm?ID=330

10. Laboratory Evaluation of Bleeding
Overview
CBC and smear Platelet count Thrombocytopenia
RBC and platelet morphology TTP, DIC, etc.
Coagulation Prothrombin time Extrinsic/common pathways
Partial thromboplastin time Intrinsic/common pathways
Coagulation factor assays Specific factor deficiencies
50:50 mix Inhibitors (e.g., antibodies)
Fibrinogen assay Decreased fibrinogen
Thrombin time Qualitative/quantitative
fibrinogen defects
FDPs or D-dimer Fibrinolysis (DIC)
Platelet function von Willebrand factor vWD
Bleeding time In vivo test (non-specific)
Platelet function analyzer (PFA) Qualitative platelet disorders
and vWD
Platelet function tests Qualitative platelet disorders

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

12. 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

13. Causes of prolonged Thrombin Time
 Hypofibrinogenemia
 Dysfibrinogenemia

14. 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

15. Initial Evaluation of a Bleeding Patient - 1
Normal PT, Abnormal PTT
Normal thrombin time
Test for factor deficiency:
Isolated deficiency in intrinsic pathway (factors VIII, IX, XI)
Multiple factor deficiencies (rare)
Repeat
with
50:50
mix
50:50 mix is normal
50:50 mix is
abnormal
Test for inhibitor activity:
Specific factors: VIII,IX, XI
Non-specific (anti-phospholipid Ab)

16. Initial Evaluation of a Bleeding Patient - 2
Abnormal PT, Normal PTT
Normal thrombin time
Test for factor deficiency:
Isolated deficiency of factor VII (rare)
Multiple factor deficiencies (common)
(Liver disease, vitamin K deficiency, warfarin, DIC)
Repeat
with
50:50
mix
50:50 mix is normal
50:50 mix is
abnormal
Test for inhibitor activity:
Specific: Factor VII (rare)
Non-specific: Anti-phospholipid (rare)

17. Initial Evaluation of a Bleeding Patient - 3
Abnormal PT, Abnormal PTT
Normal or abnormal thrombin time
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)
Repeat
with
50:50
mix
50:50 mix is normal
50:50 mix is
abnormal
Test for inhibitor activity:
Specific : Factors V, X, Prothrombin,
fibrinogen (rare)
Non-specific: anti-phospholipid (common)

18. Tests are normal-Now what?
Factor XIII deficiency
alpha-2-antiplasmin deficiency
PAI-1 deficiency
mild factor deficiency
vascular disorders: hereditary hemorrhagic
telangiectasia

19. Initial Evaluation of a Bleeding Patient - 4
Normal PT, Normal PTT
Normal thrombin time
Consider evaluating for:
Mild factor deficiency Monoclonal gammopathy
Abnormal fibrinolysis Platelet disorder
( 2 anti-plasmin def) Vascular disorder
Elevated FDPs
Urea
solubility
Normal
Abnormal
Factor XIII deficiency

20. PAI-1 deficiency
Autosomal recessive
Glycoprotein serpin synthesized in liver
Bleeding in homozygotes with wide spectrum of
clinical symptoms
Measure PAI-1 activity

21. Alpha-2 Antiplasmin
Autosomal recessive
Single chain glycoprotein synthesized in the liver
Bleeding in homozygotes
Intracranial hemorrhage in full term neonates
Intramedullary hematomas of long bones
Measure alpha 2 antiplasmin level
Shapiro, A. and Parameswaran, R. (2007) Miscellaneous Rare Bleeding Disorders, in Textbook of Hemophilia (eds C. A. Lee, E. E.
Berntorp, W. K. Hoots and L. M. Aledort), Blackwell Publishing Ltd, Oxford, UK. doi: 10.1002/9780470987124.ch58

22. Factor XIII deficiency
 Composed of 2 subunits A and B: A synthesis is in hematopoietic
cells and B synthesis in the Liver
 FXIII-A def is know as Type 2 , FXIII-B def os Type-1(<%5).
 Associated with delayed bleeding
 Autosomal recessive
Hsieh , L., & Nugent , D. (2008). Factor xiii deficiency. Haemophilia, 14(6), 1190-
200. doi: 10.1111/j.1365-2516.2008.01857.x

23. Rare Clotting Factor Deficiencies
What are rare clotting factor deficiencies?. (2012, May). Retrieved from
http://www.wfh.org/en/page.aspx?pid=662

24. Platelet Function Analyzer 100®
 Tests primary hemostasis in artificial vessel
 The PFA-100® system was designed to measure primary hemostasis in vitro by
uniquely simulating the in vivo hemodynamic conditions of platelet adhesion,
activation and aggregation.
 Results are of Collagen/Epinephrine and Collagen/ADP
 Results may distinguish between normal, a drug effect, and inherent
platelet dysfunction
 http://www.platelet-research.org/3/pfa.htm

25. PFA 100
Normal Aspirin vWD Glanzmann's
Thrombasthenia
Collagen/Epi Normal Abnormal Abnormal Abnormal
Collagen/ADP Normal Normal Abnormal Abnormal
 Closure Time was abnormal in 64% of patients diagnosed with vWD as
compared to 43% by Bleeding Time.
 Some studies indicate poor discrimination between normal control and
patients with platelet dysfunction.
 The best “test” for detection of platelet dysfunction is medical history.

