Bleeding Disorders

Bleeding Disorders
Bleeding disorders may be due to a variety of abnormalities of coagulation. Initial laboratory testing consists of
a prothrombin time (PT), partial thromboplastin time (PTT) and platelet count (part of a CBC).

Common causes for an abnormal PT include disorders affecting coagulation factors II, V, VII, and X that are
synthesized in the liver and are vitamin K dependent (vitamin K carboxylates glutamate residues). Thus, liver
disease and coumadin therapy will prolong the PT.

Common causes for an abnormal PTT include deficiencies in factors II, V, VIII, IX, X, XI, and XII. This includes
hemophilia A (diminished factor VIII activity), hemophilia B (decreased factor IX), and heparin therapy.

Abnormalities in platelet numbers (thrombocytopenia) may be due to decreased marrow production (aplastic anemia)
or increased peripheral consumption (secondary hypersplenism, anti-platelet antibodies [ITP], microangiopathic hemolytic
anemias [DIC, TTP]).

Platelet Function
Abnormalities in platelet function must be considered when the platelet count is normal. The bleeding time is increased,
but a more useful analysis is a platelet function analysis (PFA).

A sample of platelets is placed into a platelet function analysis instrument that usually measures the aggregation of
platelets in response to an added stimulatory agent, and the response measured by an increase in turbidity with diminished
light transmission, plotted on a graph. The appearance of the graph can be used to determine different types of platelet
function problems.

The normal response of platelets to ADP is shown below at the left. Note that when ADP is added (indicated by the spike)
there is an initial small upward curve as platelets undergo shape change, followed by a progressive downward curve from
the primary wave of aggregation to a small plateau. At this point the secondary wave of platelet aggregation begins,
followed by another downward curve. The graph of platelet response to epinephrine below at the right shows no initial
upward peak from shape change, but there is a similar primary wave of aggregation followed by a plateau and then
a secondary wave of aggregation.

Normal response to ADP Normal response to epinephrine



In response to addition of collagen, the graph below at the left illustrates a short lag before a peak from shape change
occurred, followed by a single wave of aggregation. The graph at the right below shows that the curve following addition
of thrombin is similar, but without an initial lag.

Normal response to collagen Normal response to thrombin



The graph of platelet response to ristocetin shows an immediate single wave of aggregation, without shape change.




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Abnormal Conditions
VonWillbrand Disease (vWD): This is a common autosomal dominant disorder of variable severity (depending upon the mutation
present) affecting up to 1% of the population. There are decreased vWF multimers which bind factor VIII, and there is
abnormal platelet adhesion. If severe, the PTT may also be elevated. There is abnormal platelet function as measured by
aggregation to ristocetin cofactor, as shown below. It is as if the platelets are covered by a lubricant, and the
ristocetin wrenches them apart easily. Aggregation to ADP, collagen, and epinephrine will be normal. A similar PFA profile
is seen with the rare autosomal recessive Bernard-Soulier syndrome, but the platelets will be abnormally large.


Normal response to ristocetin von Willebrand disease




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Glanzmann Thrombasthenia: This rare autosomal recessive disorder is due to a lack of glycoprotein IIb/IIIa complex on
platelet surfaces, leading to abnormal binding of fibrinogen which prevents cross-linking and aggregation. Thus, PFA will
show a normal response to ristocetin, but abnormal reduced responses to ADP, collagen, and epinephrine, as shown below.

Normal response to thrombin Glanzmann thrombasthenia




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Storage Pool Disorder: There are rare disorders of deficient platelet granules. The characteristic PFA shows initial primary
aggregation to ADP, but not the secondary wave from granule release, as shown below.

Normal response to ADP Storage pool disorder