1. Approach to Patients with
Coagulation Disorders
Professor doctor Yousry Alzohairy
Professor of Hematology ,Faculty of medicine
Alazhar University Cairo-Egypt
Membership of American society of Hematology
2. Approach to Patients with Coagulation
Disorders
I. BLEEDING DISORDERS are among the most common
problems in hematology.
A bleeding disorder may be obvious or so subtle that it is
overlooked. Occasionally, the problem is identified by
routine screening tests. The evaluation of a patient with a bleeding
disorder should be performed in
a logical sequence, as expediently as possible. A careful, detailed
history is critical and may uncover
clues to the nature of the disorder, thus facilitating the choice of
laboratory studies.
3. Approach to Patients with
Coagulation Disorders
1-History
A-Bleeding history)Congenital-Acquired-Nature of bleeding)
B-Medical history
C-Medication history
2-Physical examination.
3-Laboratory studies
4. A. History
1. Bleeding history. lt is very useful to know if the bleeding disorder has been
this may be difficult to ascertain lifelong, although
a. CIues to a congenital bleeding disorder
(1) Specific questioning may uncover a history of excessive bleeding initiated by
common
childhood traumas or after dental extractions, which suggests that the disorder is life-long
(2) A history of bleeding disorders in family members is extremely useful and,
when the
mode of inheritance can be determined, may even suggest a specific
diagnosis.
(a) Hemophilia (A or B) is suggested when the inheritance is X-linked.
(b) von Willebrand's disease is suggested in a patient with a low level of factor Vlll:C
and a family history consistent with an autosomal inheritance
5.
b. Clues to an acquired bleeding
disorder
(1) A patient who presents with a bleeding disorder and who gives a history of tolerating
stress
to the coagulation system (e.g., excessive bleeding after extraction of a permanent tooth) usually
can be assumed to have an acquired disorder.
(2) The time between exposure to potentially causative factors and the onset of the
bleeding disorder may provide clues to the etiology and, particularly in-medication-
related disorders, the treatment of the bleeding problem.
6.
c. Nature of bleeding
(1) Sites of bleeding may suggest where in the coagulation process the defect may be.
(a) Mucous membrane bleeding and petechiae are often seen in platelet-related disorders.
(b) Hemarthroses are common in hemophilia.
(c) Soft tissue hematomas without petechiae or mucous membrane bleeding suggest
a defect in the coagulation cascade.
(2) Severity of the bleeding disorder influences therapeutic decisions and may be from
deduced
the degree of trauma necessary to induce excessive bleeding.
(a) Spontaneous bleeding usually occurs only in the most severe disorders.
(b) A history of bleeding only after major trauma or surgery suggests a mild bleeding
disorder. ln this case, factor levels should be evaluated even if screening test results
are normal, because very mild decreases in factor levels may not prolong the pro-thrombin
time (PT) or partial thromboplastin time (PTT).
(3) Timing of episodes. Bleeding that is uncontrolled from the onset suggests a defect in
primary hemostasis, whereas a history of bleeding after initial apparent hemostasis is
more consistent with a factor deficiency. A marked delay in bleeding after the initiating
event is sometimes seen in factor Xlll deficiency.
7. 2.Medical history
A review of all medical conditions, and their treatment,can provideinsight
into the possible nature of the bleeding disorder.
a. Malnourished, hospitalized patients who have been treated with multiple antibiotics
highly prone to vitamin K deficiency.
b. Systemic lupus erythematosus (SLE) and human immunodeficiency virus (HlV)
are associated with syndromes of immnune-mediated (idiopathic) thrombocvtopenic.-
pura (lTP).
C. Septicemia is the most common underlying cause of disseminated intravascular -
(DlC).
3. Medications history.
Careful review of all medications is critical in evaluating a patient with a coagulation abnormality.
a. Aspirin is a conman cause of altered platelet function.
b. incidental heparin, which often is used for flushing intravenous access lines, can causes
thrombocytopenia and inadvertent anticoagulation.
c. An extensive number of drugs are known to induce thrombocytopenia.
d. Acquired factor inhibitors have been associated with medications (e.g., penicillin).
8. B. Physical examination
May provide valuable clues as to where in the coagulation system normality is likely to be found
1' petechiae is usually indicate bleeding at the level of the microvasculature and are associated ,
with abnormalities of platelet number and function.
