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
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
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
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
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.
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
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
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
The initial fibrin clot, held together by noncovalent bonds, is soluble in urea. Subsequent transglutamination by factor XIII covalently crosslinks overlapping fibrin strands, which then become resistant to solubilization. The ability of 5M urea or monochloroacetic acid to solubilize the clot reflects deficiency of factor XIII
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.ch58Editor Information1 Professor of Haemophilia, Director and Consultant Haematologist, Haemophilia Centre and Haemostasis Unit, The Royal Free Hospital, London, UK2 Professor of Hemophilia, Lund University;, Director, Department of Coagulation Disorders, Malmö University Hospital, Malmö, Sweden3 Professor of Pediatrics, University of Texas M.D. Anderson Cancer Center;, Professor of Pediatrics and Internal Medicine, University of Texas Medical School at Houston;, Medical Director, Gulf States Hemophilia and Thrombophilia Center, Houston, TX, USA4 The Mary Weinfeld Professor of Clinical Research in Hemophilia, Mount Sinai School of Medicine, New York, NY, USAPublication HistoryPublished Online: 4 OCT 2007 Published Print: 12 JAN 2005ISBN InformationPrint ISBN: 9781405127691Online ISBN: 9780470987124