# 50 - SECTION 3 Disorders of Hemostasis

## SECTION 3 Disorders of Hemostasis

Section 3	 Disorders of Hemostasis
Barbara A. Konkle

Disorders of Platelets 

and Vessel Wall
Hemostasis is a dynamic process in which the platelet and the blood 
vessel wall play key roles. Platelets are activated upon adhesion to von 
Willebrand factor (VWF) and collagen in the exposed subendothelium 
after injury. Platelet activation is also mediated through shear forces 
imposed by blood flow itself, particularly in areas where the vessel wall 
is diseased, and is also affected by the inflammatory state of the endo­
thelium. The activated platelet surface provides the major physiologic 
site for coagulation factor activation, which results in further platelet 
activation and fibrin formation. Genetic and acquired influences on 
the platelet and vessel wall, as well as on the coagulation and fibrino­
lytic systems, determine whether normal hemostasis or bleeding or 
clotting symptoms will result.
THE PLATELET
Platelets are released from the megakaryocyte, likely under the influ­
ence of flow in the capillary sinuses. The normal blood platelet count is 
150,000–450,000/μL. The major regulator of platelet production is the 
hormone thrombopoietin (TPO), which is synthesized in the liver and 
other organs. Synthesis is increased with inflammation and specifically 
by interleukin 6. TPO binds to its receptor on platelets and megakaryo­
cytes, by which it is removed from the circulation. Thus, a reduction 
in platelet and megakaryocyte mass increases the level of TPO, which 
then stimulates platelet production. Platelets circulate with an average 
life span of 7–10 days. Approximately one-third of the platelets reside 
in the spleen, and this number increases in proportion to splenic size, 
although the platelet count rarely decreases to <40,000/μL as the spleen 
enlarges. Platelets are physiologically very active, but are anucleate, and 
thus have limited capacity to synthesize new proteins.
Normal vascular endothelium contributes to preventing thrombosis 
by inhibiting platelet function (Chap. 69). When vascular endothelium 
is injured, these inhibitory effects are overcome, and platelets adhere 
to the exposed intimal surface primarily through VWF, a large multi­
meric protein present in both plasma and in the extracellular matrix of 
the subendothelial vessel wall. Platelet adhesion results in the genera­
tion of intracellular signals that lead to activation of the platelet glyco­
protein (Gp) IIb/IIIa (αIIbβ3) receptor and resultant platelet aggregation.
Activated platelets undergo release of their granule contents, which 
include nucleotides, adhesive proteins, growth factors, and procoagu­
lants that serve to promote platelet aggregation and blood clot forma­
tion and influence the environment of the forming clot. During platelet 
aggregation, additional platelets are recruited to the site of injury, 
leading to the formation of an occlusive platelet thrombus. The platelet 
plug is stabilized by the fibrin mesh that develops simultaneously as the 
product of the coagulation cascade.
THE VESSEL WALL
Endothelial cells line the surface of the entire circulatory tree, totaling 
1–6 × 1013 cells, enough to cover a surface area equivalent to about 
six tennis courts. The endothelium is physiologically active, control­
ling vascular permeability, flow of biologically active molecules and 
nutrients, blood cell interactions with the vessel wall, the inflammatory 
response, and angiogenesis.
The endothelium normally presents an antithrombotic surface 
(Chap. 69) but rapidly becomes prothrombotic when stimulated, 
which promotes coagulation, inhibits fibrinolysis, and activates plate­
lets. In many cases, endothelium-derived vasodilators are also platelet 
inhibitors (e.g., nitric oxide), and conversely, endothelium-derived 

vasoconstrictors (e.g., endothelin) can also be platelet activators. 
The net effect of vasodilation and inhibition of platelet function is to 
promote blood fluidity, whereas the net effect of vasoconstriction and 
platelet activation is to promote thrombosis. Thus, blood fluidity and 
hemostasis are regulated by the balance of antithrombotic/prothrom­
botic and vasodilatory/vasoconstrictor properties of endothelial cells.

DISORDERS OF PLATELETS
■
■THROMBOCYTOPENIA
Thrombocytopenia results from one or more of three processes: (1) 
decreased bone marrow production; (2) sequestration, usually in an 
enlarged spleen; and/or (3) increased platelet destruction. Disorders of 
production may be either inherited or acquired. In evaluating a patient 
with thrombocytopenia, a key step is to review the peripheral blood 
smear and to first rule out “pseudothrombocytopenia,” particularly in 
a patient without an apparent cause for the thrombocytopenia. Pseu­
dothrombocytopenia (Fig. 120-1B) is an in vitro artifact resulting from 
platelet agglutination via antibodies (usually IgG, but also IgM and 
IgA) when the calcium content is decreased by blood collection in eth­
ylenediamine tetraacetic (EDTA) (the anticoagulant present in tubes 
[purple top] used to collect blood for complete blood counts [CBCs]). 
If a low platelet count is obtained in EDTA-anticoagulated blood, a 
blood smear should be evaluated and a platelet count determined in 
blood collected into sodium citrate (blue top tube) or heparin (green 
top tube), or a smear of freshly obtained unanticoagulated blood, such 
as from a finger stick, can be examined.
CHAPTER 120
Disorders of Platelets and Vessel Wall 
APPROACH TO THE PATIENT
Thrombocytopenia
The history and physical examination, results of the CBC, and 
review of the peripheral blood smear are all critical components in 
the initial evaluation of thrombocytopenic patients (Fig. 120-2). 
The overall health of the patient and whether they are receiving 
drug treatment will influence the differential diagnosis. A healthy 
young adult with thrombocytopenia will have a much more lim­
ited differential diagnosis than an ill hospitalized patient who is 
receiving multiple medications. Except in less common inherited 
disorders, decreased platelet production usually results from bone 
marrow disorders that also affect red blood cell (RBC) and/or white 
blood cell (WBC) production. Because myelodysplasia can present 
with isolated thrombocytopenia, the bone marrow should be exam­
ined in patients presenting with isolated thrombocytopenia who are 
older than 60 years of age or who do not respond to initial therapy. 
While inherited thrombocytopenia is uncommon, any prior platelet 
counts should be retrieved and a family history regarding thrombo­
cytopenia obtained. A careful history of drug ingestion should be 
obtained, including nonprescription and herbal remedies, because 
drugs are the most common cause of thrombocytopenia.
The physical examination can document an enlarged spleen, 
evidence of chronic liver disease, and other underlying disorders. 
Mild to moderate splenomegaly may be difficult to appreciate in 
many individuals due to body habitus and/or obesity but can be eas­
ily assessed by abdominal ultrasound. A platelet count of approxi­
mately 5000–10,000 is required to maintain vascular integrity in the 
microcirculation. When the count is markedly decreased, petechiae 
first appear in areas of increased venous pressure, the ankles and 
feet in an ambulatory patient. Petechiae are pinpoint, nonblanching 
hemorrhages and are usually a sign of a decreased platelet num­
ber and not platelet dysfunction. Wet purpura, blood blisters that 
form on the oral mucosa, are thought to denote an increased risk 
of life-threatening hemorrhage in the thrombocytopenic patient. 
Excessive bruising is seen in disorders of both platelet number and 
function.
Infection-Induced Thrombocytopenia 
Many viral and bacte­
rial infections result in thrombocytopenia and are the most common