2. Mucous membrane bleeding can result from any defect in coagulation, but when mucous
membranes are the only bleeding sites, thrombocytopenia, platelet function disorders, or
Willebrand's disease is likely.
3. Hemoarthrosis or evidence of recurrent joint bleeding is almost always associated with a severe.
form of hemophilia, although this type of bleeding can occur in severe acquired factor defciencies as well.
4. Diffuse bleeding from multiple sites, both mucous membrane and sites of trauma such a. ..
venipuncture sites, is often seen with severe combined coagulation defects, such as DlC, severe liver disease.
5. Other physical findings may suggests underlying medical conditions that could predispose .
the bleeding disorder, such as splenomegaly in a patient with SLE and thrombocytopenia ,
fever and evidence of sepsis in a patient with DlC
9.
C. Laboratory studies (Table 16.-1). ldeally, the choice of laboratory studies is guided by the
hisii-and
physical examination of the patient. However, for general screening prrposes or when :--
history and examination provide no clues, a battery of ippropriate tests often is the most erpt.
dient approach.
1. Platelet tests
a. Platelet count determination is the first step in evaluating disorders of primary hemostas:.
aAbnormal platelet counts must be confirmed by peripheral blood smear.
b. Platelet function
(1) Bleedingtime.Thetenrplatebleedingtimeisacrudetestofthetimeittakesforasran-dardized
incision to stop bleeding. When the test is done properly, this time shoulc
be dependent only on the presence of adequate numbers of normally functionine
platelets. However, the test is extremely susceptible to variability introduced bv the
person performing the test and, therefore, must be interpreted with caution.
(2) Platelet aggregation studies require experience both to per{orm and to interpret.
10. Screening test of
coagulation
Test Interpretation
Platelet count Platelet number
Peripheral blood smear Cell morphology &count
Bleeding time Platelet function
Prothombin time Extrinsic pathway
Partial thomboplastin time Intrinsic pathway
Thrombin time Fibrinogen conversion to fibrin
11.
(a) Aggregation with.adenosine diphosphate (ADP), epinephrine, or coltagen will
uncover abnormalities of fibrinogen binding (thrombasthenia) or of arachidonic
acid metabolism (i.e., cyclooxygenase inhibition secondary to aspirin) or secre-tion
(storage pool disease).
(b) Aggregation with ristocetin is abnormal in von Willebrand's disease and in
Bernard-Sou lier syndrome
12. 2. Tests of coagulation
a. Screenin!testsofcoagulationmustalwaysbeinterpretedinlightoftheclinical situation.
in general, however, screening provides invaluable information.
(1) PTT reflects the function of the intrinsic pathway from the contact phase through the
common pathway.
(2) PT reflects the function of the extrinsic pathway including the common pathway.
(3) Thrombin time (TT) measures the ability of thrombin to cbnvert fibrinogen to fibrin.
It is abnormal in the setting of hypofibrinogenemia and dysfibrinogenemia and is
markedly sensitive to the anti-thrombin effect caused by heparin.
(4) Ureaclotlysistestmeasuresfibrinstabilization.AlthoughfactorXllldeficiencyisrare,
it should be considered in a patient with an appropriate history and normal results on
the other screening tests; PT, PTT, and TT do not evaluate factor Xlll activity.
13.
b. Mixing test is critical once a prolonged screening test is identified. The test is performed
by mixing equal amounts of the patient's plasma and a known normal plasma and deter-mining
if the normal plasmacorrects the defect. A 50% level of any plasma factor is usually
associated with normal results on screening tests; therefore, correciion implies a factor de'-
ficiency. However, failure of the admixed normal plasma to correct the ciotting defect in-dicates
that there is an antibody to a coagulation factor present, which inhibitithat factor
in both the normal and the patient's plasma. This factor inhibitor will need to be identified
by further, specific tests.
C. Specific factor assays can further define abnormalities of the coagulation cascade once
they have been localized by means of screening tests. The choice of which factors to assay
should be guided by such factors as family history and statistical likelihood. Factor assayi
may also be useful in patients with normal screening tests but compelling family or clinical
evidence suggesting a mild factor deficiency.
14.
3. Peripheral blood smear. ln addition to tests of platelets and coagulation, the
peripheral smear
must be examined. Findings such as red cell fragmentation (suggesting a
concomitant mi-croangiopathic
process), unusual platelet morphology, or other hematopoietic
abnormalities
would also influence the evaluation.