26. Platelet aggregation assay
http://reddymed.com/lab/plateletftests_paggregati
on.htm
An overview of lab diagnosis in bleeding disorders: Platelet function tests. (2003).
Retrieved from http://reddymed.com/lab/plateletftests_paggregation.htm

27. Platelet aggregation patterns
Modified with permission from: Rodgers, GM. Qualitative platelet disorders and von Willebrand's disease. In: Practical Diagnosis of Hematologic Disorders,
2nd ed., Kjeldsberg, C, Foucar, K, McKenna, RW, et al. (Eds), ASCP Press, Chicago 1995. Copyright © 1995-2010 American Society for
Clinical Pathology and ASCP Press.

28. Vascular Disorders
Hereditary hemorrhagic telangiectasia
scurvy
Ehlers-Danlos syndrome?
Henoch-Schonlein purpura
the un-diagnosable fibrinolytic defect

29. Coagulation factor deficiencies
Summary
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

30. Objectives - III
 Approach to acquired bleeding disorders
– Hemostasis in liver disease
– Acquired thrombocytopenia
– Surgical patients
– DIC
– Warfarin toxicity

31. Liver Disease and Hemostasis
1. Decreased levels of II, VII, IX, X, XI, and
fibrinogen except factor VIII ( synthesized in
vascular endothelial cells and sinusoidal liver
cells)
2. Dietary Vitamin K deficiency (Inadequate
intake or malabsortion)
3. Dysfibrinogenemia
4. Enhanced fibrinolysis (Decreased alpha-2-
antiplasmin)
5. DIC
6. Thrombocytopenia due to hypersplenism

32. Common clinical conditions associated with
Disseminated Intravascular Coagulation
 Sepsis
 Trauma
– Head injury
– Fat embolism
 Malignancy
 Obstetrical complications
– Amniotic fluid embolism
– Abruptio placentae
 Vascular disorders
 Reaction to toxin (e.g.
snake venom, drugs)
 Immunologic disorders
– Severe allergic reaction
– Transplant rejection
Activation of both coagulation and fibrinolysis
Triggered by

33. Thrombocytopenia
 Many competing causes to consider in setting of multiple
drugs and multiple comorbidities in our patients with
concomitant bleeding and thrombosis risks
 Confusion can prevail : Drug-induced, DIC,HIT, ITP,
TTP
 Arriving at correct diagnosis almost always a process of
exclusion

34. When do we worry about bleeding?

35. Thrombocytopenia
Immune-mediated
Idioapthic
Drug-induced
Collagen vascular disease
Lymphoproliferative disease
Sarcoidosis
Non-immune mediated
DIC
Microangiopathic hemolytic anemia

36. Warkentin, T. E. Hematology 2006;2006:408-414
Platelet count nadirs in heparin-induced thrombocytopenia (HIT),
quinine-induced immune thrombocytopenic purpura (Q-ITP), and
thrombotic thrombocytopenic purpura (TTP) with absent
ADAMTS-13 activity
Warkentin, MD, T. E. (n.d.). Think of hit. American society of hematology, 2006(1), 408-414 . doi:
10.1182/asheducation-2006.1.408

37. Approach to the thrombocytopenic patient
 History
– Is the patient bleeding?
– Are there symptoms of a secondary illness? (neoplasm,
infection, autoimmune disease)
– Is there a history of medications, alcohol use, or recent
transfusion?
– Are there risk factors for HIV infection?
– Is there a family history of thrombocytopenia?
– Do the sites of bleeding suggest a platelet defect?
 Assess the number and function of platelets
– CBC with peripheral smear
– Bleeding time or platelet aggregation study

38. How I begin an approach to sudden
severe thrombocytopenia at the bedside
Sudden severe drop
in platelets <10-20K
without hemolysis
Immune
Drugs
Idiopathic or
Autoimmune
Sepsis DIC
Transfusion

39. Bleeding time and bleeding
 Essentially an obsolete test

40. Approach to Post-operative bleeding
1. Is the bleeding local or due to a hemostatic failure?
1. Local: Single site of bleeding usually rapid with minimal
coagulation test abnormalities
2. Hemostatic failure: Multiple site or unusual pattern with
abnormal coagulation tests
2. Evaluate for causes of peri-operative hemostatic failure
1. Preexisting abnormality
2. Special cases (e.g. Cardiopulmonmary bypass)
3. Diagnosis of hemostatic failure
1. Review pre-operative testing
2. Obtain updated testing

41. Approach to bleeding disorders
Summary
 Detailed clinical history will help direct you to
identify a defect of hemostasis
– Laboratory testing is almost always needed to establish the cause of
bleeding
– Screening tests (PT,PTT, thrombin time, platelet count) will often
allow placement into one of the broad categories
– Specialized testing is usually necessary to establish a specific
diagnosis

42. Summary
History & Physical Examination
Laboratory tests
– screening tests
– specific diagnostic tests
Diagnosis-specific therapy
– Factor replacement
– Drugs