4. Bone marrow evaluation is used primarily to assess platelet production. lf
megakaryocytes are
plentiful in the bone marrow of a patient with severe thrombocytopenia,
peripheral destruc-tion
must be involved. lf megakaryocytes are decreased, failure of production
is the cause
15. D. Approach to the patient with a bleeding disorder
1. Patients with an isolated platelet abnormality
a. Thrombocytopenia. The evaluation of a patient in whom the only abnormality is isolated
thrombocytopenia is summarized in Figure 16-1 . An understanding of the role of the fol-lowing
tests is fundamental to this evaluation.
(1 ) Peripheral smear. Because platelet counts almost universally are done by automated
counter, it is important to examine the blood smear to confirm the presence of throm-bocytopenia.
Occasionally, platelets clump in the automated counter, causing an in-appropriately
low platelet count (pseudothrombocytopenia); but adequate numbers
of platelets can be clearly discerned on the smear. Also, evaluation of oiher blood cell
morphology may suggest an underlying disorder [e.g., fragmented red cells in throm-botic
thrombocytopenic purpura (TTP)].
(2) Bone marrow examination for the presence of megakaryocytes may be critical for de-termining
the mechanism of the thrombocytopenia. An increased number of mega-karyocytes
suSSests that thrombocytopenia is the result of a destructive mechanrlm
and not decreased production.
(3) Antiplatelet.antibodies. Although the presence of antiplatelet antibodies supports a
diagnosis of ITP or an ITP-Iike syndrome, this study usually is not necessary in itiaight-forward
cases. However, detection of antibodies io sp"cifi. platelet antifens ;;;b;
necessary to confirm certain diagnoses, such as post-iransfuiion prrprru-or neonatal
al loimmune thrombocytopenia.
17.
b. Thrombocytosis. Much of the evaluation of a patient with isolated thrombocytosis is based
on clinical findings and is aimed at excluding a cause for secondary thrombocytosis'
(1) Clinical features
' ' (a) Thrombocytosis that results from a myeloproliferative disorder ,[e.8., essential
thrombocythemia, polycythemia vera (PV)l may be.associated with bleeding due
tofunctional abnormalities of the platelets produced by the_abnormal clone. How-ever,
it also .r" pi"JGpoie to thrombosis. The presence of splenomegaly strongly
irgg"ttt the preience'of a myeloproliferative disorder'
(b) Thi6mbocytosii that is part of a reactive process does not,predispose to bleeding,
nor is it g"n"rully u$ociated with thrombosis. Patients who have iust undergone
splenect6my or *ho have certain underlying disorders (e.g., iron deficiency) are
lit<ely to have reactive (secondary) thrombocytosis'
2) Laboratory findings
(a) Support for the diagnosis of a myeloproliferative disorder can be obtained by test-ing
the leukocyte alkaline phosphatase (LAP) activity and the vitamin 8,, level.
The bone marrow also should be evaluated for chromosome abnormalities, cel-lularity,
and evidence of fibrosis.
(b) Platelet function tests often are abnormal when the thrombocytosis is the result of
a myeloproliferative disorder and should be normal in secondary thrombocytosis
18.
c. Prolonged bleeding time
(t) Bleedingtimeshouldnotbemeasuredintheabsenceofaplateletcount,asitgenerally
is prolonged in the setting of thrombocytopenia. ldeally, the relationship between
platelet count and the degiee to which bleeding time is prolonged should be
defined
in the laboratory where bleeding time is measured, so the results can be interpreted
in mildly thrombocytopenic patients. ln general, platelet count and bleeding time
are
inversely related when the platelet count is 20,000-1 00,000/pl.
(2) When bleeding time is prolonged and platelet count is normal (Figure 16-2),
tional studies may be indicated to define the nature of the disorder'
19.
2. Patients with a single abnormal screening test
a. Prolonged PTT (-Figure 16-3). An isolated abnormality of the.PTT suggests an abnormality
in the i'ntrinsic coagulation pathway. The patient history and the context in which the pa-tient
presents may give clues as to the most likely etiology. .
(t ) lnherited abnoimalities may be associated with a strong family history. lf a sex-linked
pattern is apparent, specific assays for factors Vlll and lX can be chosen; if there is an
autosomal pattern, an assay for factor Xl can be used'
(2) Acquiredabnormalitieswithbleedingmanifestationsorasymptomaticandpreviously
' unsuspected abnormalities may be the result of acquired,inhibitors or contact factor
abnormalities. A mixing test to screen for the presence of an inhibitor will guide the
next steps of the evaluaiion. Correction of the PTT by admixed normal plasma would.
suggest a factor deficiency such as factor Xll or prekallikrein deficiency, while lack of
coiiection suggests an inhibitor, which would then need specific characterization.
3) Drugs, especially heparin, may be the cause detected on a careful history or review
of records.
b. prolongedpT(Figure16-4).AnisolatedprolongedPTsuggestsanabnormalityoffactorVll'
Th is is ieldom the resu lt of a congenital def iciency but is often associated with liver disease,
vitamin K deficiency, or therapy with vitamin K antagonists. Rarely, coagulation factor in-hibitors
occur that can cause this abnormality; these can be detected by a mixing test.
c. irolonged TT should be evaluated along with the fibrinogen level, as prolongation occurs
with hfpofibrinogenemia. More commonly, however, the antithrombin action of small
nrnounii of heparin prolongs the TT. Other conditions that can interfere with fibrin poly-merization
must also be co-nsidered, such as inherited dysfibrinogenemias, the presence
of fibrin split products (FSPs), or even the presence of myeloma proteins
20. Algorithm for evaluation of a patient with a prolonged bleeding
time and a normal platelet count.
22.
3) Drugs, especially heparin, may be the cause detected on a careful history or review
of records.
b. prolongedpT(Figure16-4).AnisolatedprolongedPTsuggestsanabnormalityoffactorVll'
Th is is ieldom the resu lt of a congenital def iciency but is often associated with liver
disease,
vitamin K deficiency, or therapy with vitamin K antagonists. Rarely, coagulation factor
in-hibitors
occur that can cause this abnormality; these can be detected by a mixing test.
c. irolonged TT should be evaluated along with the fibrinogen level, as prolongation
occurs
with hfpofibrinogenemia. More commonly, however, the antithrombin action of small
nrnounii of heparin prolongs the TT. Other conditions that can interfere with fibrin poly-merization
must also be co-nsidered, such as inherited dysfibrinogenemias, the presence
of fibrin split products (FSPs), or even the presence of myeloma proteins
23.
3. patients with multiple coagulation defects.
When multiple defects of the coagulation system
are found, a unifying diagnosis is likely (Table 16-2)'
a. Vitamin f aeiiciency"most commonly presents as an isolated prolongation of the PT, but
pTT also may be proionged. Coincident thrombocytopenia does not.occur. The diagnosis
usually i, ,rgg"rt"Jbt i'he clinical presentation and is easily tested by an empiric trial of
vitamin K.
b. DIC. The combination of thrombocytopenia, prolonged PT, and prolonged PTT suggests
- ionrrrptionofcoagulationfactorsandplatelets,especiallyinthe-settingofaprecipitating
cause for DlC. Additonal tests to support the diagnosis include fibrinogen levels, tests for
FSPs, and examinatir:n of the peripheral smear for the presence of fragmented red blood
ce lls.
c.Liver disease results in decreased production of most coagulation factors‘
(1) The earty stages of ];;;;i;;" may be associated with only prolonged. Pl and the
"'p.rri6,fiiv"iiitrri"Kdeficiencymustbeconsidered.Withmoresevereliverdisease,
both pT anO eii rie pltong"J,'Urt, again, vitamin K deficiency must be excluded'
ln either case, a theiapeutic-trial of vitimin K may be diagnostically useful' ..
(zl prolonsed TT u;;;lly;;;its when fibrinogen production also is diminished, a finding
not consistent with vitamin K deficiency'
(3) Thrombocytopenia in patients with liver disease can result from hypersplenism and
sequestration of platelets. Thrombocytopenia in such a patient combined with pro-longed
PT, PTT, and TT may be difficult to differentiate from DlC. This may be com-pounded
by finding elevated FSPs, since the diseased liver has a decreased ability to
clear FSPs. Most of1en, the distinction can be made on clinical grounds.
4. Acquired clotting factor inhibitors may be suspected in a patient with recent marked prolon-gatign
of one or hore screening tests. This suspicion should be confirmed by a mixing test,
in which the prolonged screening test is not corrected when performed on a 1:1 mixture of
the patient's plasma with normal plasma. Tests for the lupus anticoagulant (usually in patients.
without clinical bleeding) or, if this is negative, for specific factors will localize the action of
the inhibitor
